PROCYSBI FDA说明书(英文)
盐酸度洛西汀FDA说明书(英文)
1HIGHLIGHTS OF PRESCRIBING INFORMATIONdays of stopping an MAOI intended to treat psychiatric disorders.These highlights do not include all the information needed to use In addition, do not start Cymbalta in a patient who is being treated CYMBALTA safely and effectively. See full prescribing with linezolid or intravenous methylene blue (4.1) information for CYMBALTA. •Use in patients with uncontrolled narrow-angle glaucoma (4.2)CYMBALTA (duloxetine hydrochloride) Delayed-Release Capsules for Oral Use.Initial U.S. Approval: 2004WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children,adolescents, and young adults taking antidepressants (5.1) • Monitor for worsening and emergence of suicidal thoughtsand behaviors (5.1) • Cymbalta is not approved for use in pediatric patients (8.4) ---------------------------RECENT MAJOR CHANGES --------------------------Dosage and Administration:Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders (2.5) 10/2012 Use of Cymbalta with Other MAOIs such as Linezolid or Methylene Blue (2.6) 10/2012 Contraindications – Monoamine Oxidase Inhibitors (4.1) 10/2012 Warnings and Precautions: Serotonin Syndrome (5.4) 10/2012 Discontinuation of Treatment with Cymbalta (5.7) 08/2012 ----------------------------INDICATIONS AND USAGE ---------------------------Cymbalta ® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: • Major Depressive Disorder (MDD) (1.1) • Generalized Anxiety Disorder (GAD) (1.2)• Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)• Fibromyalgia (FM) (1.4)• Chronic Musculoskeletal Pain (1.5)------------------------DOSAGE AND ADMINISTRATION-----------------------• Cymbalta should generally be administered once daily withoutregard to meals. Cymbalta should be swallowed whole andshould not be chewed or crushed, nor should the capsule beopened and its contents be sprinkled on food or mixed with liquids (2) Indication Starting Dose Target DoseMaximumDose MDD (2.1, 2.2)40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD (2.1) 60 mg/day 60 mg/day (once daily) 120mg/day DPNP (2.1) 60 mg/day 60 mg/day (once daily) 60 mg/day FM (2.1)30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2.1)30 mg/day 60 mg/day (once daily) 60 mg/day • Some patients may benefit from starting at 30 mg once daily (2.1) • There is no evidence that doses greater than 60 mg/day confersadditional benefit, while some adverse reactions were observed to be dose-dependent (2.1) • D iscontinuing Cymbalta: A gradual dose reduction isrecommended to avoid discontinuation symptoms (2.4, 5.7) ----------------------DOSAGE FORMS AND STRENGTHS---------------------20 mg, 30 mg, and 60 mg capsules (3)-------------------------------CONTRAINDICATIONS ------------------------------• Serotonin Syndrome and MAOIs: Do not use MAOIs intended totreat psychiatric disorders with Cymbalta or within 5 days ofstopping treatment with Cymbalta. Do not use Cymbalta within 14------------------------WARNINGS AND PRECAUTIONS -----------------------• Suicidality: Monitor for clinical worsening and suicide risk (5.1) • Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2)• Orthostatic Hypotension and Syncope: Cases have been reportedwith duloxetine therapy (5.3)• Serotonin Syndrome: Serotonin syndrome has been reported withSSRIs and SNRIs, including with Cymbalta, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue Cymbalta and initiate supportive treatment. If concomitant use of Cymbalta with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4) • Abnormal Bleeding: Cymbalta may increase the risk of bleedingevents. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4)• Severe Skin Reactions: Severe skin reactions, including erythemamultiforme and Stevens-Johnson Syndrome (SJS), can occur with Cymbalta. Cymbalta should be discontinued at the firstappearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. (5.6)• Discontinuation: May result in symptoms, including dizziness,headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7) • Activation of mania or hypomania has occurred (5.8)• Seizures: Prescribe with care in patients with a history of seizuredisorder (5.9)• Blood Pressure: Monitor blood pressure prior to initiatingtreatment and periodically throughout treatment (5.10)• Inhibitors of CYP1A2 or Thioridazine: Should not administer withCymbalta (5.11)• Hyponatremia: Cases of hyponatremia have been reported (5.12) • Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be administered to these patients (5.13)• Controlled Narrow-Angle Glaucoma: Use cautiously in thesepatients (5.13)• Glucose Control in Diabetes: In diabetic peripheral neuropathicpain patients, small increases in fasting blood glucose, and HbA 1c have been observed (5.13)• Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.13)• Urinary Hesitation and Retention (5.14)-------------------------------ADVERSE REACTIONS------------------------------• Most common adverse reactions (≥5% and at least twice theincidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or /medwatch.-------------------------------DRUG INTERACTIONS ------------------------------• Potent inhibitors of CYP1A2 should be avoided (7.1). • Potent inhibitors of CYP2D6 may increase duloxetineconcentrations (7.2).• Duloxetine is a moderate inhibitor of CYP2D6 (7.9). ------------------------USE IN SPECIFIC POPULATIONS-----------------------• Pregnancy and Nursing Mothers: Use only if the potential benefitjustifies the potential risk to the fetus or child (2.3, 8.1, 8.3).See 17 for PATIENT COUNSELING INFORMATION and MedicationGuide Revised: 10/20122FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: SUICIDAL THOUGHTS AND BEHAVIORS1 INDICATIONSANDUSAGE1.1 Major Depressive Disorder1.2 Generalized Anxiety Disorder1.3 Diabetic Peripheral Neuropathic Pain1.4 F ibromyalgia1.5 Chronic Musculoskeletal Pain2 DOSAGEANDADMINISTRATION2.1 I nitialTreatment2.2 M aintenance/Continuation/ExtendedTreatment2.3 Dosing in Special Populations2.4 D iscontinuingCymbalta2.5 Switching a Patient To or From a Monoamine OxidaseInhibitor (MAOI) Intended to Treat Psychiatric Disorders2.6 Use of Cymbalta with Other MAOIs such as Linezolid orMethylene Blue3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS4.1 Monoamine Oxidase Inhibitors (MAOIs)4.2 U ncontrolledNarrow-AngleGlaucoma5 WARNINGSANDPRECAUTIONS5.1 Suicidal Thoughts and Behaviors in Adolescents andYoung Adults5.2 H epatotoxicity5.3 Orthostatic Hypotension and Syncope5.4 S erotoninSyndrome5.5 A bnormalBleeding5.6 Severe Skin Reactions5.7 Discontinuation of Treatment with Cymbalta5.8 Activation of Mania/Hypomania5.9 S eizures5.10 Effect on Blood Pressure5.11 Clinically Important Drug Interactions5.12 H yponatremia5.13 Use in Patients with Concomitant Illness5.14 Urinary Hesitation and Retention5.15 L aboratoryTests6 ADVERSEREACTIONS6.1 Clinical Trial Data Sources6.2 Adverse Reactions Reported as Reasons forDiscontinuation of Treatment in Placebo-Controlled Trials6.3 Most Common Adverse Reactions6.4 Adverse Reactions Occurring at an Incidence of 5% orMore Among Duloxetine-Treated Patients in Placebo-Controlled Trials6.5 Adverse Reactions Occurring at an Incidence of 2% orMore Among Duloxetine-Treated Patients in Placebo-Controlled Trials6.6 Effects on Male and Female Sexual Function6.7 Vital Sign Changes6.8 W eightChanges6.9 L aboratoryChanges6.10 E lectrocardiogramChanges6.11 Other Adverse Reactions Observed During thePremarketing and Postmarketing Clinical Trial Evaluationof Duloxetine6.12 Postmarketing Spontaneous Reports7 DRUGINTERACTIONS7.1 Inhibitors of CYP1A27.2 Inhibitors of CYP2D67.3 Dual Inhibition of CYP1A2 and CYP2D67.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs,Aspirin, and Warfarin)7.5 L orazepam7.6 T emazepam7.7 Drugs that Affect Gastric Acidity7.8 Drugs Metabolized by CYP1A27.9 Drugs Metabolized by CYP2D67.10 Drugs Metabolized by CYP2C97.11 Drugs Metabolized by CYP3A7.12 Drugs Metabolized by CYP2C197.13 Monoamine Oxidase Inhibitors (MAOIs)7.14 S erotonergicDrugs7.15 A lcohol7.16 C NSDrugs7.17 Drugs Highly Bound to Plasma Protein8 USE IN SPECIFIC POPULATIONS8.1 P regnancy8.2 Labor and Delivery8.3 N ursingMothers8.4 P ediatricUse8.5 G eriatricUse8.6 G ender8.7 S mokingStatus8.8 R ace8.9 H epaticInsufficiency8.10 Severe Renal Impairment9 DRUGABUSEANDDEPENDENCE9.2 A buse9.3 D ependence10 OVERDOSAGE10.1 Signs and Symptoms10.2 M anagementofOverdose11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 P harmacodynamics12.3 P harmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Major Depressive Disorder14.2 Generalized Anxiety Disorder14.3 Diabetic Peripheral Neuropathic Pain14.4 F ibromyalgia14.5 Chronic Musculoskeletal Pain16 HOW SUPPLIED/STORAGE AND HANDLING16.1 H owSupplied16.2 S torage17 PATIENT COUNSELING INFORMATION17.1 Information on Medication Guide17.2 Suicidal Thoughts and Behaviors17.3 M edicationAdministration17.4 Continuing the Therapy Prescribed17.5 H epatotoxicity17.6 A lcohol17.7 Orthostatic Hypotension and Syncope17.8 S erotoninSyndrome17.9 A bnormalBleeding17.10 Severe Skin Reaction17.11 Discontinuation of Treatment17.12 Activation of Mania or Hypomania17.13 Seizures17.14 Effects on Blood Pressure17.15 Concomitant Medications17.16 Hyponatremia17.17 Concomitant Illnesses17.18 Urinary Hesitancy and Retention17.19 Pregnancy and Breast Feeding17.20 Interference with Psychomotor Performance* Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATIONWARNING: SUICIDAL THOUGHTS AND BEHAVIORSAntidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)].In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)].Cymbalta is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].USAGEAND1 INDICATIONS1.1 Major Depressive DisorderCymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults [see Clinical Studies (14.1)].A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.AnxietyDisorder1.2 GeneralizedCymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term trials and one maintenance trial in adults [see Clinical Studies (14.2)].Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.1.3 Diabetic Peripheral Neuropathic PainCymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy [see Clinical Studies (14.3)].1.4 FibromyalgiaCymbalta is indicated for the management of fibromyalgia (FM) [see Clinical Studies (14.4)].PainMusculoskeletal1.5 ChronicCymbalta is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis [see Clinical Studies (14.5)].2 DOSAGE AND ADMINISTRATIONCymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Cymbalta can be given without regard to meals.Treatment2.1 InitialMajor Depressive Disorder — Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see Clinical Studies (14.1)].Generalized Anxiety Disorder — For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)].Diabetic Peripheral Neuropathic Pain — The recommended dose for Cymbalta is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].Fibromyalgia — The recommended dose for Cymbalta is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.4)].Chronic Musculoskeletal Pain — The recommended dose for Cymbalta is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].Treatment2.2 M aintenance/Continuation/ExtendedMajor Depressive Disorder — It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].Generalized Anxiety Disorder — It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].Diabetic Peripheral Neuropathic Pain — As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.Fibromyalgia — Fibromyalgia is recognized as a chronic condition. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Cymbalta was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.Chronic Musculoskeletal Pain — The efficacy of Cymbalta has not been established in placebo-controlled studies beyond 13 weeks.2.3 Dosing in Special PopulationsHepatic Insufficiency — It is recommended that Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].Severe Renal Impairment — Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)].Elderly Patients — No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].Pregnant Women — There are no adequate and well-controlled studies in pregnant women; therefore, Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Cymbalta while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Cymbalta during pregnancy by calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting Nursing Mothers — Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended [see Use in Specific Populations (8.3)].2.4 D iscontinuingCymbaltaSymptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat PsychiatricDisordersAt least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Cymbalta. Conversely, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].2.6 Use of Cymbalta with Other MAOIs such as Linezolid or Methylene BlueDo not start Cymbalta in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].In some cases, a patient already receiving Cymbalta therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Cymbalta should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Cymbalta may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Cymbalta is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].3 DOSAGE FORMS AND STRENGTHSCymbalta is available as delayed release capsules:20 mg opaque green capsules imprinted with “Lilly 3235 20mg”30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”60 mg opaque green and blue capsules imprinted with “Lilly 3237 60mg”60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”4 CONTRAINDICATIONS4.1 Monoamine Oxidase Inhibitors (MAOIs)The use of MAOIs intended to treat psychiatric disorders with Cymbalta or within 5 days of stopping treatment with Cymbalta is contraindicated because of an increased risk of serotonin syndrome. The use of Cymbalta within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5) and Warnings and Precautions (5.4)].Starting Cymbalta in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6) and Warnings and Precautions (5.4)].4.2 Uncontrolled Narrow-Angle GlaucomaIn clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.13)].PRECAUTIONS5 WARNINGSAND5.1 Suicidal Thoughts and Behaviors in Adolescents and Young AdultsPatients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.Table 1Age Range Drug-Placebo Difference in Number of Cases ofSuicidality per 1000 Patients TreatedIncreases Compared to Placebo<18 14 additional cases18-24 5 additional cases Decreases Compared to Placebo25-64 1 fewer case≥65 6 fewer casesNo suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was notsufficient to reach any conclusion about drug effect on suicide.It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, thereis substantial evidence from placebo-controlled maintenance trials in adults with depression that the use ofantidepressants can delay the recurrence of depression.All patients being treated with antidepressants for any indication should be monitored appropriately andobserved closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initialfew months of a course of drug therapy, or at times of dose changes, either increases or decreases.The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatricpatients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatricand nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening ofdepression and/or the emergence of suicidal impulses has not been established, there is concern that such symptomsmay represent precursors to emerging suicidality.Consideration should be given to changing the therapeutic regimen, including possibly discontinuing themedication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptomsthat might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset,or were not part of the patient’s presenting symptoms.If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible,but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4)and Warnings and Precautions (5.7) for descriptions of the risks of discontinuation of Cymbalta].Families and caregivers of patients being treated with antidepressants for major depressive disorder orother indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should bewritten for the smallest quantity of capsules consistent with good patient management, in order to reduce therisk of overdose.Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolardisorder. It is generally believed (though not established in controlled trials) that treating such an episode with anantidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolardisorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior toinitiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened todetermine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including afamily history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approvedfor use in treating bipolar depression.5.2 HepatotoxicityThere have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases havepresented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Otherpostmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patientswith chronic liver disease or cirrhosis.Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Livertransaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of Cymbalta-treated patients. In mostpatients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.。
盐酸西那卡塞FDA说明书
__________________________________________________________________________________________________________________________________FDA approved label August 1, 2011HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Sensipar safely and effectively. See full prescribing information for Sensipar. Sensipar ® (cinacalcet) Tablets Initial US Approval: 2004 ----------------------------RECENT MAJOR CHANGES -------------------------Indications and Usage: Primary Hyperparathyroidism (1.3)02/2011 Dosage and Administration: Parathyroid Carcinoma / PrimaryHyperparathyroidism (2.2) 02/2011 Contraindications: Hypocalcemia (4) 02/2011 ----------------------------INDICATIONS AND USAGE--------------------------- Sensipar is a calcium-sensing receptor agonist indicated for:•Secondary Hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis. (1.1)•Hypercalcemia in patients with Parathyroid Carcinoma (PC). (1.2) •Severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy. (1.3)----------------------DOSAGE AND ADMINISTRATION-----------------------For all indications, Sensipar should be taken with food or shortly after a mealand should always be taken whole and not divided.•Secondary HPT in patients with CKD on dialysis (2.1): oStarting dose is 30 mg once daily. oTitrate dose no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily as necessary to achieve targeted intact parathyroid hormone (iPTH) levels.oiPTH levels should be measured no earlier than 12 hours after most recent dose.•Hypercalcemia in patients with PC or severe hypercalcemia in patients with primary HPT (2.2):oStarting dose is 30 mg twice daily. oTitrate dose every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three orfour times daily as necessary to normalize serum calcium levels.---------------------DOSAGE FORMS AND STRENGTHS---------------------- Tablets: 30, 60, and 90 mg tablets (3) -------------------------------CONTRAINDICATIONS ---------------------------- Hypocalcemia: Sensipar treatment should not be initiated if serum calcium isless than the lower limit of the normal range. (4, 5.1)-----------------------WARNINGS AND PRECAUTIONS-----------------------• Hypocalcemia and/or seizures: May occur due to significant reductions inserum calcium. (5.1, 5.2) • Isolated, idiosyncratic occurrences of hypotension, worsening heart failure, and/or arrhythmia: Have been reported in patients with impaired cardiacfunction during Sensipar treatment, which may be mediated by reductionsin serum calcium. (5.3)• Adynamic bone disease: May develop if iPTH levels are suppressed below100 pg/mL. (5.4)• Laboratory tests: Serum calcium, serum phosphorus, and iPTH levelsshould be monitored during the dose initiation, dose titration, and maintenance therapy. (5.6) • Hepatic Impairment: Cinacalcet exposure is increased in patients withmoderate and severe hepatic impairment. Patients should be closelymonitored throughout treatment. (5.5, 8.7)------------------------------ADVERSE REACTIONS------------------------------- The most frequently reported adverse reactions (incidence in patients ≥ 5% inthe Sensipar group) were nausea, vomiting, and diarrhea. (6.1, 6.2)To report SUSPECTED ADVERSE REACTIONS, contact AmgenMedical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at1-800-FDA-1088 or/medwatch . ------------------------------DRUG INTERACTIONS-------------------------------• Co-administration with a strong CYP3A4 inhibitor may increase serumlevels of cinacalcet. Dose adjustment and monitoring of iPTH serumphosphorous and serum calcium may be required. (7.1)• Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may berequired for concomitant medications that are predominantly metabolizedby CYP2D6. (7.2) -----------------------------USE IN SPECIFIC POPULATIONS------------------ • Pregnancy: Sensipar should only be used if the potential benefit justifiesthe potential risk to the fetus. Pregnancy registry available. (8.1)See 17 for PATIENT COUNSELING INFORMATION Revised:08/2011 FULL PRESCRIBING INFORMATION: CONTENTS*1 I NDICATIONS AND USAGE1.1 Secondary Hyperparathyroidism 1.2 P arathyroid Carcinoma 1.3 P rimary Hyperparathyroidism2 D OSAGE AND ADMINISTRATION2.1 S econdary Hyperparathyroidism in Patients with Chronic KidneyDisease on Dialysis 2.2 Parathyroid Carcinoma and Primary Hyperparathyroidism3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 H ypocalcemia5.2 S eizures5.3 Hypotension and/or Worsening Heart Failure5.4 Adynamic Bone Disease 5.5 H epatic Impairment 5.6 Laboratory Tests6 A DVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience with Sensipar7 D RUG INTERACTIONS7.1 Strong CYP3A4 Inhibitors 7.2 CYP2D6 Substrates8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy: Category C8.3 N ursing Mothers 8.4 P ediatric Use 8.6 R enal Impairment 8.7 H epatic Impairment 10 OVERDOSAGE 11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 N ONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 C LINICAL STUDIES 14.