OE/04

Transcription

1 Adalat Capsules Nifedipine 狀 療 / 降 主 成 分 nifedipine 10 (mg ) 特 性 Nifedipine 1,4-dihydropyridine 類 離 類 離 離 離 (slow calcium channel) nifedipine 狀 滑 nifedipine 狀 nifedipine 降 狀 滑 力 塞 (poststenotic) 流 量 nifedipine 降 力 nifedipine 狀 狀 Nifedipine 降 滑 力 力 降 降 nifedipine 療 量 不 不 量 不 論 nifedipine 都 Nifedipine 降 Nifedipine 雷 諾 適 應 症 用 量 與 用 法 本 藥 須 由 醫 師 處 方 使 用 量 ( 量 ) 療 度 臨 量 量 降 nifedipine 度 療 量 nifedipine 療 5 來 量 量 : 1. 療 狀 ( ) (3 10 mg/day) 5 療 量 不 60mg ( 異 Prinzmetal s angina) (3 10 mg/day) 5 療 量 不 60mg 2. 療 (3 10 mg/day) 5 療 量 不 60mg 3. 療 狀 量 (1 10mg) 5 ( ) -1-

2 量 (1 10mg) ( ) : 量 (1 10mg) : 量 (1 10mg) nifedipine nitroglycerine clonidine dihydralazine 療 sodium nitroprusside 療 nifedipine 10mg(Adalat ) 量 4. 療 雷 諾 (3 10 mg/day) 5 療 量 不 60mg 療 參 療 nifedipine 降 量 量 量 不 降 ( Adalat Capsules)20mg 量 禁 忌 nifedipine 不 不 nifedipine 不 Nifedipine 不 rifampicin nifedipine 度 Nifedipine 不 不 塞 警 語 及 注 意 事 項 ( 90 mmhg) 例 Nifedipine 療 降 Nifedipine 療 數 塞 60mg nifedipine 量 療 率 罹 率 Nifedipine 塞 復 nifedipine 硫 量 車 力 車 力 異 療 精 易 與 其 他 藥 物 和 其 他 形 式 的 交 互 作 用 Nifedipine 降 降 Nifedipine β-receptor blockers 惡 -2-

3 Nifedipine cytochrome P450 3A4 都 nifedipine (first pass effect) nifedipine digoxin digoxin digoxin 度 digoxin 量 digoxin 度 來 glycoside 量 Phenytoin cytochrome P450 3A4 phenytoin nifedipine 率 降 療 兩 nifedipine 臨 nifedipine 量 兩 nifedipine 量 phenytoin 療 nifedipine 量 Quinidine nifedipine quinidine quinidine 度 降 nifedipine quinidine 度 不 論 nifedipine 都 quinidine 度 quinidine 量 兩 nifedipine 度 nifedipine 力 quinidine nifedipine 療 nifedipine 量 Quinupristin/Dalfopristin quinupristin/dalfopristin nifedipine nifedipine 度 降 nifedipine 量 Cimetidine cytochrome P450 3A4 nifedipine 度 降 Rifampicin 烈 cytochrome P450 3A4 rifampicin 降 nifedipine 率 兩 Diltiazem nifedipine 兩 nifedipine 量 cytochrome P450 3A4 降 nifedipine (First pass metabolism) nifedipine 度 降 若 < > Cisapride : cisapride nifedipine nifedipine 度 降 nifedipine 量 理 論 Erythromycin nifedipine erythromycin erythromycin cytochrome P450 3A4 erythromycin nifedipine 不 nifedipine 度 Fluoxetine 臨 nifedipine Fluoxetine Fluoxetine cytochrome P450 3A4 nifedipine 兩 不 nifedipine 度 Fluoxetine nifedipine nifedipine 量 Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir 臨 nifedipine amprenavir indinavir nelfinavir ritonavir saquinavir 類 cytochrome P450 3A4 料 amprenavir indinavir nelfinavir ritonavir saquinavir cytochrome P450 3A4 nifedipine nifedipine 不 nifedipine 度 nifedipine 量 Ketoconazole Itraconazole Fluconazole nifedipine ketoconazole itraconazole fluconazole 類 cytochrome P450 3A4 nifedipine 不 nifedipine 率 nifedipine 量 Nefazodone 臨 nifedipine nefazodone Nefazodone cytochrome P450 3A4 兩 不 nifedipine 度 nefazodone nifedipine nifedipine 量 Tacrolimus cytochrome P450 3A4 料 nifedipine tacrolimus 降 tacrolimus 量 tacrolimus 度 tacrolimus 量 -3-

