尼可地尔注射液药品说明书(英文)

Revised: March 2010 (10th version)

- DRUG FOR TREATMENT OF UNSTABLE ANGINA PECTORIS AND ACUTE HEART FAILURE -

SIGMART?Injection 2 mg

SIGMART?Injection 12 mg

SIGMART?Injection 48 mg

INDICATIONS

Unstable angina pectoris

Acute heart failure (including acute decompensation of chronic heart failure)

DOSAGE AND ADMINISTRATION

Unstable angina pectoris

SIGMART is dissolved in isotonic sodium chloride solution or 5% glucose injection to prepare a 0.01%-0.03% solution. The usual adult dosage for intravenous drip infusion is 2 mg of nicorandil per hour. The dosage may be adjusted according to symptoms, while not exceeding 6 mg per hour. Acute heart failure (including acute decompensation of chronic heart failure)

SIGMART is dissolved in isotonic sodium chloride solution or 5% glucose injection to prepare a 0.04%-0.25% solution. The usual adult dosage is 0.2 mg/kg of nicorandil to be given by intravenous administration over about 5 minutes, followed by 0.2 mg/kg/hr of nicorandil to be given by continuous intravenous infusion. The dosage may be adjusted in the range of 0.05-0.2 mg/kg/hr according to changes in blood pressure and symptoms.

PRECAUTIONS

1. Careful Administration (SIGMART Injection should be

administered with care in the following patients.)

(1) Elderly (see 4, "Use in the Elderly".)

(2) Patients with hypotension (Since SIGMART lowers

blood pressure, this symptom may be exacerbated.)

(3) Patients with hepatic or renal dysfunction (Since

metabolic and excretory functions are impaired, the

blood concentration of SIGMART may become high).

(4) Patients with left ventricular outflow stenosis,

hypertrophic obstructive cardiomyopathy, or aortic

stenosis due to acute heart failure (Difference in

pressure may be increased and lead to aggravation of

symptoms.)

2. Important Precautions

(1) While SIGMART is being administered, blood pressure

and hemodynamics should be monitored frequently.

Dosage should be adjusted gradually according to

patient's hemodynamics and symptoms.

(2) When abnormalities such as hypotension are observed

while SIGMART is being administered or when

patients may suffer from hypotension, dosage should be

reduced or administration discontinued. If necessary,

appropriate measures such as elevation of lower

extremities or administration of vasopressors

(catecholamine preparations) should be taken.

(3) Since coadministration with drugs with

PDE5-inhibiting effect(sildenafil citrate, vardenafil

hydrochloride hydrate, or tadalafil) may enhance the

hypotensive effect of SIGMART and excessively

decrease blood pressure, confirmation should be made

before administering SIGMART that these drugs are

not being used. Moreover, the patient should be

cautioned against using these drugs during or after

taking SIGMART.

(4) When used in patients with acute heart failure,

SIGMART should be administered with sufficient

management of the patient’s general condition

including blood pressure, heart rate, urinary output,

body fluids and electrolytes, as well as pulmonary

arterial wedge pressure, cardiac output and blood gases

if possible.

(5) When used in patients with acute heart failure,

SIGMART may cause a serious decrease in blood

pressure. Therefore, blood pressure should be

frequently measured during treatment with SIGMART.

If any abnormality is observed, treatment should be

discontinued and appropriate measures taken.

(6) If expected improvement is not achieved following

treatment with SIGMART in patients with acute heart

failure, appropriate measures such as change of

treatment to another should be taken.

(7) In patients with acute heart failure, if hemodynamics

and clinical symptoms improve and the patient’s

condition becomes stabilized (recover from the acute

stage) following treatment with SIGMART, treatment

should be switched to another. SIGMART has rarely

been used for more than 48 hours in patients with acute

heart failure. Therefore, if it is necessary to use

SIGMART for more than 48 hours, the drug should be

administered with sufficient management of the

patient’s blood circulation and general condition.

