Adalat PA10 (Nifedipine)

ADALAT® PA 10 ADALAT® PA 20

Bayer

Nifedipine

Antihypertensive

Action And Clinical Pharmacology: Nifedipine is a calcium ion influx inhibitor (calcium channel blocker or calcium ion antagonist).

The antihypertensive action of this group of drugs is believed to be related to its specific cellular action of selectively inhibiting transmembrane influx of calcium ions into vascular smooth muscles. The contractile processes of vascular smooth muscle are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Nifedipine selectively inhibits the transmembrane influx of calcium through the slow channel without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within the muscle cells and an inhibition of the contractile processes. Nifedipine does not alter total serum calcium.

The specific mechanisms by which nifedipine reduces blood pressure have not been fully determined but are believed to be brought about largely by its vasodilatory action on peripheral blood vessels, which thereby reduces peripheral vascular resistance.

The negative inotropic effect is usually not of major clinical significance because at therapeutic doses, nifedipine’s vasodilatory property evokes a baroreceptor mediated reflex tachycardia which tends to counterbalance this negative inotropic effect. Continued administration of nifedipine to hypertensive patients has shown no significant increase in heart rate.

Although nifedipine causes a slight depression of sinoatrial node function and AV conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong AV conduction or sinus node recovery time, or to slow sinus rate.

Pharmacokinetics: In man, after oral administration of a single tablet of Adalat PA 20, nifedipine was detected in plasma after about 30 minutes and peak plasma concentrations (approximately 26 ng/mL) were reached in about 4 hours. The subsequent decline in concentrations was slow, with a terminal (absorption) half-life of 10 hours, such that concentrations of 10 to 15 ng/mL were still present after 12 hours. The absorption and disposition data were not dose dependent nor did the pharmacokinetic character of the tablet vary after prolonged administration (2 tablets daily for 7 days).

The absolute bioavailability of nifedipine from Adalat PA 10 or 20 is between 50 and 70%. Administration of Adalat PA with food increases the rate of drug absorption and the extent of drug bioavailability possibly due to an increase in hepatic blood flow as a result of the meal.

Nifedipine is transformed into 2 pharmacologically inactive metabolites. The main metabolite (95%) is the hydroxycarboxylic acid derivative which is mainly excreted in the urine; the other (5%) is the corresponding lactone. Protein binding of circulating nifedipine exceeds 90%.

Nifedipine is metabolized by the cytochrome P450 enzyme system, predominantly via CYP3A4, but also by CYP1A2 and CYP2A6 isoenzymes.

Pharmacokinetic studies in patients with hepatic cirrhosis showed a clinically significant alteration in the kinetics of nifedipine (prolonged elimination half-life and decreased total clearance). In these patients, there is a considerable risk of accumulation (see Precautions).

Compounds found in grapefruit juice inhibit the cytochrome P450 system, especially isoenzyme CYP3A4. In a grapefruit juice-nifedipine interaction study in healthy male volunteers, pharmacokinetics of nifedipine showed significant alteration. Following administration of a single dose of nifedipine 10 mg with 250 mL grapefruit juice, the mean value of nifedipine AUC increased by 34% and the Tmax increased from 0.8 to 1.2 hours as compared to water (see Precautions, Interaction With Grapefruit Juice).

Indications And Clinical Uses: In the treatment of essential hypertension. Nifedipine should normally be used in those patients in whom treatment with diuretics or beta-blockers has been ineffective, or has been associated with unacceptable adverse effects.

Nifedipine can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated, or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Combination of nifedipine with a diuretic or beta-blocker has been found to be compatible, and has shown added antihypertensive effect (see Precautions).

Contra-Indications: Pregnancy and Lactation: In pregnancy, during lactation, and in women of childbearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals.

An increase in the number of fetal mortalities and resorptions occurred after the administration of 30 and 100 mg/kg of nifedipine to pregnant mice, rats and rabbits. Fetal malformations occurred after the administration of 30 and 100 mg/kg nifedipine to pregnant mice and 100 mg/kg to pregnant rats.

Adalat PA 10 or 20 is contraindicated in patients with hypersensitivity to nifedipine.

Nifedipine is contraindicated in patients with cardiovascular shock.

Manufacturers’ Warnings In Clinical States: Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those who have severe obstructive coronary artery disease have developed well-documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.

