OE/04

Transcription

1 樂 30, 60 ( ) Adalat OROS 30, 60 Nifedipine 狀 療 / 降 成 分 樂 30 nifedipine 30 (mg ) 樂 60 nifedipine 60 (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 年 Adalat (Nifedipine GITS) 利 尿 療 Adalat OROS 24 率 nifedipine 零 度 理 來 不 ph 不 不 便 適 應 症 用 量 與 用 法 本 藥 須 由 醫 師 處 方 使 用 量 ( 量 ) 療 臨 量 不 量 量 1. 療 狀 ( ) (30 ) (60 ) 2. 療 (30 ) (60 ) 30 療 度 量 120 療 參 療 -1-

2 量 飯 飯 不 弄 禁 忌 樂 不 nifedipine 不 nifedipine 不 nifedipine Nifedipine 不 rifampicin nifedipine 度 警 語 及 注 意 事 項 ( < 90 mmhg) 例 Adalat OROS 不 ( 見 ) 塞 狀 數 例 療 塞 異 Kock ( 切 ) 不 Adalat OROS 行 X Adalat OROS ( ) nifedipine 硫 ( 參 ) 量 車 力 車 力 異 不 更 量 精 易 與 其 他 藥 物 和 其 他 形 式 的 交 互 作 用 Antihypertensive drugs 降 nifedipine 降 Beta-receptor blockers nifedipine beta-receptor blocker 例 惡 Cytochrome P450 3A4 nifedipine cytochrome P450 3A4 都 nifedipine (First pass effect) Digoxin nifedipine digoxin digoxin digoxin 度 digoxin 量 digoxin 度 來 glycoside 量 Phenytoin cytochrome P450 3A4 phenytoin 降 nifedipine 率 若 兩 nifedipine 臨 nifedipine 量 若 兩 nifedipine 量 phenytoin 降 nifedipine 量 Quinidine nifedipine quinidinequinidine 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 兩 降 nifedipine 量 Cimetidine cytochrome P450 3A4 nifedipine 度 降 Rifampicin 烈 cytochrome P450 3A4 rifampicin 降 nifedipine 率 兩 -2-

3 Diltiazem diltiazem nifedipine 兩 nifedipine 量 Grapefruit juicecytochrome P450 3A4 降 nifedipine (First pass metabolism) nifedipine 度 降 若 Cisapride cisapride nifedipine nifedipine 度 兩 降 nifedipine 量 理 論 Erythromycin nifedipine erythromycin erythromycin cytochrome P450 3A4 erythromycin nifedipine 不 nifedipine 度 Fluoxetine 臨 nifedipine fluoxetinefluoxetine 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 indinavir ritonavir cytochrome P450 3A4 nifedipine nifedipine 不 nifedipine 度 nifedipine 量 Nefazodone 臨 nifedipine nefazodonenefazodone cytochrome P450 3A4 兩 不 nifedipine 度 nefazodone nifedipine nifedipine 量 Ketoconazole Itraconazole Fluconazole nifedipine ketoconazole itraconazole fluconazole 類 cytochrome P450 3A4 nifedipine 不 nifedipine 率 nifedipine 量 Tacrolimus tacrolimus cytochrome P450 3A4 料 nifedipine tacrolimusnifedipine 量 降 兩 tacrolimus 量 Carbamazepine nifedipine carbamazepine carbamazepine 降 nimodipine( 類 離 ) 度 不 carbamazepine 降 nifedipine 度 降 Phenobarbitone nifedipine phenobarbitone phenobarbitone 降 nimodipine( 類 離 ) 度 不 phenobarbitone 降 nifedipine 度 降 Valproic acid nifedipine valproic acid valproic acidnimodipine( 類 離 ) 度 不 valproic acid nifedipine 度 料 Ajmalin Benazepril Debrisoquine Doxazosin Irbesartan Omeprazole Orlistat Pantoprazole Ranitidine Rosiglitazone Talinolol Triamterene Hydrochlorothiazide 力 Aspirin nifedipine aspirin 100(100 mg) nifedipine 力 不 aspirin 100 mg Candesartan Cilexetil nifedipine candesartan cilexetil 力 -3-

4 Nifedipine 度 尿 HPLC 不 孕 婦 和 授 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 樂 臨 CIOMS III 類 率 COSTART 狀 列 見 (n= ) 率 1 % < 10 % 力 便 神 暈 率 0.1 % < 1 % 不 暈 不 良 神 暈 泌 尿 尿 尿 率 0.01 % < 0.1 % ( 不 ) GGT 不 神 狀 狀 狀 不 泌 尿 尿 尿 CIOMS III 類 率 COSTART 狀 列 (n 2886 例 ) -4-

5 率 < 0.01 % 塞 SGPT 淋 糖 落 女 力 不 降 過 量 狀 列 nifedipine 狀 識 不 狀 降 律 糖 理 nifedipine 復 狀 Adalat OROS nifedipine nifedipine 不 不 nifedipine 離 ( nifedipine ) beta-sympathomimetics 療 狀 律 律 療 (10% calcium gluconate ml ) 療 度 狀 類 神 dopamine, noradrenaline 量 都 注 意 樂 不 便 樂 立 不 包 裝 Bayer HealthCare AG D Leverkusen, Germany 北 路 7 54 樓 (02) Adalat OROS 30, 60 / OE13 / TW04 /

