泊沙康唑说明书
《泊沙康唑临床应用专家共识》(2020)要点
《泊沙康唑临床应用专家共识》（2020）要点近年来,随着各类免疫缺陷人群及危重疾患的增多,侵袭性真菌病(IFD)的整体发病率逐年上升,且非白念珠菌、曲霉及毛霉等真菌感染的比例在血液科、呼吸科、器官移植科等科室普遍呈升高趋势。
泊沙康唑属于第二代三唑类抗真菌药物,其抗菌谱和药物代谢过程有别于其他三唑类药物,口服混悬液、肠溶片和注射剂分别于2005、2013和2014年经美国食品药品监督管理局批准先后上市。
在我国,泊沙康唑口服混悬液于2013年上市,肠溶片也于2018年12月上市,在IFD的预防和治疗领域适用范围广泛。
1 临床药理学特性1 1 作用机制及分子结构特征1 2 药代动力学(PK)泊沙康唑的吸收会因剂型不同而有差异,主要在胃部溶解,在十二指肠部位吸收。
肠溶缓释片剂使用独特的热熔挤压工艺将药物分散在pH敏感的高分子聚合体中,有效避免药物在低pH的胃部释放,利于在中性pH的小肠溶解,从而使泊沙康唑吸收达到最大化。
注射针剂几乎在注射完毕时即可达血药峰浓度,且除首日双倍剂量外每日仅需给药1次,适用于不能耐受口服剂型的患者。
1 3 治疗药物监测(TDM)在深部真菌病的预防治疗中,基础疾病、合并用药、饮食情况、诊疗措施等多种因素都会对抗真菌药物的吸收、分布、代谢和清除产生影响,TDM 既是保证治疗充分的重要手段,又是避免过度药物暴露、减少药物相关不良反应的重要措施。
专家建议：有条件的医疗机构应积极开展泊沙康唑的TDM,监测指标为泊沙康唑血药谷浓度。
首次泊沙康唑血药谷浓度监测的采血时间建议为用药后第5天。
用于预防IFD时,泊沙康唑的血药谷浓度应维持在0.7mg/L以上；用于治疗IFD时,泊沙康唑的血药谷浓度应维持在1.0～1.25mg/L以上。
1 4 药物间相互作用泊沙康唑的主要药物相互作用结果及应对措施见表2。
1 5 安全性及耐受性泊沙康唑口服混悬液常见不良反应为恶心、头痛、呕吐、腹痛、皮疹等,症状较轻微,大多数情况下不需要停药,长期治疗(≥6个月)时QT间期延长、肝酶升高等不良反应的发生率仍然保持在较低水平。
泊沙康唑的临床药7.28效——【血液内科】
菌种
数量 AMB FCZ
ICZ
新生隐球菌 罗伦隐球菌
5 0.25-2 1-4 0.25-1 2 0.5-1 2-4 0.5-1
VCZ
0.030.125 0.125
POS
CAS
MCF
0.125-1 16->16 16->16 0.25-1 16->16 >16
阿萨希毛孢子菌 3
Trichosporon loubieri
白念珠菌热带念珠菌近平滑念珠菌克柔念珠菌光滑念珠菌新生隐球菌烟曲霉土曲霉毛霉镰刀霉荚膜组织胞浆菌皮炎芽生菌球孢子菌对耐flc念珠菌的mic值范围gml菌种数量ambfcziczvczposcasmcffczr白念珠菌05116640062003050030125006025003fczs白念珠菌051012520125050030250030060125025003025光滑念珠菌05116640540062003050125025003近平滑念珠菌012505025100300301250125286414003025003012512052140510030030060250500305克柔念珠菌32050250501250125葡萄牙念珠菌0510500602500300302501250500305希木龙念珠菌26401250500610250500605012505解脂念珠菌02500301250250125对其他酵母菌的mic值范围gml菌种数量ambfcziczvczposcasmcf新生隐球菌025214025100301250125116161616罗伦隐球菌051240510125025116161612240125050030060125051616trichosporonloubieri050125051616马尔尼菲篮状菌0250512003006003003012505白地霉02505对耐唑类的曲霉的micmec值gml菌种数量ambfcziczvczposcasmcficzr烟曲霉641605202516003006003vczr烟曲霉640516025003003其他烟曲霉1012640125100620060250030125003iczr黄曲霉0505003其他黄曲霉051003012500311264120252006025003003黑曲霉01251640060250030030250030125003土曲霉2464006025003003025012505003对其他丝状真菌的micmec值gml菌种数量ambfcziczvczposcasmcf16641616161864241205105茄病镰刀菌161616161612641605116161616不规则毛霉025056424160511616卷枝毛霉641616161616冻土毛霉05641602516161605
泊沙康唑预防或挽救性治疗血液病患者侵袭性真菌病的临床研究
泊沙康唑预防或挽救性治疗血液病患者侵袭性真菌病的临床研究泊沙康唑属于新型广谱三唑类抗真菌药物，主要用于免疫缺陷患者侵袭性真菌病（IFD）的预防性治疗，被批准的适应证包括急性髓系白血病（AML）和骨髓增生异常综合征（MDS）化疗引起的中性粒细胞减少症患者及造血干细胞移植（HSCT）后发生移植物抗宿主病（GVHD）患者IFD的预防。
泊沙康唑具有广泛的抗菌活性，对念珠菌属、曲霉菌属，甚至既往唑类药物不敏感的接合菌属（如毛霉菌等）等均具有良好的作用，在国外已经得到广泛应用。
由于泊沙康唑在我国被批准应用于临床的时间较短（2013年6月批准注册），国内文献尚鲜见其用于IFD预防或治疗的临床报道。
我们回顾性分析25例接受泊沙康唑预防或挽救性治疗IFD的血液病患者的临床资料，对其疗效及安全性进行探讨。
1 资料与方法1.1 一般资料2014年2月至2015年2月共有25例血液病患者接受了泊沙康唑预防性或挽救性治疗，平均年龄32.6岁（16~ 64岁）。
其中18例接受了泊沙康唑预防性治疗，包括急性白血病患者8例[6例为AML, 2例为急性淋巴细胞白血病（ALL）]，均为化疗后严重骨髓抑制期（中性粒细胞计数<0.5×109/L）；HSCT患者10例，其中非血缘脐血移植7例，自体外周血干细胞移植（PBSCT）、人类白细胞抗原（HLA）相合同胞PBSCT及非血缘PBSCT各1例。
10例HSCT患者接受泊沙康唑预防性治疗主要是由于移植前3个月曾发生过侵袭性肺部真菌病（IPFD），经过伏立康唑治愈（7例）（即泊沙康唑二级预防）或出现Ⅲ～Ⅳ度急性GVHD(aGVHD）（3例）。
7例患者接受了泊沙康唑挽救性治疗，其中4例为HSCT患者，1例为极重型再生障碍性贫血患者，接受抗胸腺细胞球蛋白（ATG）、环孢素（CsA）免疫抑制治疗联合脐血输注，1例为ALL患者（化疗后骨髓抑制期间），1例为多发性骨髓瘤（MM）患者。
所有接受泊沙康唑挽救性治疗的患者均是在伏立康唑预防期间出现肺部真菌感染的突破或IPFD治疗无效（6例）或不耐受（1例）者。
泊沙康唑 美国说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use NOXAFIL ORAL SUSPENSION safely and effectively. See full prescribing information for NOXAFIL ORAL SUSPENSION. NOXAFIL® (Posaconazole) ORAL SUSPENSION 40 mg/mLInitial U.S. Approval: 2006---------------------------INDICATIONS AND USAGE----------------------------- NOXAFIL is a triazole antifungal agent indicated for: •prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk ofdeveloping these infections due to being severelyimmunocompromised, such as HSCT recipients with GVHD orthose with hematologic malignancies with prolonged neutropenia from chemotherapy. (1.1)•the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole. (1.2)-------------------------DOSAGE AND ADMINISTRATION---------------------- Indication Dose and Duration of therapyProphylaxis of Invasive Fungal Infections 200 mg (5 mL) three times a day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.1)Oropharyngeal Candidiasis (OPC) Loading dose of 100 mg (2.5 mL) twice a day on the first day, then 100 mg (2.5 mL) once a day for 13 days. (2.1)OPC Refractory(rOPC) to Itraconazole and/or Fluconazole 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response. (2.1)-----------------------DOSAGE FORMS AND STRENGTHS-------------------- NOXAFIL Oral Suspension 40 mg per mL (3)-----------------------------CONTRAINDICATIONS--------------------------------- • Do not administer to persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azoleantifungal agents (4.1)• Do not coadminister NOXAFIL with the following drugs;NOXAFIL increases concentrations of:o Sirolimus: can result in sirolimus toxicity (4.2, 7.1)o CYP3A4 substrates (pimozide, quinidine): can result