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ADALAT® (nifedipine) is an antianginal drug belonging to a class of pharmacological agents, the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C 17 H 18 N 2 O 6 , and has the structural formula:
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Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. ADALAT® CAPSULES are formulated as soft gelatin capsules for oral administration each containing 10 mg or 20 mg of nifedipine.
Inert ingredients in the formulations are: glycerin, peppermint oil, polyethylene glycol 400; soft gelatin capsules (which contain FD&C Yellow No. 6, Red Ferric Oxide and other inert ingredients), and water. The 10 mg capsules also contain saccharin sodium.
ADALAT® is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. ADALAT® selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without changing serum calcium concentrations.
The precise means by which this inhibition relieves angina has not been fully determined, but includes at least the following two mechanisms:
ADALAT® dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of ADALAT® in vasospastic (Prinzmetal's or variant) angina. Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.
ADALAT® regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of ADALAT® in chronic stable angina.
ADALAT® is rapidly and fully absorbed after oral administration. The drug is detectable in serum 10 minutes after oral administration, and peak blood levels occur in approximately 30 minutes. Bioavailability is proportional to dose from 10 to 30 mg; half-life does not change significantly with dose. There is little difference in relative bioavailability when ADALAT® capsules are given orally and swallowed whole, bitten and swallowed, or bitten and held sublingually. However, biting through the capsule prior to swallowing does result in slightly earlier plasma concentrations (27 ng/mL 10 minutes after 10 mg) than if capsules are swallowed intact. It is highly bound by serum proteins. ADALAT® is extensively converted to inactive metabolites and approximately 80 percent of ADALAT® and metabolites are eliminated via the kidneys. The half-life of nifedipine in plasma is approximately two hours. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
In healthy subjects, the elimination half-life of a sustained release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration.
Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max , due to inhibition of CYP3A4 related first-pass metabolism.
Like other slow channel blockers, ADALAT® exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, ADALAT® causes decreased peripheral vascular resistance and a fall in systolic and diastolic pressure, usually modest (5-10mm Hg systolic), but sometimes larger. There is usually a small increase in heart rate, a reflex response to vasodilation. Measurements of cardiac function in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.
Although like other members of its class, ADALAT® decreases sinoatrial node function and atrioventricular 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 system, ADALAT® has had no tendency to prolong atrioventricular conduction, prolong sinus node recovery time, or slow sinus rate.
ADALAT® (nifedipine) is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. ADALAT® may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta blockers.
ADALAT® is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate dose of beta blockers and/or organic nitrates or who cannot tolerate those agents.
In chronic stable angina (effort-associated angina) ADALAT® has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long term safety in these patients are incomplete.
Controlled studies in small numbers of patients suggest concomitant use of ADALAT® and beta blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction 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 ).
Known hypersensitivity reaction to ADALAT®.
Although in most patients, the hypotensive effect of ADALAT® CAPSULES is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. 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.
Although not approved for this purpose, ADALAT® CAPSULES and other immediate-release nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe profound hypotension, myocardial infarction, and death when immediate-release nifedipine capsules were used in this way. ADALAT® CAPSULES should not be used for acute reduction of blood pressure.
ADALAT® CAPSULES and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension although no properly-controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. ADALAT® CAPSULES should not be used for the control of essential hypertension.
Several well-controlled, randomized trials studied the use of immediate-release nifedipine capsules in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. ADALAT® CAPSULES should not be administered for 1 week after myocardial infarction, and it should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving ADALAT® 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 ADALAT® and a beta blocker, but the possibility that it may occur with ADALAT® alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In ADALAT® treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient' condition permits, sufficient time (at least 36 hours) should be allowed for ADALAT® to be washed out of the body prior to surgery.
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 ADALAT® or at the time of dosage increase. The mechanism of this effect is not established.
Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of ADALAT® 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 ADALAT® initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning ADALAT®.
Rarely, patients (usually those receiving a beta blocker) have developed heart failure after beginning ADALAT®. Patients with tight aortic stenosis may be at greater risk for such an event since the unloading effect of ADALAT® would be expected to be of less benefit to these patients, owing to the fixed impedance to flow across the aortic valve.
General: Hypotension: Because ADALAT® decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of ADALAT® is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (See ).
Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients treated with ADALAT® (nifedipine). 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.
Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to ADALAT® therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
ADALAT®, like other calcium channel blockers, decreases platelet aggregation in vitro . Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in some ADALAT® patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia has been reported.
Although ADALAT® has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect in certain cases, rare reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to ADALAT® therapy is uncertain in most cases but probable in some.
Drug Interactions: Beta-adrenergic blocking agents : (See INDICATIONS and ). Experience in over 1400 patients in a non-comparative clinical trial has shown that concomitant administration of ADALAT® and beta blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina.
Long acting nitrates: ADALAT® may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine to avoid possible over- or under-digitalization.
Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom ADALAT® was administered. However, the relationship to ADALAT® therapy is uncertain.
Cimetidine A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.
Quinidine There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine).
Grapefruit Juice: Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max , due to inhibition of CYP3A4 related first-pass metabolism. Co-administration of nifedipine with grapefruit juice is to be avoided.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
Pregnancy: Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentoxic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within one order of magnitude of it.
The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. ADALAT® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use: Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (See : and Metabolism ), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In multiple-dose U.S. and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of ADALAT®.
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There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The most common adverse events were:
Cardiovascular peripheral edema
Cardiovascular: palpitation
Respiratory: nasal and chest congestion, shortness of breath
Gastrointestinal: diarrhea, constipation, cramps, flatulence
Musculoskeletal: inflammation, joint stiffness, muscle cramps
Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance
Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties.
Cardiovascular syncope. Syncopal episodes occurred mostly with initial dose and/or increase of dosage.
Hematologic: thrombocytopenia, anemia, leukopenia, purpura
Gastrointestinal: allergic hepatitis
Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia
CNS: depression, paranoid syndrome
Musculoskeletal: myalgia
Special Senses: transient blindness at the peak of plasma level
Urogenital: nocturia, polyuria
Other: erythromelalgia, arthritis with ANA (+), gynecomastia, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of ADALAT® therapy was associated with an increase in anginal pain, possibly due to associated hypotension.
In addition, more serious adverse events were 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. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving ADALAT® with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of ADALAT® (nifedipine) treated patients (See PRECAUTIONS ).
In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.
Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
The dosage of ADALAT® needed to suppress angina and that can be tolerated by the patient must be established by titration. Excessive doses can result in hypotension.
Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10-20 mg three 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 20-30 mg three or four times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg per day is not recommended.
In most cases, ADALAT® titration should proceed over a 7-14 day period so that the physician can assess the response to each dose level and monitor the blood pressure before proceeding to higher doses.
If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed frequently. Based on the patient' physical activity level, attack frequency, and sublingual nitroglycerin consumption, the dose of ADALAT® CAPSULES may be increased from 10 mg t.i.d. to 20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period.
In hospitalized patients under close observation, the dose may be increased in 10 mg increments over four to six-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg.
No "rebound effect" has been observed upon discontinuation of ADALAT®. However, if discontinuation of ADALAT® is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision.
Co-administration of nifedipine with grapefruit juice is to be avoided (See and PRECAUTIONS ).
Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during ADALAT® titration. See PRECAUTIONS , Drug Interactions , for information on co-administration of ADALAT® with beta blockers or long acting nitrates.
ADALAT® soft gelatin capsules are supplied in:
Bottles of 100: 10 mg (NDC 0026-8811-51) orange
20 mg (NDC 0026-8821-51) orange and light brown
Bottles of 300: 10 mg (NDC 0026-8811-18) orange
20 mg (NDC 0026-8821-18) orange and light brown
Unit dose packages of 100: 10 mg (NDC 0026-8811-48) orange
20 mg (NDC 0026-8821-48) orange and light brown
The capsules are identified as follows: 10 mg (Adalat 10), 20 mg (Adalat 20).
The capsules should be protected from light and moisture and stored at controlled room temperature 59° to 77°F (15° to 25°C). Dispense in tight, light resistant containers (USP).
Bayer Corporation
Pharmaceutical Division
West Haven, CT 06516 USA
Encapsulated by
R. P. Scherer N.A., Clearwater, FL 33518
Rx Only
PZ500138 6/00 BAY a 1040 9749 ©2000 Bayer Corporation
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