3. Drug Interactions

Contraindications for coadministration (SIGMART

4. Adverse Reactions

Unstable angina pectoris

The following adverse reactions to this drug were reported in 227 patients (6.64%) and 301 events of 3,420 patients analyzable for safety. The major adverse reactions were headache (53 events, 1.55%), hepatic function disorder (37 events, 1.08%), increased ALT (GPT) (29 events, 0.85%), decreased blood pressure (24 events, 0.70%), increased AST (GOT) (19 events, 0.56%), increased Al-P (15 events,

0.44%), thrombocytopenia (15 events, 0.44%), increased total bilirubin (13 events, 0.38%), increased LDH (9 events, 0.26%), anemia (9 events, 0.26%), and increased γ-GTP (8 events, 0.23%) (at the end of the reexamination period). Acute heart failure (including acute decompensation of chronic heart failure)

The following adverse reactions to this drug were reported in 50 of 193 patients (25.9%, 79 events), who were the subjects of safety analysis. The main adverse reactions were throm-bocytopenia (11 events, 5.7%), headache (10 events, 5.2%), decreased blood pressure (7 events, 3.6%), increased total bilirubin (7 events, 3.6%), decreased serum total protein (5 events, 2.6%), increased AST (GOT) (3 events, 1.6%), increased ALT (GPT) (3 events, 1.6%), increased blood creatinine (3 events, 1.6%), leucocytosis (3 events, 1.6%), urinary protein positive (3 events, 1.6%), increased LDH (2 events, 1.0%), increased CK (CPK) (2 events, 1.0%), ventricular tachycardia (2 events, 1.0%), increased blood potassium (2 events, 1.0%) and decreased HDL cholesterol (2 events, 1.0%) (at the time of approval).

(1) Clinically Significant Adverse Reactions

1) Hepatic dysfunction and jaundice (incidence unknown):

Jaundice may develop. Hepatic dysfunction, with in-

creased AST (GOT), ALT (GPT) and γ-GTP may occur.

Patients should be carefully monitored, and administra-

tion of the drug should be discontinued and appropriate

therapeutic measures taken, if such

abnormalities are observed.

2) Thrombocytopenia (incidence unknown): Thrombocy-

topenia may occur. If any abnormalities are observed,

the drug should be discontinued immediately and ap-

propriate therapeutic measures must be taken.

(2) Other adverse reactions

If any of the following adverse reactions are observed,

appropriate measures such as dosage reduction or

Note 4)In the event of such symptom, administration should be discontinued.

5. Use in the Elderly

Since the elderly often have reduced physiological function and are more likely to experience adverse reactions,

SIGMART should be administered while closely and

frequently monitoring blood pressure and hemodynamics.

The dosage should be carefully and gradually adjusted in

view of the patient’s hemodynamics and symptoms. (See

"Important Precautions".)

In particular, caution should be taken for decrease in blood pressure, which is apt to occur in elderly patients with acute heart failure.

6. Use during Pregnancy, Delivery or Lactation

Since the safety of SIGMART in pregnant women has not been established, use of SIGMART in pregnant women or women who may possibly be pregnant is not recommended.

7. Pediatric Use

The safety of SIGMART in children has not been

established (no clinical experience).

8. Precautions concerning Use

Preparation method

SIGMART should be dissolved in physiological saline or 5% glucose solution for injection and used within 24 hours of preparation.

PHARMACOKINETICS

1. Blood concentration

(1) Single administration1)

To five healthy volunteers, 2 mg of SIGMART Injection

was administered once over a two minute period Note 5).

administration

Note 5) This is different from the approved dosage and

administration of SIGMART. (See "DOSAGE AND ADMINISTRATION”.)

(2) Continuous administration 2), 3)

To five healthy volunteers, SIGMART Injection was intravenously administered for six hours continuously Note 6)

6h completion of continuous intravenous administration

(3) Long-term administration (in patients with acute heart

failure) 4)

SIGMART Injection was intravenously administered to 14 patients with acute heart failure at a dose of 0.2 mg/kg for 5 minutes, and then at a rate of 0.2 mg/kg/hr for 48 hours continuously. The time course of plasma nicorandil concentration is shown below.