Since there has not been a study of Adalat PA in acute myocardial infarction reported, similar effects of Adalat PA to that of immediate-release nifedipine cannot be excluded. Immediate-release nifedipine is contraindicated in acute myocardial infarction.

Beta-blocker Withdrawal: Patients with angina recently withdrawn from beta-blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta-blocker withdrawal and initiation of nifedipine. If a beta-blocker has to be discontinued, it must be tapered off gradually rather than stopped abruptly.

Patients with Heart Failure: There have been isolated reports of severe hypotension and a lowering of cardiac output following administration of nifedipine to patients with severe heart failure. Rarely, patients, usually 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 of the drug may produce heart failure if the end-diastolic pressure is raised.

Caution should therefore be exercised when using nifedipine in patients with these conditions.

Precautions: Heart Rate: Because nifedipine is an arterial and arteriolar vasodilator, a compensatory increase in heart rate may occur in some patients. Thus, heart rate should be monitored carefully during nifedipine therapy.

Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, has been reported to occur in patients treated with nifedipine (see Adverse Effects). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Hypotension: Symptomatic hypotension may occasionally occur in hypertensive patients treated with nifedipine. Careful monitoring of blood pressure during the initial administration and titration of the drug is recommended, especially in patients with a history of cerebrovascular insufficiency, and those who are taking medications known to lower blood pressure.

Geriatrics: Nifedipine should be administered cautiously to the elderly since the incidence of adverse reactions reported in these patients is approximately 10% higher than in patients below 65 years of age. The adverse reactions occurring more frequently in this group include syncope, peripheral edema and palpitations (see Dosage).

Diabetic Patients: The use of nifedipine in diabetic patients may require adjustment of their control.

Patients With Impaired Liver Function: Nifedipine should be used with caution in patients with impaired liver function (see Pharmacology). A dose reduction, particularly in severe cases, may be required. Close monitoring of response and metabolic effect should apply.

Interaction With Grapefruit Juice: Published data indicate that through inhibition of cytochrome P450, flavonoids present in the grapefruit juice can increase plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel blockers, including nifedipine (see Pharmacology, Pharmacokinetics). Therefore, consumption of grapefruit juice prior to or during treatment with nifedipine should be avoided.

Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP3A4 isoenzyme. Coadministration of nifedipine with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered nifedipine to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine and warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin and rifampin.

Drugs known to be biotransformed via cytochrome P450 include: benzodiazepines, flecainide, theophylline, imipramine and propafenone.

Nifedipine may potentiate the effects of other agents having antihypertensive activity. The concomitant administration of nifedipine with beta-blockers warrants caution and careful monitoring of blood pressure and pulmonary signs and symptoms of congestive failure (see Warnings).

Concomitant use of nifedipine with short-acting nitrates, furosemide and anticoagulants has shown no interaction or unusual toxic effects. There have been no controlled studies to evaluate the concurrent use of long-acting nitrates and nifedipine.

Administration of nifedipine with digoxin may lead to reduced digoxin clearance, and therefore, an increase in the plasma digoxin level. It is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine to avoid possible under- or over-dosing with digitalis.

The addition of nifedipine to a stable quinidine regimen may reduce the quinidine concentration by 50%; an enhanced response to nifedipine may also occur. The addition of quinidine to a stable nifedipine regimen may result in elevated nifedipine concentrations and a reduced response to quinidine. Some patients have experienced elevated quinidine levels when nifedipine was discontinued. Therefore patients receiving concomitant therapy of nifedipine and quinidine, or those who had their nifedipine discontinued while still receiving quinidine, should be closely monitored, including determination of plasma levels of quinidine. Consideration should be given to dosage adjustment.

Pharmacokinetic studies have shown that concurrent administration of cimetidine or ranitidine with nifedipine results in significant increases in nifedipine plasma levels (approximately 80% with cimetidine, and 70% with ranitidine). Patients receiving either of these drugs concomitantly with nifedipine should be monitored carefully for the possible exacerbation of effects of nifedipine, such as hypotension. Adjustment of nifedipine dosage may be necessary.

Adverse Reactions: Safety evaluations of controlled and open studies have been carried out for Adalat PA 20.

In 814 hypertensive patients treated with Adalat PA 20, either alone or in combination with other antihypertensive agents, adverse effects were reported in 32.3% of patients and required discontinuation of therapy in 3.8% of patients. The most common adverse effects were: flushing and heat sensation (13.9%), headache (7.9%), peripheral edema (4.7%), tiredness/weakness (4.7%) and dizziness/lightheadedness (4.5%).