4 Carbamazepine carbamazepine nifedipine carbamazepine 降 類 離 nimodipine 度 不 carbamazepine 降 nifedipine 度 降 不 Phenobarbitone phenobarbitone nifedipine phenobarbitone 降 類 離 nimodipine 度 不 phenobarbitone 降 nifedipine 度 降 不 Valproic acid : valproic acid nifedipine valproic acid 類 離 nimodipine 度 不 valproic acid nifedipine 度 降 不 Nifedipine 列 Nifedipine 力 Ajmalin Benazepril Debrisoquine Doxazosin Irbesartan Omeprazole Orlistat Pantoprazole Ranitidine Rosiglitazone Talinolol Triamterene Hydrochlorothiazide nifedipine Candesartan Cilexetil 力 Aspirin nifedipine aspirin 100 mg nifedipine 力 不 aspirin 100 mg Nifedipine 度 尿 HPLC 不 孕 婦 和 哺 乳 婦 女 的 使 用 nifedipine nifedipine 老 異 異 流 Nifedipine 不 ( ) 不 ( ) ( ) / ( ) 量 量 類 量 離 nifedipine 精 精 精 理 離 nifedipine 女 Nifedipine 泌 不 nifedipine 不 不 良 反 應 臨 CIOMS III 類 率 COSTART 狀 列 見 (n= 年 1 31 ) 率 1% 10% 神 暈 率 0.1% 1% 力 不 便 不 良 不 神 易 怒 神 暈 -4-

5 異 異 率 0.01% 0.1% 暈 糖 神 不 泌 尿 尿 CIOMS III 類 率 COSTART HARTS 狀 列 (n 1329 例 2000 年 1 31 ) 率 0.01% Q-T 異 淋 粒 糖 落 女 過 量 狀 列 nifedipine 狀 識 不 狀 降 律 糖 理 nifedipine 復 狀 Adalat nifedipine nifedipine nifedipine 不 不 nifedipine 離 ( nifedipine ) β-sympathomimetics 療 狀 律 律 療 (10% calcium gluconate 10-20ml ) 療 度 狀 類 神 dopamine, noradrenaline 量 都 使 用 之 注 意 事 項 Nifedipine 不 立 不 易 度 不 25 包 裝

6 R. P. Scherer GmbH & Co. KG, Gammelsbacher Str. 2, D Eberbach, Baden, Germany Bayer HealthCare AG, D Leverkusen, Germany 北 路 7 54 樓 (02) Adalat Capsules / OE20 / TW02 /

7 Composition Active ingredient: nifedipine Coronary therapeutic/antihypertensive Immediate release soft gelatine capsules 1 capsule contains 10 mg nifedipine Indications Adalat Capsules 1. Treatment of coronary heart disease - Chronic stable angina pectoris (angina of effort) - vasospastic angina pectoris (Prinzmetal s angina, variant angina) 2. Treatment of hypertension 3. Treatment of hypertensive crisis 4. Treatment of Raynaud s syndrome (primary and secondary Raynaud s syndrome) Posology and Method of Administration Dosage (Dose and interval) As far as possible the treatment must be tailored to the needs of the individual according to the severity of the disease and the patient s response. Depending on the clinical picture in each case, the basic dose must be introduced gradually. In patients with impaired liver function careful monitoring and, in severe cases, a dose reduction may be necessary. Dose titration is recommended for hypertensives with severe cerebrovascular disease and for patients, who because of low body weight or multiple therapy with other antihypertensive drugs, are likely to have an excessive reaction to nifedipine. In addition, patients in whom side effects in response to the nifedipine treatment make a finer dose adjustment desirable should be individually stabilized with Adalat 5. Unless otherwise prescribed, the following dosage guidelines apply for adults: 1. In coronary heart disease: Chronic stable angina pectoris 1 Adalat capsule 3 times daily (Angina of effort) (3 x 10 mg/day) Starting dose should be Adalat 5 mg preferably If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily. Vasospastic angina pectoris 1 Adalat capsule 3 times daily (Prinzmetal s angina, variant angina) (3 x 10 mg/day) Starting dose should be Adalat 5 mg preferably If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily. 2. In hypertension: 1 Adalat capsule 3 times daily (3 x 10 mg/day) Starting dose should be Adalat 5 mg preferably If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily. 3. In hypertensive crisis: 1 Adalat capsule as a single oral dose (1 x 10 mg) Starting dose should be Adalat 5 mg preferably For established diagnosis of hypertensive urgency (= without target organ damage): 1 Adalat capsule as a single oral dose (1 x 10 mg) For established diagnosis of hypertensive emergency (= with target organ damage): Primary care 1 Adalat capsule as a single oral dose (1 x 10 mg) Secondary care 1 Adalat capsule as a single oral dose (1 x 10 mg) followed by i.v. infusion with nifedipine -1-