inQTc interval prolongation and rare occurrences of TdP(4.3, 7.2)o Simvastatin: can result in rhabdomyolysis (4.4,7.3)o Ergot alkaloids: can result in ergotism (4.5, 7.4)-----------------------WARNINGS AND PRECAUTIONS------------------------ •Calcineurin Inhibitor Toxicity: NOXAFIL increasesconcentrations of cyclosporine or tacrolimus; reduce dose ofcyclosporine and tacrolimus and monitor concentrationsfrequently. (5.1)•Arrhythmias and QTc Prolongation: NOXAFIL has beenshown to prolong the QTc interval and cause rareoccurrences of TdP. Administer with caution to patients withpotentially proarrhythmic conditions. Do not administer withdrugs known to prolong QTc interval and metabolizedthrough CYP3A4. Correct K+, Mg++, and Ca++ before startingNOXAFIL. (5.2)•Hepatic Toxicity: elevations in LFTs (generally reversible ondiscontinuation) may occur. Discontinuation should beconsidered in patients who develop abnormal LFTs ormonitor LFTs during treatment. (5.3)● Midazolam: NOXAFIL can prolong hypnotic/sedative effects.Monitor patients and benzodiazepine receptor antagonistsshould be available. (5.4, 7.5)-------------------------------ADVERSE REACTIONS------------------------------•Common treatment-emergent adverse reactions (>30%) inprophylaxis studies are fever, diarrhea and nausea.(6.2)• Common treatment-emergent adverse reactions (>5%) incontrolled OPC pool are diarrhea, nausea, headache, andvomiting. Common adverse reactions (>20%) in the refractoryOPC pool are fever, diarrhea, nausea, and vomiting (6.2).To report SUSPECTED ADVERSE REACTIONS, contact ScheringCorporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099or FDA at 1-800-FDA-1088 or /medwatch.-------------------------------DRUG INTERACTIONS------------------------------Interaction Drug InteractionRifabutin, phenytoin, efavirenz,cimetidine, esomeprazoleAvoid co-administration unlessthe benefit outweighs the risks(7.6, 7.7, 7.8, 7.9)Other drugs metabolized byCYP3A4 (tacrolimus,cyclosporine, vinca alkaloids,calcium channel blockers)Consider dosage adjustment andmonitor for adverse effects andtoxicity (7.1,7.10, 7.11)Digoxin Monitor digoxin plasmaconcentrations (7.12)Metoclopramide Monitor for breakthrough fungalinfections (7.13)--------------------------USE IN SPECIFIC POPULATIONS---------------------• Pregnancy: Based on animal data, may cause fetal harm. (8.1)• Nursing Mothers: Discontinue drug or nursing, taking in toconsideration the importance of drug to the mother. (8.3)• Severe renal impairment: Monitor closely for breakthrough fungalInfections. (8.6)See 17 for PATIENT COUNSELING INFORMATION.Revised:10/2011FULL PRESCRIBING INFORMATION: CONTENTS*1.INDICATIONS AND USAGE1.1 Prophylaxis of Invasive Aspergillus and Candida Infections1.2 Treatment of Oropharyngeal Candidiasis IncludingOropharyngeal Candidiasis Refractory to Itraconazoleand/or Fluconazole2.DOSAGE AND ADMINISTRATION2.1 Dosage2.2 Administration Instructions3.DOSAGE FORMS AND STRENGTHS4.CONTRAINDICATIONS4.2 Use With Sirolimus4.3 QT Prolongation With Concomitant Use With CYP3A4Substrates4.4 Use With Simvastatin4.5 Use With Ergot Alkaloids5.WARNINGS AND PRECAUTIONS5.1 Calcineurin-Inhibitor Drug Interactions5.2Arrhythmias and QT Prolongation5.3 Hepatic Toxicity5.4 Use With Midazolam6.ADVERSE REACTIONS6.1Serious and Otherwise Important Adverse Reactions6.2Clinical Trials Experience6.3 Postmarketing Experience7.DRUG INTERACTIONS7.1 Immunosuppressants Metabolized by CYP3A47.2 CYP3A4 Substrates7.3 HMG-CoA reductase Inhibitors (Statins) Metabolized ThroughCYP3A47.4 Ergot Alkaloids7.5 Benzodiazepines Metabolized by CYP3A47.6 Anti-HIV Drugs7.7 Rifabutin7.8 Phenytoin7.9 Gastric Acid Suppressors/Neutralizers7.10 Vinca Alkaloids7.11 Calcium Channel Blockers Metabolized by CYP3A47.12 Digoxin7.13 Gastrointestinal Motility Agents7.14 GlipizideE IN SPECIFIC POPULATIONS8.1Pregnancy8.3Nursing Mothers8.4Pediatric Use8.5Geriatric Use8.6Renal Insufficiency8.7Hepatic Insufficiency8.8Gender8.9Race10.OVERDOSAGE11.DESCRIPTION12.CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics12.4 Microbiology13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2Animal Toxicology and/or Pharmacology14. CLINICAL STUDIES14.1Prophylaxis of Aspergillus and Candida Infections14.2Treatment of Oropharyngeal Candidiasis14.3Treatment of Oropharyngeal Candidiasis Refractory toTreatment With Fluconazole or Itraconazole16.HOW SUPPLIED/STORAGE AND HANDLING17.PATIENT COUNSELING INFORMATION17.1 Administration With Food17.2 Drug Interactions17.3 Serious and Potentially Serious Adverse Reactions17.4See Accompanying FDA-Approved Patient Labeling* Sections or subsections omitted from the full prescribing information are not listed.