Adipine MR 10

Adipine MR 20

One modified release tablet contains: 10mg of Nifedipine

One modified release tablet contains: 20mg of Nifedipine

Modified release tablets for oral use.

Round, slightly biconvex, pink coated tablets with smooth surface.

Hypertension

Prophylaxis of chronic stable angina pectoris

The treatment should be as individual as possible according to the seriousness of the disease and the responsiveness of the patient.

Dependent on the respective clinical picture stabilisation with reference to the final dose should be made slowly.

Nifedipine should be taken with a little water.

The recommended starting dose of nifedipine is 10mg every 12 hours swallowed with water with subsequent titration of dosage according to response. The dose may be adjusted to 40mg every 12 hours.

The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored. Patients with renal impairment should not require adjustment of dosage.

Nifedipine is not recommended for use in children.

The simultaneous intake of food delays, but does not reduce overall absorption.

The intervals between the recommended individual maximal daily doses of nifedipine should be not less than 4 hours. Discontinuation of Adipine MR especially from high doses should be made gradually.

Treatment may be continued indefinitely.

Hypersensitivity to nifedipine or other dihydropyridines because of the theoretical risk of cross reactivity.

Nifedipine should not be used in clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.

Nifedipine must not be administered in cases of cardiogenic shock.

Nifedipine should not be used for the treatment of acute attacks of angina.

The safety of nifedipine in malignant hypertension has not been established.

Nifedipine should not be used for secondary prevention of myocardial infarction.

Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.

Caution is required in cases of markedly low blood pressure (severe hypotension with less than 90mm Hg systolic) as well as in cases of cardiac failure.

None

The hypotensive effect of nifedipine can be increased by other hypotensive drugs as well as by tricyclic antidepressants. When combined with nitrates the effects on blood pressure and heart rate increase.

When administering nifedipine and beta-receptor blockers at the same time, careful surveillance of the patient is necessary as this might produce a major lowering of the blood pressure; occasional cardiac failure has also been observed.

Adipine MR is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal. Any such withdrawal should be a gradual reduction of the dose of the beta blocker preferably over 8 to 10 days. Adipine MR will not prevent possible rebound effects after cessation of other hypertensive therapy.

Certain calcium antagonists may increase the negatively inotropic effect of antiarrhythmics such as amiodarone and quinidine. In this connection, no observations were made with nifedipine. In individual cases, nifedipine causes a drop of the quinidine plasma level or after discontinuation of nifedipine a marked increase of the quinidine plasma level so that in combined therapy the control of the quinidine plasma level is recommended.

Nifedipine may cause an increase of theophylline plasma levels so that the control of the latter is recommended.

Cimetidine and, to a lesser extent, ranitidine may lead to an increase in the nifedipine plasma level and thus to a more intensive action of Nifedipine.

As with other dihydropyridines, nifedipine should not be taken with grapefruit juice because bioavailability is increased.

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in the plasma digoxin. Digoxin levels should be monitored and, if necessary, the digoxin dose reduced.

Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see Contra-indications).

Nifedipine must not be administered during the entire pregnancy as experimental studies have shown foetal deformities. There is no information on humans. Nifedipine penetrates into the mother's milk. As there is no information with respect to possible effects on babies, the child should be weaned, if treatment with nifedipine should be necessary during the lactation period.

The treatment of high blood pressure with this therapy requires regular medical control. Due to different reactions occurring in individual cases, the ability to drive or of operating machines might be affected. This happens much the more at the start of treatment and when changing preparations and is increased by co-administration of alcohol.

Especially at the beginning of therapy nifedipine often might cause temporary headaches and flushing with a sensation of warmth (erythema, erythromelalgia).

Occasionally, tachycardia, palpitations as well as lower leg oedema due to vasodilatation may occur. Furthermore, vertigo and fatigue have been observed. Also occasionally, there may be paraesthesia and a drop in blood pressure.

In rare cases, treatment with nifedipine may cause gastro-intestinal disturbances such as nausea, a sensation of fullness and diarrhoea. Furthermore, hypersensitivity reactions of the skin such as pruritis, urticaria and rashes, and in individual cases exfoliative dermatitis, have been observed.

Reductions in the blood count such as anaemia, leucopenia, thrombopenia, thrombocytic purpura after the administration of nifedipine have been described.

Very rarely, after long-term treatment, alterations of the gingiva (hyperplasia of the gingiva) might occur which disappear completely after stopping treatment.

In individual cases, liver dysfunctions (intrahepatic cholestasis, increases of transaminases) have been observed which disappear after stopping treatment.

Rarely, especially in elderly patients, gynaecomastia has been described in connection with long-term therapy, which so far has disappeared in all cases after discontinuation of the treatment.

In individual cases - especially with higher doses - courbature, trembling of the fingers (tremor) as well as a minor temporary alteration of optical perception have been observed.

In individual cases an increase in the blood sugar level in the serum (hyperglycaemia) has been observed. This should be taken into account above all with patients suffering from diabetes mellitus.

Exacerbation of angina pectoris may occur frequently at the start of treatment with sustained release formulations of nifedipine. The occurrence of myocardial infarction has been described although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.

In dialysis patients with malignant hypertension and hypovolaemia, caution is required as due to vasodilatation a marked drop in the blood pressure may be produced. Also, during the first weeks of therapy, daily urine volume may be increased.

In case of renal insufficiency during the administration of nifedipine renal function may be temporarily impaired.

a) Symptoms of intoxication

Clouding of consciousness and even coma, a fall in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia and cardiogenic shock with pulmonary oedema have been described.

b) Therapy for intoxications

The most important therapeutic objectives are the elimination of the drug and the restoration of a stable circulation.

