Action And Clinical Pharmacology: Nifedipine is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). The antianginal effect of this group of drugs is believed to be related to its specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Nifedipine blocks 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 cells of the above tissues. Nifedipine does not alter total serum calcium.
The specific mechanism by which nifedipine relieves angina has not been fully determined, but it is believed to be brought about largely by its vasodilatory action.
Nifedipine dilates the main coronary arteries and coronary arterioles both in normal and ischemic regions and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery and is responsible for the effectiveness of nifedipine in vasospastic angina.
Nifedipine, by its vasodilatory action on peripheral arterioles, reduces the total peripheral vascular resistance. This reduces the workload of the heart and thus reduces the myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of nifedipine in chronic stable angina.
The negative inotropic effect of nifedipine 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.
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, oral administration of 10 mg 4-nifedipine resulted in more than 90% absorption of the drug. Radioactivity was detectable in the serum 20 minutes after oral ingestion and peak serum levels were reached in 1 to 2 hours. 70 to 80% of the activity was eliminated via the kidneys and the remainder via the feces.
The bi-exponential analysis of the disappearance of nifedipine in the plasma yields an initial fast half-life (T1/2a) of 2.5 to 3 hours and a terminal slow half-life (Tt1/2) of 5 hours.
Studies in man, dog, and rat showed that nifedipine is almost completely metabolized in the body. It is transformed into 2 pharmacologically inactive metabolites. The main metabolite is the hydroxycarboxylic acid derivative which represents about 95%. The other is the corresponding lactone, which represents 5%. The acid form is mainly excreted in the urine. 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 of 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: For the management of angina resulting from coronary artery spasm.
For the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates, or who cannot tolerate those agents.
Nifedipine may be used in combination with beta-blocking drugs in patients with chronic stable angina. However, information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac condition abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs (see Warnings).
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 nifedipine to pregnant mice, rats and rabbits. Fetal malformations occurred after the administration of 30 and 100 mg/kg of nifedipine to pregnant mice and 100 mg/kg to pregnant rats.
In patients with acute myocardial infarction (See Warnings, Patients With Myocardial Infarction).
In patients with cardiovascular shock.
In patients with hypersensitivity to nifedipine.
In patients with severe hypotension.
Manufacturers’ Warnings In Clinical States: Nifedipine should be used with care in the following conditions:
Excessive Hypotension: Since nifedipine lowers peripheral vascular resistance and blood pressure, it should be used cautiously in patients who are prone to develop hypotension. Occasional patients have had excessive and poorly tolerated hypotension. Syncope has been reported (see Adverse Effects). These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta-blockers. If excessive hypotension occurs, dosage should be lowered or the drug should be discontinued (see Contraindications).
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta-blocker, but with the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient’s condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
Patients With Myocardial Infarction: Immediate-release nifedipine should not be used within 1 week after myocardial infarction and not before the patient has stabilized. Randomized, placebo-controlled clinical trials have indicated that nifedipine may increase the risk of reinfarction and worsen survival in patients treated early after myocardial infarction.
Patients With Unstable Angina: Some clinical trials have shown that treatment with immediate-release nifedipine in this setting increases the risk of myocardial infarction and recurrent ischemia.
Hypertension: Immediate-release nifedipine should not be used for the management of essential hypertension.
Acute Reduction of Blood Pressure: Immediate-release nifedipine should not be used for acute reduction of blood pressure. Strokes have occurred when nifedipine was used in this setting.
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.
Beta-Blocker Withdrawal: Patients 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 nifedipine initiation. It is important to taper beta-blockers if possible, rather than stopping them abruptly before beginning nifedipine.
Patients With Heart Failure: There have been isolated reports of severe hypotension and 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: Hypotension: Because nifedipine is an arterial and arteriolar vasodilator, hypotension, and a compensatory increase in heart rate may occur. Thus, blood pressure and heart rate should be monitored carefully during nifedipine therapy. Close observation is especially recommended for patients who are prone to develop hypotension, those with a history of cerebrovascular insufficiency, and those who are taking medications that are known to lower blood pressure (see Warnings).
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 angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
Geriatrics: Nifedipine should be administered cautiously to elderly patients, especially to those with a history of hypotension or cerebral vascular insufficiency (see Dosage).
Diabetic Patients: The use of nifedipine in diabetic patients may require adjustment of their control.