Time after the start of administration (hr)

Time course of plasma nicorandil concentration in patients with acute heart failure (mean±SE)

2. Metabolism and excretion 3), 5)

The metabolism and excretion of SIGMART were

investigated by intravenously administering 2, 4 or 6 mg/hr of SIGMART Injection (as nicorandil) to five healthy men Note 6)

and 6 mg/hr of nicorandil labelled with deuterium to four healthy men for six hours, respectively. Most nicorandil was subjected to a denitration reaction and metabolized to N-(2-hydroxy ethyl) nicotinamide. This metabolite, N-(2-hydroxy ethyl) nicotinamide, was

detectable in the plasma 0.25-0.5 hours after the start of continuous intravenous administration, and reached a

plateau 3 to 9 hours after administration. The cumulative urinary excretion of nicorandil and the metabolite [N-(2-hydroxy ethyl) nicotinamide] 24 hours after administration was 0.2% to 0.4% and 2% to 5%, respectively.

Note 6) This is different from the approved dosage and

administration of SIGMART for acute heart failure (including acute decompensation of chronic heart failure).(See "DOSAGE AND ADMINISTRATION".)

3. Serum protein binding rate 6)

In an in vitro test using human serum, the serum protein binding rate ranged from 34.2% to 41.5% (nicorandil concentration: 1-100 μg/mL)

CLINICAL STUDIES

1. The usefulness of SIGMART Injection was confirmed by a double-blind comparative study on patients with unstable

angina pectoris 7)

.

2. In clinical studies including double-blind study on patients with unstable angina pectoris, overall improvement rates ranged from 68.4% to 75.0%7, 8) in a total of 134 assessable patients.

3. In clinical studies including a double-blind study of patients with acute heart failure (including acute decompensation of chronic heart failure, with a pulmonary arterial wedge pressure of 18 mmHg or more), SIGMART Injection was intravenously administered to 54 patients at a dose of 0.2 mg/kg for 5 minutes, and then at a rate of 0.2 mg/kg/hr continuously. As a result, their pulmonary arterial wedge pressure decreased by 21.2%9-11).

PHARMACOLOGY

1. Pharmacological action

(1) Coronary vasodilating activity

1) In a canine Langendorff preparation, nicorandil dilated relatively small coronary arteries under normal-pressure perfusion, whereas under

low-pressure perfusion during ischemia, it dilated large coronary arteries. In unanesthetized dogs, intravenous administration of nicorandil dilated large coronary arteries in a dose-dependent manner irrespective of coronary blood flow 12, 13). 2) When SIGMART Injection (2 mg to 6 mg or 0.05-0.1 mg/kg of nicorandil) was administered intravenously once to patients with coronary artery disease Note 7), coronary angiography showed

020040060080010001200140016000

12

24

36

48

Time after the start of administration (hr)

Time course of plasma nicorandil concentration (mean±SE)

Continuous i.v. administration

P l a s m a c o n c e n t r a t i o n (n g /m L )

P l a s m a c o n c e n t r a t i o n (n g /m L )

significant coronary vasodilation in a dose-dependent

manner. The rate of dilation (in relation to the

internal diameter of non-stenotic vessels) ranged from

108% to 127%14-16).

(2) Effects on coronary blood flow

1) Nicorandil produced a dose-dependent, sustained

increase in coronary blood flow following intravenous

or intraduodenal administration in open-chested

anesthetized dogs. The same responses were shown

in conscious dogs, isolated canine heart-lung

preparations, and canine Langendorff's

preparations13,17-20).

2) SIGMART Injection (0.1 mg/kg of nicorandil) was

administered intravenously once Note 7) to patients with

angina pectoris having no significant stenosis or an

organic stenosis of 75% or greater in the left coronary

artery and to people with no significant stenosis.

The great cardiac vein flow was then measured three

to five minutes after administration (continuous

thermal dilution method). In the non-stenosis group

(n=5), the average volume increased from 115 to 187

mL/min., and in the stenosis group (n=4), it increased

from 38 to 69 mL/min., thus confirming significant

increases in coronary blood flow16).