After oral ingestion, a thorough stomach lavage and charcoal instillation if need be, in combination with a lavage of the small intestine are indicated.

Especially, in the case of an overdose with the controlled release preparation, an elimination as complete as possible, including also from the small intestine, should be aimed at in order to avoid the inevitable re-absorption of the drug.

When administering laxatives, however, the reduction of the muscular tone of the intestines and even intestinal atony due to the effect of a calcium antagonist must be taken into account. As haemodialysis is not recommended since nifedipine cannot be dialysed (high plasma protein bound, relatively low distribution volume) plasmapheresis, however, is recommended.

Bradycardia is symptomatically treated with atropine and/or beta-sympathomimetics, in cases of very serious bradycardia a temporary pacemaker therapy will be necessary.

Low blood pressure as a consequence of cardiogenic shock and arterial vasodilatation can be treated with calcium (1-2g of calcium gluconate administered intravenously), dopamine (up to 25µg for each kilogram of weight per minute), dobutamine (up to 15µg for each kilogram of weight per minute), adrenaline and/or noradrenaline. The dosage of these drugs can be titrated according to the effect obtained on the blood pressure. The serum-calcium level should be kept at the upper limit of the normal range.

Additional intake of fluid should be monitored carefully to prevent overload.

Nifedipine is a calcium antagonist of the 1,4-dihydro-pyridine type. Calcium antagonists exert an inhibitory effect on the calcium ion inflow through the slow calcium channel in the cell. Nifedipine acts primarily on the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. This effect causes a vasodilatation. Administered in therapeutic doses, nifedipine has virtually no direct effect on the myocardium.

In the heart, nifedipine mainly dilates the large coronary arteries. Furthermore, nifedipine reduces the muscle tone of the coronary arteries, which may produce an improvement in blood circulation. At the same time, nifedipine, due to vasodilatation, reduces the peripheral resistance (afterload).

At the start of treatment with this calcium antagonist, the heart rate and the cardiac output will be increased by a reflex action. This increase, however, is not sufficient to compensate the vasodilatation.

In long-term treatment with nifedipine, the cardiac output increases at first and then returns to the initial value. A particularly marked decrease in blood pressure after the administration of nifedipine can be observed with concurrent use of anti-hypertensive agents.

The active substance nifedipine is rapidly and almost completely absorbed from the gastro-intestinal tract after oral administration on an empty stomach. Nifedipine is subject to a "first pass metabolism" in the liver, resulting in a systemic availability of orally administered nifedipine of between 50 to 70%. Following administration of a nifedipine-containing solution maximum serum concentrations are reported to occur after approx. 15 minutes. After the administration of other preparations having an immediate release peak serum concentrations are attained after 15 to 75 minutes.

Approx. 95% of nifedipine is bound to plasma proteins.

Nifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes. These metabolites do not show any pharmacodynamic activity.

About 70 to 80% of a nifedipine dose is excreted in the urine in the form of its metabolites, the main metabolite (M-I) accounts for about 60 to 80% of the administered nifedipine dose. The rest is excreted in form of metabolites with the faeces. The unaltered substance is found only in traces (less than 0.1%) in the urine.

The elimination half-life is about 2 to 5 hours.

A cumulation of the substance during permanent therapy with usual doses has not been described.

In cases of reduced hepatic function, the elimination half-life is markedly prolonged and total clearance is reduced. In some cases dose reduction may be necessary.

Bioavailability

A bioavailability study with Adipine MR 20 made in the year 1991 with 24 volunteers showed the following results compared to the reference preparation:

Acute toxicity:

Acute toxicity has been studied on various species of animals. No specific sensibility was found.

Subchronic and chronic toxicity:

Studies on rats and dogs did not show any toxic effect of nifedipine.

Tumorigenicity:

A long-time study (2 years) on the rat did not yield any indications for oncogenous effects of nifedipine.

Mutagenicity:

The studies in vivo and in vitro were negative without exception so that any mutagenic action in human beings can be excluded sufficiently.

Reproduction toxicology:

Experimental studies carried out with three species of animals brought about indications for teratogenous effects (cleft palate, cardiovascular anomalities) in two species of animals. There is no experience with the application to human beings during the first six months of pregnancy. The administration of nifedipine without detrimental consequences during the last three months has been described for a small number of cases. Nifedipine has a tocolytical effect.

Nifedipine penetrates into the mother's milk. For its administration during the nursing period the experience gathered is not sufficient.

Lactose, microcrystalline cellulose, macrogol 6000, magnesium stearate, maize starch, hydroxypropylmethylcellulose, polysorbate 80 (Tween 80), talc, colourants E171, E172.

None known

2 years

The medication should not be used after the printed expiration date.

To be kept protected from light. Store below 25°C.

Note: The active substance nifedipine is light sensitive and is protected by special packaging.

When modified release tablets are taken out, they should not be exposed unnecessarily to intensive light for a prolonged period of time.

The modified release tablets are sealed in blister packages made of aluminium foil and PVC film. The blisters are packed, along with the package leaflet, in a folded cardboard box.

Packs containing 10 modified release tablets.

Packs containing 20 modified release tablets.

Packs containing 30 modified release tablets.

Packs containing 50 modified release tablets.

Packs containing 56 modified release tablets.

Packs containing 60 modified release tablets.

Packs containing 100 modified release tablets.

Not all pack sizes may be marketed.

No special precautions.

STADA Arzneimittel AG

Stadastrasse 2-18,

61118 Bad Vilbel, FRG

PL 11204/0038

PL 11204/0005

18/05/2007

18/05/2007

POM