Patients With Impaired Liver Function: Use 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 P450 include: benzodiazepines, flecainide, theophylline, imipramine and propafenone.
The antihypertensive effect of beta-blockers may be augmented by nifedipine’s reduction of peripheral vascular resistance. The concomitant administration of nifedipine with beta-adrenergic blocking drugs warrants caution and careful monitoring of the blood pressure and pulmonary signs and symptoms of congestive failure (see Warnings).
Long-acting Nitrates: Nifedipine may be safely coadministered with nitrates but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
Antihypertensives: Nifedipine may potentiate the effects of hypotensive agents.
Concomitant use of nifedipine with short-acting nitrates, furosemide and anticoagulants has shown no interaction or unusual toxic effects.
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: A safety analysis from the world literature (controlled and open studies) was carried out in a heterogeneous group of 7 146 patients who were treated with nifedipine. Adverse effects were reported in 27.9% of patients and required discontinuation of treatment in 5.5% of patients.
The most common adverse effects, which generally result from nifedipine’s vasodilating effects, were: headache (7.2%); dizziness, lightheadedness and giddiness (6.7%); nausea, vomiting and gastrointestinal distress (6.7%); flushing and heat sensation (5.8%); peripheral edema (3.7%) and hypotension (2.0%).
As a part of the above analysis, a more comprehensive safety evaluation (controlled and open studies) was carried out in 3 074 patients, some of whom were severely ill and were receiving a variety of concomitant drugs, such as beta-blockers, nitrates, antiarrhythmics, cardiac glycosides, diuretics and antiplatelet drugs, etc.
The following adverse effects divided by systems were reported in these 3 074 patients:
Cardiovascular: peripheral edema, fluid retention, swelling (8.3%); flushing, heat sensation (7.4%); hypotension (3.5%); palpitation and increased heart rate (2.6%); syncope (0.4%).
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 included myocardial infarction, congestive heart failure or pulmonary edema, and ventricular arrhythmias or conduction disturbances.
CNS: dizziness, lightheadedness, giddiness (11.9%); headache (7.8%); general weakness (6.3%); shakiness, nervousness and jitteriness (1.9%); sleep disturbances (1.1%); blurred vision (0.9%); depression (0.6%).
Gastrointestinal: nausea and vomiting (6.4%); abdominal discomfort and heartburn (2.0%); diarrhea (0.9%); constipation (0.6%).
Musculoskeletal: joint stiffness, muscle pain and cramps (4.3%).
Respiratory Tract: shortness of breath, dyspnea (1.3%); nasal congestion (0.5%).
Others: pruritus, dermatitis, urticaria and rash (1.9%); fever, sweating and chills (1.4%).
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 resulting in an allergic hepatitis which resolved when the drug was discontinued. In 1 case, recurrence was observed on rechallenge.
Nifedipine has been reported to cause, in a small number of patients, gingival hyperplasia similar to that caused by diphenylhydantoin. The lesions usually regressed on discontinuation of nifedipine. 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. 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: In all cases, dosage should be adjusted to individual patient requirements.
The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10 to 20 mg 3 times daily. Some patients, especially those with evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or both. In such patients, doses of 20 to 30 mg 3 or 4 times daily may be effective. A maximum daily dose of 120 mg may be used.
In general, there should be an interval of at least 3 days between increases in dose in order to adequately assess the response to a particular dose level. In hospitalized patients under close observation, the titration phase may proceed more rapidly.
Nifedipine should be administered cautiously to elderly patients and the dosage should be carefully and gradually adjusted depending on patient tolerance and response (see Precautions).
Adalat 5 mg capsules provide for greater flexibility of dose titration, e.g., in elderly patients.
Availability And Storage: 5 mg: Each gelatin capsule contains: nifedipine 5 mg. Nonmedicinal ingredients: gelatin, glycerol, iron oxide yellow, peppermint oil, polyethylene glycol, purified water and titanium dioxide. Bottles of 100.
10 mg: Each gelatin capsule contains: nifedipine 10 mg. Nonmedicinal ingredients: gelatin, glycerol, iron oxide yellow, peppermint oil, polyethylene glycol, purified water and titanium dioxide. Bottles of 500. Blister packs of 120 (12-10 capsules).
Store below 30°C and avoid freezing. Protect from light. (Shown in Product Recognition Section)
ADALAT® Bayer Nifedipine Antianginal
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