(3) Coronary vasospasmolytic activity

1) In dogs with partially constricted coronary arteries,

nicorandil inhibited cyclical reductions of coronary

blood flow and ST elevations in ECG. Coronary

vasoconstriction induced by the intracoronary

injection of methacholine or norepinephrine in

miniature pigs was also suppressed by nicorandil21,22).

2) In 10 patients with coronary spastic angina pectoris,

0.1 mg/kg of nicorandil was administered

intravenously to treat coronary spasms induced by

ergonovine load test or naturally occuring coronary

spasms Note 7). The results showed that nicorandil

attenuated coronary spasms 23).

(4) Effects on cardio-hemodynamics

1) Nicorandil slightly decreased systemic blood pressure

dose-dependently when injected intravenously in

open chest dogs under general anesthesia. There

were no appreciable effects on heart rate, myocardial

contractility, myocardial oxygen consumption and

atrioventricular conduction time at doses causing a

significant decrease in coronary vascular resistance17,

18, 24)

.

2) When SIGMART Injection (2 to 6 mg or

0.05-0.1 mg/kg of nicorandil) was administered

intravenously once to patients with coronary angina

pectoris at rest Note 7), heart rate increased, and BP

dynamics index (e.g., systolic aortic pressure),

systemic vascular resistance, and pressure-rate

product decreased in a dose-dependent manner.

However, the range of these fluctuations were slight

to mild14-16). While right intraventricular pacing was

utilized, SIGMART Injection (0.05mg/kg of

nicorandil) was administered intravenously once Note

7)to eight patients with angina pectoris with 75% or

greater stenosis. In terms of left ventricular function,

nicorandil suppressed increases in the left ventricular

end-diastolic pressure and increased the cardiac

index25).

Note 7) This is different from the approved dosage

and administration of SIGMART. (See

"DOSAGE AND ADMINISTRATION”.) (5) Effects on heart failure

1) In a canine model of acute heart failure, treatment with

nicorandil decreased right atrial pressure and left

ventricular pressure in the late diastolic phase (a

decrease in the preload), with a concurrent decrease in

the total peripheral vascular resistance (a decrease in

the afterload). Consequently, by improving the left

ventricular contractility and increasing the cardiac

output, the treatment improved the hemodynamics in

heart failure26).

2) Patients with acute heart failure (including acute

decompensation of chronic heart failure) received

intravenous administration of SIGMART at a dose of

0.2 mg/kg/5 min followed by a 2-hour continuous

intravenous infusion at a rate of 0.2 mg/kg/hr. As a

result, a significant decrease was found in the

pulmonary arterial wedge pressure, diastolic pressure,

systolic pulmonary arterial pressure, diastolic

pulmonary arterial pressure, and total peripheral

vascular resistance, while a significant increase was

seen in the cardiac index, cardiac output, output per

stroke, and output index per stroke. No significant

change was found in the heart rate, systolic blood

pressure, mean right atrial pressure, or pressure-rate

Product11).

3) In patients with congestive heart failure who received

a long-term continuous intravenous infusion of

SIGMART, a decrease in the pulmonary arterial

wedge pressure was maintained, which suggested that

drug resistance would hardly occur27).

2. Vasodilating effect and its mechanism

The vasohypotonic effect of nicorandil on extracted blood vessels is suppressed by ATP-sensitive K channel inhibitors or guanylate cyclase inhibitors28). Moreover, in a canine

model of acute heart failure, the cardiac

hemodynamics-improving effect of the drug (e.g. effect of increasing the aortic blood flow) was suppressed by

ATP-sensitive K channel inhibitors29). Furthermore, the drug caused an increase in the cGMP content in extracted blood vessels30). These facts suggest that the vasodilating effect of the drug is related to the effect of opening the ATP-sensitive K channel, as well as to the effect of increasing production of cGMP.

