Afeditab CR

AFEDITAB CR- nifedipine tablet, film coated, extended release
Carilion Materials Management

AFEDITAB® CR
(NIFEdipineExtended-Release Tablets)

Revised: September 2014

Rx only

40-9252

DESCRIPTION

Afeditab® CR 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, C17 H18 N2 O6 , and has the structural formula:

nifedipine structural formula
(click image for full-size original)

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3.

Afeditab® CR tablets contain either 30 mg or 60 mg of nifedipine for once-a-day oral administration.

Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate (60 mg), magnesium stearate, and microcrystalline cellulose (30 mg). The inert ingredients in the film coating are: hypromellose, iron oxide, polyethylene glycol, and titanium dioxide. The ingredients of the printing ink are: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.

Does not meet USP Drug Release Test.

CLINICAL PHARMACOLOGY

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.

Mechanism of Action:

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 that is 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.

Pharmacokinetics and Metabolism:

Nifedipine is completely absorbed after oral administration. The bioavailability of nifedipine as Afeditab® CR relative to immediate release nifedipine is in the range of 84%-89%. After ingestion of Afeditab® CR 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 Afeditab® CR is approximately 7 hours in contrast to the known 2 hour elimination half-life of nifedipine administered as an immediate release capsule.

When Afeditab® CR 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 Afeditab® CR tablets may be interchanged with a 60 mg Afeditab® CR tablet. Three 30 mg Afeditab CR tablets, however, result in substantially higher Cmax values than those after a single 90 mg Afeditab® CR tablet. Three 30 mg tablets should, therefore, not be considered interchangeable with a 90 mg tablet.

Once daily dosing of nifedipine extended-release tablets 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 nifedipine extended-release tablets, administered under fasting conditions, is approximately 115 ng/mL. When nifedipine extended-release tablets 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 nifedipine extended-release tablets 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 nifedipine extended-release tablets are 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.

No studies have been performed with nifedipine extended-release tablets 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 Afeditab® CR could be modified by renal disease, caution should be exercised in treating such patients.

Because hepatic biotransformation is the predominant route for the disposition of nifedipine, its pharmacokinetics may be altered in patients with chronic liver disease. Nifedipine extended-release tablets have 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 nifedipine extended-release tablets to healthy elderly men and women (age > 60 years), the mean Cmax 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 Cmax , due to inhibition of CYP3A4 related first-pass metabolism.

Clinical Studies:

Nifedipine extended-release tablets 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 nifedipine extended-release tablets 30, 60 or 90 mg once daily for 6 weeks. In the first study, nifedipine extended-release tablets was given as monotherapy and in the second study, nifedipine extended-release tablets 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:

MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg) SYSTOLIC/DIASTOLIC
* Placebo response subtracted.
STUDY 1
NIFEDIPINE EXTENDED-
RELEASE TABLETS MEAN TROUGH
DOSE N REDUCTION *
30 MG 60 5.3/2.9
60 MG 57 8.0/4.1
90 MG 55 12.5/8.1
STUDY 2
NIFEDIPINE EXTENDED-
RELEASE TABLETS MEAN TROUGH
DOSE N REDUCTION *
30 MG 58 7.6/3.8
60 MG 63 10.1/5.3
90 MG 62 10.2/5.8

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

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