Adalat cc (Nifedipine) is an extended release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, CHNO, and has the structural formula:

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Adalat cc (Nifedipine) tablets consist of an external coat and an internal core. Both contain nifedipine, the coat as a slow release formulation and the core as a fast release formulation. Adalat cc (Nifedipine) tablets contain either: 30, 60, or 90 mg of nifedipine for once-a-day oral administration.

Inert ingredients in the formulation are: hydroxypropylcellulose, lactose, corn starch, crospovidone, microcrystalline cellulose, silicon dioxide, and magnesium stearate. The inert ingredients in the film coating for Adalat cc (Nifedipine) 30 and 60 are: hypromellose, polyethylene glycol, ferric oxide, and titanium dioxide. The inert ingredients in the film coating for Adalat cc (Nifedipine) 90 are: hypromellose, polyethylene glycol and ferric oxide

Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of vascular smooth muscle and cardiac muscle without altering serum calcium concentrations.

The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and, consequently, a reduction in peripheral vascular resistance. The increased peripheral vascular resistance, an underlying cause of hypertension, results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.

Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.

Nifedipine is completely absorbed after oral administration. The bioavailability of nifedipine as Adalat cc (Nifedipine) relative to immediate release nifedipine is in the range of 84%-89%. After ingestion of Adalat cc (Nifedipine) tablets under fasting conditions, plasma concentrations peak at about 2.5-5 hours with a second small peak or shoulder evident at approximately 6-12 hours post dose. The elimination half-life of nifedipine administered as Adalat cc (Nifedipine) is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule.

When Adalat cc (Nifedipine) is administered as multiples of 30 mg tablets over a dose range of 30 mg to 90 mg, the area under the curve (AUC) is dose proportional; however, the peak plasma concentration for the 90 mg dose given as 3 x 30 mg is 29% greater than predicted from the 30 mg and 60 mg doses.

Two 30 mg Adalat cc (Nifedipine) tablets may be interchanged with a 60 mg Adalat cc (Nifedipine) tablet. Three 30 mg Adalat cc (Nifedipine) tablets, however, result in substantially higher C values than those after a single 90 mg Adalat cc (Nifedipine) tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.

Once daily dosing of Adalat cc (Nifedipine) under fasting conditions results in decreased fluctuations in the plasma concentration of nifedipine when compared to t.i.d. dosing with immediate release nifedipine capsules. The mean peak plasma concentration of nifedipine following a 90 mg Adalat cc (Nifedipine) tablet, administered under fasting conditions, is approximately 115 ng/mL. When Adalat cc (Nifedipine) is given immediately after a high fat meal in healthy volunteers, there is an average increase of 60% in the peak plasma nifedipine concentration, a prolongation in the time to peak concentration, but no significant change in the AUC. Plasma concentrations of nifedipine when Adalat cc (Nifedipine) is taken after a fatty meal result in slightly lower peaks compared to the same daily dose of the immediate release formulation administered in three divided doses. This may be, in part, because Adalat cc (Nifedipine) is less bioavailable than the immediate release formulation.

Nifedipine is extensively metabolized to highly water soluble, inactive metabolites accounting for 60% to 80% of the dose excreted in the urine. Only traces (less than 0.1% of the dose) of the unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.

Nifedipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine.

No studies have been performed with Adalat cc (Nifedipine) in patients with renal failure; however, significant alterations in the pharmacokinetics of nifedipine immediate release capsules have not been reported in patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis. Since the absorption of nifedipine from Adalat cc (Nifedipine) could be modified by renal disease, caution should be exercised in treating such patients.

Because nifedipine is metabolized via the cytochrome P450 3A4 system, its pharmacokinetics may be altered in patients with chronic liver disease. Adalat cc (Nifedipine) has not been studied in patients with hepatic disease; however, in patients with hepatic impairment (liver cirrhosis) nifedipine has a longer elimination half-life and higher bioavailability than in healthy volunteers.

The degree of protein binding of nifedipine is high (92%-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

After administration of Adalat cc (Nifedipine) to healthy elderly men and women (age > 60 years), the mean C is 36% higher and the average plasma concentration is 70% greater than in younger patients.