________________________________________________________FULL PRESCRIBING INFORMATION1. INDICATIONS AND USAGE1.1 Prophylaxis of Invasive Aspergillus and Candida InfectionsNOXAFIL Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or FluconazoleNOXAFIL is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.2. DOSAGE AND ADMINISTRATION2.1DosageIndication Dose and Duration of TherapyProphylaxis of Invasive Fungal Infections 200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.Oropharyngeal Candidiasis Loading dose of 100 mg (2.5 mL) twice a day on the first day, then100 mg (2.5 mL) once a day for 13 days.Oropharyngeal Candidiasis Refractory to itraconazole and/or fluconazole 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response.2.2Administration InstructionsShake NOXAFIL Oral Suspension well before use.Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.It is recommended that the spoon is rinsed with water after each administration and before storage.Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g. ginger ale) in patients who cannot eat a full meal.To enhance the oral absorption of posaconazole and optimize plasma concentrations:•Each dose of NOXAFIL should be administered during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eata full meal, each dose of NOXAFIL should be administered with a liquid nutritional supplement or an acidic carbonated beverage. For patientswho cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.•Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.•Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections [see Drug Interactions(7.6, 7.7, 7.8, 7.9, 7.13)].3. DOSAGE FORMS AND STRENGTHSNOXAFIL Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing105 mL of suspension (40 mg of posaconazole per mL).4. CONTRAINDICATIONS4.1HypersensitivityNOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents.4.2 Use With SirolimusNOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].4.3 QT Prolongation With Concomitant Use With CYP3A4 SubstratesNOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].4.4 Use With SimvastatinConcomitant administration of NOXAFIL with simvastatin increases the simvastatin plasma concentrations by approximately 10 fold. Increased plasma statin concentrations can be associated with rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].4.5 Use With Ergot AlkaloidsPosaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].5. WARNINGS AND PRECAUTIONS5.1 Calcineurin-Inhibitor Drug InteractionsConcomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.5.2 Arrhythmias and QT ProlongationSome azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, rare cases of torsades de pointes have been reported in patients taking posaconazole.Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc (F) interval ≥500 msec or an increase ≥60 msec in their QTc (F) interval from baseline.Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.5.3 Hepatic ToxicityHepatic reactions (e.g.,mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Isolated cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.5.4 Use With MidazolamConcomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].6. ADVERSE REACTIONS6.1 Serious and Otherwise Important Adverse ReactionsThe following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Hypersensitivity[see Contraindications (4.1)]•Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)][see Warnings and Precautions (5.3)]• HepaticToxicity6.2 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of NOXAFIL cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. Thisrepresents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, graft vs. host disease post hematopoietic stem cell transplant, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 1 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 2 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies, the safety of posaconazole 200 mg threetimes a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea and nausea.The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders,specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).TABLE 1: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)Body SystemPreferred Term Posaconazole(n=605)Fluconazole(n=539)Itraconazole(n=58)Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100) Body as a Whole - General DisordersFever 274 (45) 254 (47) 32 (55) Headache 171 (28) 141 (26) 23 (40) Rigors 122 (20) 87 (16) 17 (29) Fatigue 101 (17) 98 (18) 5 (9) Edema Legs 93 (15) 67 (12) 11 (19) Anorexia 92 (15) 94 (17) 16 (28) Dizziness 64 (11) 56 (10) 5 (9) Edema 54 (9) 68 (13) 8 (14) Weakness 51 (8) 52 (10) 2 (3) Cardiovascular Disorders, GeneralHypertension 106 (18) 88 (16) 3 (5) Hypotension 83 (14) 79 (15) 10 (17) Disorders of