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis 14.2 Parathyroid Carcinoma 14.3 Patients with Severe Hypercalcemia Due to Primary Hyperparathyroidism 16 HOW SUPPLIED/STORAGE AND HANDLING 17PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.1 FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE 1.1 Secondary Hyperparathyroidism Sensipar is indicated for the treatment of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis [see Clinical Studies (14.1)]. 1.2 Parathyroid Carcinoma Sensipar is indicated for the treatment of hypercalcemia in patients with Parathyroid Carcinoma [see Clinical Studies (14.2)]. 1.3 Primary Hyperparathyroidism Sensipar is indicated for the treatment of severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy [see Clinical Studies (14.3)]. 2 DOSAGE AND ADMINISTRATION Sensipar tablets should be taken whole and should not be divided. Sensipar should be taken with food orshortly after a meal. Dosage must be individualized. 2.1 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on DialysisThe recommended starting oral dose of Sensipar is 30 mg once daily. Serum calcium and serum phosphorusshould be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeksafter initiation or dose adjustment of Sensipar. Sensipar should be titrated no more frequently than every2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with Sensipar. Sensipar can be used alone or in combination with vitamin D sterols and/or phosphate binders.During dose titration, serum calcium levels should be monitored frequently and if levels decrease below thenormal range, appropriate steps should be taken to increase serum calcium levels, such as by providingsupplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating orincreasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar [see Warnings andPrecautions (5.1, 5.6)]. 2.2 Parathyroid Carcinomaand Primary Hyperparathyroidism The recommended starting oral dose of Sensipar is 30 mg twice daily. The dose of Sensipar should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels [see Warnings and Precautions (5.6)].DOSAGE FORMS AND STRENGTHS Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one sideand “30” or “60” or “90” on the opposite side of the 30 mg, 60 mg, or 90 mg strengths, respectively.34 CONTRAINDICATIONSHypocalcemia: Sensipar treatment should not be initiated if serum calcium is less than the lower limit of the normal range [see Warnings and Precautions (5.1)].5 WARNINGS AND PRECAUTIONS5.1 HypocalcemiaSensipar lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping, tetany, and convulsions.Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium should be measured approximately monthly [see Dosage and Administration (2.1)].If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of Sensipar [see Dosage and Administration (2.1)].In 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.Sensipar is not indicated for patients with CKD not on dialysis. In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of Sensipar have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet,102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of Sensipar-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.5.2 SeizuresIn clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar, particularly in patients with a history of a seizure disorder [see Warnings and Precautions (5.1)].5.3 Hypotension and/or Worsening Heart FailureIn postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure,and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions (6.2)].5.4 Adynamic Bone DiseaseAdynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar for 1 year. Three patients with mildhyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with Sensipar had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.5.5 Hepatic ImpairmentCinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Sensipar [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].5.6 Laboratory TestsSecondary Hyperparathyroidism in Patients with Chronic Kidney Disease on DialysisSerum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to4 weeks after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and iPTH every 1 to 3 months [see Dosage and Administration (2.1)]. Measurements of PTH during the Sensipar studies were obtained using the Nichols iPTH immunoradiometric assay (IRMA).In patients with end-stage renal disease, testosterone levels are often below the normal range. In aplacebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following 6 months of treatment with Sensipar. Levels of total testosterone decreased by a median of 15.8% in the Sensipar-treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar-treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.Patients with Parathyroid Carcinoma or Primary HyperparathyroidismSerum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once maintenance dose levels have been established, serum calcium should be measured every 2 months [see Dosage and Administration (2.2)].REACTIONS6 ADVERSE6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on DialysisIn three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions (incidence of at least 5% in the Sensipar group and greater than placebo) are provided in Table 1. The most frequently reported adverse reactions in the Sensipar group were nausea, vomiting, and diarrhea.Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials.Table 1. Adverse Reaction Incidence (≥ 5%) in Patients on DialysisEvent*: Placebo(n = 470) (%)Sensipar (n = 656) (%) Nausea Vomiting Diarrhea Myalgia Dizziness Hypertension Asthenia Anorexia Pain Chest, Non-Cardiac Access Infection 19 15 20 14 8 5 4 4 4 431 27 21 15 10 7 7 6 6 5 The incidence of serious adverse reactions was similar in the Sensipar and placebo groups (29% vs. 31%,respectively). 12-Month Experience with Sensipar in Secondary HyperparathyroidismTwo hundred sixty-six patients from two of the phase 3 studies in patients with CKD on dialysis continued toreceive Sensipar or placebo treatment in a 6-month, double-blind extension study (12-month total treatmentduration). The incidence and nature of adverse reactions in this long term extension study were comparable tothose observed in the original phase 3 studies. Parathyroid Carcinoma and Primary HyperparathyroidismThe safety profile of Sensipar in these patient populations is generally consistent with that seen in patients withCKD on dialysis. Forty six patients were treated with cinacalcet in a single arm study, 29 with ParathyroidCarcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverseevents. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead todehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patientswith these symptoms. Eight patients died while on study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT.Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage(1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in threepatients (7%). Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.Table 2. Adverse Reactions Occurring in ≥10% of Total SubjectsCinacalcetParathyroid IntractableCarcinoma pHPT Total Preferred Term (N=29) (N=17) (N=46)n (%) n (%) n (%) Number of Subjects Reporting Adverse 28 (97) 17 (100) 45 (98) EventsNausea 19 (66) 10 (59) 29 (63) Vomiting 15 (52) 6 (35) 21 (46) Paresthesia 4 (14) 5 (29) 9 (20) Fatigue 6 (21) 2 (12) 8 (17) Fracture 6 (21) 2 (12) 8 (17) Hypercalcemia 6 (21) 2 (12) 8 (17) Anorexia 6 (21) 1 (6) 7 (15) Asthenia 5 (17) 2 (12) 7 (15) Dehydration 7 (24) 0 (0) 7 (15) Anemia 5 (17) 1 (6) 6 (13) Arthralgia 5 (17) 1 (6) 6 (13) Constipation 3 (10) 3 (18) 6 (13) Depression 3 (10) 3 (18) 6 (13) Headache 6 (21) 0 (0) 6 (13) Infection Upper Respiratory 3 (10) 2 (12) 5 (11) Pain Limb 3 (10) 2 (12) 5 (11)6.2 Postmarketing Experience with SensiparThe following adverse reactions have been identified during postapproval use of Sensipar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Rash, hypersensitivity reactions (including angioedema and urticaria), diarrhea, and myalgia have been identified as adverse reactions during postapproval use of Sensipar. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar-treated patients with impaired cardiac function in postmarketing safety surveillance.INTERACTIONSDRUG77.1 Strong CYP3A4 InhibitorsCinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology (12.3)].7.2 CYP2D6 SubstratesCinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants) [see Clinical Pharmacology (12.3)].8 USESPECIFIC POPULATIONSIN8.1 Pregnancy: Category CIn pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve [AUC] comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of12 and 25 mg/kg/day. Sensipar has been shown to cross the placental barrier in rabbits.In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.There are no adequate and well-controlled studies of Sensipar in pregnant women. Sensipar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Women who become pregnant during Sensipar treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.Mothers8.3 NursingStudies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are excreted in human milk and there is a potential for clinically significant adverse reactions in infants who ingest Sensipar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.8.4 Pediatric UseThe safety and efficacy of Sensipar in pediatric patients have not been established.Use8.5 GeriatricOf the 1136 patients enrolled in the Sensipar phase 3 clinical program in patients with CKD on dialysis,26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Sensipar were observed in patients greater or less than 65 years of age. No dosage adjustment is required for geriatric patients [see Clinical Pharmacology (12.3)].8.6 RenalImpairmentNo dosage adjustment is necessary for renal impairment [see Clinical Pharmacology (12.3)].Impairment8.7 HepaticPatients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-inf) is increased by 2.4 and 4.2 fold, respectively, in these patients [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].10 OVERDOSAGEDoses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels [see Warnings and Precautions (5.1)].Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.11 DESCRIPTIONSensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N⋅HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:Inactive IngredientsThe following are the inactive ingredients in Sensipar tablets: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide and magnesium stearate. Tablets are coated with color (Opadry® II green), clear film coat (Opadry® clear), and carnauba wax.PHARMACOLOGY12 CLINICAL12.1 Mechanism of ActionSecondary HPT in patients with CKD is a progressive disease, associated with increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resultingin cortical bone resorption and marrow fibrosis. The goals of treatment of secondary HPT are to lower the levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Sensipar directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Measurements of PTH during the Sensipar studies were obtained using the Nichols IRMA.12.2 PharmacodynamicsReduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (C max) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.12.3 PharmacokineticsAbsorption and DistributionAfter oral administration of cinacalcet, C max is achieved in approximately 2 to 6 hours. Cinacalcet C max and AUC(0-inf) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The C max and AUC(0-inf) of cinacalcet were increased by65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting. After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and C max of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL. Metabolism and ExcretionCinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized viaβ-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.Drug InteractionsIn vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2,CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer ofCYP450 enzymes. Tables 3 and 4 list the findings from in vivo drug-drug interaction studies.。
帕博西尼（Ibrance，Palbociclib）FDA 官方说明书
帕博西尼（Ibrance，Palbociclib）FDA官方说明书1 适应症和用途IBRANCE是适用与来曲唑联用对有雌激素受体(ER)-阳性，人表皮生长因子受体2(HER2)-阴性晚期乳癌绝经后妇女作为初始基于内分泌治疗对其转移疾病的治疗。
这个适应症是根据无进展生存(PFS)在加速批准下被批准的[见临床研究(14)]。
对此适应症的继续批准可能取决于在验证性试验中临床获益的证明和描述。
2 剂量和给药方法2.1 一般给药信息IBRANCE的推荐剂量是一粒125 mg胶囊口服服用每天一次共21天，接着不用治疗7天组成一个28天完整疗程。
IBRANCE应与食物服用[见临床药理学(12.3)]与来曲唑2.5 mg每天一次联用连续28-天疗程自始至终给予。
应鼓励患者在每天接近相同时间服用他们的剂量。
如患者呕吐或丢失一剂，在那天不应服用另外剂量。
在寻常的时间服用下一次处方剂量。
IBRANCE胶囊应被整吞(在吞咽前不要咀嚼，压碎或打开胶囊)。
如破碎，压碎或不完整时不应摄入胶囊。
2.2 剂量调整建议根据个体安全性和耐受性调整IBRANCE剂量[见警告和注意事项(5)]。
某些不良反应的处理[见警告和注意事项(5)]可能需要暂时中断剂量/延迟和/或减低剂量，或永久终止如同表1，2和3提供每种剂量减低计划[见警告和注意事项(5)，不良反应(6)和临床研究(14)]。
见制造商处方资料对共同给药产品，来曲唑，在毒性事件中剂量调整指导原则和其他相关安全性资料或禁忌证。
为与强CYP3A抑制剂使用剂量调整避免强CYP3A抑制剂的同时使用和考虑没有或小CYP3A抑制作用另外同时药物。
如患者必须用强CYP3A抑制剂共同给药，减低IBRANC剂量至75 mg每天一次。
如强抑制剂被终止，增加IBRANCE剂量(抑制剂的3–5个半衰期后)至强CYP3A抑制剂使用前剂量[见药物相互作用(7.1)和临床药理学(12.3)]。
3 剂型和规格125 mg胶囊：不透明硬明胶胶囊，大小0，有焦糖帽和体，帽上用白墨汁印，体上“PBC 125”。
碧云天生物技术 PreScission Protease 产品说明书
碧云天生物技术/Beyotime Biotechnology订货热线：400-168-3301或800-8283301订货e-mail：******************技术咨询：*****************碧云天网站微信公众号网址：PreScission Protease产品编号产品名称包装P2302 PreScission Protease 100U产品简介：PreScission Protease是一种大肠杆菌中重组表达的带GST标签的人鼻病毒14型的3C蛋白酶(human rhinovirus (HRV) type14 3C protease)，也称HRV 3C Protease或HRV3C Protease，能在低温条件下(4°C)特异性地识别八肽序列Leu-Glu-Val-Leu-Phe-Gln-Gly-Pro或核心五肽序列Leu-Phe-Gln-Gly-Pro，并在Gln和Gly氨基酸残基之间进行酶切，常用于去除融合蛋白的Glutathione S-transferase (GST)、His或者其它标签的蛋白酶。
建议把GST或His等标签设计在融合蛋白的N 端，在GST或His等标签与目的蛋白之间设计加入PreScission Protease 专一性识别与酶切的上述八肽序列，这样在GST或His标签被酶切后，在目的蛋白的N端仅有两个额外的Gly-Pro氨基酸残基，从而最大限度地减少了对其结构和功能的影响。
本PreScission Protease带有GST标签，特别适合用于GST标签蛋白的在柱酶切。
在切割GST标签蛋白的时候，切下的GST标签和PreScission Protease可结合于GST纯化柱(GST-tag Purification Resin)上，而目的蛋白在穿透液中，这样洗脱下来的蛋白中就不会含有GST标签和PreScission Protease，从而极大地方便了目的蛋白的纯化。
利塞膦酸钠FDA说明书
____________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useACTONEL safely and effectively. See full prescribing information forACTONEL. ACTONEL ® (risedronate sodium) tabletsInitial U.S. Approval: 1998----------------------------RECENT MAJOR CHANGES--------------------------Warnings and Precautions (5.3) 7/2009 ----------------------------INDICATIONS AND USAGE---------------------------ACTONEL is a bisphosphonate indicated for: •Treatment and prevention of postmenopausal osteoporosis (1.1), •Treatment to increase bone mass in men with osteoporosis (1.2), •Treatment and prevention of glucocorticoid-induced osteoporosis (1.3), •Treatment of Paget’s disease (1.4). ----------------------DOSAGE AND ADMINISTRATION-----------------------Must be taken with plain water (6 to 8 oz) at least 30 minutes before the firstfood or drink of the day; do not lie down for 30 minutes (2) Treatment of Osteoporosis in Postmenopausal Women: 5 mg daily, 35 mg once a week, 75 mg taken on two consecutive days each month, or 150 mg once a month (2.1) Prevention of Osteoporosis in Postmenopausal Women: 5 mg daily, or 35 mg once a week (2.2)Men with Osteoporosis: 35 mg once a week (2.3)Treatment and Prevention of Glucocorticoid-Induced Osteoporosis: 5 mg daily(2.4)Paget’s Disease: 30 mg daily for 2 months (2.5)---------------------DOSAGE FORMS AND STRENGTHS----------------------Tablets: 5, 30, 35, 75, and 150 mg (3) -------------------------------CONTRAINDICATIONS------------------------------• Inability to stand or sit upright for at least 30 minutes (4, 5.1) • Hypocalcemia (4, 5.2)• Known hypersensitivity to any component of this product (4, 6.2) -----------------------WARNINGS AND PRECAUTIONS------------------------• Upper gastrointestinal irritation may occur. Dosing instructions should be followed. Discontinue use if new or worsening symptoms occur (5.1). • Hypocalcemia may worsen and must be corrected prior to use (5.2). • Osteonecrosis of the jaw has been reported rarely (5.3). • Severe bone, joint, or muscle pain may occur. Consider discontinuing use if severe symptoms develop (5.4, 6.2). • Before initiating treatment in patients with glucocorticoid-induced osteoporosis, sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered (5.6). • Bisphosphonates may interfere with bone-imaging agents (5.7). ------------------------------ADVERSE REACTIONS-------------------------------Most common adverse reactions reported in >10% of patients treated with ACTONEL and with a higher frequency than placebo are: back pain, arthralgia, abdominal pain, and dyspepsia (6.1). Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions), and eye inflammation (iritis, uveitis) have been reported rarely (6.2). To report SUSPECTED ADVERSE REACTIONS, contact Procter & Gamble Pharmaceuticals, Inc. at 1-800-836-0658 or FDA at 1-800-FDA1088 or /medwatch.------------------------------DRUG INTERACTIONS-------------------------------Calcium, antacids, or oral medications containing divalent cations interfere with the absorption of ACTONEL (7.1). -----------------------USE IN SPECIFIC POPULATIONS------------------------ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) (5.5, 8.6, 12.3). ACTONEL is not indicated for use in pediatric patients (8.4).See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 07/2009 FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 1.1 Postmenopausal Osteoporosis 1.2 Osteoporosis in Men 1.3 Glucocorticoid-Induced Osteoporosis 1.4 Paget’s Disease 2DOSAGE AND ADMINISTRATION 2.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]2.2 Prevention of Postmenopausal Osteoporosis [see Indications and Usage (1.1)] 2.3Treatment to Increase Bone Mass in Men with Osteoporosis [see Indications and Usage (1.2)] 2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis [see Indications and Usage (1.3)] 2.5 Treatment of Paget’s Disease [see Indications and Usage (1.4)] 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Upper Gastrointestinal Adverse Reactions 5.2 Mineral Metabolism 5.3 Jaw Osteonecrosis 5.4 Musculoskeletal Pain 5.5 Renal Impairment 5.6 Glucocorticoid-Induced Osteoporosis 5.7 Laboratory Test Interactions 6ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Calcium Supplements/Antacids 7.2 Hormone Replacement Therapy 7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs 7.4 H 2 Blockers and Proton Pump Inhibitors (PPIs) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Treatment of Osteoporosis in Postmenopausal Women 14.2 Prevention of Osteoporosis in Postmenopausal Women 14.3 Men with Osteoporosis 14.4 Glucocorticoid-Induced Osteoporosis 14.5 Treatment of Paget’s Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 FDA-Approved Patient Labeling *Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEOsteoporosis1.1 PostmenopausalACTONEL is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ACTONEL reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see Clinical Studies (14.1, 14.2)].1.2 Osteoporosis in MenACTONEL is indicated for treatment to increase bone mass in men with osteoporosis.Osteoporosis1.3 Glucocorticoid-InducedACTONEL is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of ≥ 7.5 mg prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.Disease1.4 Paget’sACTONEL is indicated for treatment of Paget’s disease of bone in men and women.2 DOSAGE AND ADMINISTRATIONACTONEL should be taken at least 30 minutes before the first food or drink of the day other than water.To facilitate delivery to the stomach, ACTONEL should be swallowed while the patient is in an upright position and with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication [see Warnings and Precautions (5.1)].Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.2)]. Calcium supplements and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of ACTONEL and should be taken at a different time of the day. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly.2.