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 mgSIGMART®Injection 12 mgSIGMART®Injection 48 mgINDICATIONSUnstable angina pectorisAcute heart failure (including acute decompensation of chronic heart failure)DOSAGE AND ADMINISTRATIONUnstable angina pectorisSIGMART 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.PRECAUTIONS1. Careful Administration (SIGMART Injection should beadministered with care in the following patients.)(1) Elderly (see 4, "Use in the Elderly".)(2) Patients with hypotension (Since SIGMART lowersblood pressure, this symptom may be exacerbated.)(3) Patients with hepatic or renal dysfunction (Sincemetabolic and excretory functions are impaired, theblood concentration of SIGMART may become high).(4) Patients with left ventricular outflow stenosis,hypertrophic obstructive cardiomyopathy, or aorticstenosis due to acute heart failure (Difference inpressure may be increased and lead to aggravation ofsymptoms.)2. Important Precautions(1) While SIGMART is being administered, blood pressureand hemodynamics should be monitored frequently.Dosage should be adjusted gradually according topatient's hemodynamics and symptoms.(2) When abnormalities such as hypotension are observedwhile SIGMART is being administered or whenpatients may suffer from hypotension, dosage should bereduced or administration discontinued. If necessary,appropriate measures such as elevation of lowerextremities or administration of vasopressors(catecholamine preparations) should be taken.(3) Since coadministration with drugs withPDE5-inhibiting effect(sildenafil citrate, vardenafilhydrochloride hydrate, or tadalafil) may enhance thehypotensive effect of SIGMART and excessivelydecrease blood pressure, confirmation should be madebefore administering SIGMART that these drugs arenot being used. Moreover, the patient should becautioned against using these drugs during or aftertaking SIGMART.(4) When used in patients with acute heart failure,SIGMART should be administered with sufficientmanagement of the patient’s general conditionincluding blood pressure, heart rate, urinary output,body fluids and electrolytes, as well as pulmonaryarterial wedge pressure, cardiac output and blood gasesif possible.(5) When used in patients with acute heart failure,SIGMART may cause a serious decrease in bloodpressure. Therefore, blood pressure should befrequently measured during treatment with SIGMART.If any abnormality is observed, treatment should bediscontinued and appropriate measures taken.(6) If expected improvement is not achieved followingtreatment with SIGMART in patients with acute heartfailure, appropriate measures such as change oftreatment to another should be taken.(7) In patients with acute heart failure, if hemodynamicsand clinical symptoms improve and the patient’scondition becomes stabilized (recover from the acutestage) following treatment with SIGMART, treatmentshould be switched to another. SIGMART has rarelybeen used for more than 48 hours in patients with acuteheart failure. Therefore, if it is necessary to useSIGMART for more than 48 hours, the drug should beadministered with sufficient management of thepatient’s blood circulation and general condition.3. Drug InteractionsContraindications for coadministration (SIGMART4. Adverse ReactionsUnstable angina pectorisThe 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 Reactions1) 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 appropriatetherapeutic measures taken, if suchabnormalities 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 reactionsIf any of the following adverse reactions are observed,appropriate measures such as dosage reduction orNote 4)In the event of such symptom, administration should be discontinued.5. Use in the ElderlySince the elderly often have reduced physiological function and are more likely to experience adverse reactions,SIGMART should be administered while closely andfrequently monitoring blood pressure and hemodynamics.The dosage should be carefully and gradually adjusted inview 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 LactationSince 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 UseThe safety of SIGMART in children has not beenestablished (no clinical experience).8. Precautions concerning UsePreparation methodSIGMART should be dissolved in physiological saline or 5% glucose solution for injection and used within 24 hours of preparation.PHARMACOKINETICS1. Blood concentration(1) Single administration1)To five healthy volunteers, 2 mg of SIGMART Injectionwas administered once over a two minute period Note 5).administrationNote 5) This is different from the approved dosage andadministration 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 heartfailure) 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 wereinvestigated 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, wasdetectable in the plasma 0.25-0.5 hours after the start of continuous intravenous administration, and reached aplateau 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 andadministration 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 STUDIES1. The usefulness of SIGMART Injection was confirmed by a double-blind comparative study on patients with unstableangina 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).PHARMACOLOGY1. Pharmacological action(1) Coronary vasodilating activity1) In a canine Langendorff preparation, nicorandil dilated relatively small coronary arteries under normal-pressure perfusion, whereas underlow-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 showed02004006008001000120014001600012243648Time after the start of administration (hr)Time course of plasma nicorandil concentration (mean±SE)Continuous i.v. administrationP 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-dependentmanner. The rate of dilation (in relation to theinternal diameter of non-stenotic vessels) ranged from108% to 127%14-16).