8 or nitroglycerine, clonidine, dihydralazine as secondary treatment and i.v. sodium nitroprusside as tertiary treatment. If the effect is insufficient, depending on the reaction of the blood pressure, a further 10 mg dose (1 Adalat capsule) can be administered after at least 30 min. If the dosage intervals are shorter and/or the dose higher, dangerous hypotensive states can occur. 4. In Raynaud s syndrome: 1 Adalat capsule 3 times daily (3 x 10 mg/day) If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily. Duration of Treatment The attending doctor will determine the duration of use. Due to their pronounced antiischemic and antihypertensive action, Adalat capsules should be discontinued gradually, particularly when high doses are used. Administration Adalat capsules are swallowed whole with a little liquid, independently of meals. Simultaneous food intake leads to delayed but not reduced absorption. Patients taking unit doses of 20 mg of immediate release formulations such as Adalat capsules should allow an interval of at least 2 h between doses. Contraindications Adalat must not be used in cases of known hypersensitivity to nifedipine or to any of the excipients. Nifedipine is contraindicated in pregnancy before week 20 and during breastfeeding. Nifedipine must not be used in cases of cardiovascular shock. Immediate release nifedipine is contraindicated in unstable angina pectoris and after acute myocardial infarction within the first 4 weeks. Nifedipine must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction. Special Warnings and Precautions for Use Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm HG), in cases of manifest heart failure and in the case of severe aortic stenosis. Treatment with immediate release Nifedipine may induce an exaggerated fall in blood pressure with reflex tachycardia, which could result in cardiovascular complications. As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm, that the occurrence of angina pectoris attacks is uncommon. In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment. The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease. There are no safety and efficacy data from well-controlled studies in pregnant women. Animal studies have shown a variety of embryotoxic,, placentotoxic and fetotoxic effects when administered during and after the period of organogenesis. From the clinical evidence available a specific prenatal risk has not been identified. Although an increase in perinatal asphyxia, caesarean delivery as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect. The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy after week 20 requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious. -2-

9 Careful monitoring of blood pressure must be exercised, also when administered nifedipine with i.v. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and fetus. In patients with impaired liver function careful monitoring and, in severe cases, a dose reduction may be necessary. Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine. Drugs, which are weak to moderate inhibitors of the cytochrom P450 3A4 system and therefore may lead to increased plasma concentrations of nifedipine are, e.g.: - macrolide antibiotics (e.g., erythromycin), - anti-hiv protease inhibitors (e.g., ritonavir), - azole antimycotics (e.g., ketoconazole), - the antidepressants nefazodone and fluoxetine, - quinupristin / dalfopristin, - valproic acid, - cimetidine. Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered. Interaction with Other Medical Products and Other Forms of Interaction Drug that affect nifedipine: Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine. The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs: Rifampicin Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated. Upon co-administration of the following weak to moderate inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered. Macrolide antibiotics (e.g., erythromycin) No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon coadministration of both drugs cannot be excluded. Azithromycin, although structurally related to the class of macrolide antibiotic is void of CYP3A4 inhibition. Anti-HIV protease inhibitors (e.g. ritonavir) A clinical study investigating the potential of a drug interaction between nifedipine and certain anti- HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded. Azole anti-mycotics (e.g., ketoconazole) A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs of this class are known to inhibit the -3-

10 cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded Fluoxetine A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded. Nefazodone A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase of nifedipine plasma concentrations upon coadministration of both drugs cannot be excluded. Quinupristin/Dalfopristin Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine. Valproic acid No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded. Cimetidine Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect. Further studies Cisapride Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine. Cytochrome P450 3A4 system inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbitone Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When both drugs are concomitantly administered, the clinical response to nifedipine should be monitored and, if necessary, an increase of the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued. No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded. Effects of nifedipine on other drugs: Blood pressure lowering drugs Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as: - diuretics, - β-blockers, -4-