Blood and Lymphatic SystemAnemia 149 (25) 124 (23) 16 (28) Neutropenia 141 (23) 122 (23) 23 (40) Febrile Neutropenia 118 (20) 85 (16) 23 (40) Disorders of the Reproductive System and BreastVaginal Hemorrhage* 24 (10) 20 (9) 3 (12) Gastrointestinal System DisordersDiarrhea 256 (42) 212 (39) 35 (60) Nausea 232 (38) 198 (37) 30 (52) Vomiting 174 (29) 173 (32) 24 (41) Abdominal Pain 161 (27) 147 (27) 21 (36) Constipation 126 (21) 94 (17) 10 (17) Mucositis NOS 105 (17) 68 (13) 15 (26) Dyspepsia 61 (10) 50 (9) 6 (10) Heart Rate and Rhythm DisordersTachycardia 72 (12) 75 (14) 3 (5) Infection and InfestationsBacteremia 107 (18) 98 (18) 16 (28) Herpes Simplex 88 (15) 61 (11) 10 (17) Cytomegalovirus Infection 82 (14) 69 (13) 0Pharyngitis 71 (12) 60 (11) 12 (21)Upper Respiratory Tract Infection 44 (7) 54 (10) 5 (9)Liver and Biliary System DisordersBilirubinemia 59 (10) 51 (9) 11 (19)Metabolic and Nutritional DisordersHypokalemia 181 (30) 142 (26) 30 (52)Hypomagnesemia 110 (18) 84 (16) 11 (19)Hyperglycemia 68 (11) 76 (14) 2 (3)Hypocalcemia 56 (9) 55 (10) 5 (9)Musculoskeletal System DisordersMusculoskeletal Pain 95 (16) 82 (15) 9 (16)Arthralgia 69 (11) 67 (12) 5 (9)Back Pain 63 (10) 66 (12) 4 (7)Platelet, Bleeding and Clotting DisordersThrombocytopenia 175 (29) 146 (27) 20 (34)Petechiae 64 (11) 54 (10) 9 (16)Psychiatric DisordersInsomnia 103 (17) 92 (17) 11 (19)Anxiety 52 (9) 61 (11) 9 (16)Respiratory System DisordersCoughing 146 (24) 130 (24) 14 (24)Dyspnea 121 (20) 116 (22) 15 (26)Epistaxis 82 (14) 73 (14) 12 (21)Skin and Subcutaneous Tissue DisordersRash 113 (19) 96 (18) 25 (43)Pruritus 69 (11) 62 (12) 11 (19)* Percentages of sex-specific adverse reactions are based on the number of males/females.NOS = not otherwise specified.HIV Infected Subjects With OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC).Of these subjects, 149 received the 800-mg/day dose and the remainder received the ≤400-mg QD dose.In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, and vomiting.The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory insufficiency (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory insufficiency (3%).TABLE 2: Treatment-Emergent Adverse Reactions With Frequency of at Least 10% in OPC Studies (Treated Population)Number (%) of SubjectsControlled OPC Pool Refractory OPC PoolPosaconazole Fluconazole PosaconazoleBody SystemPreferred Term n=557 n=262 n=239356 (64) 175 (67) 221 (92)Subjects Reporting any AdverseReaction*Body as a Whole – General DisordersFever 34 (6) 22 (8) 82 (34)Headache 44 (8) 23 (9) 47 (20)Anorexia 10 (2) 4 (2) 46 (19)Fatigue 18 (3) 12 (5) 31 (13)Asthenia 9 (2) 5 (2) 31 (13)Rigors 2 (<1) 4 (2) 29 (12)Pain 4 (1) 2 (1) 27 (11)Disorders of Blood and Lymphatic SystemNeutropenia 21 (4) 8 (3) 39 (16)Anemia 11 (2) 5 (2) 34 (14)Gastrointestinal System DisordersDiarrhea 58 (10) 34 (13) 70 (29)Nausea 48 (9) 30 (11) 70 (29)Vomiting 37 (7) 18 (7) 67 (28)Abdominal Pain 27 (5) 17 (6) 43 (18)Infection and InfestationsCandidiasis, Oral 3 (1) 1 (<1) 28 (12)Herpes Simplex 16 (3) 8 (3) 26 (11)Pneumonia 17 (3) 6 (2) 25 (10)Metabolic and Nutritional DisordersWeight Decrease 4 (1) 2 (1) 33 (14)Dehydration 4 (1) 7 (3) 27 (11)Psychiatric DisordersInsomnia 8 (1) 3 (1) 39 (16)Respiratory System DisordersCoughing 18 (3) 11 (4) 60 (25)Dyspnea 8 (1) 8 (3) 28 (12)Skin and Subcutaneous Tissue DisordersRash 15 (3) 10 (4) 36 (15)Sweating Increased 13 (2) 5 (2) 23 (10)OPC=oropharyngeal candidiasis; SGOT=serum glutamic oxaloacetic transaminase (same as AST);SGPT=serum glutamic pyruvic transaminase (same as ALT).* Number of subjects reporting treatment-emergent adverse reactions at least once during the study,without regard to relationship to treatment. Subjects may have reported more than 1 event.Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).Less Common Adverse Reactions: Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:•Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated •Endocrine disorders: adrenal insufficiency•Nervous system disorders: paresthesia•Immune system disorders: allergic reaction [see Contraindications (4.1)]•Cardiac disorders: Torsades de pointes [see Warnings and Precautions (5.2)]•Vascular disorders: pulmonary embolism•Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, SGOT Increased, SGPT Increased•Metabolic and Nutritional Disorders: Hypokalemia•Platelet, Bleeding, and Clotting Disorders: Thrombocytopenia•Renal & Urinary System Disorders: Renal Failure AcuteClinical Laboratory Values: In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy.For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 3.TABLE 3: Study 1 and Study 2. Changes in Liver Function Test Results From CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4Number (%) of Patients With Change*Study 1Laboratory Parameter Posaconazolen=301Fluconazolen=299AST 11/266 (4) 13/266 (5)Number (%) of Patients With Change*ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3)Study 2Laboratory Parameter Posaconazole(n=304)Fluconazole/Itraconazole(n=298)AST 9/286 (3) 5/280 (2)ALT 18/289 (6) 13/284 (5)Bilirubin 20/290 (7) 25/285 (9)Alkaline Phosphatase 4/281 (1) 1/276 (<1)* Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.These data are presented in the form X/Y, where X represents the numberof patients who met the criterion as indicated, and Y represents the numberof patients who had a baseline observation and at least one post-baselineobservation.CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;ALT= Alanine Aminotransferase.The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 4. (LFT abnormalities were present in some of these patients prior to initiation of the study drug).TABLE 4: Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline ValueControlled RefractoryPosaconazole Fluconazole PosaconazoleLaboratory Test n= 557(%) n=262(%) n=239(%)ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11)AST > 3.0 x ULN 33/537 (6) 26/254(10)39/223 (17)Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5)Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13)ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.6.3 Postmarketing ExperienceNo clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.7. DRUG INTERACTIONSPosaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology (12.3)].7.1 Immunosuppressants Metabolized by CYP3A4Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].Tacrolimus: Posaconazole has been shown to significantly increase the C max and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].7.2 CYP3A4 SubstratesConcomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs. [see Contraindications (4.3), and Warnings and Precautions (5.2)].。
立普妥用法
立普妥用法立普妥用法立普妥（Liputan）是一种常用的治疗皮肤问题的药膏，它含有有效成分泊沙康唑，可用于治疗真菌感染。
立普妥能够快速缓解搔痒和炎症，有效杀灭真菌，促进皮肤修复。
以下是关于立普妥的一些常见用法和详细讲解：1. 抹患处立普妥主要适用于外用，使用前请读取药品说明书并按照医生或药师的建议使用。
首先，将受感染部位进行清洁和干燥，之后取适量立普妥药膏，用指尖轻轻涂抹在患处上。
2. 避免接触眼睛和黏膜立普妥是外用药物，避免接触眼睛和黏膜，以免引起不必要的刺激和不适。
如果不慎接触到眼睛或黏膜，应立即用清水冲洗，并向医生咨询。
3. 用量和使用时机立普妥的使用量和使用时机根据个人受感染程度和医生建议而定。
通常情况下，每日使用1-2次，持续使用1-2周。
具体用量和使用时机请咨询医生或药师。
4. 保持治疗持续性对于真菌感染，及时治疗并保持治疗持续性是很重要的。
即使症状消失，也应继续使用立普妥药膏，以确保真菌完全清除，防止复发。
5. 避免与其他药品同时使用在使用立普妥期间，避免与其他药品同时使用，以免发生相互作用或削弱药效。
如果需要同时使用其他药品，请事先咨询医生或药师。
6. 注意保持清洁和干燥除了使用立普妥药膏外，保持清洁和干燥对于治疗真菌感染也非常重要。
勤换洗衣物和床单，并保持患处干燥通风，有助于加速康复。
以上是关于立普妥用法的一些列举和详细讲解。
在使用立普妥或任何其他药物之前，请务必咨询专业医生或药师的建议。
7. 注意个人卫生在治疗期间，要特别注意个人卫生，包括勤洗手、勤洗澡，使用自己的毛巾和洗衣物等。
避免与他人共用个人物品，以免交叉感染。
8. 遵守用药时间和频率使用立普妥时，要严格遵守用药时间和频率。
按照医生或药师的指示，准时使用药膏，并控制每次使用的剂量。
不要过量使用，也不要跳过任何一次用药。
9. 注意药物保存立普妥药膏应存放在干燥、阴凉的地方，远离高温和阳光直射。
确保儿童无法接触到药物，以防止误食或误用。
泊沙康唑合成工艺
泊沙康唑合成工艺
泊沙康唑是一种广谱抗真菌药物，在临床治疗中被广泛应用。
该药物的合成工艺可以分为以下几个步骤：
1. 乙酰丙酮的合成：将丙酮加入硫酸和磷酸的混合物中，反应生成乙酰丙酮。
2. 咪唑环的合成：将3-氨基-1H-咪唑和乙酰丙酮在醋酸中反应，生成咪唑环。
3. 反应物的反应：将咪唑环和2-氯-1-(2,4-二氯苯基)-2-甲基乙烷反应，得到2-(2,4-二氯苯基)-1-(1H-咪唑基)-2-甲基乙烷。
4. 氧化反应：将2-(2,4-二氯苯基)-1-(1H-咪唑基)-2-甲基乙烷和过氧化苯甲酰在二氯甲烷中反应，得到2-(2,4-二氯苯
基)-1-[(1H-咪唑-1-基)甲基]-2-氧代乙烷。
5. 氯化反应：将2-(2,4-二氯苯基)-1-[(1H-咪唑-1-基)甲
基]-2-氧代乙烷和氯化亚铜在甲醇中反应，得到2-(2,4-二氯苯
基)-1-[(1H-咪唑-1-基)甲基]-2-氯乙烷。
6. 脱保护反应：将2-(2,4-二氯苯基)-1-[(1H-咪唑-1-基)甲基]-2-氯乙烷和甲醇在氢氟酸中反应，去除甲基保护基，得到泊沙康唑。
以上是泊沙康唑的合成工艺，通过这些步骤可以得到高纯度、高产率的泊沙康唑药物。
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泊沙康唑肠溶片说明书
9（16）尚未在妊娠女性中开展充分且对照良好的研究。
除非潜在获益超过对胎儿的潜在风险，否则孕妇不得使用本品。
在大鼠中，剂量≥27mg/kg（根据健康志愿者中的稳态血浆浓度，暴露水平为400 mg，口服混悬液每日2次给药方案的≥ 1.4倍）的泊沙康唑可导致骨骼畸形（颅骨畸形和肋骨缺失。
在大鼠中，未观察到骨骼畸形的剂量（无效应剂量）为9mg/ kg，其暴露水平为400mg，口服混悬液每日2次给药方案的0.7倍。
在家兔中，最大剂量80mg/kg下未观察到任何畸形。
在家兔中，无效应剂量为20mg/kg，而大剂量40mg/kg和80mg/kg可导致吸收胎增加，这些剂量产生的暴露水平分别为400mg口服混悬液每日2次给药方案的2.9或5.2倍。
在家兔中，80mg/kg剂量下可观察到雌性动物体重增量减少和窝仔数减少。
哺乳期妇女泊沙康唑可排泄至哺乳大鼠的乳汁中。
尚未知本品是否会排泄至人乳汁中。
因为本品在哺乳期婴儿中存在发生严重不良反应的潜在可能，应该考虑药物对于母亲的重要性做出是停止哺乳还是停止药物治疗的决定。
生育力最大剂量180mg/kg（根据健康志愿受试者中的稳态血浆浓度，暴露水平为300mg，每日2次给药方案的3.4倍）或45mg/kg（暴露水平为300mg，每日2次给药方案的2.6倍）的泊沙康唑分别对于雄性大鼠或雌性大鼠的生育力不存在任何影响。
尚没有评估泊沙康唑对人类生育力的影响的临床经验。
【儿童用药】在13～17岁年龄组中证实了泊沙康唑口服混悬液以及泊沙康唑肠溶片的安全性和有效性。
充分并且良好对照的成人研究为泊沙康唑在这些人群中的使用提供了佐证。
尚未确定泊沙康唑在13岁以下（从出生至12岁）儿童患者中的安全性和有效性。
共有12名13至17岁的患者接受泊沙康唑口服混悬液每日600mg（200mg，每日三次）剂量，以预防侵袭性真菌感染。
这些小于18岁的患者中的安全性与成人相似。
根据10名儿童患者中的药代动力学数据，这些患者和成人（≥ 18岁）中的稳态泊沙康唑浓度（Cavg）平均值相似。
泊沙康唑预防和治疗侵袭性真菌病
47(1-2): p. 40-6.
毛霉菌感染
• 毛霉菌分布极为广泛，土壤、空气、食物中均较常见。 毛霉菌易感者主要是白血病及恶性肿瘤化疗所致中性粒 细胞减少的患者。
• 美国一项人群监测项目报告在1992年至1993年间毛霉菌 的发病率为1.7/100万人 [1] 。
• 欧洲的2004年SEIFEM数据调查表明毛霉病病死率在血液 肿瘤病人中接近65% [2]。
细胞色素P450同工酶的抑制剂或诱导剂 --- 三唑类之间存在很大差异
泊沙康唑仅仅作为CYP3A4的抑制剂与P450酶系统存在相互作用
Dodds Ashley ES, CID 2006; 43: S28-39
泊沙康唑： 可能的药物相互作用
• 泊沙康唑主要以原型形式排泄
• 仅抑制CYP3A4，不抑制其他的同工酶1 • 不是CYP酶的底物，因此不会受到这些酶的诱导剂或者抑制
Time, h
3. Courtney R, Wexler D, Radwanski E, et al. Br J Clin Pharmacol.
2004;57:218–222.