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]The recommended regimen is:•one 5 mg tablet orally, taken dailyor•one 35 mg tablet orally, taken once a weekor•one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each monthor•one 150 mg tablet orally, taken once a month2.2 Prevention of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]The recommended regimen is:•one 5 mg tablet orally, taken dailyor•one 35 mg tablet orally, taken once a weekor•alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be consideredor•alternatively, one 150 mg tablet orally, taken once a month may be considered2.3 Treatment to Increase Bone Mass in Men with Osteoporosis [see Indications andUsage (1.2)]The recommended regimen is:•one 35 mg tablet orally, taken once a week2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis [see Indicationsand Usage (1.3)]The recommended regimen is:•one 5 mg tablet orally, taken daily2.5 Treatment of Paget’s Disease [see Indications and Usage (1.4)]The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.3 DOSAGE FORMS AND STRENGTHS• 5 mg film-coated, oval, yellow tablet with RSN on 1 face and 5 mg on the other.•30 mg film-coated, oval, white tablet with RSN on 1 face and 30 mg on the other.•35 mg film-coated, oval, orange tablet with RSN on 1 face and 35 mg on the other.•75 mg film-coated, oval, pink tablet with RSN on 1 face and 75 mg on the other.•150 mg film-coated, oval, blue tablet with RSN on 1 face and 150 mg on the other.4 CONTRAINDICATIONS•Inability to stand or sit upright for at least 30 minutes [see Dosage andAdministration (2), Warnings and Precautions (5.1)]•Hypocalcemia [see Warnings and Precautions (5.2)]•Known hypersensitivity to any component of this product [see Adverse Reactions(6.2)]5 WARNINGS AND PRECAUTIONS5.1 Upper Gastrointestinal Adverse ReactionsBisphosphonates, including ACTONEL, may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. ACTONEL should be taken according to the dosing instructions to minimize the risk of these events. Patients should discontinue use if new or worsening symptoms occur. [see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].Metabolism5.2 MineralHypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated [see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1)].Osteonecrosis5.3 JawOsteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ACTONEL. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. [see Adverse Reactions (6.2)]5.4 MusculoskeletalPainIn postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.5.5 Renal ImpairmentACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).Osteoporosis5.6 Glucocorticoid-InducedBefore initiating ACTONEL treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.5.7 Laboratory Test InteractionsBisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.REACTIONS6 ADVERSE6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Treatment of Postmenopausal OsteoporosisDaily DosingThe safety of ACTONEL 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to ACTONEL 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 IU per day if their 25-hydroxyvitamin D3 level was below normal at baseline.The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the ACTONEL 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the ACTONEL 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the ACTONEL5 mg group. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in ≥5% of patients. Adverse events are shown without attribution of causality.Table 1Adverse Events Occurring at a Frequency ≥5% in Either Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment TrialsBody System PlaceboN = 16195 mg ACTONELN = 1613% %Body as a WholeInfection 29.931.1 Back Pain 26.1 28.0Accidental Injury 16.8 16.9Pain 14.014.1 Abdominal Pain 9.9 12.2Flu Syndrome 11.6 10.5Headache 10.89.9 Asthenia 4.55.4 Neck Pain 4.7 5.4Chest Pain 5.1 5.0Allergic ReactionCardiovascular System5.9 3.8Hypertension Digestive System 9.810.5Constipation 12.612.9 Diarrhea 10.010.8 Dyspepsia 10.610.8Nausea Metabolic & Nutritional Disorders 11.210.5Peripheral EdemaMusculoskeletal System8.8 7.7Arthralgia 22.123.7 Arthritis 10.19.6 Traumatic Bone Fracture 12.3 9.3Joint Disorder 5.3 7.0Myalgia 6.26.7 Bone PainNervous System4.85.3Dizziness 5.77.1 Depression 6.16.8Insomnia Respiratory System 4.65.0Bronchitis 10.410.0 Sinusitis 9.18.7 Rhinitis 5.16.2 Pharyngitis 5.06.0 Increased CoughSkin and Appendages6.3 5.9Rash Special Senses 7.17.9Cataract Urogenital System 5.76.5Urinary Tract Infection 10.4 11.1Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and ACTONEL 5 mg daily groups were: abdominal pain (9.9% vs. 12.2%), diarrhea (10.0% vs. 10.8%), dyspepsia (10.6% vs. 10.8%), and gastritis (2.3% vs. 2.7%). Duodenitis and glossitis have been reported uncommonly in the ACTONEL 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and ACTONEL 5 mg daily groups.Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and ACTONEL 5 mg daily groups were: back pain (26.1% vs. 28.0%), arthralgia (22.1% vs. 23.7%), myalgia (6.2% vs. 6.7%), and bone pain (4.8% vs. 5.3%).Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (<1%) and serum phosphate (<3%) and compensatory increases in serum PTH levels (<30%) were observed within 6 months in patients in osteoporosis clinical trials treated with ACTONEL 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and ACTONEL 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and ACTONEL 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with ACTONEL5 mg once daily. There have been rare reports (<0.1%) of abnormal liver function tests.Endoscopic Findings: In the ACTONEL clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 (14.5%) placebo; 75 (11.9%) ACTONEL]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% ACTONEL).Once-a-Week DosingThe safety of ACTONEL 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing ACTONEL5 mg daily and ACTONEL 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to ACTONEL 5 mg daily and 485 exposed to ACTONEL 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 IU per day if their25-hydroxyvitamin D3 level was below normal at baseline.The incidence of all-cause mortality was 0.4% in the ACTONEL 5 mg daily group and 1.0% in the ACTONEL 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the ACTONEL 5 mg daily group and 8.2% in the ACTONEL 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the ACTONEL 5 mg daily group and 11.5% in the ACTONEL 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar.Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the ACTONEL 5 mg daily group and the ACTONEL 35 mg once-a-week group: dyspepsia (6.9% vs. 7.6%), diarrhea (6.3% vs. 4.9%), and abdominal pain (7.3% vs. 7.6%).Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the ACTONEL 5 mg daily group and 14.2% of patients in the ACTONEL 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the ACTONEL 5 mg daily group and 6.2% of patients in the ACTONEL 35 mg once-a-week group.Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively, for serum calcium (0.4% vs. 0.7%), phosphate (-3.8% vs. -2.6%) and PTH (6.4% vs. 4.2%).Monthly DosingTwo Consecutive Days per MonthThe safety of ACTONEL 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to ACTONEL 5 mg daily and 616 were exposed to ACTONEL 75 mg two consecutive days per month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 IU of vitamin D supplementation per day.The incidence of all-cause mortality was 1.0% for the ACTONEL 5 mg daily group and 0.5% for the ACTONEL 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the ACTONEL 5 mg daily group and 14.4% in the ACTONEL75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the ACTONEL 5 mg daily group and 13.0% in the ACTONEL 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar.Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on ACTONEL 5 mg daily and 7.6% of patients on ACTONEL 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on ACTONEL 5 mg daily and 0.6% of patients on ACTONEL 75 mg two consecutive days per month.Gastrointestinal Adverse Events: The ACTONEL 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% vs. 0.2%) and diarrhea (1.0% vs. 0.3%) compared to the ACTONEL 5 mg daily group. Most of these events occurred within a few days of dosing.Ocular Adverse Events: None of the patients treated with ACTONEL 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis;1 patient treated with ACTONEL 5 mg daily reported uveitis.Laboratory Test Findings: When ACTONEL 5 mg daily and ACTONEL 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the ACTONEL 5 mg daily group, ACTONEL 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% vs. 3.0%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.Once-a-MonthThe safety of ACTONEL 150 mg administered once a month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with642 patients exposed to ACTONEL 5 mg daily and 650 exposed to ACTONEL 150 mg once-amonth. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 IU of vitamin D supplementation per day.The incidence of all-cause mortality was 0.5% for the ACTONEL 5 mg daily group and 0.0% for the ACTONEL 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the ACTONEL 5 mg daily group and 6.2% in the ACTONEL 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the ACTONEL 5 mg daily group and 8.6% in the ACTONEL 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar.Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the ACTONEL 5 mg daily group and 5.2% in the ACTONEL 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on ACTONEL 5 mg daily and 1.4% of patients on ACTONEL 150 mg once-a-month.Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with ACTONEL 150 mg once-a-month compared to 5 mg daily (8.2% vs. 4.7%, respectively). The ACTONEL 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% vs. 1.4%) and diarrhea (0.8% vs. 0.0%) compared to the ACTONEL 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% vs.0.3%).Ocular Adverse Events: None of the patients treated with ACTONEL 150 mg once-amonth reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with ACTONEL 5 mg daily reported iritis.Laboratory Test Findings: When ACTONEL 5 mg daily and ACTONEL 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the ACTONEL 5 mg daily regimen, ACTONEL 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% vs. 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.Prevention of Postmenopausal OsteoporosisDaily DosingThe safety of ACTONEL 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and ACTONEL-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to ACTONEL 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to ACTONEL 5 mg. All women received 1000 mg of elemental calcium per day.In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the ACTONEL 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the ACTONEL 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the ACTONEL 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of ACTONEL 5 mg group.In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the ACTONEL5 mg group. The percentage of patients who withdrew from treatment due to adverse events was6.4% in the placebo group and 5.4% in the ACTONEL 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the ACTONEL 5 mg group. Once-a-Week DosingThere were no deaths in a 1-year, double-blind, placebo-controlled study of ACTONEL 35 mg once a week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on ACTONEL reported arthralgia (placebo 7.8%; ACTONEL 13.9%), myalgia (placebo 2.1%; ACTONEL 5.1%), and nausea (placebo 4.3%; ACTONEL 7.3%) than subjects on placebo.。
palbociclib英文说明书
6 7 7
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE
IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies (14)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 2 2.1 DOSAGE AND ADMINISTRATION General Dosing Information
----------------------- WARNINGS AND PRECAUTIONS ---------------------- • Hematologic: Neutropenia may occur. Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. (5.1) • Infections: Monitor for signs and symptoms and withhold dosing as appropriate. (5.2) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) ------------------------------ ADVERSE REACTIONS ----------------------------- Most common adverse reactions (incidence ≥10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or /medwatch. ------------------------------ DRUG INTERACTIONS------------------------------ • CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the IBRANCE dose. (2.2, 7.1) • CYP3A Inducers: Avoid concurrent use of IBRANCE with strong and moderate CYP3A inducers. (7.2) • CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with IBRANCE. (7.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: [02/2015]
硫酸吗啡FDA说明书(英文)
• AVINZA is not for use:
•
As an as-needed (prn) analgesic (1) For pain that is mild or not expected to persist for an extended period of time (1) For acute pain (1) For postoperative pain, unless the patient is already receiving chronic opioid therapy prior to surgery, or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time (1) AVINZA 90 mg and 120 mg capsules are only for patients in whom tolerance to an opioid of comparable potency is established. (1)
-----------------------WARNINGS AND PRECAUTIONS----------------------- Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. (5.5, 5.6) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. (5.7, 7.2) Hypotensive effect: Monitor during dose initiation and titration (5.8) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of AVINZA in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. (5.9) ------------------------------ADVERSE REACTIONS------------------------------Most common adverse reactions (≥10%) are constipation, nausea, somnolence, vomiting and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or /medwatch ------------------------------DRUG INTERACTIONS------------------------------ Mixed agonist/antagonist opioid analgesics: Avoid use with AVINZA because they may reduce analgesic effect of AVINZA or precipitate withdrawal symptoms. (5.12, 7.3) Muscle relaxants: Avoid use with AVINZA because of increased risk of respiratory depression. (7.4) Monoamine oxidase inhibitors (MAOIs): Avoid AVINZA in patients taking MAOIs or within 14 days of stopping such treatment. (7.5) -----------------------USE IN SPECIFIC POPULATIONS----------------------- Pregnancy: Based on animal data, may cause fetal harm. (8.1) Nursing mothers: Morphine has been detected in human milk. Closely monitor infants of nursing women receiving AVINZA. (8.3)
Probios产品指南说明书
9 Better Off With Probios®Page 1...the world leader in probioticsProbios® and Probiocin® are registered trademarks of Chr. Hansen, Inc.Intelli ora® is a registered trademark of Vets Plus, Inc.®Why use Probios® brand? Probios is the world’s most widely used, researched, and recognized brand of direct-fed microbials (DFMs).Science-Based Research: More than 95 individual studies have been performed at universities and under practical field conditions. These trials, involving 30,000 microbial products in dairy, beef, swine, and sheep. Additional studies have shown positive results for Probios in horses and in starter, grower, and finisher pigs, chickens, and turkeys.Backed by Quality: Probios is safe and effective when fed to animals. Probios contains guaranteed levels of Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus plantarum.Stability and Viability: Probios contains bacteria of proven efficacy in numbers capable of remaining viable during manufacturing and storage. Additionally, every guaranteed bacterium (expressed in CFUs or Colony Forming Units) will be available to the animal upon use.Manufactured in the U.S.A. Vets Plus, Inc. is the exclusive manufacturer of Probios microbial products in the U.S. These products are manufactured in an SQF Level 3 Edition 7.2 certified facility.For questions about Probios, call 715.231.1234.The ABCs of DFMs(Direct-fed microbials)Direct-fed microbials are also known as probiotics. The word “probiotic” literally means “for life” and is the opposite of the word antibiotic. Probiotics are good bacteria that can help boost the levels of beneficial bacteria in the gut, whereas antibiotics attack and kill infections and unwanted bacteria. For animals, probiotics are more commonly referred to as direct-fed microbials, or DFMs.DFMs help maintain intestinal balance, overall health and performance by:Helping maintain natural immunitiesHelping maintain pH in the gutHelping maintain nutrient absorptionHelping maintain gut microflora balanceEvery animal with a digestive system, including humans, has bacteria in their digestive system. Without bacteria an animal could not digest food. Animals have an extremely complex collection of about 100 trillion micro-organisms in their entire digestive tract. The intestine of animals contains billions of bacteria, some of which are beneficial (good bacteria) and some of which are pathogenic (bad bacteria).Under certain conditions, such as stress, the natural balance of beneficial bacteria in the digestive system is disrupted. The number of pathogens increases while the number of beneficial organisms decreases, causing digestive upsets including diarrhea, constipation, and discomfort. In animals, DFMs may help restore the normal microbial balance in the gut and overall health of the animal.Newborn animals do not have bacteria in their intestine. The intestine rapidly becomes colonized by natural means from the mother and the environment. Studies have shown providing DFMs to an animal at birth plays an important role in the growth and health of animals.CHR-980: 120 g jar, 6 per caseCHR-985: 240 g jar, 6 per case Suggested Use:Probios Soft Chews feature a highly palatable chicken liver flavor that makes administering them to your dog a breeze. Each soft chew provides two strains of live (viable) bacteria that help support proper digestion. These provide the ideal supplement for your pet’s stomach caused by situations like travel or visits to the vet.Feeding Recommendations:120 g jar: 2 chews per 10 lbs of body weight240 g jar: 1-3 chews per 50 lbs of body weightPage 3Probios® Digestive TabletsAvailable Sizes:CHR-910: 45 ct jar, 6 per caseCHR-911: 180 ct jar, 6 per caseSuggested Use:Probios Digestive Dog Tablets are a chewable, probiotic supplement that contain a source of live, naturally occurring micro-organisms to help support proper digestion during diet changes, kenneling and travel.Feeding Recommendations:Puppies: 1 tablet per dayDogs: 1 tablet per 20 lbs body weight per dayPage 4Probios® Chewables for DogsDigestion SupportAvailable Sizes:CHR-950/6: 1 lb pouch, 6 per case Suggested Use:Probios Digestion Support Treats for Dogs are suggested for daily use to maintain a healthy digestive system. Also suggested for use during traveling, kenneling, or training to help support proper digestion.Feeding Recommendations:Give 3-6 treats daily. Repeat as needed.Page 5Probios ® Chewables for Dogs Joint Support Page 6Available Sizes: CHR-951/6: 1 lb pouch, 6 per caseSuggested Use: Probios Joint Support Treats are suggested to deliver probiotic benefits and help support healthy joint function. For use in all breeds of dogs.Feeding Recommendations:Give 3-6 treats daily. Repeat as needed.Probios® Dispersible PowderAvailable Sizes:CHR-404: 240 g jar, 12 per caseCHR-403: 5 lb jar, 6 per caseCHR-402: 25 lb pail, 1 per case Suggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Dogs: (under 1 lb): 1/4 tsp / pet / dayDogs: (1 to 10 lbs): 1/2 tsp / pet / dayDogs: (>10 lbs): 1 tsp / pet / dayPage 7Probios® Pro-Pill Pods™Page 8 Available Sizes:CHR-991: (3.7 oz) 30 ct jar, 12 per case (Chicken)CHR-992: (7.4 oz) 30 ct jar, 12 per case (Chicken)CHR-996: (3.7 oz) 30 ct jar, 12 per case (Peanut Butter)CHR-997: (7.4 oz) 30 ct jar, 12 per case (Peanut Butter) Suggested Use:Highly palatable Pro-Pill Pods take the hassle out of medicating your dogs by concealing medicinal odors and taste. Ideal size that fits most tablets and capsules. May be cut in half for smaller pills.Directions for Use:Hold the pod with thumb and forefinger. Insert pill. Squeeze ends shut. Pro-Pill Pod is now ready to offer to your pet. Provide fresh water at all times.Probios® Intelliflora® for DogsAvailable Sizes:CHR-800: 1 g packets (30 ct), 6 per case, 24 per master case Suggested Use:Probios Intelliflora is designed to be used as a daily supplement to help support normal digestion. Feeding Recommendations:Sprinkle one packet daily on top of your pet’s food.Page 9Probiocin® Pet GelAvailable Sizes:CHR-900: 15 cc tube, 72 per case Suggested Use:Probiocin is a probiotic supplement that helps maintain a healthy digestive system by supporting the proper bacterial balance in the lower intestine.Feeding Recommendations:Newborns: 1 g at birthPage 10Made with realyogurtHelps freshenbreathCarefully crafted with natural ingredientsProbiotics, prebiotics, and soluble fiber help maintain proper digestionSpecifically designed for maximum tooth abrasionfor cleaner teethDental SticksAvailable Sizes:CHR-970: 8.11 oz pouch, 12 per caseSuggested Use:Helps reduce plaque