INFORMATION FOR HEALTH PROFESSIONALS
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ALPHA-NIFEDIPINE retard tablets are red-brown, round, biconvex, film coated tablets 8.0 mm in diameter. Each tablet contains 20 mg of nifedipine and typically weighs 170 mg.
Nifedipine is a calcium ion influx inhibitor (calcium channel blocker or calcium ion antagonist). Nifedipine selectively inhibits the transmembrane influx of calcium through the "slow channels" in cardiac muscle and vascular smooth muscle without affecting to any significant degree, the transmembrane influx of sodium through the "fast channel". Contractile processes evoked by intracellular calcium ions in these tissues are inhibited due to the reduced levels of free calcium ions available within the muscle cells. Nifedipine does not alter total serum calcium.
Although the specific mechanisms are not fully known, it is believed that nifedipine reduces blood pressure by dilation of the coronary and peripheral vasculature. In the management of moderate to severe hypertension, the vasodilating properties of nifedipine results in decreased peripheral resistance and heart work load with a resultant decrease in blood pressure. Nifedipine has little or no effect on sinoatrial and atrioventricular nodal conduction.
The negative inotropic effect of nifedipine is usually not of major clinical significance because at therapeutic doses its vasodilating properties evoke a baroreceptor-mediated reflex tachycardia which tends to counterbalance the negative inotropic effect. Continued administration of nifedipine to hypertensive patients has shown no significant increase in heart rate. At usual therapeutic doses nifedipine does not possess antiarrhythmic properties.
Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract, but undergoes an extensive hepatic first-pass metabolism, resulting in a systemic availability of about 46%. Maximum plasma concentrations are reached within 1.5 to 4 hours. Simultaneous intake of food delays but does not reduce absorption.
Nifedipine is about 95% bound to plasma proteins and the distribution half-life after intravenous administration is about 5 to 6 minutes.
Nifedipine is primarily metabolised in the gut wall and liver into inactive metabolites - the hydroxycarboxylic acid derivative (95%) and the corresponding lactone (5%) with 70-80% of a dose being excreted in the urine as these metabolites. Less than 1% of unchanged nifedipine is recovered in the urine.
The elimination half-life is about 6 to 11 hours. In cases of impaired liver function the elimination half-life is prolonged considerably and total clearance reduced. In severe cases a dose reduction may be indicated due to the risk of accumulation.
ALPHA-NIFEDIPINE RETARD is indicated in the treatment of moderate to severe cases of hypertension. Treatment with nifedipine may be initiated as monotherapy, or in combination with other classes of antihypertensive agents.
Nifedipine may be useful when treatment with diuretics and/or beta-blockers is contraindicated, ineffective, or is accompanied by unacceptable adverse effects.
The dosage should be individualised according the patient's response and tolerance.
In order to assess adequately the response to a particular dose level, there should be an interval of at least 3 weeks before increasing the dosage, as it may take this long for the full reduction in blood pressure to occur.
The recommended initial dose is 10mg to 20mg twice daily with the usual adult dose being 20mg twice daily. If required the dose may be increased to 40mg twice daily. A maximum daily dose of 80mg should not be exceeded.
ALPHA-NIFEDIPINE RETARD tablets should be swallowed intact and should not be chewed or crushed. Simultaneous intake of food will delay but not reduce absorption.
The recommended dosing interval is 12 hours and should not be less than 4 hours.
Nifedipine should be administered cautiously to elderly patients especially those prone to developing hypotension or with a history of cardiovascular insufficiency. Dosage changes should be made gradually and the response monitored carefully.
Hepatic dysfunction may prolong the elimination and reduce the clearance of nifedipine resulting in accumulation. Careful monitoring is required and the dosage level or dosing interval may need to be adjusted.
ALPHA-NIFEDIPINE RETARD tablets are not recommended for children.
Increased frequency, duration, and/or severity of angina or acute myocardial infarction may occur rarely, especially in patients who have severe obstructive coronary artery disease, when starting nifedipine or at the time of dosage increase.