26
可编辑
唑类的与细胞色素P450酶的相互作用
• 泊沙康唑不是CYP酶系统底物11 • 仅抑制CYP3A412
11. Drug interactions. Med Letter. 2003;45(W1158B):46–48. 12. Wexler D, et al. Eur J Pharm Sci. 2004;21:645-653.
泊沙康唑化学结构式
泊沙康唑化学结构式
泊沙康唑是一种广谱抗真菌药物，常用于治疗真菌感染疾病。
它的化学结构式如下：
C17H13ClN4
泊沙康唑的分子式为C17H13ClN4，它是一种白色晶体粉末，在水中溶解度较低。
泊沙康唑属于三唑类抗真菌药物，通过抑制真菌细胞壁合成的酵母菌色素14α-脱甲基酶，从而阻断真菌细胞壁酵母菌色素的合成，最终导致真菌细胞死亡。
泊沙康唑具有广谱的抗真菌活性，可以有效治疗多种真菌感染疾病，包括念珠菌属、白念珠菌属、皮肤癣菌属等引起的感染。
它可以通过口服或外用的方式使用，用于治疗口腔念珠菌感染、阴道念珠菌感染、皮肤癣等疾病。
泊沙康唑的药理作用机制是通过抑制真菌的细胞壁合成，阻断真菌的生长和繁殖。
它与真菌细胞内的酵母菌色素14α-脱甲基酶结合，干扰酵母菌色素的合成过程，导致真菌细胞壁的合成受阻，最终导致真菌细胞死亡。
泊沙康唑在临床上的应用非常广泛，它可以治疗口腔念珠菌感染、阴道念珠菌感染、皮肤癣等常见真菌感染疾病。
在使用泊沙康唑治疗真菌感染时，需要根据病情和患者的具体情况确定剂量和疗程。
泊沙康唑作为一种抗真菌药物，虽然效果显著，但也有一定的不良反应。
常见的不良反应包括恶心、呕吐、腹泻、头痛等。
在使用泊沙康唑治疗时，应遵医嘱，注意药物的正确使用和剂量控制，以减少不良反应的发生。
总的来说，泊沙康唑是一种广谱抗真菌药物，可以有效治疗多种真菌感染疾病。
它通过抑制真菌细胞壁合成的酵母菌色素14α-脱甲基酶，从而阻断真菌细胞壁酵母菌色素的合成，最终导致真菌细胞死亡。
在使用泊沙康唑治疗真菌感染时，需要根据病情和患者的具体情况确定剂量和疗程，并注意药物的不良反应。
泊沙康唑国内外临床研究介绍PPT课件
氟康唑 或伊曲康唑 (n = 298)
随机化疗后100天
主要终点时段 次要终点时段
主要终点时段：随机从每个化疗期开始直至粒缺恢复或发生突破性真菌感染。如随机至84天 则可停止给药。
次要终点时段：随机化后的100天和疗程结束后的30天
Cornely OA et al. N Engl J Med. 2007;356:348-359.
Slide 14
实验设计
N = 600
Posaconazole (n = 301)
首剂
末剂
末剂 +7天
第112天
第112天 +2月
(n = 299) Fluconazole
次要终点时间
主要终点时间
随访
固定治疗期 （固定时期）：112天（主要终点时间）。 暴露期 （治疗期）： 首剂至末剂后7天（次要终点时间）。
随机化后100d突破性感染/死亡的发生率泊沙康唑 优于标准唑类
7
Cornely OA et al. N Engl J Med. 2007;356:348-359.
治疗期失败率泊沙康唑低于标准唑类
*治疗期被定义为随机化开始至最后一个化疗疗程结束用药的第7d. 病人被确定为预防失败可能是基于不止一个原因。临床失败包括那些被随机分入各组，但是没有进行 治疗的患者 (泊沙康唑组, 7 [2%]; 标准唑类组, 6 [2%]).
主要功效 终点指标
固定治疗期（随机化开始至第112d）突破性感染（确诊/临床诊断） 发生率
次要功效 终点指标
在暴露期（首剂至末剂后7d），确诊或临床诊断突破侵袭性真菌感 染的发病率；在固定治疗期和暴露期，由曲霉菌引起的侵袭性真菌 感染的发病率；全因死亡率；从首剂至侵袭性真菌感染的时间
泊沙康唑原料药的质量标准
泊沙康唑原料药的质量标准
泊沙康唑（C22H17ClN2O2S）是一种抗真菌药物，其质量标准包括以下几个方面：
1. 外观：泊沙康唑应为白色或类白色结晶性粉末。
2. 含量：泊沙康唑原料药的含量应在98.0%至101.0%之间。
3. 溶解度：泊沙康唑在甲醇中的溶解度应在≥10mg/mL。
4. 比旋光度：泊沙康唑的比旋光度应在-0.10°至+0.10°之间。
5. 水分：泊沙康唑原料药的水分含量应在≤0.5%。
6. 残留溶剂：泊沙康唑原料药中的有机溶剂残留量应符合国家相关规定。
7. 杂质：泊沙康唑原料药中的有机杂质和重金属杂质的含量应符合国家相关规定。
这些质量标准是为了确保泊沙康唑原料药的纯度、稳定性和安全性，以保证其在药物制剂中的质量。
具体的标准可能会因不同国家、地区或药品监管机构的要求而略有差异。
泊沙康唑使用指南
泊沙康唑使用指南
药物说明
泊沙康唑是一种治疗真菌感染的药物。
它能抑制真菌细胞膜的生长，达到抑制菌丝伸长和繁殖的效果，从而抑制真菌的增殖。
使用方法
泊沙康唑的使用方法如下：
1. 用药前请确保患处已经干燥。
2. 取适量泊沙康唑药膏涂于患处。
3. 患处每日使用2-3次，每次使用间隔至少6个小时。
4. 使用药物的时间视确诊的真菌感染病情决定，一般建议至少使用2-4周。
使用注意事项
使用泊沙康唑的过程中需要注意以下事项：
1. 切勿将药物接触到眼睛或口腔黏膜。
2. 请勿使用泊沙康唑治疗其他皮肤病。
3. 患者在使用泊沙康唑过程中注意个人卫生，不易交叉感染。
不良反应
尽管泊沙康唑是一种常用的治疗真菌感染的药物，但是在使用过程中仍然可能引起不良反应，如瘙痒，烧灼感，红斑等皮肤过敏症状。
如果您使用泊沙康唑期间出现不适症状，请及时停药并咨询医师。
总结
泊沙康唑是一种治疗真菌感染的药物，在使用泊沙康唑药物的过程中需要注意使用方法和注意事项，以避免不必要的不良反应，同时也能更好地发挥泊沙康唑的疗效。
泊沙康唑(posaconazole)