In healthy subjects, the elimination half-life of a different 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 Cdue to inhibition of CYP3A related first-pass metabolism. Ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

Adalat cc (Nifedipine) produced dose-related decreases in systolic and diastolic blood pressure as demonstrated in two double-blind, randomized, placebo-controlled trials in which over 350 patients were treated with Adalat cc (Nifedipine) 30, 60 or 90 mg once daily for 6 weeks. In the first study, Adalat cc (Nifedipine) was given as monotherapy and in the second study, Adalat cc (Nifedipine) was added to a beta-blocker in patients not controlled on a beta-blocker alone. The mean trough (24 hours post-dose) blood pressure results from these studies are shown below:

The trough/peak ratios estimated from 24 hour blood pressure monitoring ranged from 41%-78% for diastolic and 46%-91% for systolic blood pressure.

Adalat cc (Nifedipine) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Concomitant administration with strong P450 inducers, such as rifampin, are contraindicated since the efficacy of nifedipine tablets could be significantly reduced. (See.)

Nifedipine must not be used in cases of cardiogenic shock.

Adalat is contraindicated in patients with a known hypersensitivity to any component of the tablet.

Although in most patients the hypotensive effect of nifedipine 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 using concomitant beta-blockers.

Severe hypotension and/or increased fluid volume requirements have been reported in patients who received immediate release capsules together with a beta-blocking agent and 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 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.

Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to nifedipine 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. A small increase (
Nifedipine, like other calcium channel blockers, decreases platelet aggregation . Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in some nifedipine 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 or without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.

Although nifedipine 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 nifedipine therapy is uncertain in most cases but probable in some.

The incidence of adverse events during treatment with Adalat cc (Nifedipine) in doses up to 90 mg daily were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg once daily was used concomitantly in 187 of the 370 patients on Adalat cc (Nifedipine) and in 64 of the 126 patients on placebo. All adverse events reported during Adalat cc (Nifedipine) therapy were tabulated independently of their causal relationship to medication.

The most common adverse event reported with Adalat cc (Nifedipine) was peripheral edema. This was dose related and the frequency was 18% on Adalat cc (Nifedipine) 30 mg daily, 22% on Adalat cc (Nifedipine) 60 mg daily and 29% on Adalat cc (Nifedipine) 90 mg daily versus 10% on placebo.

Other common adverse events reported in the above placebo-controlled trials include:

Where the frequency of adverse events with Adalat cc (Nifedipine) and placebo is similar, causal relationship cannot be established.

The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg:

Other adverse events reported with an incidence of less than 1.0% were:

The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor and urticaria.

Experience with nifedipine overdosage is limited. Symptoms associated with severe nifedipine overdosage include loss of consciousness, drop in blood pressure, heart rhythm disturbances, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema. 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. After oral ingestion, thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. In cases involving overdosage of a slow-release product like nifedipine, elimination must be as complete as possible, including from the small intestine, to prevent the subsequent absorption of the active substance.Additional liquid or volume must be administered with caution because of the risk of fluid overload.

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.

There has been one reported case of massive overdosage with tablets of another extended release formulation of nifedipine. The main effects of ingestion of approximately 4800 mg of nifedipine in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post ingestion. Blood chemistry abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed.

The effect of a single 900 mg ingestion of nifedipine capsules in a depressed anginal patient on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment.

A young hypertensive patient with advanced renal failure ingested 280 mg of nifedipine capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.

Bradycardiac heart rhythm disturbances may be treated symptomatically with ß-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable.

Dosage should be adjusted according to each patient’s needs. It is recommended that Adalat cc (Nifedipine) be administered orally once daily on an empty stomach. Adalat cc (Nifedipine) is an extended release dosage form and tablets should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7-14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended.

If discontinuation of Adalat cc (Nifedipine) 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 ).

Care should be taken when dispensing Adalat cc (Nifedipine) to assure that the extended release dosage form has been prescribed.

Adalat cc (Nifedipine) extended release tablets are supplied as 30 mg, 60 mg, and 90 mg round film coated tablets. The different strengths can be identified as follows:

Adalat cc (Nifedipine) Tablets are supplied in:

The tablets should be protected from light and moisture and stored below 86°F (30°C). Dispense in tight, light-resistant containers.

Manufactured by:

Bayer HealthCare Pharmaceuticals Inc.Wayne, NJ 07470Made in Germany

Distributed by:

Schering Corporation, subsidiary of Whitehouse Station, NJ 08889, USA

Adalat is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering Corporation.

08935206, R.3 2/11

©2011 Bayer HealthCare Pharmaceuticals Inc. Printed in U.S.A.