Patients with angina recently withdrawn from beta-blocker treatment may develop an increase in angina probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and may exacerbate it by provoking reflex catecholamine release. If a beta-blocker has to be discontinued it must be tapered off gradually.
There have been isolated reports of severe hypotension and lowering of cardiac output after administration of nifedipine to patients with severe heart failure. Rarely, patients, usually those receiving a beta-blocker have developed heart failure after beginning nifedipine therapy.
In patients with severe aortic stenosis, nifedipine will not produce its usual afterload reducing effects and there is a possibility that an unopposed negative inotropic action may result in heart failure if the end-diastolic pressure is raised.
Caution should be exercised when using nifedipine in patients with these conditions.
A compensatory increase in heart rate may occur in some patients due to nifedipine's vasodilatory action. Heart rate should be carefully monitored during nifedipine therapy.
Mild to moderate peripheral oedema which primarily occurs in the lower extremities has been reported. It usually responds to diuretic therapy. In patients whose hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.
Symptomatic hypotension may occasionally occur. Careful monitoring of blood pressure during the initial administration and during titration of the dose is recommended especially in patients with a history of cerebrovascular insufficiency and those taking medications known to lower blood pressure.
Nifedipine should be administered cautiously to the elderly, as the incidence of adverse reactions is approximately 10% higher in patients over 65 years of age. Syncope, peripheral oedema and palpitations occur more frequently.
Diabetic patients may need adjustment of their control.
Category C. Safe use in pregnancy has not been established. Calcium channel blockers have the potential to produce foetal hypoxia associated with maternal hypotension. Nifedipine administration is associated with teratogenic, embryotoxic and fetotoxic effects in animals. Nifedipine should not be administered during pregnancy.
Nifedipine should not be administered to nursing mothers.
Reactions to the medication can impair the ability to drive and operate machinery. This particularly applies to the start of the treatment, or changing medication and in combination with alcohol.
In safety evaluation studies of nifedipine retard tablets, either alone or in combination with other hypertensive agents, adverse effects were reported in 32.3% of patients and required discontinuation of therapy in 3.8% of patients. Most of the common adverse reactions to nifedipine result from its vasodilating effects on vascular smooth muscle.
Flushing, heat sensation or reddening of skin (13.9%), peripheral oedema, fluid retention or swelling (4.7%), palpitation or tachycardia (1.2%), hypotension (0.5%) and syncope (0.2%).
In patients with angina, rarely, and possibly due to tachycardia, nifedipine has been reported to have precipitated an angina pectoris attack. In addition, more serious events e.g. myocardial infarction, congestive heart failure or pulmonary oedema, and ventricular arrhythmias or conduction disturbances were occasionally observed, not readily distinguishable from the natural history of the disease in these patients. It is possible that some of these events were drug related.
Headache (7.9%), tiredness or weakness (4.7%), dizziness, light-headedness or giddiness (4.5%) and shakiness, nervousness or jitteriness (0.6%).
Nausea or vomiting (2.2%), abdominal discomfort or heartburn (3.3%) and constipation (0.6%).
Joint stiffness, muscle pain or cramps (2.2%)
Pruritis, dermatitis, urticaria or rash (1.4%) and polyuria (1.6%)
The following effects have occurred in an incidence of less than 0.5% in clinical trials: insomnia, hypokalemia, numbness/tingling, paresthesia, dry mouth, dyspnoea on effort, extrasytole, chest pain, vision disturbance, nightmares, neuralgia, diminished concentration, impotence and decreased libido.
Two cases of hypersensitivity have been reported resulting in allergic hepatitis which resolved when nifedipine was discontinued. In one case recurrence was observed on rechallenge.
In a small number of patients nifedipine has been reported to cause gingival hyperplasmia but the lesions usually regressed on discontinuation of the medicine although occasionally gingivectomy was necessary.
Long term therapy has been associated with the occasional incidence of reversible gynaecomastia in elderly male patients.