and tartar as your dog chews.Prebiotics and probiotics help support proper digestion.Feeding Recommendations:Small Dogs (5-25 lbs): 1/2 chew, twice dailyMedium and Large Dogs (20-60+ lbs): 1 chew, twice dailyPage 11Page 12Probios® Dispersible PowderAvailable Sizes:CHR-404: 240 g jar, 12 per caseCHR-403: 5 lb jar, 6 per caseCHR-402: 25 lb pail, 1 per case Suggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Cats: (under 1 lb): 1/4 tsp / pet / dayCats: (1 to 10 lbs): 1/2 tsp / pet / dayCats: (>10 lbs): 1 tsp / pet / dayPage 13Probiocin® Pet GelAvailable Sizes:CHR-900: 15 cc tube, 72 per case Suggested Use:Probiocin is a probiotic supplement that helps maintain a healthy digestive system by supporting the proper bacterial balance in the lower intestine.Feeding Recommendations: Newborns: 1 g at birthPage 14Probios® Intelliflora® for CatsAvailable Sizes:CHR-805: 1 g packets (30 ct), 6 per case, 24 per master case Suggested Use:Probios Intelliflora is designed to be used as a daily supplement to help support normal digestion. Feeding Recommendations:Sprinkle one packet daily on top of your pet’s food.Page15Page 15Probios ® Cat Product ChartPage16Probios® Chewables for HorsesJoint SupportAvailable Sizes:CHR-752/6: 1 lb pouch, 6 per case Suggested Use:Probios Chewables for Horses Joint Support are recommended to support healthy joints, joint flexibility and mobility in addition to supplying probiotic benefits. Feeding Recommendations:3 to 6 treats daily.Page 17Available Sizes:CHR-750/6 - 1 lb pouch, 6 per caseSuggested Use:Probios Equine Digestion Support treats are recommended to support healthy digestion. The beneficial bacteria helps maintain appetite and gut function during situations like travel or showing.Feeding Recommendations:Provide 1-2 treats daily. Repeat as needed.Probios ® Chewables for HorsesDigestion SupportPage18Available Sizes:CHR-795 - 1.32 lbs pouch, 6 per caseSuggested Use:Probios Equine Digestion Support soft chews arerecommended to support healthy digestion. The beneficial bacteria helps maintain appetite and gut function during situations like travel or showing.Feeding Recommendations:Provide 1-2 treats daily. Repeat as needed.Probios ® Soft Chews for HorsesDigestion SupportPage 19Probios® Equine One Oral GelAvailable Sizes:CHR-700: 30 cc tube, 72 per case Suggested Use:Probios Equine One Oral Gel helps support microbial balance in your horse’s gastrointestinal tract. This probiotic formula utilizes four different strains of lactic acid bacteria and includes more than 10 million colony forming units per gram.Feeding Recommendations: Newborns: 10 g at birth and day 4Adults: 15 g / head / dayPage 20Probios® Dispersible PowderAvailable Sizes:CHR-404: 240 g jar, 12 per caseCHR-403: 5 lb jar, 6 per caseCHR-402: 25 lb pail, 1 per case Suggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Equine-Foals: 5 g / head / dayAdults: 10 g-15 g / head / dayPage 21 Page 21Probios® Horse Product ChartPage 22Probios ® Bovine One Oral GelAvailable Sizes:CHR-100: 300 cc tube, 24 per case CHR-101: 60 cc tube, 72 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units per gram of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Beef:Newborns:5 g at birthCalves: <400 lbs, 10 g >400 lbs, 15 g Incoming Feedlot/ <400 lb, 10 g Stockers: >400 lb, 15 g Hospital: 15 g on first and lastday of therapyGoats/Sheep:Newborns: 5 g at birthPage 23Dairy: Calves: 5 g at birth Heifers <400 lb, 10 g >400 lb, 15 g Cows: 30 g at freshening Hospital: 15 g on first and last day of therapyProbios ® Bovine One Oral GelMAXAvailable Sizes:CHR-110: 300 cc tube, 24 per case CHR-111: 60 cc tube, 72 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 15 million colony forming units per 10 grams of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Beef:Newborns:5 g at birthCalves: <400 lbs, 10 g >400 lbs, 15 g Incoming Feedlot/ <400 lb, 10 g Stockers: >400 lb, 15 gHospital: 15 g on first and lastday of therapyGoats/Sheep:Newborns: 5 g at birthPage 24Dairy: Calves: 5 g at birth Heifers <400 lb, 10 g >400 lb, 15 g Cows: 30 g at fresheningHospital: 15 g on first and last day of therapyProbios ® Bovine One Oral Gelwith Natural EAvailable Sizes:CHR-120: 300 cc tube, 24 per case CHR-121: 60 cc tube, 72 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units per gram of four different strains of lactic acid bacteria that work to naturally facilitate digestion with natural Vitamin E.Feeding Recommendations:Beef:Newborns:5 g at birthCalves: <400 lbs, 10 g >400 lbs, 15 g Incoming Feedlot/ <400 lb, 10 g Stockers: >400 lb, 15 gHospital: 15 g on first and lastday of therapyPage 25Dairy: Calves: 5 g at birth Heifers: <400 lb, 10 g >400 lb, 15 g Cows: 30 g at fresheningHospital: 15 g on first and last day of therapyProbios ® Dispersible PowderAvailable Sizes:CHR-404: 240 g jar, 12 per case CHR-403: 5 lb jar, 6 per case CHR-402: 25 lb pail, 1 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units of four different strains of lactic acid bacteria that work to naturally facilitate digestion.Feeding Recommendations:Dairy/Beef: Calves: 5 g / head / day Adult: 15 g / head / day Swine: Nursery: 2 g / head / day Adult:5 g / head / dayPage 26Equine:Foals: 5 g / head / day Adult: 10-15 g / head / day Sheep/Goat:All: 5 g / head / dayProbios® Oral Bolus1/4 ozAvailable Sizes:CHR-501: 50 ct, 12 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 49 million colony forming units per bolus of four different strains of lactic acid bacteria that work to naturally facilitate digestion. Feeding Recommendations:Dairy/Beef:Newborns: 1 bolus at birthCalves: < 400 lbs, 1 bolus / head / day> 400 lbs, 2 boluses / head / day Cows: 4 boluses at fresheningSheep/Goats: 1 bolusPage 27Probios® Oral Bolus1/2 ozAvailable Sizes:CHR-500: 50 ct, 12 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 98 million colony forming units per bolus of four different strains of lactic acid bacteria that work to naturally facilitate digestion. Feeding Recommendations:Dairy/Beef:Newborns: 1 bolus at birthCalves: < 400 lbs, 1/2 bolus / head / day> 400 lbs, 1 boluses / head / day Cows: 2 boluses at fresheningSheep/Goats: 1/2 bolusPage 28Page 29Probios® Feed GranulesAvailable Sizes:CHR-406: 5 lb, 6 per caseCHR-405: 50 lb, 1 per caseSuggested Use:This unique product helps support proper digestion. The supplement provides more than 10 million colony forming units per bolus of four different strains of lactic acid bacteria that work to naturally facilitate digestion. Feeding Recommendations:Calves: 5 g / head / dayIncomingFeedlot/ 10-15 g / head / dayStocker:Heifers: 10 g / head / dayCows: 10 g / head / dayPage 29Probios® Livestock Product ChartPage 30Questions? Check out our websitefor more information: Learn more about our products!We’re a Social Bunch!Better Off With Probios®。
脯氨酸含量检测试剂盒说明书
脯氨酸（Pro ）含量检测试剂盒说明书可见分光光度法注意：本产品试剂有所变动，请注意并严格按照该说明书操作。
货号：BC0290规格：50T/48S产品组成：使用前请认真核对试剂体积与瓶内体积是否一致，有疑问请及时联系索莱宝工作人员。
试剂名称规格保存条件提取液液体60mL×1瓶4℃保存试剂一液体45 mL×1瓶（自备）4℃保存试剂二液体45 mL×1瓶4℃保存标准品粉剂×1支4℃保存溶液的配制：1．试剂一：自备冰乙酸。
2．标准品：脯氨酸10 mg ，临用前加入1 mL 蒸馏水，配成10 mg/mL 标准品。
产品说明：脯氨酸（Pro ）广泛存在于动物、植物、微生物和培养细胞中，逆境条件下，植物体内Pro 含量显著增加。
Pro 增加量在一定程度上反映了抗逆性，抗旱性强的品种往往积累较多的脯氨酸。
因此，脯氨酸增加量可以作为抗逆育种的生理指标之一。
用磺基水杨酸（SA ）提取Pro ，加热处理后，Pro 与酸性茚三酮溶液反应生成红色，在520nm 测定吸光度。
技术指标：最低检出限：0.1791 μg/mL 线性范围：0.5-40 μg/mL注意：实验之前建议选择2-3个预期差异大的样本做预实验。
如果样本吸光值不在测量范围内建议稀释或者增加样本量进行检测。
需自备的仪器及用品：可见分光光度计、水浴锅、台式离心机、可调式移液器、1mL 玻璃比色皿、冰乙酸、研钵/匀浆器、冰和蒸馏水。
操作步骤：一、样本处理（可适当调整待测样本量，具体比例可以参考文献）1、细胞、细菌或组织样本的制备：细菌或细胞：先收集细菌或细胞到离心管内，弃上清；按照每500万细菌或细胞加入1mL 提取液，超声波破碎细菌或细胞（功率20％，超声3秒，间隔10秒，重复30次），之后置沸水浴振荡提取10min ；10000g ，常温离心10min ，取上清，冷却后待测。
组织：称取约0.1g组织，加入1mL提取液进行冰浴匀浆；之后置沸水浴振荡提取10min，10000g，常温离心10min，取上清，冷却后待测。
舒降之FDA说明书20110608
9992856HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZOCOR safely and effectively. See full prescribing information for ZOCOR.ZOCOR (simvastatin) TabletsInitial U.S. Approval: 1991---------------------------RECENT MAJOR CHANGES ---------------------------Dosage and AdministrationRecommended Dosing (2.1) 06/2011 Restricted Dosing for 80 mg (2.2) 06/2011 Coadministration with Other Drugs (2.3) 06/2011 Patients with Homozygous FamilialHypercholesterolemia (2.4) 06/2011 Chinese Patients Taking Lipid-Modifying Doses(≥1 g/day Niacin) of Niacin-Containing Products (2.7) 06/2011 Contraindications (4) 06/2011 Warnings and PrecautionsMyopathy/Rhabdomyolysis (5.1) 06/2011 Liver Dysfunction (5.2) 06/2011 ----------------------------INDICATIONS AND USAGE ----------------------------ZOCOR® is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to:• Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. (1.1)• Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (1.2)• Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbetalipoproteinemia. (1.2)• Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. (1.2)• Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.(1.2, 1.3)Limitations of UseZOCOR has not been studied in Fredrickson Types I and V dyslipidemias. (1.4)-----------------------DOSAGE AND ADMINISTRATION------------------------• Dose range is 5 to 40 mg/day. (2.1)• Recommended usual starting dose is 10 or 20 mg once a day in the evening. (2.1)• Recommended starting dose for patients at high risk of CHD is40 mg/day. (2.1)• Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80-mg dose of ZOCOR should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. (2.2)• Patients who are currently tolerating the 80-mg dose of ZOCOR who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.(2.2)• Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. (2.2)• Adolescents (10-17 years of age) with HeFH: starting dose is10 mg/day; maximum recommended dose is 40 mg/day. (2.5) ---------------------DOSAGE FORMS AND STRENGTHS ---------------------Tablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg (3)-------------------------------CONTRAINDICATIONS -------------------------------• Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1) • Concomitant administration of gemfibrozil, cyclosporine, or danazol.(4, 5.1)• Hypersensitivity to any component of this medication. (4, 6.2)• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. (4, 5.2)• Women who are pregnant or may become pregnant. (4, 8.1)• Nursing mothers. (4, 8.3)------------------------WARNINGS AND PRECAUTIONS------------------------• Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80-mg dose. (5.1)• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. (4, 5.1,8.5, 8.6)• Patients should be advised to report promptly any symptoms of myopathy. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table.(5.1)• Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. (5.2)------------------------------ADVERSE REACTIONS-------------------------------Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or /medwatch.-------------------------------DRUG INTERACTIONS-------------------------------Drug Interactions Associated with Increased Risk ofMyopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)Interacting Agents Prescribing Recommendations Itraconazole, ketoconazole,posaconazole, erythromycin,clarithromycin, telithromycin,HIV protease inhibitors,nefazodone, gemfibrozil,cyclosporine, danazolContraindicated with simvastatinAmiodarone, verapamil,diltiazemDo not exceed 10 mg simvastatindailyAmlodipine, ranolazine Do not exceed 20 mg simvastatindailyGrapefruit juice Avoid large quantities of grapefruitjuice (>1 quart daily)• Coumarin anticoagulants: Concomitant use with ZOCOR prolongs INR. Achieve stable INR prior to starting ZOCOR. Monitor INR frequently until stable upon initiation or alteration of ZOCOR therapy. (7.6)-----------------------USE IN SPECIFIC POPULATIONS -----------------------• Severe renal impairment: patients should be started at 5 mg/day and be closely monitored. (2.6, 8.6)See 17 for PATIENT COUNSELING INFORMATION.Revised: 06/2011FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1 Reductions in Risk of CHD Mortality and CardiovascularEvents1.2 H yperlipidemia1.3 Adolescent Patients with Heterozygous FamilialHypercholesterolemia (HeFH)1.4 Limitations of Use2 DOSAGE AND ADMINISTRATION2.1 R ecommendedDosing2.2 Restricted Dosing for 80 mg2.3 Coadministration with Other Drugs2.4 Patients with Homozygous Familial Hypercholesterolemia2.5 Adolescents (10-17 years of age) with Heterozygous FamilialHypercholesterolemia2.6 Patients with Renal Impairment2.7 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/dayNiacin) of Niacin-Containing Products3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 M yopathy/Rhabdomyolysis5.2 L iverDysfunction6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 P ost-MarketingExperience7 DRUG INTERACTIONS7.1 Strong CYP3A4 Inhibitors, cyclosporine, or danazol7.2 Lipid-Lowering Drugs That Can Cause Myopathy WhenGiven Alone7.3 Amiodarone, Ranolazine, or Calcium Channel Blockers7.4 N iacin7.5 D igoxin7.6 C oumarinAnticoagulants7.7 C olchicine8 USE IN SPECIFIC POPULATIONS8.1 P regnancy8.3 N ursingMothers8.4 P ediatricUse8.5 G eriatricUse8.6 R enalImpairment8.7 H epaticImpairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Clinical Studies in Adults14.2 Clinical Studies in Adolescents16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Muscle Pain17.2 Liver Enzymes17.3 Pregnancy17.4 Breastfeeding*Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGETherapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, ZOCOR1 can be started simultaneously with diet.1.1 Reductions in Risk of CHD Mortality and Cardiovascular EventsIn patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, ZOCOR is indicated to: • Reduce the risk of total mortality by reducing CHD deaths.• Reduce the risk of non-fatal myocardial infarction and stroke.• Reduce the need for coronary and non-coronary revascularization procedures.1.2 HyperlipidemiaZOCOR is indicated to:• Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).• Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.1Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.Copyright © 1999-2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)ZOCOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:1. LDL cholesterol remains ≥190 mg/dL; or2. LDL cholesterol remains ≥160 mg/dL and• There is a positive family history of premature cardiovascular disease (CVD) or• Two or more other CVD risk factors are present in the adolescent patient.The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.1.4 Limitations of UseZOCOR has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).2 DOSAGE AND ADMINISTRATION2.1 Recommended DosingThe usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, ZOCOR can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.2.2 Restricted Dosing for 80 mgDue to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of ZOCOR should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].Patients who are currently tolerating the 80-mg dose of ZOCOR who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.2.3 Coadministration with Other DrugsPatients taking Amiodarone, Verapamil, or Diltiazem• The dose of ZOCOR should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].Patients taking Amlodipine or Ranolazine• The dose of ZOCOR should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].2.4 Patients with Homozygous Familial HypercholesterolemiaThe recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.2.5 Adolescents (10-17 years of age) with Heterozygous Familial HypercholesterolemiaThe recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should beindividualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines2 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more.2.6 Patients with Renal ImpairmentBecause ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when ZOCOR is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].2.7 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-ContainingProductsBecause of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1).]3 DOSAGE FORMS AND STRENGTHS• Tablets ZOCOR 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and ZOCOR 5 on the other.• Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other.• Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other.• Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other.• Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other.4 C ONTRAINDICATIONSZOCOR is contraindicated in the following conditions:• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1)].• Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions(5.1)].• Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].• Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ZOCOR may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome2National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlledstudies of use with ZOCOR during pregnancy; however, in rare reports congenital anomalies wereobserved following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patientbecomes pregnant while taking this drug, ZOCOR should be discontinued immediately and thepatient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential forserious adverse reactions in nursing infants, women who require treatment with ZOCOR should notbreastfeed their infants [see Use in Specific Populations (8.3)].5 WARNINGS AND PRECAUTIONS5.1 Myopathy/RhabdomyolysisSimvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness withcreatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes theform of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalitieshave occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposingfactors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, andrenal impairment.The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database inwhich 41,413 patients were treated with ZOCOR, 24,747 (approximately 60%) of whom were enrolled instudies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) wasdisproportionately higher than that observed at the lower doses. In these trials, patients were carefullymonitored and some interacting medicinal products were excluded.In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated withZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscleweakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence ofrhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day wasapproximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, includingrhabdomyolysis, was highest during the first year and then notably decreased during the subsequentyears of treatment. In this trial, patients were carefully monitored and some interacting medicinal productswere excluded.The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of ZOCOR should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. If, however, a patient who is currently tolerating the 80-mg dose of ZOCOR needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2).]All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations maybe considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.Drug InteractionsThe risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). Combination of these drugs with simvastatin is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1).] In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the simvastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with simvastatin. [See Drug Interactions (7.1).] The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered [see Drug Interactions (7.2)].Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7)].The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), amiodarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)].Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)].Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3), Drug Interactions (7), Clinical Pharmacology (12.3)].TABLE 1Drug Interactions Associated with IncreasedRisk of Myopathy/RhabdomyolysisInteracting Agents Prescribing RecommendationsItraconazoleContraindicated with simvastatinKetoconazolePosaconazoleErythromycinClarithromycinTelithromycinHIV protease inhibitorsNefazodoneGemfibrozilCyclosporineDanazolAmiodaroneDo not exceed 10 mg simvastatin dailyVerapamilDiltiazemDo not exceed 20 mg simvastatin dailyAmlodipineRanolazineGrapefruit juice Avoid large quantities of grapefruit juice(>1 quart daily)5.2 Liver DysfunctionPersistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3X ULN or greater persist, withdrawal of therapy with ZOCOR is recommended. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.。
耐信-FDA最新版说明书-2014-3-27
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Atrophic gastritis has been noted with long-term omeprazole therapy (5.2) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.3) Avoid concomitant use of NEXIUM with clopidogrel. (5.4) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.5) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. (5.6) Avoid concomitant use of NEXIUM with St John’s Wort or rifampin due to the potential reduction in esomeprazole levels (5.7, 7.3) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.8, 12.2)
非诺贝酸说明书(FDA)2009.8