The following percentage of adverse effects, divided by system, were reported.

Cardiovascular: flushing, heat sensation or reddening of skin (13.9%); peripheral edema, fluid retention or swelling (4.7%); palpitation or tachycardia (1.2%); hypotension (0.5%); 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 were occasionally observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. These events include myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmias or conduction disturbances.

CNS: headache (7.9%); tiredness or weakness (4.7%); dizziness, lightheadedness or giddiness (4.5%); shakiness, nervousness or jitteriness (0.6%).

Gastrointestinal: nausea or vomiting (2.2%), abdominal discomfort or heartburn (3.3%), constipation (0.6%).

Musculoskeletal: joint stiffness, muscle pain or cramps (2.2%).

Others: pruritus, dermatitis, urticaria or rash (1.4%); polyuria (1.6%).

The following additional adverse effects have occurred in an incidence of less than 0.5% in clinical trials: insomnia, hypokalemia, numbness/tingling, paresthesia, dry mouth, dyspnea on effort, extrasystole, chest pain, vision disturbance, nightmares, neuralgia, diminished concentration, impotence and decreased libido.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.

One case of anaphylactic reaction has been reported.

Two cases of hypersensitivity have been reported following nifedipine administration, resulting in allergic hepatitis, which resolved when the drug was discontinued. In 1 case, recurrence was observed on rechallenge.

In a small number of patients nifedipine has been reported to cause gingival hyperplasia similar to that caused by diphenylhydantoin. The lesions usually regressed on discontinuation of the drug. However, on occasion, gingivectomy was necessary.

Gynecomastia has been observed rarely in older men on long-term therapy, but has so far always regressed completely on discontinuation of the drug.

Laboratory Tests: Rarely, mild to moderate transient elevations of enzymes such as alkaline phosphatase, CPK, LDH, AST and ALT have been noted after treatment with nifedipine. These laboratory abnormalities have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice has been reported. Infrequent reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency taking nifedipine.

Symptoms And Treatment Of Overdose: Symptoms: There are several well documented cases of nifedipine overdosage. The following symptoms are observed in cases of severe nifedipine intoxication: disturbance of consciousness to the point of coma, a drop in blood pressure, tachycardia/bradycardia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema.

Treatment: 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 PA, elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance. Hemodialysis serves no purpose, as nifedipine is not dialyzable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).

Clinically significant hypotension calls for active cardiovascular support including monitoring of cardiac and respiratory function including elevation of extremities and attention to circulating fluid volume and urine output.

Hypotension as a result of arterial vasodilation can also be treated with calcium (10 mL of 10% calcium gluconate solution administered slowly via i.v. route 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 norepinephrine are additionally administered as a last resort only in patients without cardiac arrhythmia or ischemic heart disease and when other safer measures have failed. 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.

Bradycardia and/or bradyarrhythmias have been observed in some cases of nifedipine overdosage. Appropriate clinical measures, according to the nature and severity of the symptoms, should be applied.

Dosage And Administration: Dosage should be individualized depending on patient’s tolerance and responsiveness to nifedipine and to concurrent antihypertensive medications (see Indications and Precautions).

The recommended initial dose is 10 to 20 mg twice daily. The usual adult dose is 20 mg twice daily. If required, the dose may be increased to 40 mg twice daily. A maximum daily dose of 80 mg should not be exceeded.

At a given dosage regimen, the full reduction in blood pressure may take at least 3 weeks. Therefore, in order to assess adequately the response to a particular dose level, there should be an interval of at least 3 weeks between increases in dose.

Availability And Storage: 10 mg: Each dusty-rose, round biconvex tablet, marked 10 on one side, contains: nifedipine 10 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, polyethylene glycol, iron oxide red, lactose, magnesium stearate, microcrystalline cellulose, polysorbate, starch and titanium dioxide. Blister packs in units of 6 strips of 10.

20 mg: Each dusty-rose, round, biconvex tablet, marked 20 on one side, contains: nifedipine 20 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, polyethylene glycol, iron oxide red, lactose, magnesium stearate, microcrystalline cellulose, polysorbate, starch and titanium dioxide. Blister packs in units of 6 strips of 10.

Store below 30°C. Avoid freezing. Protect from light. Broken tablets should not be used. (Shown in Product Recognition Section)

ADALAT® PA 10 ADALAT® PA 20 Bayer Nifedipine Antihypertensive

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