6 Composition Active ingredient: nifedipine Coronary therapeutic/antihypertensive Extended release tablets Adalat OROS 30, 60 Adalat OROS 30: 1 extended release tablet contains 30 mg nifedipine Adalat OROS 60: 1 extended release tablet contains 60 mg nifedipine Indication 1. Treatment of coronary heart disease Chronic stable angina pectoris (angina of effort) 2. Treatment of hypertension Posology and Method of Administration Dosage (Dose and interval) As far as possible the treatment must be tailored to the needs of the individual. 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. Unless otherwise prescribed, the following dosage guidelines are recommended for adults: 1. For coronary heart disease: Chronic stable angina pectoris (Angina of effort) 1 Adalat OROS 30 tablet once daily (1 x 30 mg/day) 1 Adalat OROS 60 tablet once daily (1 x 60 mg/day) 2. For hypertension: 1 Adalat OROS 30 tablet once daily (1 x 30 mg/day) 1 Adalat OROS 60 tablet once daily (1 x 60 mg/day) In general therapy should be initiated with 30 mg once daily. Depending on the severity of the disease and the patient's response the dose can be increased in stages to 120 mg once daily. Duration of Treatment The attending doctor will determine the duration of use. Administration As a rule the tablets are swallowed whole with a little liquid, independently of meals. The tablets must not be chewed or broken up! Contraindications Adalat OROS 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. Nifedipine must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction. -1-

7 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. There are no safety and efficacy data from well-controlled studies in pregnant women. Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxiceffects (see Preclinical safety data ) 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. 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. As with other non-deformable material (see Instructions for Use / Handling) care should be used when administering Adalat OROS in patients with pre-existing severe gastrointestinal narrowing because obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention. In single cases obstructive symptoms have been described without known history of gastrointestinal disorders. Adalat OROS must not be used in patients with Kock pouch (ileostomy after proctocolectomy). When doing barium contrast X-ray, Adalat OROS may cause false positive effects (e.g. filling defects interpreted as polyp). 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. One Adalat OROS contains 24 mg sodium. Dose titration up to the maximal daily dose of 120 mg nifedipine with the lowest dose strength will possibly result in a sodium uptake of 144 mg (2 mmol sodium) per daily dose. To be taken into consideration by patients on a controlled sodium diet. Interaction with Other Medicaments and Other Forms of Interaction Drugs 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 acount when administering nifedipine together with the following drugs: -2-

8 Rifampicin Rifampicin strongly induces the cytochrome P450 3A4 system. Upon coadministration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contra-indicated. 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 co-administration of both drugs cannot be excluded. Azithromycin, although structurally related to the class of macrolide antibiotics 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 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 co-administration 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. -3-

9 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, - ACE-inhibitors, - A1-antagonists, - other calcium antagonists, - α-adrenergic blocking agents, - PDE5 inhibitors, - α-methyldopa. When nifedipine is administered simultaneously with β-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. -4-

10 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 uneffected. 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 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: 15 Feb 2006) are printed in italic. Incidence of frequency 1% < 10% (Common) Nervous system disorders Vascular disorders Gastrointestinal disorders General disorders and administration site conditions Incidence of frequency 0.1 % < 1% (Uncommon) Immune system disorders headache edema, vasodilatation constipation dizziness allergic reaction, allergic edema/angioedema -5-

11 Psychiatric disorders Nervous system disorders Eye disorders Cardiac disorders Vascular disorders Respiratory disorders Gastrointestinal diisorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Renal and urinary disorders Reproductive system disorders Gerneral disorders and administration site conditions Incidence of frequency 0.01 % < 0.1 % (Rare) Immune system disorders Nervous system disorders Gastrointestinal disorders Incidence of frequency < 0.01 % (Very rare) Immune system disorders Respiratory disorders Gastrointestinal disorders anxiety reactions, sleep disorders vertigo, migraine, dizziness, tremor visual disturbances tachycardia, palpitations hypotension, Syncope nosebleed, nasal congestion gastrointestinal and abdominal pain, nausea, dyspepsia, flatulence, dry mouth transient increase in liver enzymes erythema muscle cramps, joint swelling polyuria, dysuria erectile dysfunction unspecific pain, chills pruritus, urticaria, rash par-/dysaesthesia gingival hyperplasia anaphylactic/anaphylactoid reaction dyspnea bezoar, dysphagia, intestinal obstruction, intestinal ulcer, vomiting In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation. 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, 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. Particularly in cases of intoxication with slow-release products like Adalat OROS elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable 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. -6-

12 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. Pharmacokinetic Properties Adalat OROS is formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The delivery rate is independent of gastrointestinal ph or motility. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell. Absorption After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (nifedipine capsules) is % owing to a first pass effect. At steady-state the bioavailability of Adalat OROS ranges from 68-86% relative to nifedipine capsules. Administration in the presence of food slightly alters the early rate of absorption, but does not influence the extent of drug availability. Distribution Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determind 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 in conventional formulations (nifedipine capsules). The terminal half-life after Adalat OROS does not represent a meaningful parameter as a plateaulike plasma concentration is maintained during release from the tablets and absorption. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In cases of impaired liver function the total clearance is reduced. A dose reduction may be necessary in severe cases. 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 and 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. -7-

13 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. Instructions for Use / Handling In Adalat OROS the medication is contained within a non-absorbable shell that slowly releases the drug for the body to absorb. When this process is completed, the empty tablet is eliminated from the body and may be noticed in the stool. The light-sensitive active substance contained in Adalat OROS is protected from light inside and outside its packaging. The tablets must be protected from humidity and must therefore only be removed from the foil immediately before use. Note Not to be stored above 30. Do not use after the expiry date. Keep drugs out of reach of children. Presentation s per box Bayer HealthCare AG, D Leverkusen, Germany Adalat OROS 30, 60 / CCDS14 / TW05 /