The antihypertensive effect of beta-blockers may be potentiated by the vasodilatory action of nifedipine. The concomitant administration of nifedipine with beta blockers warrants caution. The blood pressure, along with the pulmonary signs and symptoms of congestive heart failure should be carefully monitored (see Warnings and Precautions). Exacerbation of anginal pain has been observed when beta-blocker therapy is withdrawn concurrent to initiating nifedipine therapy.
Nifedipine may potentiate the affects of other anti hypertensive agents and blood pressure should be monitored carefully.
Acute hypotension has occurred during surgery in patients receiving nifedipine, beta-blocker and fentanyl concomitantly. It is recommended that nifedipine should be withheld temporarily for at least 36 hours before surgery in which high dose fentanyl is contemplated, if the condition of the patient permits.
Administration of nifedipine with digoxin may reduce the clearance of digoxin and therefore, increase the plasma digoxin level. It is therefore advisable to monitor plasma digoxin levels when concomitant treatment with nifedipine is initiated, discontinued or adjusted.
The addition of nifedipine to a stable quinidine treatment programme may reduce the plasma quinidine level by 50% and an enhanced response to nifedipine may also occur. Conversely, the addition of quinidine to a stable nifedipine treatment programme may elevate the plasma nifedipine level with a reduced response to quinidine. Some patients have experienced elevated plasma quinidine levels when nifedipine treatment was discontinued. It is therefore advisable to monitor plasma digoxin levels when concomitant treatment with nifedipine is initiated, discontinued or adjusted.
Cimetidine and ranitidine elevate the plasma nifedipine level (80% with cimetidine and 70% with ranitidine) and may potentiate the hypotensive effect. Adjustment of nifedipine dosage may be necessary.
Isolated incidences of phenytoin toxicity have been reported following initiation of nifedipine therapy. The exact mechanism has not been elucidated but it is advised that plasma phenytoin levels should be monitored carefully when starting or withdrawing nifedipine therapy.
Reduced plasma theophylline levels resulting from concomitant therapy with nifedipine have been observed.
Nifedipine therapy may potentiate salbutamol- or terbutaline- induced bronchodilation in asthmatic patients.
Because of its enzyme inducing action rifampicin accelerates the metabolism of nifedipine which may reduce the efficacy of nifedipine. Concomitant use is not recommended.
Diltiazem reduces the clearance of nifedipine. A reduction in the nifedipine dose may need to be considered.
Simultaneous intake of food delays but does not reduce absorption
Grapefruit juice inhibits the oxidative metabolism of nifedipine resulting in increased plasma concentration which may increase the blood pressure lowering effect.
In rare cases nifedipine therapy has been associated with significant elevations in plasma levels of enzymes including alkaline phosphatase, CPK, LDH, AST and ALT. These laboratory abnormalities have rarely been associated with clinical symptoms.
Nifedipine may falsely increase spectrophotometric values of urinary vanillymandelic acid although measurement with HPLC is unaffected.
Disturbances of consciousness up to the point of coma, hypotension, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
Elimination of nifedipine and restoration of stable cardiovascular conditions have priority. Gastric lavage is indicated possibly in combination with irrigation of the small intestine. Haemodialysis is of no benefit but plasmapheresis is recommended.
Bardycardia may be treated symptomatically with β-sympathomimetics and in life threatening situations use of temporary pacemaker therapy should be considered.
Hypotension due to cardiogenic shock and arterial vasodilation can be treated with 10-20mL of 10% calcium gluconate solution administered slowly IV (repeated if necessary). If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics e.g. dopamine or noradrenaline may be administered. Dosage is determined by the effect obtained.
Care must be taken when administering additional liquid or volume due to the danger of overloading the heart.
Store below 25°C. Protect from heat, light and moisture.
Keep container tightly closed.
Prescription Medicine
Bottles of 60
Nifedipine active material is highly light sensitive and the tablets should not be broken.
ALPHA PHARMACEUTICALS LTD
Melville House
159 Broadway Avenue
PO Box 705
Palmerston North
Phone: (06) 355 1066
Fax: (06) 356 6293
May 4, 1999