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use FIBRICOR TM (fenofibric acid) Tablets safely and effectively. See full prescribing information for FIBRICOR.FIBRICOR TM (fenofibric acid)Initial U.S. Approval: 2009--------------------------- INDICATIONS AND USAGE --------------------------- FIBRICOR is a peroxisome proliferator receptor alpha (PPARα) activator indicated:• To reduce triglyceride (TG) levels in patients with severehypertriglyceridemia (> 500 mg/dl) (1.1).• To reduce elevated total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), TG and apolipoprotein (Apo) B and toincrease high-density lipoprotein cholesterol (HDL-C) in patientswith primary hyperlipidemia or mixed dyslipidemia (1.2).General Considerations for Treatment: The active moiety of FIBRICOR is fenofibric acid. The pharmacological effects of fenofibric acid have been extensively studied through oral administration of fenofibrate, which is converted in vivo to fenofibric acid (1.3).Limitations of use: Fenofibrate as a dose equivalent to 105 mg of FIBRICOR was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus (1.3).---------------------- DOSAGE AND ADMINISTRATION ----------------------- • FIBRICOR may be taken without regards to meals (2.1).• Severe hypertriglyceridemia: 35 to 105 mg/day; the dose should be adjusted according to patient response (2.2).• Primary hyperlipidemia or mixed dyslipidemia: 105 mg/day (2.2).--------------------- DOSAGE FORMS AND STRENGTHS --------------------- Tablets: 35 mg and 105 mg (3)------------------------------ CONTRAINDICATIONS ----------------------------- • Severe renal dysfunction, including patients receiving dialysis (4)• Active liver disease (4)• Gallbladder disease (4)• Nursing Mothers (4)• Known hypersensitivity to fenofibric acid or fenofibrate (4)FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1 Severe Hypertriglyceridemia1.2 Primary Hyperlipidemia or Mixed Dyslipidemia1.3 Considerations of Treatment2 DOSAGE AND ADMINISTRATION2.1 Dosing Information2.2 Recommended Adult Dose2.3 RenalImpairment2.4 GeriatricPatients3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Abnormal Liver Tests5.2 Cholelithiasis5.3 Concomitant Use with Oral Anticoagulants5.4 Myopathy5.5 Elevated Serum Creatinine5.6 Coronary Heart Disease Morbidity and Mortality5.7 Pancreatitis5.8 Venothromboembolic Disease5.9 Hypersensitivity Reactions5.10 Hematological Changes6 ADVERSE REACTIONS6.1 Clinical Trial Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Oral Anticoagulants7.2 Bile-Acid Binding Resins7.3 Immunosuppressants ----------------------- WARNINGS AND PRECAUTIONS -----------------------• Fenofibrate can increase serum transaminases. Monitor liver tests periodically (5.1).• Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.2).• Exercise caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications (5.3).• Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. The risks of myopathy and rhabdomyolysis appears to be increased in elderly patients and patients with diabetes, renal failure, or hypothyroidism (5.4).• Fenofibrate can reversibly increase serum creatinine levels. Monitor renal function periodically in patients with renal insufficiency (5.5).------------------------------ ADVERSE REACTIONS ------------------------------ Most common adverse reactions (> 2% and greater than placebo) are increased liver tests, abdominal pain, back pain, and headache (6).To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or FDA at 1-800-FDA-1088 or /medwatch.------------------------------ DRUG INTERACTIONS ------------------------------ • Oral Anticoagulants (7.1)• Bile-Acid Binding Resins (7.2)• Immunosuppressants (7.3)----------------------- USE IN SPECIFIC POPULATIONS ---------------------- • Pediatric use: The safety and effectiveness in pediatric patients have not been established (8.4).• Geriatric use: Determine dose selection based on renal function (8.5).• Renal impairment: Avoid in patients with severe renal impairment; dose reduction required in patients with mild to moderate renal impairment (8.6). • Hepatic impairment: FIBRICOR has not been evaluated in patients with hepatic impairment (8.7).Revised: 8/20098 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Severe Hypertriglyceridemia14.2 Primary Hyperlipidemia (Heterozygous Familial and Nonfamilial)and Mixed Dyslipidemia16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION response after two months of treatment with themaximum recommended dose of 105 mg per day.1 INDICATIONS AND USAGE1.1 SevereHypertriglyceridemia Consideration should be given to reducing the dosage of FIBRICOR is indicated as adjunctive therapy to diet for FIBRICOR if lipid levels fall significantly below the treatment of severe hypertriglyceridemia (≥ 500 mg/dl). targeted range.Improving glycemic control in diabetic patients showingfasting chylomicronemia will usually obviate the need for 2.2 Recommended Adult Dosepharmacologic intervention. Severe Hypertriglyceridemia: The initial dose is 35 to105 mg per day. Dosage should be individualized Levels of serum triglycerides > 1000 mg/dl may increase according to patient response, and should be adjusted if the risk of developing pancreatitis. The effect of necessary following repeat lipid determinations at 4 to 8 FIBRICOR on reducing this risk has not been studied. week intervals.1.2 Primary Hyperlipidemia or Mixed Dyslipidemia Primary Hyperlipidemia or Mixed Dyslipidemia: TheFIBRICOR is indicated as adjunctive therapy to diet to dose of FIBRICOR is 105 mg per day.reduce elevated LDL-C, total-C, TG, and Apo B, and toincrease HDL-C in patients with primary The maximum dose of FIBRICOR is 105 mg per day.hypercholesterolemia or mixed dyslipidemia.2.3 Renal Impairment1.3 Considerations of Treatment In patients with mild-to-moderate renal impairment,Fenofibrate at a dose equivalent to 105 mg of FIBRICOR treatment with FIBRICOR should be initiated at a dose of was not shown to reduce coronary heart disease morbidity 35 mg/day, and increased only after evaluation of the and mortality in a large, randomized controlled trial of effects on renal function and lipid levels at this dose. The patients with type 2 diabetes mellitus [see Warnings and use of FIBRICOR should be avoided in patients with Precautions (5.6)]. severe renal impairment [see Use in Specific Populations The active moiety of FIBRICOR is fenofibric acid. The(8.6) and Clinical Pharmacology (12.3)].pharmacological effects of fenofibric acid have been 2.4 GeriatricPatientsextensively studied through oral administration of fenofibrate, which is converted in vivo to fenofibric acid.Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.6)].3 DOSAGE FORMS AND STRENGTHS2 DOSAGE AND ADMINISTRATION• 35 mg: White, round tablets. Debossed “AR 787”.2.1 Dosing Information • 105 mg: White, modified oval tablets. DebossedFIBRICOR can be given without regard to meals. “AR 788”.Patients should be placed on an appropriate lipid-lowering 4 CONTRAINDICATIONSdiet before receiving FIBRICOR and should continue this FIBRICOR is contraindicated in patients with:diet during treatment with fenofibric acid. • severe renal impairment, including those receivingdialysis [see Clinical Pharmacology (12.3)].Laboratory studies should be done to ascertain that the • active liver disease, including those with primary lipid levels are consistently abnormal before instituting biliary cirrhosis and unexplained persistent liver FIBRICOR therapy. Every attempt should be made to function abnormalities [see Warnings and Precautions control serum lipids with appropriate diet, exercise, (5.3)].weight loss in obese patients, and control of any medical • preexisting gallbladder disease.problems such as diabetes mellitus and hypothyroidism • known hypersensitivity to fenofibric acid orthat are contributing to the lipid abnormalities. fenofibrate [see Warnings and Precautions (5.9)].Medications known to exacerbate hypertriglyceridemia • FIBRICOR is also contraindicated in nursing mothers (beta blockers, thiazides, estrogens) should be [see Use in Specific Populations (8.3)].discontinued or changed if possible prior to considerationof triglyceride-lowering drug therapy. 5 WARNINGS AND PRECAUTIONSPeriodic determination of serum lipids should be obtained 5.1 Abnormal Liver Testsduring initial therapy in order to establish the lowest Fenofibrate (administered over a range of doses with the effective dose of FIBRICOR. Therapy should be higher dose equivalent to 105 mg fenofibric acid) has withdrawn in patients who do not have an adequate been associated with increases in serum transaminases[AST (SGOT) or ALT (SGPT)].In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal of ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. The incidence of increases in transaminases observed with fenofibrate therapy may be dose related.Chronic active hepatocellular and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.Periodic monitoring of liver tests (e.g., ALT) should be performed for the duration of therapy with FIBRICOR, and therapy discontinued if enzyme levels persist above three times the normal limit.5.2 CholelithiasisFIBRICOR, like fenofibrate, clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. FIBRICOR therapy should be discontinued if gallstones are found.5.3 Concomitant Use with Oral Anticoagulants Caution should be exercised when FIBRICOR is given in conjunction with oral anticoagulants. FIBRICOR may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/INR. Frequent monitoring of prothrombin time/INR and dose adjustment of the anticoagulant are recommended until the prothrombin time/INR has stabilized in order to prevent bleeding complications [see Drug Interactions (7.1)].5.4 MyopathyFibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin).Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and FIBRICOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed. 5.5 Elevated Serum CreatinineElevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Renal monitoring should be considered for patients with renal impairment and for patients at risk for renal insufficiency, such as the elderly and patients with diabetes.5.6 Coronary Heart Disease Morbidity andMortalityThe effect of FIBRICOR on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75–1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80–0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57],p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibric acid.In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age – adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p<0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk = 0.91–1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (relative risk=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (HR 2.2, 95% confidence interval: 0.94–5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p=0.07). There was a statistically significant difference in the number of appendectomies in the gemfibrozil group(6/311 vs. 0/317, p = 0.029).5.7 PancreatitisPancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.5.8 VenothromboembolicDiseaseIn the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,875 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p=0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p=0.022).In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).5.9 HypersensitivityReactionsAcute hypersensitivity reactions including severe skin rashes such as Stevens-Johnson syndrome and toxicepidermal necrolysis requiring patient hospitalization andtreatment with steroids have been reported in individualstreated with fenofibrate.5.10 Hematological ChangesMild-to-moderate hemoglobin, hematocrit, and whiteblood cell decreases have been observed in patientsfollowing initiation of fenofibrate therapy.Thrombocytopenia and agranulocytosis have beenreported in individuals treated with fenofibrate. Periodicmonitoring of red and white blood cell counts isrecommended during the first 12 months of FIBRICORadministration.6 ADVERSE REACTIONS6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared torates in the clinical trials of another drug and may notreflect the rates observed in clinical practice.Adverse reactions reported by 2% or more of patientstreated with fenofibrate (and greater than placebo) duringthe double-blind, placebo-controlled trials are listed inTable 1. Adverse reactions led to discontinuation oftreatment in 5% of patients treated with fenofibrate and in3% treated with placebo. Increases in liver tests were themost frequent events, causing discontinuation offenofibrate treatment in 1.6% of patients.Table 1. Adverse Reactions Reported by 2% or Moreof Patients Treated with Fenofibrate* During theDouble-Blind, Placebo-Controlled TrialsBODY SYSTEMAdverse ReactionsFenofibrate*(N=439)Placebo(N=365)BODY AS A WHOLEAbdominal Pain 4.6% 4.4%Back Pain 3.4% 2.5%Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC ANDNUTRITIONAL DISORDERSAbnormal Liver Tests 7.5% 1.4%Increased ALT 3% 1.6%Creatine Phosphokinase Increased 3% 1.4%Increased AST 3.4% 0.5% RESPIRATORYRespiratory Disorder 6.2% 5.5%Rhinitis 2.3% 1.1%* Fenofibric acid is the active moiety of fenofibrate; Fenofibrate dosage equivalent to 105 mg fenofibric acid.6.2 Postmarketing ExperienceThe following adverse reactions have been identifiedduring postapproval use of fenofibrate. Because thesereactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationshipto drug exposure: myalgia, rhabdomyolysis, increased creatinine phosphokinase, pancreatitis, increased alanine aminotranaminase, increased aspartate aminotranaminase, muscle spasm, acute renal failure, hepatitis, cirrhosis, nausea, abdominal pain, anemia, headache, arthralgia and asthenia. period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (20 times that at the MRHD of fenofibric acid). No developmental findings were observed at 15 mg/kg/day (an exposure to fenofibric acid that is 7 times that at the MRHD of fenofibric acid).7 DRUG INTERACTIONS7.1 OralAnticoagulantsCaution should be exercised when FIBRICOR is given in conjunction with coumarin anticoagulants. FIBRICORmay potentiate the anticoagulant effect of these agentsresulting in prolongation of the prothrombin time/INR.Frequent monitoring of prothrombin time/INR and dose adjustment of the oral anticoagulant are recommendeduntil the prothrombin time/INR has stabilized in order to prevent bleeding complications [see Warnings andPrecautions (5.3)].7.2 Bile-AcidBindingResinsSince bile-acid binding resins may bind other drugs given concurrently, patients should take FIBRICOR at least 1hour before or 4 to 6 hours after taking another drug.7.3 ImmunosuppressantsImmunosuppressant agents such as cyclosporine andtacrolimus can impair renal function. Whenimmunosuppressants and other potentially nephrotoxicagents are co-administered with FIBRICOR, the lowesteffective dose of FIBRICOR should be employed andrenal function should be monitored. In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at an exposure to fenofibric acid that is approximately 50 times that at the MRHD of fenofibric acid [see Nonclinical Toxicology (13.1)].8.3 NursingMothersFIBRICOR should not be used by nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug [see Contraindications (4)].8.4 PediatricUseSafety and effectiveness of FIBRICOR in pediatric patients have not been established.8.5 GeriatricUseFIBRICOR is substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients have a higher incidence of renal impairment, the dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.3) Clinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category C: Safety in pregnant women hasnot been established. There are no adequate and wellcontrolled studies of FIBRICOR in pregnant women.FIBRICOR should be used during pregnancy only if thepotential benefit justifies the potential risk to the fetus.In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to matingthrough weaning, maternal toxicity was observed at adose that results in exposure to fenofibric acid that is 50times that at the MRHD of fenofibric acid.In pregnant rats given oral dietary doses of 14, 127, and361 mg/kg/day from gestation day 6–15 during the period of organogenesis, adverse developmental findings werenot observed at 14 mg/kg/day (a dose that results inexposure to fenofibric acid that is approximately twicethat at the MRHD of fenofibric acid). At higher multiples of human doses evidence of maternal toxicity wasobserved.8.6 RenalImpairmentThe use of FIBRICOR should be avoided in patients who have severe renal impairment. Dose reduction is required in patients with mild-to-moderate renal impairment.Monitoring renal function in patients with renalimpairment is recommended. [See Dosage andAdministration (2.3) and Clinical Pharmacology (12.3)].8.7 HepaticImpairmentThe use of FIBRICOR has not been evaluated in patients with hepatic impairment [see Contraindications (4)].10 OVERDOSAGEThere is no specific treatment for overdose withFIBRICOR. General supportive care of the patient isindicated, including monitoring of vital signs andobservation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should beachieved by emesis or gastric lavage; usual precautionsshould be observed to maintain the airway. BecauseFIBRICOR is highly bound to plasma proteins,hemodialysis should not be considered.In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6–18 during the11 DESCRIPTION FIBRICOR is a lipid regulating agent available as tablets for oral administration. Each tablet contains 35 mg or 105 mg of fenofibric acid. The chemical name for fenofibric acid is 2-[4-(4-chlorobenzoyl)phenoxy]-2methylpropanoic acid with the following structuralformula:Fenofibric acid is a white to almost white crystallinepowder that is stable under ordinary conditions, and has a melting point of 179 – 183°C. Its empirical formula is C 17H 15ClO 4 and molecular weight 318.75. Fenofibric acid is insoluble in water; its solubility increases with pH in buffered media. Inactive Ingredients: Each tablet contains copovidone, crospovidone, magnesium stearate and microcrystalline cellulose. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPAR α). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particlesfrom plasma by activating lipoprotein lipase and reducingproduction of apoprotein C-III (an inhibitor of lipoproteinlipase activity). The resulting fall in triglyceridesproduces an alteration in the size and composition of LDLfrom small, dense particles to large buoyant particles.These larger particles have a greater affinity forcholesterol receptors and are catabolized rapidly.Activation of PPAR α also induces an increase in thesynthesis of apoproteins A-I, A-II and HDL-cholesterol.12.2 PharmacodynamicsElevated levels of Total-C, LDL-C, and Apo B, and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis.Epidemiologic studies have established thatcardiovascular morbidity and mortality vary directly withthe levels of Total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raisingHDL-C or lowering TG on the risk of cardiovascularmorbidity and mortality has not been determined.12.3 Pharmacokinetics The extent and rate of absorption of fenofibric acid after administration of 105 mg FIBRICOR tablets areequivalent to those after administration of 145 mgfenofibrate tablets (TriCor) under fasted conditions.AbsorptionThe absolute bioavailability of FIBRICOR has not beendetermined. Following oral administration of FIBRICORin healthy volunteers, median peak plasma levels offenofibric acid occur by approximately 2.5 hours afteradministration. Exposure after administration of 3 X35 mg FIBRICOR tablets is comparable to 1 X 105 mgFIBRICOR tablets. A food-effect study involving administration ofFIBRICOR to healthy volunteers under fasting conditionsand with a high-fat meal indicated that the C max was decreased by approximately 35% while the AUC remained unchanged. This decrease in exposure is not considered clinically significant, and thereforeFIBRICOR can be taken without regards to meals.Distribution Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasmaconcentrations of fenofibric acid at steady state areslightly more than double those following a single dose.Serum protein binding was approximately 99% in normaland hyperlipidemic subjects. MetabolismFenofibric acid is primarily conjugated with glucuronicacid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to abenzhydrol metabolite which is, in turn, conjugated withglucuronic acid and excreted in urine.In vitro and in vivo metabolism data indicate thatfenofibric acid does not undergo oxidative metabolism(e.g. cytochrome P450) to a significant extent. The enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8,CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4do not play a role in the metabolism of fenofibric acid.EliminationFenofibric acid is eliminated with a half-life ofapproximately 20 hours, allowing once-daily dosing.Specific Populations Geriatrics: In five elderly volunteers 77 – 87 years of age,the oral clearance of fenofibric acid following a singleoral dose of fenofibrate was 1.2 L/h, which compares to1.1 L/h in young adults. This indicates that an equivalentdose of FIBRICOR can be used in elderly subjects with normal renal function, without increasing accumulation ofthe drug or metabolites [see Use in Specific Populations(8.5)].。