PHYSICOCHEMISTRY

Nonproprietary name:

Nicorandil (JAN)

Chemical name:

N-[2-(Nitrooxy) ethyl] pyridine-3-carboxamide Structural formula:

Molecular formula: C 8H 9N 3O 4

Molecular weight: 211.17 Description:

Nicorandil occurs as white crystals.

It is freely soluble in methanol, ethanol (99.5), acetic acid (100); soluble in acetic anhydride; sparingly soluble in water.

Melting point:

About 92° C (to be decomposed)

PACKAGING

2 mg Injection

Boxes of 10 vials. 12 mg Injection

Boxes of 10 vials. 48 mg Injection

Boxes of 10 vials.

REFERENCES

1) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 15 (11), 4779, 1987

2) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 18 (9), 3479, 1990

3) Internal document: Azuma J. et al.: Pharmacokinetics following intravenous continuous administration of nicorandil in healthy adults (1990)

4) Internal document: Phase III study in patients with acute heart failure (long-term administration)

5) Internal document: Ishitani H. et al.: Investigation on urinary metabolites following continuous intravenous administration of nicorandil in healthy adults (1990) 6) Internal document: Ida S. et al.: in vivo and in vitro serum protein binging of nicorandil (1991)

7) Kato K. et al.: Rinsho Iyaku (J. of Clinical Ther. & Medicines), 7 (9), 2031, 1991

8) Kato K. et al.: Rinsho To Kenkyu (Jpn. J. of Clinical and Experi. Medicine), 68 (11), 3480, 1991

9) Internal document: Early phase II study in patients with acute heart failure (single + continuous administration) 10) Internal document: Late phase II study in patients with acute heart failure

11) Internal document: Phase III study in patients with acute heart failure (placebo-controlled)

12) Yamada A. et al.: Arzneim. -Forsch. (Drug Res.), 37 (11), 1252, 1987

13) Nakagawa Y. et al.: Jpn. Heart J., 20 (6), 881, 1979 14) Hata N. et al.: Myakkangaku (Vessels), 31 (4), 333, 1991

15) Gomyo Y. et al.: Therapeutic Research, 10 (4), 1615, 1989

16) Motohara S. et al.: Therapeutic Research, 10(4), 1307, 1989

17) Uchida Y. et al.: Jpn. Heart J., 19 (1), 112, 1978

18) Satoh K. et al.: Shinzo (Heart), 12 (4), 371, 1980 19) Mizukami M. et al.: Arzneim-Forsch. (Drug Res.), 31 (2), 1244, 1981

20) Sakanashi M. et al.: Oyo Yakuri (Pharmacotrics), 15 (3), 385, 1978

21) Uchida Y. et al.: Jpn. Heart J., 19 (6), 904, 1978

22) Sakai K. et al.: J. Pharmacol. Exp. Ther., 227 (1), 220, 1983

23) Matsumura Y. et al.: Therapeutic Research, 11 (5), 1448, 1990

24) Sakai K. et al.: J. Cardiovasc. Pharmacol., 3 (1), 139, 1981

25) Kambara H. et al.: Am. J. Cardiol., 63, 56J, 1989 26) Kamijo, T. et al.: J. Cardiovasc. Pharmacol., 33: 93 (1999)

27) Larsen, A. I. et al.: Am. Heart J., 134: 435 (1997) 28) Internal document: Fukazawa M. et al.:

Pharmacological study using extracted blood vessels of rats (2001)

29) Kamijo, T. et al.: Asia Pac. J. Pharmacol., 11: 141 (1996)

30) Internal document: Imagawa J. et al.: Influence on cAMP and cGMP in aortas of rats (2000)

REQUEST FOR LITERATURE SHOULD BE MADE TO:

Requests for any of the internal documents listed in the

“REFERENCES” section can also be made to the following: Drug Information Center

Chugai Pharmaceutical Co., Ltd.

1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, Japan TEL: 0120-189706 FAX: 0120-189705

http://www.chugai-pharm.co.jp

Manufactured and Distributed by:

Chugai Pharmaceutical Co., Ltd., Roche Group.

1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, Japan

BRAND NAMES IN OTHER COUNTRIES

Sigmart Injection (Korea)