泊沙康唑(posaconazole)
刘晓平;胡春
【期刊名称】《中国药物化学杂志》
【年(卷),期】2007(17)4
【总页数】2页(P266-267)
【关键词】泊沙康唑;Plough公司;三唑类抗真菌药;FDA批准;曲霉菌病;真菌感染;药物耐药;镰刀菌病
【作者】刘晓平;胡春
【作者单位】沈阳药科大学
【正文语种】中文
【中图分类】R519
【相关文献】
1.三唑类广谱抗真菌新药——泊沙康唑 [J], 江丽;马道铭;刘维达
2.三唑类抗真菌新药泊沙康唑和伏立康唑简介 [J], 刘洁;胡小平;刘伟
3.三唑类抗真菌药物泊沙康唑注射液无菌检查方法研究 [J], 陈青连;姚振;万超
4.FDA批准抗真菌新药泊沙康唑（posaconazole） [J],
因版权原因，仅展示原文概要，查看原文内容请购买。
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使用前请充分振摇本品。
建议在每次给药后和储存前用水清洗量匙。
必须在进餐期间服用本品，或者对于无法进餐的患者，可以伴随营养液或碳酸饮料（如：姜汁汽水）服用本品。
为了增加泊沙康唑的口服吸收并且优化血浆浓度：1.必须在进餐期间或进餐后立即（20分钟内）服用本品。
对于无法进餐的患者，可以伴随营养液或碳酸饮料（如：姜汁汽水）服用本品。
而对于无法进餐或不能耐受口服营养液或碳酸饮料的患者，考虑采用其他抗真菌治疗或对患者出现的突破性真菌感染进行密切监测。
2.在出现重度腹泻或呕吐的患者中，必须对突破性真菌感染进行密切监测。
3.通常应避免可导致泊沙康唑血浆浓度降低的联合用药，除非获益超过风险。
如果需要使用这类药物，必须对患者出现的突破性真菌感染进行密切监测。
3.肾功能不全单次服用400 mg口服混悬液后，轻度（CLcr：50 ～80 ml/min/1.73m2，n = 6）和中度（CLcr：20～49 ml/min/1.73m2，n = 6）肾功能不全对于泊沙康唑的药代动力学不存在显著的影响，因此，在轻度至中度肾功能受损患者中，不需要进行剂量调整。
在重度肾功能不全患者（CLcr：< 20 ml/min/1.73m2）中，平均血浆暴露水平（AUC）与肾功能正常的患者（CLcr：> 80ml/min/1.73m2）相似；然而与其它肾功能受损组（变异系数< 40％）相比，重度肾功能不全患者中，AUC估计值范围存在较高的变异性（变异系数= 96％）。
由于暴露水平存在变异性，必须对重度肾功能受损患者出现的突破性真菌感染进行密切监测。
4.肝功能不全在轻度（Child-Pugh A级，N = 6）、中度（Child-Pugh B级，N = 6）和重度（Child-Pugh C 级，N = 6）肝功能不全患者中，单次口服泊沙康唑400 mg后，平均AUC与肝功能正常的受试者（N = 18）相比分别升高43%、27%和21%。
与肝功能正常的受试者相比，在轻度、中度和重度肝功能不全患者中，平均C max分别升高1%、升高40%和降低34%。
与肝功能正常的受试者相比，在轻度、中度和重度肝功能不全患者中，平均表观口服清除率（CL/F）分别下降18%、36%和28%。
在肝功能正常的受试者以及轻度、中度和重度肝功能不全患者中，消除半衰期（t1/2）分别为27小时、39小时、27小时和43小时。
在轻度至重度肝功能不全（Child-Pugh A、B和C级）患者中，不建议对本品进行剂量调整【见注意事项】。
5.性别在男性和女性中，泊沙康唑的药代动力学相似。
不需要根据性别对本品进行剂量调整。
6.人种泊沙康唑的药代动力学性质不受人种的显著影响。
不需要根据人种对本品进行剂量调整。
不良反应:1.严重不良反应和其他重要不良反应下列严重不良反应和其他重要不良反应在本说明书的其他章节进行详细讨论：1.过敏反应。
2.心律失常和QT间期延长。
3.肝毒性。
2.临床试验经验因为临床试验在各种不同条件下开展，不能将本品临床试验中的不良反应率与其他药物临床试验的结果进行直接比较，并且不能代表临床实践中的实际发生率。
在临床试验的1844名患者中对泊沙康唑治疗的安全性进行了评估。
其中包括参加活性对照预防研究的605名患者、参加活性对照口咽念珠菌病研究的557名患者、参加难治性口咽念珠菌病研究的239名患者，以及参加其他适应症研究的443名患者。
这反映了不同的人群，包括免疫功能受损患者，如恶性血液病、化疗后中性粒细胞减少、造血干细胞移植后移植物抗宿主反应和HIV感染，以及非中性粒细胞减少患者。
该患者人群中71%为男性，平均年龄为42岁（范围为8～84岁，56%的患者≥ 65岁，1%的患者< 18岁），64%为白人，16%为西班牙裔，36%非白人人种（包括14%的黑人）。
171名患者接受了≥ 6个月的泊沙康唑治疗，其中58名患者接受了≥ 12个月的泊沙康唑治疗。
表2显示了泊沙康唑预防研究中发生率大于10％的治疗中出现的不良反应。
表3显示了口咽念珠菌病（OPC）/难治性口咽念珠菌病（rOPC）研究中发生率至少为10％的治疗中出现的不良反应。
曲霉菌和念珠菌的预防：在2项随机、比较性预防研究中，在重度免疫功能受损患者中，将泊沙康唑200 mg，每日3次方案与氟康唑400 mg，每日1次或伊曲康唑200 mg，每日2次方案的安全性进行了比较。
预防临床研究中最频繁报告的不良反应（> 30%）包括发热、腹泻和恶心。
预防临床研究中最常导致停止泊沙康唑治疗的不良反应与胃肠病症相关，具体而言包括恶心（2%）、呕吐（2%）和肝酶水平升高（2%）。
表2：研究1和研究2。
报告治疗中出现的不良反应的随机化受试者数量（%）：泊沙康唑或氟康唑治疗组之发生频率至少为10%（汇总预防安全性分析）发生口咽念珠菌病的HIV感染受试者：在2项关于口咽念珠菌病的随机、对照研究中，对557名HIV感染患者接受泊沙康唑≤ 400 mg，每日1次的安全性与262名HIV感染患者接受氟康唑100 mg，每日1次的安全性进行了比较。