11 - ACE-inhibitors, - AT-1 antagonists, - other calcium antagonists, - α-adrenergic blocking agents, - PDE5 inhibitors, - α-methyldopa. When nifedipine is administered simultaneously with ß-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases. Digoxin The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in plasma concentrations of digoxin. The patient should therefore be checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin. Quinidine When nifedipine and quinidine have been administered simultaneously, lowered quinidine or, after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine have been observed in individual cases. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration and, if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon co-administration of both drugs, while others did not observe an alteration in the pharmacokinetics of nifedipine. Therefore, the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with nifedipine. If necessary, the dose of nifedipine should be decreased. Tacrolimus Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered. Drug-food interactions: Grapefruit juice Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect may be increased. After regular intake of grapefruit juice this effect may last for at least 3 days after the last ingestion of grapefruit juice. Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking nifedipine. Other forms of interaction: Nifedipine may cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected. Pregnancy and Lactation Pregnancy and Fertility Nifedipine is contraindicated in pregnancy before week 20. There are no adequate and well-controlled studies in pregnant women. In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity. In single cases of in-vitro fertilization calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa s head section that may result in impaired -5-

12 sperm function. In those men who are repeatedly unsuccessful in fathering a child by in-vitro fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes. Lactation Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period. Undesirable Effects Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below: ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%). ADRs derived from post marketing reports (status: 31 Mar 2006) are printed in bold italic. Incidence of frequency 1% < 10%(Common) Nervous system disorders headache Vascular disorders oedema vasodilatation Gastrointestinal disorders constipation General disorders and administration site conditions feeling unwell Incidence of frequency 0.1 % < 1%(Uncommon) Immune system disorders allergic reaction, allergic oedema/ angioedema (incl. larynx oedema*) Psychiatric disorders anxiety reactions, sleep disorders Nervous system disorders vertigo, migraine, dizziness, tremor Eye disorders visual disturbances Cardiac disorders tachycardia, palpitations Vascular disorders hypotension, syncope Respiratory, thoracic and mediastinal disorders nasal congestion, nosebleed Gastrointestinal disorders gastrointestinal and abdominal pain, nausea, dyspepsia, flatulence, dry mouth Hepatobiliary disorders transient increase in liver enzymes Skin and subcutaneous tissue disorders erythema Musculoskeletal, connective tissue and bone disorders muscle cramps, joint swelling Renal and urinary disorders polyuria, dysuria Reproductive system erectile dysfunction General disorders and administration site conditions unspecific pain, chills Incidence of frequency 0.01 % < 0.1 %(Rare) Immune system disorders pruritus, urticarcia, rash Nervous system disorders Par-/Dysaesthesia Gastrointestinal disorders gingival hyperplasia Incidence of frequency < 0.01 %(Very rare) Immune system disorders anaphylactic/anaphylactoid reaction Respiratory, thoracic and mediastinal disorders dyspnea Gastrointestinal disorders vomiting Overdose Symptoms The following symptoms are observed in cases of severe nifedipine intoxication: Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardiac/bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, -6-

13 cardiogenic shock with pulmonary oedema. Management of overdose in man As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular conditions have priority. After oral ingestion thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. In case of intoxication with Adalat elimination must be as complete as possible, including the small intestine, to prevent subsequent absorption of the active substance. Haemodialysis serves no purpose, as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution). Bradycardiac heart rhythm disturbances may be treated symptomatically with β-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable. Hypotension as a result of cardiogenic shock and arterial vasodilation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered slowly i.v. and repeated if necessary). As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline are additionally administered. The dosage of these drugs is determined solely by the effect obtained. Additional liquid or volume must be administered with caution because of the danger of overloading the heart. Pharmacodynamic Properties Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. In Raynaud's syndrome nifedipine can prevent or reduce the occuring digital vasospasm. Pharmacokinetic Properties Absorption After oral administration nifedipine is immediately and almost completely absorbed. The systemic availability of orally administered nifedipine is % owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 min. Simultaneous food intake leads to delayed, but not reduced absorption. Distribution Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration was determined to be 5 to 6 minutes. Biotransformation After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5-15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine. Elimination The terminal elimination half-life is 1.7 to 3.4 h. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In cases of impaired liver function the elimination half-life is distincly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases. -7-

14 Preclinical Safety Data Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential. Reproduction toxicology: Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after end of the organogenesis period. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy / decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans. Special Precautions for Use The active substance nifedipine is highly light-sensitive. Therefore capsules must not be broken, as otherwise the protection against light due to the pigment film-coating is no longer ensured. The light-sensitive active substance contained in the capsules is protected from light inside and outside its packaging. Nevertheless, capsules must only be removed from the packaging immediately before use. Adalat capsules must not be used after the expiry date. Keep drugs out of reach of children. Do not store above 25 C. Presentation Below 1000 s per bottle R. P. Scherer GmbH & Co. KG, Gammelsbacher Str. 2, D Eberbach, Baden, Germany Bayer HealthCare AG, D Leverkusen, Germany Adalat Capsules / CCDS23 / TW03 /