(2) Effects on coronary blood flow1) Nicorandil produced a dose-dependent, sustainedincrease in coronary blood flow following intravenousor intraduodenal administration in open-chestedanesthetized dogs. The same responses were shownin conscious dogs, isolated canine heart-lungpreparations, and canine Langendorff'spreparations13,17-20).2) SIGMART Injection (0.1 mg/kg of nicorandil) wasadministered intravenously once Note 7) to patients withangina pectoris having no significant stenosis or anorganic stenosis of 75% or greater in the left coronaryartery and to people with no significant stenosis.The great cardiac vein flow was then measured threeto five minutes after administration (continuousthermal dilution method). In the non-stenosis group(n=5), the average volume increased from 115 to 187mL/min., and in the stenosis group (n=4), it increasedfrom 38 to 69 mL/min., thus confirming significantincreases in coronary blood flow16).(3) Coronary vasospasmolytic activity1) In dogs with partially constricted coronary arteries,nicorandil inhibited cyclical reductions of coronaryblood flow and ST elevations in ECG. Coronaryvasoconstriction induced by the intracoronaryinjection of methacholine or norepinephrine inminiature pigs was also suppressed by nicorandil21,22).2) In 10 patients with coronary spastic angina pectoris,0.1 mg/kg of nicorandil was administeredintravenously to treat coronary spasms induced byergonovine load test or naturally occuring coronaryspasms Note 7). The results showed that nicorandilattenuated coronary spasms 23).(4) Effects on cardio-hemodynamics1) Nicorandil slightly decreased systemic blood pressuredose-dependently when injected intravenously inopen chest dogs under general anesthesia. Therewere no appreciable effects on heart rate, myocardialcontractility, myocardial oxygen consumption andatrioventricular conduction time at doses causing asignificant decrease in coronary vascular resistance17,18, 24).2) When SIGMART Injection (2 to 6 mg or0.05-0.1 mg/kg of nicorandil) was administeredintravenously once to patients with coronary anginapectoris at rest Note 7), heart rate increased, and BPdynamics index (e.g., systolic aortic pressure),systemic vascular resistance, and pressure-rateproduct decreased in a dose-dependent manner.However, the range of these fluctuations were slightto mild14-16). While right intraventricular pacing wasutilized, SIGMART Injection (0.05mg/kg ofnicorandil) was administered intravenously once Note7)to eight patients with angina pectoris with 75% orgreater stenosis. In terms of left ventricular function,nicorandil suppressed increases in the left ventricularend-diastolic pressure and increased the cardiacindex25).Note 7) This is different from the approved dosageand administration of SIGMART. (See"DOSAGE AND ADMINISTRATION”.) (5) Effects on heart failure1) In a canine model of acute heart failure, treatment withnicorandil decreased right atrial pressure and leftventricular pressure in the late diastolic phase (adecrease in the preload), with a concurrent decrease inthe total peripheral vascular resistance (a decrease inthe afterload). Consequently, by improving the leftventricular contractility and increasing the cardiacoutput, the treatment improved the hemodynamics inheart failure26).2) Patients with acute heart failure (including acutedecompensation of chronic heart failure) receivedintravenous administration of SIGMART at a dose of0.2 mg/kg/5 min followed by a 2-hour continuousintravenous infusion at a rate of 0.2 mg/kg/hr. As aresult, a significant decrease was found in thepulmonary arterial wedge pressure, diastolic pressure,systolic pulmonary arterial pressure, diastolicpulmonary arterial pressure, and total peripheralvascular resistance, while a significant increase wasseen in the cardiac index, cardiac output, output perstroke, and output index per stroke. No significantchange was found in the heart rate, systolic bloodpressure, mean right atrial pressure, or pressure-rateProduct11).3) In patients with congestive heart failure who receiveda long-term continuous intravenous infusion ofSIGMART, a decrease in the pulmonary arterialwedge pressure was maintained, which suggested thatdrug resistance would hardly occur27).2. Vasodilating effect and its mechanismThe vasohypotonic effect of nicorandil on extracted blood vessels is suppressed by ATP-sensitive K channel inhibitors or guanylate cyclase inhibitors28). Moreover, in a caninemodel of acute heart failure, the cardiachemodynamics-improving effect of the drug (e.g. effect of increasing the aortic blood flow) was suppressed byATP-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.PHYSICOCHEMISTRYNonproprietary name:Nicorandil (JAN)Chemical name:N-[2-(Nitrooxy) ethyl] pyridine-3-carboxamide Structural formula:Molecular formula: C 8H 9N 3O 4Molecular 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)PACKAGING2 mg InjectionBoxes of 10 vials. 12 mg InjectionBoxes of 10 vials. 48 mg InjectionBoxes of 10 vials.REFERENCES1) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 15 (11), 4779, 19872) Azuma J. et. al.: Yakuri To Chiryo (Jpn. Pharmacol. & Ther.), 18 (9), 3479, 19903) 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, 19918) Kato K. et al.: Rinsho To Kenkyu (Jpn. J. of Clinical and Experi. Medicine), 68 (11), 3480, 19919) 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 failure11) 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, 198713) Nakagawa Y. et al.: Jpn. Heart J., 20 (6), 881, 1979 14) Hata N. et al.: Myakkangaku (Vessels), 31 (4), 333, 199115) Gomyo Y. et al.: Therapeutic Research, 10 (4), 1615, 198916) Motohara S. et al.: Therapeutic Research, 10(4), 1307, 198917) Uchida Y. et al.: Jpn. Heart J., 19 (1), 112, 197818) Satoh K. et al.: Shinzo (Heart), 12 (4), 371, 1980 19) Mizukami M. et al.: Arzneim-Forsch. (Drug Res.), 31 (2), 1244, 198120) Sakanashi M. et al.: Oyo Yakuri (Pharmacotrics), 15 (3), 385, 197821) Uchida Y. et al.: Jpn. Heart J., 19 (6), 904, 197822) Sakai K. et al.: J. Pharmacol. Exp. Ther., 227 (1), 220, 198323) Matsumura Y. et al.: Therapeutic Research, 11 (5), 1448, 199024) Sakai K. et al.: J. Cardiovasc. Pharmacol., 3 (1), 139, 198125) 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 CenterChugai Pharmaceutical Co., Ltd.1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, Japan TEL: 0120-189706 FAX: 0120-189705http://www.chugai-pharm.co.jpManufactured and Distributed by:Chugai Pharmaceutical Co., Ltd., Roche Group.1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8324, JapanBRAND NAMES IN OTHER COUNTRIESSigmart Injection (Korea)。