另有239名出现难治性口咽念珠菌病的HIV感染患者在2项关于难治性口咽念珠菌病（rOPC）的非比较性临床试验中接受了泊沙康唑治疗。
在这些受试者中，149名接受每日800 mg剂量治疗，其余受试者接受剂量≤ 400 mg，每日1次治疗。
在OPC/rOPC研究中，最常见的不良反应包括发热、腹泻、恶心、头痛和呕吐。
在对照OPC汇总研究中，最常导致停止泊沙康唑治疗的不良反应包括呼吸功能不全（1%）和肺炎（1%）。
在难治性OPC汇总研究中，最常导致停止泊沙康唑治疗的不良反应包括AIDS（7%）和呼吸功能不全（3%）。
表3：OPC研究中发生频率至少为10%的治疗中出现的不良反应（治疗人群）较不常见的不良反应：▪血液和淋巴系统：溶血性尿毒性综合征、血栓形成性血小板减少性紫癜、中性白细胞减少加重。
▪内分泌系统：肾上腺功能不全。
▪神经系统：感觉异常。
▪免疫系统：过敏反应。
▪心脏：尖端扭转型室性心动过速。
▪血管：肺栓塞。
▪肝胆系统：胆红素血症、肝酶水平升高、肝功能异常、肝炎肝肿大、黄疸、SGOT水平升高、SGPT水平升高。
▪代谢和营养：低钾血症。
▪血小板、出血和凝血：血小板减少症。
▪肾脏和泌尿系统：急性肾衰竭。
临床实验室检查值：在健康志愿者和患者中，肝功能检查参数值升高与泊沙康唑血浆浓度升高无关。
大多数肝功能检查异常结果为轻微、一过性并且不会导致停止治疗。
在预防研究中，肝功能检查结果从基线期的通用毒性标准（CTC）0、1或2度变为研究期间的3或4度的患者人数可参见表4。
表4：研究1和研究2，肝功能检查结果从基线期的CTC 0、1或2度变为3或4度在研究期的任何时间出现临床显著的肝功能检查（LFT）异常的口咽念珠菌病患者人数可参见表5（部分患者在开始研究药物治疗前已出现肝功能检查异常）。
表5：临床显著的实验室检查异常，不考虑基线值3.上市后经验本品上市后没有发现在临床试验期间未被披露的具有临床意义的不良反应。
禁忌:1.过敏反应对泊沙康唑、本品的任何成分或其他唑类抗真菌药过敏者禁用本品。
2.与西罗莫司联用禁止本品与西罗莫司联合使用。
本品与西罗莫司联合用药可导致西罗莫司血液浓度约升高9倍，从而会导致西罗莫司中毒。
3.与CYP3A4底物联合用药可导致QT间期延长禁止本品与CYP3A4底物联合使用，因为联合使用会导致QT间期延长。
本品与CYP3A4底物匹莫齐特和奎尼丁联合用药可导致上述药品的血浆浓度升高，从而导致QTc间期延长和罕见的尖端扭转型室性心动过速。
4.主要通过CYP3A4代谢的HMG-CoA还原酶抑制剂禁止本品与主要通过CYP3A4代谢的HMG-CoA还原酶抑制剂联合使用，例如：阿托伐他汀、洛伐他汀和辛伐他汀。
由于联合使用后这些药物的血药浓度会增加，从而会导致横纹肌溶解。
5.与麦角生物碱联用禁止本品与麦角生物碱联合使用。
泊沙康唑会导致麦角生物碱（麦角胺和双氢麦角胺）血浆浓度升高，可能导致麦角中毒。
注意事项:1.与神经钙蛋白抑制剂的药物相互作用本品与环孢菌素或他克莫司联合用药可导致这些神经钙蛋白抑制剂的全血浓度谷值升高。
临床疗效研究中，对环孢菌素浓度升高患者已有肾毒性和脑白质病（包括孤立的死亡病例）报告。
在泊沙康唑治疗期间和停止治疗后应该频繁监测环孢菌素或他克莫司的全血浓度谷值，并且依据此调整环孢菌素或他克莫司的剂量。
2.心律失常和QT间期延长某些唑类药物，包括泊沙康唑在内会导致心电图QT间期延长。
另外，使用泊沙康唑的患者已有罕见的尖端扭转型室性心动过速病例报告。
健康志愿者中的多重时间匹配心电图分析结果显示QTc间期平均值没有任何升高。
在基线和稳态时，记录了接受泊沙康唑400 mg，每日2次，伴随高脂肪膳食的173名健康男性和女性志愿者（年龄为18 ～85岁）在12小时内采集的多重时间匹配心电图。
在该汇总分析中，按推荐临床剂量给药后，QTc间期（Fridericia）平均值相对于基线的变化为-5 msec。
在给予安慰剂的少数受试者（n = 16）中也发现QTc（F）间期减低（-3 msec）。
安慰剂调整后的最大QTc（F）间期平均值相对于基线的变化< 0 msec（-8 msec）。
接受泊沙康唑的健康受试者没有出现QTc（F）间期≥ 500 msec或QTc（F）间期与基线相比升高≥ 60 msec。
本品不得与属于CYP3A4底物和已知可延长QTc间期的药品联合使用。
可能发生药物性心律失常状况的患者应该慎用泊沙康唑。
在出现过心律失常状况的患者中，必须慎用本品，例如：▪先天性或获得性QTc间期延长▪窦性心动过缓▪已出现症状性心律失常▪联合使用已知可导致QTc间期延长的药品（除了在禁忌中提到的药物）。
电解质紊乱，在泊沙康唑治疗前和治疗过程中，必要时应对电解质紊乱，特别是钾离子、镁离子或钙离子水平进行监测和纠正。
泊沙康唑是CYP3A4抑制剂，在其它通过CYP3A4代谢的药品治疗期间，只能在特殊情况下使用（参见药物相互作用）。
3.肝毒性在临床试验中，出现了肝脏不良反应（例如轻度至中度丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶、总胆红素水平升高和/或临床肝炎）。
肝功能检查参数升高通常在停止治疗时可逆转，在某些情况下，在未暂停药物治疗时，这些试验结果可恢复正常，极少需要停药。
在罕见情况下，患有严重基础疾病（例如血液系统恶性肿瘤）的患者在泊沙康唑治疗期间出现更重度的肝脏不良反应，包括胆汁淤积或肝功能衰竭，甚至死亡。
这些重度肝脏不良反应主要见于一项临床试验中接受每日800 mg（400 mg，每日2次或200 mg，每日4次）治疗的受试者。