苹果酸卡博替尼胶囊FDA说明书(中)
COMETRIQ说明书警告：穿孔、瘘管和出血穿孔、瘘管：服用COMETRIQ的患者3%发生胃肠穿孔，1%出现瘘管。
出现穿孔或瘘管则终止治疗[警告和注意事项（5.1）]。
出血：经COMETRIQ治疗的患者中有3%发生严重，有时致命的出血，出血包括咯血和胃肠道出血。
监测患者出血症状和体征。
有严重出血的患者不要给予COMETRIQ[警告和注意事项（5.2）]。
1适应症COMETRIQ适用于治疗进展期、转移的甲状腺髓样癌(MTC)患者。
2用法用量1.1推荐剂量COMETRIQ推荐剂量为每日140 mg（1粒80 mg胶囊和3粒20 mg胶囊）。
避免与食物同服。
指导患者服药前2小时、服药后1小时内不要进食。
持续用药直至疾病进展或出现无法耐受的不良反应。
不要打开COMETRIQ，整粒吞服。
服药12小时内不再服用漏服药物。
服药期间，不要摄取已知可抑制细胞色素P450酶的食物(如葡萄柚，葡萄柚汁)或营养添加剂。
2.2 剂量调整不良反应出现NCI CTC AE 4级血液学毒性反应，3级或以上的非血液学不良反应或者无法耐受的2级不良反应时，暂停COMETRIQ。
不良反应缓解或改善(即达到基线或恢复至1度)后，按下列方式降低剂量：●既往每天服药140 mg，下一步治疗每天剂量100 mg(1粒80 mg胶囊和1粒20 mg胶囊)。
●既往每天服药100 mg，下一步治疗每天剂量60 mg(3粒20 mg胶囊)。
●既往每天服药60 mg，下一步可耐受的情况下服用60 mg，否则终止用药。
出现以下任一条的情况，永久停药：●发生内脏穿孔或形成瘘管●严重出血●出现严重动脉血栓事件(如心肌梗死，脑梗死)●肾病综合征●恶性高血压，高血压危象，采用最佳治疗却仍持续无法控制的高血压●下颌骨坏死●可逆的后部白质脑病综合征肝功能异常中、重度肝功能异常患者不建议服用COMETRIQ[警告和注意事项（5.11）和特殊人群用药（8.6）]。
使用CYP3A4抑制剂接受COMETRIQ治疗的患者避免联合使用强效CYP3A4抑制剂（如酮康唑、伊曲康唑、克拉霉素、阿扎那韦、奈法唑酮、沙奎那韦、泰利霉素、利托那韦、印地那韦、奈非那韦、伏立康唑）[警告和注意事项（5.10）和药物相互作用（7.1）]。
孟鲁司特-FDA说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use SINGULAIR safely and effectively. See full prescribing information for SINGULAIR.SINGULAIR®(montelukast sodium) tablets, chewable tablets, and oral granules Initial U.S. Approval: 1998---------------------------RECENT MAJOR CHANGES --------------------------Warnings and Precautions, Neuropsychiatric Events (5.4) 04/2010 ----------------------------INDICATIONS AND USAGE ---------------------------SINGULAIR® is a leukotriene receptor antagonist indicated for:• Prophylaxis and chronic treatment of asthma in patients12 months of age and older (1.1).• Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2).• Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 6 months of age and older (1.3).-----------------------DOSAGE AND ADMINISTRATION-----------------------Administration (by indications):• Asthma (2.1): Once daily in the evening for patients 12 months and older.• Acute prevention of EIB (2.2): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older.• Seasonal allergic rhinitis (2.3): Once daily for patients 2 years and older.• Perennial allergic rhinitis (2.3): Once daily for patients 6 months and older.Dosage (by age):• 15 years and older: one 10-mg tablet.• 6 to 14 years: one 5-mg chewable tablet.• 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules.• 6 to 23 months: one packet of 4-mg oral granules.Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). For oral granules: Must administer within 15 minutes after opening the packet (with or without mixing with food) (2.5). ---------------------DOSAGE FORMS AND STRENGTHS --------------------• SINGULAIR 10-mg Film-Coated Tablets• SINGULAIR 5-mg and 4-mg Chewable Tablets• SINGULAIR 4-mg Oral Granules-------------------------------CONTRAINDICATIONS ------------------------------• Hypersensitivity to any component of this product (4).------------------------WARNINGS AND PRECAUTIONS-----------------------• Do not prescribe SINGULAIR to treat an acute asthma attack.• Advise patients to have appropriate rescue medication available(5.1).• Inhaled corticosteroid may be reduced gradually. Do not abruptlysubstitute SINGULAIR for inhaled or oral corticosteroids (5.2).• Patients with known aspirin sensitivity should continue to avoidaspirin or non-steroidal anti-inflammatory agents while takingSINGULAIR (5.3).• Neuropsychiatric events have been reported with SINGULAIR.Instruct patients to be alert for neuropsychiatric events. Evaluatethe risks and benefits of continuing treatment with SINGULAIR ifsuch events occur (5.4 and 6.2).• Systemic eosinophilia, sometimes presenting with clinical featuresof vasculitis consistent with Churg-Strauss syndrome, has beenreported. These events usually, but not always, have beenassociated with the reduction of oral corticosteroid therapy (5.5and 6.2).• Inform patients with phenylketonuria that the 4-mg and 5-mgchewable tablets contain phenylalanine (5.6).------------------------------ADVERSE REACTIONS------------------------------Most common adverse reactions (incidence ≥5% and greater thanplacebo listed in descending order of frequency): upper respiratoryinfection, fever, headache, pharyngitis, cough, abdominal pain,diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis (6.1).To report SUSPECTED ADVERSE REACTIONS, contact MerckSharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877888-4231 or FDA at 1-800-FDA-1088 or /medwatch.See 17 for PATIENT COUNSELING INFORMATION andFDA-approved patient labeling.Revised:12/2010FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1 A sthma1.2 E xercise-InducedBronchoconstriction1.3 A llergicRhinitis2 DOSAGE AND ADMINISTRATION2.1 A sthma2.2 E xercise-Induced Bronchoconstriction (EIB) in Patients 15Years of Age and Older2.3 Allergic Rhinitis2.4 Asthma and Allergic Rhinitis2.5 Instructions for Administration of Oral Granules3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 A cuteAsthma5.2 Concomitant Corticosteroid Use5.3 A spirinSensitivity5.4 N europsychiatricEvents5.5 E osinophilicConditions5.6 P henylketonuria6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 P ost-MarketingExperience7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS8.1 P regnancy8.3 N ursingMothers8.4 P ediatricUse8.5 G eriatricUse8.6 H epaticInsufficiency8.7 R enalInsufficiency10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Asthma14.2 Exercise-Induced Bronchoconstriction (EIB)14.3 Allergic Rhinitis (Seasonal and Perennial)16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Information for Patients17.2 FDA-Approved Patient Labeling*Sections or subsections omitted from the full prescribing information are not listed.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGE1.1 AsthmaSINGULAIR1 is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.1.2 Exercise-Induced BronchoconstrictionSINGULAIR is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.1.3 Allergic RhinitisSINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older.2 DOSAGE AND ADMINISTRATION2.1 AsthmaSINGULAIR should be taken once daily in the evening. The following doses are recommended:For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.For pediatric patients 12 to 23 months of age: one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and OlderFor prevention of EIB, a single 10 mg dose of SINGULAIR should be taken at least 2 hours before exercise. An additional dose of SINGULAIR should not be taken within 24 hours of a previous dose. Patients already taking SINGULAIR daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.2.3 Allergic RhinitisFor allergic rhinitis, SINGULAIR should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.1 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.Copyright © 1998-2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesThe following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10-mg tablet.For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet or one packet of 4-mg oral granules.For pediatric patients 6 to 23 months of age: one packet of 4-mg oral granules.Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.2.4 Asthma and Allergic RhinitisPatients with both asthma and allergic rhinitis should take only one SINGULAIR dose daily in the evening.2.5 Instructions for Administration of Oral GranulesSINGULAIR 4-mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, SINGULAIR oral granules must not be stored for future use. Discard any unused portion. SINGULAIR oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. SINGULAIR oral granules can be administered without regard to the time of meals.3 DOSAGE FORMS AND STRENGTHS• SINGULAIR 10-mg Film-Coated Tablets are beige, rounded square-shaped tablets, with code MRK 117 on one side and SINGULAIR on the other.• SINGULAIR 5-mg Chewable Tablets are pink, round, bi-convex-shaped tablets, with code MRK 275 on one side and SINGULAIR on the other.• SINGULAIR 4-mg Chewable Tablets are pink, oval, bi-convex-shaped tablets, with code MRK 711 on one side and SINGULAIR on the other.• SINGULAIR 4-mg Oral Granules are white granules with 500 mg net weight, packed in a child-resistant foil packet.4 CONTRAINDICATIONSHypersensitivity to any component of this product.5 WARNINGS AND PRECAUTIONS5.1 Acute AsthmaSINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with SINGULAIR can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist.5.2 Concomitant Corticosteroid UseWhile the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.5.3 Aspirin SensitivityPatients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal antiinflammatory agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate(Montelukast Sodium) Tablets, Chewable Tablets, and Oral Granulesbronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)].5.4 Neuropsychiatric EventsNeuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect.Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur [see Adverse Reactions (6.2)].5.5 Eosinophilic ConditionsPatients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between SINGULAIR and these underlying conditions has not been established [see Adverse Reactions (6.2)].5.6 PhenylketonuriaPhenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame), 0.674 and 0.842 mg per 4-mg and 5-mg chewable tablet, respectively.6 ADVERSEREACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.Adults and Adolescents 15 Years of Age and Older with AsthmaSINGULAIR has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesTABLE 1Adverse Experiences Occurring in ≥1% of Patientswith an Incidence Greater than that in Patients Treated with PlaceboSINGULAIR 10 mg/day(%)(n=1955) Placebo(%) (n=1180)Body As A WholePain, abdominal 2.9 2.5Asthenia/fatigue 1.8 1.2Fever 1.5 0.9TraumaDigestive System Disorders1.0 0.8Dyspepsia 2.1 1.1Pain, dental 1.7 1.0Gastroenteritis, infectiousNervous System/Psychiatric1.5 0.5Headache 18.4 18.1DizzinessRespiratory System Disorders1.9 1.4Influenza 4.2 3.9Cough 2.7 2.4Congestion, nasalSkin/Skin Appendages Disorder1.6 1.3RashLaboratory Adverse Experiences*1.6 1.2ALT increased 2.1 2.0AST increased 1.6 1.2Pyuria 1.0 0.9* Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.The frequency of less common adverse events was comparable between SINGULAIR and placebo.The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for SINGULAIR.Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.Pediatric Patients 6 to 14 Years of Age with AsthmaSINGULAIR has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with SINGULAIR for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse experience profile did not significantly change.In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for SINGULAIR. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving SINGULAIR, the following events not previously observed with the use of SINGULAIR in this age group occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesPediatric Patients 2 to 5 Years of Age with AsthmaSINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.Pediatric Patients 6 to 23 Months of Age with AsthmaSafety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.SINGULAIR has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23 months of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo.Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with SINGULAIR with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic RhinitisSINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. SINGULAIR administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis SINGULAIR has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical studies. SINGULAIR administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with SINGULAIR with a frequency ≥1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.Pediatric Patients 6 Months to 14 Years of Age with Perennial Allergic Rhinitis The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.6.2 Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia.Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.(Montelukast Sodium) Tablets, Chewable Tablets, and Oral GranulesPsychiatric disorders: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor [see Warnings and Precautions (5.4)].Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.Cardiac disorders: palpitations.Respiratory, thoracic and mediastinal disorders: epistaxis.Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting.Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these occurred in combination with other confounding factors, such as use of other medications, or when SINGULAIR was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.Skin and subcutaneous tissue disorders: angioedema, bruising, erythema nodosum, pruritus, urticaria.Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps.General disorders and administration site conditions: edema.Patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)].7 DRUGINTERACTIONSNo dose adjustment is needed when SINGULAIR is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SINGULAIR should be used during pregnancy only if clearly needed.Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see Nonclinical Toxicology (13.2)].During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with SINGULAIR during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and SINGULAIR has not been established.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to SINGULAIR while pregnant. Patients and healthcare providers are encouraged to report any prenatal exposure to SINGULAIR by calling the Pregnancy Registry at 1-800-986-8999.8.3 Nursing MothersStudies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SINGULAIR is given to a nursing mother.8.4 Pediatric UseSafety and efficacy of SINGULAIR have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are(Montelukast Sodium) Tablets, Chewable Tablets, and Oral Granulessimilar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Special Populations (12.3), and Clinical Studies (14.1)].The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.The safety of SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study [see Adverse Reactions (6.1)]. Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.The safety of SINGULAIR 4-mg and 5-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see Adverse Reactions (6.1)]. The safety of SINGULAIR 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 15 years with exercise-induced bronchoconstriction have not been established.Growth Rate in Pediatric PatientsA 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of SINGULAIR on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included SINGULAIR 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between SINGULAIR and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the SINGULAIR, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for SINGULAIR minus placebo, beclomethasone minus placebo, and SINGULAIR minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1.FIGURE 1Change in Height (cm) from Randomization Visit by Scheduled Week(Treatment Group Mean ± Standard Error† of the Mean)。
醋酸艾司利卡西平说明书 英文
------------------------------DRUG INTERACTIONS------------------------------
---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 200 mg, 400 mg, 600 mg, 800 mg (3)
-------------------------------CONTRAINDICATIONS---------------------------- Hypersensitivity to eslicarbazepine acetate or oxcarbazepine. (4)
adjustment may be needed for phenytoin based on clinical response and serum levels of phenytoin. (2.3, 7.2, 7.3) • Phenobarbital or Primidone: Higher dosage of APTIOM may be
5.3 Drug Reaction with Eosinophilia and Systemic Symptoms
Humans
(DRESS)/Multiorgan Hypersensitivity
10.2 Treatment or Management of Overdose
5.4 Anaphylactic Reactions and Angioedema
-----------------------USE IN SPECIFIC POPULATIONS----------------------- Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Probuphine (buprenorphine) 子皮下吸吮片说明文件说明书
Probuphine® (buprenorphine)(Subdermal Implant)Document Number: IC-0464 Last Review Date: 10/01/2018Date of Origin: 10/01/2018Dates Reviewed: 10/2018I.Length of Authorization∙Initial: 6 months∙Renewal: 6 monthsII.Dosing LimitsA.Quantity Limit (max daily dose) [Pharmacy Benefit]:∙Probuphine implant kit: 1 implant kit every 6 monthsB.Max Units (per dose and over time) [Medical Benefit]:∙ 1 implant kit (4 billable units) every 6 monthso 2 implant kits per memberIII.Initial Approval Criteria•Patient is 16 years of age or older; AND•Patient has diagnosis of opiate abuse/dependence; AND•Prescribed by a qualified provider with Substance Abuse and Mental Health Services Administration (SAMHSA) Drug Addiction Treatment Act (DATA) 2000 Waiver andProbuphine Risk Evaluation and Mitigation Strategy (REMS) certification; AND •Patient is compliant with addiction counseling and psychosocial support; AND•Patient does not have prior hypersensitivity reaction to buprenorphine; AND•Patient has been taking a buprenorphine-containing transmucosal product for at least the prior 6 months based on pharmacy fill history; AND•Buprenorphine-containing transmucosal product has been stable for the past 3 months and does NOT exceed the following:o8 mg/day of Suboxone or Subutex equivalent; ORo 5.7 mg/day of Zubsolv; ORo 4.2 mg/day Bunavail; AND•Patient is NOT pregnant (women of childbearing age have a negative pregnancy test dated within prior 30 days); AND• A urine drug screen, including buprenorphine, within the past 30 days of prior authorization submission is provided (if negative for buprenorphine or positive for otheropioids, the provider must provide an explanation); AND•Patient is not prescribed concurrent opioid medication without explanation (verified by state opioid database, if available) other than buprenorphine transmucosal product, andbuprenorphine transmucosal product will be discontinued upon insertion of implant; AND •Patient does not have “as needed” prescription for buprenorphine-containing products; AND •Patient has NOT used the implant twice previously (if received once previously, must be for opposite arm); AND•Patient has not had any episodes of hospitalizations (addiction or mental health), emergency room visits, or crisis intervention in the past 90 days related to opioiddependence; AND•Patient reports minimal to no desire or need to use illicit opioids; AND•Patient dose NOT have moderate to severe hepatic impairment (Child-Pugh B or C).IV.Renewal Criteria•Prescribed by a qualified provider with SAMHSA DATA 2000 Waiver and•Probuphine REMS certification; AND•Patient is compliant with addiction counseling and psychosocial support; AND•Patient does not have prior hypersensitivity reaction to buprenorphine or implant; AND•Patient is NOT pregnant (women of childbearing age have a negative pregnancy test dated within prior 30 days); AND• A urine drug screen, including buprenorphine, within the past 30 days of prior authorization submission is provided (if negative for buprenorphine or positive for other opioids, theprovider must provide an explanation); AND•Patient is not prescribed concurrent opioid medication without explanation (including routine use of buprenorphine transmucosal products in addition to implant and verified by stateopioid database, if available); AND•Patient has demonstrated efficacy on prior buprenorphine implant; AND•Patient has been compliant with clinic visit requirement plan established by provider for first implant; AND•Patient has NOT used the implant more than once previously and insertion site is the opposite arm of prior implant; AND•There was no indication of patient tampering with insertion site/implant; AND•Patient has not had any episodes of hospitalizations (addiction or mental health), emergency room visits, or crisis intervention in the past 90 days related to opioid dependence; AND •Patient reports minimal to no desire or need to use illicit opioids; AND•Patient dose NOT have moderate to severe hepatic impairment (Child-Pugh B or C).V.Dosage/AdministrationVI.Billing Code/Availability InformationHCPCS:∙J0570 – Buprenorphine implant, 74.2 mg: 1 billable unit = 74.2 mgNDC:∙Probuphine implant kit consisting of four individually packaged sterile implants of 74.2 mg each and one individually packaged sterile disposable applicator: 52440-0100-xxVII.References1.Probuphine [package insert]. Princeton, NJ; Braeburn; February 2018.2.Psychopharmacology Drugs Advisory Committee to the FDA meeting materials. January 12,2016. Available at:/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psychopharma cologicDrugsAdvisoryCommittee/ucm475314.htm. Accessed October 23, 2018.3.Opioid Overdose. Centers for Disease Control and Prevention. Available at:/drugoverdose/index.html. Accessed October 23, 2018.4.Psychopharmacology Drugs Advisory Committee to the FDA meeting materials. January 12,2016. Available at:/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psychopharma cologicDrugsAdvisoryCommittee/ucm475314.htm. Accessed October 23, 2018.5.Kleber HD, Weiss RD, Anton RF, et al. Practice guideline for the treatment of patients withsubstance abuse disorders. 2006; American Psychiatric Association; 1-275. Available at:/guidelines.aspx. Accessed October 23, 2018.6.*********************:/scripts/cder/drugsatfda/index.cfm.Accessed October 23, 2018.Appendix 1 – Covered Diagnosis CodesAppendix 2 – Centers for Medicare and Medicaid Services (CMS)Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD) and Local Coverage Determinations (LCDs) may exist and compliance with these policies isrequired where applicable. They can be found at: /medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan.Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD): N/A。
FDA英文药品说明书规定项目中英对照
FDA英文药品说明书规定项目中英对照--------------------------------------------------------------------------------药品说明书旧称description,instruction,direction.今称insert,package insert美国FDA规定其应包括十项。
一.drug names(药物名称)1.通常每种药物有三个名字(1)proprietary name（商品名称）(2)popular name（俗名）(3)chemical name（化学名）2.说明书标题多用商品名其右上角标有R者，表示registered trademark（注册商标）二.description（性状）(常用description,introduction,composition)包括药品的chemical structure（化学结构）、chemical composition（化学成分）、physical and chemical properties（物理和化学性质）三.clinical pharmacology（临床药理学）常用的还有：clinical data（临床数据）、clinical experience（临床经验）、clinical use（临床应用）、clinical observation（临床观察）、clinical effect（临床疗效）、clinical discussion（临床讨论）、mode of mechanism of action（临床机理及途径）、pharmacological actions（药理作用）、therapeutical actions（治疗作用）、bacteriology（细菌学）、microbiology（微生物学）、physiology（生理学）、toxicology（毒理学）四.indications and usage（适应证和用法）常用标题：indications,major indications,clinical indications,principal indications,condications,uses,treatment五.contraindications（禁忌证）1.常用标题contraindications,restriction on use(限制使用)2.常用词（组）pregnant women孕妇women of childbeating age育龄妇女be hypersensitive to 对......过敏者allergic reaction变态反应lactation,early infancy乳期heart,cardiac,myocardial心脏，心脏的，心肌的kidney,renal肾，肾脏的liver,hepatic肝，肝脏的insufficiency,impairment机能不全damage,danger,failure损伤，危险，衰?BR>六.precautions（注意事项）常用标题:causions,remark,note,notice,attention,awakening, N.B.七.warnings（警告）常用标题：additional warnings(告戒事项)八.adverse reactions（不良反应）常用标题：side reaction（副反应）、untoward reaction（不良反应）、toxicity reaction（毒性反应）、anaphylactic reaction（过敏反应）、side effects,by-effects,after effects,undesirable effects（副作用）、double infection（双重感染）九.overdosage（用药过量）常用标题：treatment of overdosage(用药过量的治疗)十.dosage and administration（剂量用法）1.常用标题：administration procedure,method for administration,method of use,direction for use,how to use,recommendation,reconstitution（用法）posology,dosage（剂量）application and dosage,usage and dosage（用法与剂量）clinical application（临床应用）2.mode of administration(给药方式)intramuscularly肌肉注射intragluteally臀肌注射intraarterially动脉注射intravenously静脉注射intrathecally鞘内注射intracerebeospinally脑脊髓腔注射orally口服parentarally肠道外给药locally局部给药subconjunctivally结膜下给药sublingually舌下给药submucously黏膜下给药现各大药厂的说明书，项目远远超过十项，如：1.animal pharmacology and animal toxicology（动物药理学和动物毒理学）2.absorption and excretion（吸收和排泄）3.tolerance（耐受性）4.drug interactions（药物相互作用）5.storage and duration of efficacy（贮藏与失效期）6.packages（包装）7.advantages（优点）8.references（参考文献）9.further information（补充说明）10.manufacturer（生产者）。
罗氟司特片说明书(美国,FDA,英文)
5 10 15 20 25 30 35 40 1 HIGHLIGHTS OF PRESCRIBING INFORMATION2 These highlights do not include all the information needed3 to use DALIRESP safely and effectively. See full4 prescribing information for DALIRESP. 6 DALIRESP ®(roflumilast) tablets 7 Initial U.S. Approval: 20XX 8 9 ------------------------INDICATIONS AND USAGE----------------------DALIRESP is indicated as a treatment to reduce the risk of11 COPD exacerbations in patients with severe COPD associated 12 with chronic bronchitis and a history of exacerbations. (1, 14) 13 14 Limitations of Use: DALIRESP is not a bronchodilator and is notindicated for the relief of acute bronchospasm. (1, 14) 16 17 ----------------DOSAGE AND ADMINISTRATION--------------------18 The recommended dosage for patients with COPD is one 50019 mcg tablet per day, with or without food. (2)21 ------------------DOSAGE FORMS AND STRENGTHS--------------- 22 Tablets: 500 mcg (3) 23 24 ----------------------CONTRAINDICATIONS---------------------------- • Moderate to severe liver impairment (Child-Pugh B or C) 26 (4)27 28 ----------------WARNINGS AND PRECAUTIONS---------------------- 29 • Acute bronchospasm: Do not use for the relief of acutebronchospasm. (5.1) 31 • Psychiatric Events including Suicidality: Advise patients ,32 their caregivers, and families to be alert for the emergence33 or worsening of insomnia, anxiety, depression, suicidal34 thoughts or other mood changes, and if such changesoccur to contact their healthcare provider. Carefully weigh36 the risks and benefits of treatment with DALIRESP in 37 patients with a history of depression and/or suicidal 38 thoughts or behavior. (5.2) 39 •Weight Decrease: Monitor weight regularly. If unexplainedor clinically significant weight loss occurs, evaluate weight41loss and consider discontinuation of DALIRESP. (5.3)7542•Drug Interactions: Use with strong cytochrome P45043 enzyme inducers (e.g. rifampicin, phenobarbital,44 carbamazepine, phenytoin) is not recommended. (5.4)45 46 -----------------------------ADVERSE REACTIONS----------------------47 Most common adverse reactions (≥ 2%) are diarrhea, weight48 decrease, nausea, headache, back pain, influenza, insomnia, 49 dizziness and decreased appetite. (6.1) 50 51 To report SUSPECTED ADVERSE REACTIONS, Contact52 Forest Laboratories, Inc. at 1-800-678-1605 or FDA at 1-80053 FDA-1088 or /medwatch. 54 55 ----------------------DRUG INTERACTIONS------------------------------ 56 •Use with inhibitors of CYP3A4 or dual inhibitors of 57 CYP3A4 and CYP1A2 (e.g, erythromycin, ketoconazole,58 fluvoxamine, enoxacin, cimetidine) will increase roflumilast59 systemic exposure and may result in increased adverse60 reactions. The risk of such concurrent use should be61 weighed carefully against benefit. (7.2) 62 63 ---------------------USE IN SPECIFIC POPULATIONS----------------64 •Nursing Mothers: DALIRESP should not be used by 65 women who are nursing as excretion of roflumilast and/or 66 its metabolites into human milk is probable and there are67 no human studies that have investigated effects of68 DALIRESP on breast-fed infants. (8.3)69 70 See 17 for PATIENT COUNSELING INFORMATON AND71 MEDICATION GUIDE 72 73 74REVISED XX/20XX76FULL PRESCRIBING INFORMATION: CONTENTS*1. INDICATIONS AND USAGE 11. DESCRIPTION2. DOSAGE AND ADMINISTRATION 12. CLINICAL PHARMACOLOGY3. DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action4. CONTRAINDICATIONS 12.2 Pharmacodynamics5. WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics5.1 Treatment of Acute Bronchospasm 13. NONCLINICAL TOXICOLOGY5.2 Psychiatric Events including Suicidality 13.1 Carcinogenesis, Mutagenesis, Impairment ofFertility5.3 Weight Decrease 14. CLINICAL STUDIES5.4 Drug Interactions 14.1 Chronic Obstructive Pulmonary Disease6. ADVERSE REACTIONS 16. HOW SUPPLIED/STORAGE AND HANDLING6.1 Adverse Reactions in Clinical Trials 16.1 How Supplied7. DRUG INTERACTIONS 16.2 Storage and Handling7.1 Drugs that induce Cytochrome P450 (CYP) 17. PATIENT COUNSELING INFORMATIONEnzymesDrugs7.2 that inhibit Cytochrome P450 (CYP) 17.1 BronchospasmEnzymes7.3 Oral combination contraceptives containing 17.2 Psychiatric Events including Suicidalitygestodene and ethinyl estradiol8. USE IN SPECIFIC PATIENT POPULATIONS 17.3 Weight Decrease8.1 Pregnancy 17.4 Drug Interactions8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment10. OVERDOSAGE10.1 Human Experience10.2 Management of Overdose*Sections or subsections omitted from the full prescribinginformation are not listed77 FULL PRESCRIBING INFORMATION7879 1 INDICATIONSUSAGEAND80 DALIRESP® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with81 chronic bronchitis and a history of exacerbations.8283 Limitations of Use84 DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.8586 2 DOSAGEADMINISTRATIONAND87 The recommended dose of DALIRESP is one 500 microgram (mcg) tablet per day, with or without food.8889 3 DOSAGE FORMS AND STRENGTHS90 DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet91 contains 500 mcg of roflumilast.9293 4 CONTRAINDICATIONS94 The use of DALIRESP is contraindicated in the following conditions:95 •Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Special Populations (8.6)].9697 5 WARNINGS AND PRECAUTIONS9899 5.1 Treatment of Acute Bronchospasm100 DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.101102 5.2 Psychiatric Events including Suicidality103 Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of 104 patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. 105 The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher 106 rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, 107 respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been 108 observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide 109 attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo.110111 Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully 112 weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of 113 the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if 114 such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing 115 treatment with DALIRESP if such events occur.116117 5.3 WeightDecrease118 Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with 119 DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1)]. In addition to being 120 reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In 121 these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) 122 compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients 123 receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of 124 patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP 125 should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be 126 evaluated, and discontinuation of DALIRESP should be considered.127128 5.4 Drug Interactions129 A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The 130 administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease 131 in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, 132 phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended. [see Drugs That Induce Cytochrome P450 (CYP) 133 Enzymes (7.1) and Clinical Pharmacology (12.3)].134135 6 ADVERSE REACTIONS136 The following adverse reactions are described in greater detail in other sections:137 • Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)]138 • Weight Decrease [see Warnings and Precautions (5.3)]139140 6.1 Adverse Reactions in Clinical Studies141 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug 142 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.143144 The safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled 145 trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 146 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1-year, respectively.147148 The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean 149 pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients 150 treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.151152 The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% 153 for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and 154 nausea (1.6%).155156 Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESP157 treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.158159 Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the DALIRESP group 8 controlled COPD clinical trials. 160161 Table 1: Adverse Reactions Reported by ≥ 2% of Patients162 Treated with DALIRESP 500 mcg daily and Greater Than PlaceboTreatmentAdverse Reactions (Preferred Term) DALIRESP Placebo (N=4438) (N=4192) n (%) n (%)Diarrhea 420 (9.5) 113 (2.7)Weight decreased 331 (7.5) 89 (2.1)Nausea 209 (4.7) 60 (1.4)Headache 195 (4.4) 87 (2.1)Back pain 142 (3.2) 92 (2.2)Influenza 124 (2.8) 112 (2.7)Insomnia 105 (2.4) 41 (1.0)Dizziness 92 (2.1) 45 (1.1)Decreased appetite 91 (2.1) 15 (0.4)163164 Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group 165 include:166167 Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting168 Infections and infestations - rhinitis, sinusitis, urinary tract infection,169 Musculoskeletal and connective tissue disorders - muscle spasms170 Nervous system disorders - tremor171 Psychiatric disorders - anxiety, depression172173 7 DRUGINTERACTIONS174 A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical 175 Pharmacology (12.3)].176177 7.1 Drugs That Induce Cytochrome P450 (CYP) Enzymes178 Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of 179 DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) 180 with DALIRESP is not recommended [see Drug Interactions (5.4) and Clinical Pharmacology (12.3)].181182 7.2 Drugs That Inhibit Cytochrome P450 (CYP) Enzymes183 The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 184 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and 185 may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. [see Clinical 186 Pharmacology (12.3)].187188 7.3 Oral Contraceptives Containing Gestodene and Ethinyl Estradiol189 The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase190 roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully 191 against benefit [see Clinical Pharmacology (12.3)].192193 8 USE IN SPECIFIC POPULATIONS194195 8.1 Pregnancy196 Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of DALIRESP in pregnant women. 197 DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESP should be used during pregnancy only if the potential benefit 198 justifies the potential risk to the fetus.199200 DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, 201 respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, 202 respectively). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD 203 (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in204 mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, 205 and 0.8 mg/kg/day, respectively).206207 Nonteratogenic effects: DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the 208 drug during pregnancy and lactation periods in mice. These studies found that DALIRESP decreased pup rearing frequencies at 209 approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP 210 also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD 211 (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.212213 8.2 Labor and Delivery214 DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on 215 preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice. 216 DALIRESP induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a 217 mg/m2 basis at a maternal dose of > 2 mg/kg/day).218219 8.3 NursingMothers220 Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human 221 milk is probable. There are no human studies that have investigated effects of DALIRESP on breast-fed infants. DALIRESP should not 222 be used by women who are nursing.223224 8.4 PediatricUse225 COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established. 226227 8.5 GeriatricUse228 Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 229 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger 230 subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, 231 but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage 232 in geriatric patients is warranted [see Clinical Pharmacology (12.3)].233234 8.6 Hepatic Impairment235 Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh 236 A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in 237 Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender238 matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A 239 subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not 240 been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who 241 have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver 242 impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].243244 8.7 RenalImpairment245 In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and 246 roflumilast N-oxide were decreased by 21% and 7%, respectively and C max were reduced by 16% and 12%, respectively. No dosage 247 adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)].248249 10 OVERDOSAGE250251 10.1 Human Experience252 No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the 253 following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: 254 headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension.255256 10.2 Management of Overdose257 In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since 258 roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether 259 roflumilast is dialyzable by peritoneal dialysis.260261 11 DESCRIPTION262 The active ingredient in DALIRESP tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective 263 phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4264 difluoromethoxy-benzamide. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.265266 The chemical structure is:267268269270271 The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and 272 hexane, sparingly soluble in ethanol and freely soluble in acetone.273274 DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet 275 contains 500 mcg of roflumilast.276277 Each tablet of DALIRESP for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, 278 povidone and magnesium stearate.279280 12 CLINICALPHARMACOLOGY281282 12.1 Mechanism of Action283 Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and 284 roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung 285 tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its 286 therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in 287 lung cells.288289 12.2 Pharmacodynamics290 In COPD patients, 4 week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, 291 and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total 292 cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) 293 challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.294295 12.3 Pharmacokinetics296 Absorption297 The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (C max) 298 of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like 299 maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has 300 no affect on total drug absorption, but delays time to maximum concentration (T max) of roflumilast by one hour and reduces C max by 301 approximately 40%, however, C max and T max of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and 302 roflumilast N-oxide did not inhibit P-gp transporter.303304 Distribution305 Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for 306 single dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the 307 blood-brain barrier.308309 Metabolism310 Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is 311 the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority 312 (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only a trace 313 metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N314 oxide were detected in urine.315316 While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of 317 roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.318319 In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is 320 mediated by CYP 1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of 321 roflumilast and roflumilast N-oxide do not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is 322 a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies 323 demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP 2B6 by roflumilast.324325 Elimination326 The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the 327 median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady 328 state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days 329 for roflumilast N-oxide following once daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70%330 of the radioactivity was recovered in the urine.331332 Special Populations333334 Hepatic Impairment335 Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh 336 A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in 337 Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender338 matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A 339 subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not 340 been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who 341 have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver 342 impairment (Child-Pugh B or C) [see Contraindications (4) and Use in Specific Populations (8.6)].343344 Renal Impairment345 In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide 346 AUCs were decreased by 21% and 7%, respectively and C max were reduced by 16% and 12%, respectively. No dosage adjustment is 347 necessary for patients with renal impairment [see Use in Specific Populations (8.7)].348349 Age350 Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly 351 (> 65 years of age) were 27% higher in AUC and 16% higher in C max for roflumilast and 19% higher in AUC and 13% higher in C max for 352 roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients [see Use in 353 Specific Populations (8.5)].354355 Gender356 In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 357 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. 358 No dosage adjustment is necessary based on gender.359360 Smoking361 The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no 362 difference in C max between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 363 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in 364 smokers was 17% more than that in non-smokers.365366 Race367 As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for 368 roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, 369 Hispanics, and Japanese showed 8%, 21%, and 5% higher C max, respectively, for roflumilast and 43%, 27%, and 17% higher C max, 370 respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.371372 Drug Interactions373 Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as 374 probes for pharmacokinetic interaction [see Drug Interactions]. No significant drug interactions were observed when 500 mcg oral 375 roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, 376 sildenafil, midazolam, or antacids.377378 The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown in the Figure 1 below.379380。
FDA说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use SOVALDI safely and effectively. See full prescribing information for SOVALDI.SOVALDI TM (sofosbuvir) tablets, for oral useInitial U.S. Approval: 2013-------------------------------INDICATIONS AND USAGE------------------------SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. (1)• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation)and those with HCV/HIV-1 co-infection. (1)------------------------DOSAGE AND ADMINISTRATION---------------------• One 400 mg tablet taken once daily with or without food. (2.1) • Should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC.Recommended combination therapy: (2.1)HCV Mono-infected andHCV/HIV-1 Co-infected Treatment DurationGenotype 1 or 4SOVALDI + peg-interferon alfa + ribavirin12 weeksGenotype 2 SOVALDI + ribavirin 12 weeksGenotype 3 SOVALDI + ribavirin 24 weeks • SOVALDI in combination with ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who areinterferon ineligible. (2.1)• Should be used in combination with ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting livertransplantation for up to 48 weeks or until liver transplantation,whichever occurs first. (2.1)• A dose recommendation cannot be made for patients with severe renal impairment or end stage renal disease. (2.4, 8.6) -----------------------DOSAGE FORMS AND STRENGTHS-------------------Tablets: 400 mg. (3)--------------------------------CONTRAINDICATIONS-----------------------------• When used in combination with peginterferon alfa/ribavirin or ribavirin alone, all contraindications to peginterferon alfa and/orribavirin also apply to SOVALDI combination therapy. (4)• Because ribavirin may cause birth defects and fetal death, SOVALDI in combination with peginterferon alfa/ribavirin orribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. (4)-------------------------WARNINGS AND PRECAUTIONS---------------------• Pregnancy: Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects;avoid pregnancy in female patients and female partners of malepatients. Patients must have a negative pregnancy test prior toinitiating therapy, use at least 2 effective non-hormonal methods of contraception and have monthly pregnancy tests. (5.1)--------------------------------ADVERSE REACTIONS----------------------------The most common adverse events (incidence greater than or equal to 20%, all grades) observed with SOVALDI in combination with ribavirin were fatigue and headache. The most common adverse events observed with SOVALDI in combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or /medwatch.---------------------------------DRUG INTERACTIONS----------------------------Drugs that are potent intestinal P-gp inducers (e.g., rifampin, St. John’s wort) may alter the concentrations of sofosbuvir. Consult the full prescribing information prior to use for potential drug-drug interactions.(5.2, 7, 12.3)---------------------------USE IN SPECIFIC POPULATIONS-------------------• Patients with HCV/HIV-1 co-infection: Safety and efficacy have been studied. (8.8, 14.4)• Patients with hepatocellular carcinoma awaiting livertransplantation: Safety and efficacy have been studied. (8.9)See 17 for PATIENT COUNSELING INFORMATION andFDA-approved patient labeling.Revised: 12/2013FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in Adults2.2 Dose Modification2.3 Discontinuation of Dosing2.4 Severe Renal Impairment and End Stage Renal Disease3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Pregnancy: Use with Ribavirin or PeginterferonAlfa/Ribavirin5.2 Use with Potent P-gp Inducers6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials Experience7 DRUG INTERACTIONS7.1 Potential for Drug Interactions7.2 Potentially Significant Drug Interactions7.3 Drugs without Clinically Significant Interactions withSOVALDI8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment8.8 Patients with HCV/HIV-1 Co-infection8.9 Patients with Hepatocellular CarcinomaAwaiting Liver Transplantation8.10 Post-Liver Transplant Patients8.11 CHC Patients with Genotype 5 or 6 HCVInfection10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis,Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Description of Clinical Trials14.2 Clinical Trials in Subjects with Genotype1 or 4 CHC14.3 Clinical Trials in Subjects with Genotype2 or3 CHC14.4 Clinical Trials in Subjects Co-infectedwith HCV and HIV-116 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGESOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or4 infection, including those with hepatocellular carcinoma meeting Milan criteria(awaiting liver transplantation) and those with HCV/HIV-1 co-infection [SeeDosage and Administration (2), Use in Specific Populations (8) and ClinicalStudies (14)].The following points should be considered when initiating treatment with SOVALDI: • Monotherapy of SOVALDI is not recommended for treatment of CHC.• Treatment regimen and duration are dependent on both viral genotype and patient population [See Dosage and Administration (2)].• Treatment response varies based on baseline host and viral factors [See Use in Specific Populations (8) and Clinical Studies (14)].2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in AdultsThe recommended dose of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food [See Clinical Pharmacology (12.3)].SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for SOVALDI combination therapy is provided in Table 1.Table 1 Recommended Regimens and Treatment Duration for SOVALDI Combination Therapy in HCV Mono-infected and HCV/HIV-1 Coinfected PatientsTreatment DurationPatients with genotype 1 or 4 CHC SOVALDI + peginterferon alfa a+ ribavirin b12 weeksPatients with genotype 2 CHC SOVALDI + ribavirin b 12 weeks Patients with genotype 3 CHC SOVALDI + ribavirin b 24 weeksa. See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC.b. Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dose of ribavirin isadministered orally in two divided doses with food. Patients with renal impairment (CrCl ≤ 50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive aninterferon-based regimen [See Use in Specific Populations (8.8) and Clinical Studies (14.4)]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.Patients with Hepatocellular Carcinoma Awaiting Liver TransplantationSOVALDI in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [See Use in Specific Populations (8.9)].2.2 Dose ModificationDose reduction of SOVALDI is not recommended.Genotype 1 and 4:If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose.Genotype 2 and 3:If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status. Table 2 Ribavirin Dose Modification Guideline for Coadministration with SOVALDILaboratory Values Reduce Ribavirin Dose to 600mg/day a If:Discontinue Ribavirin If:bHemoglobin in patients with nocardiac disease<10 g/dL <8.5 g/dLHemoglobin in patients with history of stable cardiac disease ≥2 g/dL decrease in hemoglobinduring any 4 week treatment period<12 g/dL despite 4 weeks atreduced dosea. The daily dose of ribavirin is administered orally in two divided doses with food.b. Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt maybe made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin be increased to the original assigned dose (1000 mg to 1200 mg daily).2.3 Discontinuation of DosingIf the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued.2.4 Severe Renal Impairment and End Stage Renal DiseaseNo dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stagerenal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].3 DOSAGE FORMS AND STRENGTHSSOVALDI is available as a yellow colored, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “7977” on the other side. Each tablet contains 400 mg sofosbuvir.4 CONTRAINDICATIONSWhen SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.SOVALDI combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].5 WARNINGS AND PRECAUTIONS5.1 Pregnancy: Use with Ribavirin or Peginterferon Alfa/RibavirinRibavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects [See Contraindications (4)]. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI, therefore, two non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin [See Contraindications (4) and Use in Specific Populations (8.1)]. Refer also to the prescribing information for ribavirin.5.2 Use with Potent P-gp InducersDrugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of SOVALDI. Rifampin and St. John’s wort should not be used with SOVALDI [See Drug Interactions (7.2)].6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials ExperienceSOVALDI should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety assessment of SOVALDI is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks.The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, <1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in Table 3. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.Table 3 Treatment-Emergent Adverse Events (All Grades) Reported in ≥ 15% of Subjects in Any Treatment ArmInterferon-free Regimens Interferon-containing RegimensPBO 12 weeks SOVALDI+ RBV a12 weeksSOVALDI+ RBV a24 weeksPeg-IFN alfa+ RBV b24 weeksSOVALDI+ Peg-IFN alfa+ RBV a12 weeksN=71 N=650 N=250 N=243 N=327 Fatigue 24% 38% 30% 55% 59%Headache 20% 24% 30% 44% 36%Nausea 18% 22% 13% 29% 34%Insomnia 4% 15% 16% 29% 25%Pruritus 8% 11% 27% 17% 17%Anemia 0% 10% 6% 12% 21%Asthenia 3% 6% 21% 3% 5%Rash 8% 8% 9% 18% 18%DecreasedAppetite10% 6% 6% 18% 18% Chills 1% 2% 2% 18% 17%InfluenzaLike Illness3% 3% 6% 18% 16% Pyrexia 0% 4% 4% 14% 18%Diarrhea 6% 9% 12% 17% 12%Neutropenia 0% <1% <1% 12% 17%Myalgia 0% 6% 9% 16% 14%Irritability 1% 10% 10% 16% 13%a. Subjects received weight-based ribavirin (1000 mg per day if weighing < 75 kg or 1200 mg per day if weighing ≥75 kg).b. Subjects received 800 mg ribavirin per day regardless of weight.With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in SOVALDI-containing regimens.Less Common Adverse Reactions Reported in Clinical Trials (<1%): The following ADRs occurred in <1% of subjects receiving SOVALDI in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant pegylated interferon).Psychiatric Disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.Laboratory Abnormalities:Changes in selected hematological parameters are described in Table 4. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.Table 4 Percentage of Subjects Reporting Selected HematologicalParametersHematological ParametersInterferon-free Regimens Interferon-containing RegimensPBO12 weeksSOVALDI+ RBV a12 weeksSOVALDI+ RBV a24 weeksPeg-IFN+ RBV b24 weeksSOVALDI+ Peg-IFN + RBV a12 weeksN=71 N=647 N=250 N=242 N=327Hemoglobin (g/dL)< 10 0 8% 6% 14% 23%< 8.5 0 1% <1% 2% 2% Neutrophils (x109/L)≥0.5 -< 0.75 1% <1% 0 12% 15%< 0.5 0 <1% 0 2% 5%Platelets (x109/L)≥25 -< 50 3% <1% 1% 7% <1%< 25 0 0 0 0 0a. Subjects received weight-based ribavirin (1000 mg per day if weighing < 75 kg or 1200 mg per day if weighing ≥75 kg).b. Subjects received 800 mg ribavirin per day regardless of weight.Bilirubin ElevationsTotal bilirubin elevation of more than 2.5xULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations.Creatine Kinase ElevationsCreatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively.Lipase ElevationsIsolated, asymptomatic lipase elevation of greater than 3xULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.7 DRUG INTERACTIONS7.1 Potential for Drug InteractionsAfter oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material [See Clinical Pharmacology (12.3)]. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI [See Warnings and Precautions (5.2)]. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters.The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs [See Clinical Pharmacology (12.3)].7.2 Potentially Significant Drug InteractionsDrug interaction information for SOVALDI with potential concomitant drugs is summarized in Table 5. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. The table is not all-inclusive [See Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].Table 5 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesor Predicted Interaction aConcomitant Drug Class: Drug NameEffect onConcentration bClinical CommentAnticonvulsants: carbamazepine phenytoin phenobarbital oxcarbazepine ↓sofosbuvir↓GS-331007Coadministration of SOVALDI with carbamazepine,phenytoin, phenobarbital or oxcarbazepine is expected todecrease the concentration of sofosbuvir, leading toreduced therapeutic effect of SOVALDI. Coadministrationis not recommended.Antimycobacterials: rifabutinrifampinrifapentine ↓sofosbuvir↓GS-331007Coadministration of SOVALDI with rifabutin or rifapentineis expected to decrease the concentration of sofosbuvir,leading to reduced therapeutic effect of SOVALDI.Coadministration is not recommended.SOVALDI should not be used with rifampin, a potentintestinal P-gp inducer [See Warnings and Precautions(5.2)].Herbal Supplements: St. John’s wort (Hypericum perforatum) ↓sofosbuvir↓GS-331007SOVALDI should not be used with St. John’s wort, apotent intestinal P-gp inducer [See Warnings andPrecautions (5.2)].HIV Protease Inhibitors: tipranavir/ritonavir ↓sofosbuvir↓GS-331007Coadministration of SOVALDI with tipranavir/ritonavir isexpected to decrease the concentration of sofosbuvir,leading to reduced therapeutic effect of SOVALDI.Coadministration is not recommended.a. This table is not all inclusive.b. ↓= decrease.7.3 Drugs without Clinically Significant Interactions with SOVALDIIn addition to the drugs included in Table 5, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug [See Clinical Pharmacology (12.3)]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category X: Use with Ribavirin or Peginterferon Alfa/RibavirinExtreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI. Therefore, two effective non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin [See Warnings and Precautions (5.1)].In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-2584263.Animal DataSignificant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant [See Contraindications (4), Warnings and Precautions (5.1) and ribavirin Package Insert]. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans [See peginterferon alfa Package Insert].Pregnancy Category B: SOVALDIThere are no adequate and well-controlled studies with SOVALDI in pregnant women. Animal DataNo effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5-to 10-fold and 12-to 28-fold the exposure in humans at the recommended clinical dose, respectively.8.3 Nursing MothersIt is not known whether SOVALDI and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin-containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin.8.4 Pediatric UseSafety and effectiveness of SOVALDI in children less than 18 years of age have not been established.8.5 Geriatric UseSOVALDI was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of SOVALDI is warranted in geriatric patients [See Clinical Pharmacology (12.3)].8.6 Renal ImpairmentNo dose adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD [See Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl <50 mL/min.8.7 Hepatic ImpairmentNo dose adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of SOVALDI have not been established in patients with decompensated cirrhosis [See Clinical Pharmacology (12.3)]. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.8.8 Patients with HCV/HIV-1 Co-infectionThe safety and efficacy of SOVALDI was assessed in 223 HCV/HIV-1 co-infected subjects [See Clinical Studies (14.4)]. See Dosage and Administration (2.1) for dosing recommendations in HCV/HIV-1 co-infected patients. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials [See Adverse Reactions (6.1)].8.9 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation SOVALDI was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA < lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor)。
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5.3 Gastrointestinal Ulcers and Bleeding
5.4 Central Nervous System Symptoms
5.5 Leukopenia and Elevated Alkaline Phosphatase Levels
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROCSYBI safely and effectively. See full prescribing information for PROCSYBI. PROCYSBI (cysteamine bitartrate) delayed-release capsules, for oral use Initial U.S. Approval: 1994 ---------------------------INDICATIONS AND USAGE (1)-----------------------PROCYSBI is a cystine depleting agent indicated for the management of nephropathic cystinosis in adults and children ages 6 years and older. (1.1) ----------------------DOSAGE AND ADMINISTRATION (2)-------------------PROCYSBI should be prescribed by a physician experienced in management of nephropathic cystinosis. (2.1) Swallow capsules whole or after sprinkling on food or in recommended liquids. Administer via gastrostomy tube (12 F or larger) after mixing with food. ( 2.3 ) Total daily dose is 1.3 gram/m2/day in two divided doses, every 12 hours. (2.2 ) Take PROCYSBI at least 2 hours after and at least 30 minutes before eating. ( 2 ) Goal of therapy is to maintain a white blood cell (WBC) cystine level < 1 nmol ½ cystine/mg protein or a plasma cysteamine concentration > 0.1 mg/L. (2.6) Switching from Immediate-Release Cysteamine to PROCYSBI Total daily dose of PROCYSBI equal to their previous total daily dose of immediate-release cysteamine bitartrate. (2.7) Initial Dosage in Cysteamine-naïve patients Starting Dose1/6 to 1/4 of the maintenance dose of PROCYSBI (2.1) Maintenance Dose: 1.3 gram/m2/day, in two divided doses every 12 hours (2.2) See Full Prescribing Information for details on administration. ( 2.3) ---------------------DOSAGE FORMS AND STRENGTHS (3)-----------------Delayed-release capsules: 25 mg and 75 mg (3) -----------------------------CONTRAINDICATIONS (4)--------------------------Hypersensitivity to penicillamine (4.1)
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES 14.1 Clinical Trials with Immediate-release Cysteamine
17.3 Use by Pregnant Women
---------------------WARNINGS AND PRECAUTIONS (5)------------------- Ehler-Danlos like Syndrome: Reduce dosage if skin and bone lesions occur. (5.1) Skin Rash: Discontinue PROCYSBI if severe skin rash such as erythema multiforme bullosa or toxic epidermal necrolysis occurs. (5.2) Gastrointestinal: Monitor for symptoms of gastrointestinal ulceration and bleeding. (5.3) Central Nervous System: Monitor for seizures, lethargy, somnolence, depression, and encephalopathy. (5.4) Leukopenia and Elevated Alkaline Phosphatase Levels: Monitor white blood count and elevated alkaline phosphatase levels. (5.6) Benign Intracranial Hypertension: Monitor for signs and symptoms of benign intracranial hypertension. (5.7) ----------------------------ADVERSE REACTIONS (6)----------------------------Most commonly reported adverse reactions (>5%) are vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Raptor Pharmaceuticals Inc. at 1-855-888-4004 or FDA at 1-800-FDA-1088 or /medwatch. ---------------------------DRUG INTERACTIONS (7)-----------------------------PROCYSBI (cysteamine bitartrate) delayed-release capsules can be administered with electrolyte (except bicarbonate) and mineral replacements necessary for management of Fanconi Syndrome as well as vitamin D and thyroid hormone (7). ---------------------USE IN SPECIFIC POPULATIONS (8)---------------------Nursing Mothers: Breastfeeding is not recommended while taking PROCYSBI. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: April 2013
2.7 Transferring Patients from Immediate-release Cysteamine
Bitartrate Capsules
DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Ehler-Danlos like Syndrome
14.2 Clinical Trials with PROCYSBI
HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION 17.1 Laboratory Monitoring
17.2 Dosing and Administration
8.3 Nursing Mothers
8.4 Pediatric Use
9 10 11 12 DRUG ABUSE AND DEPENDENCE OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action