Afeditab CR

Name: Afeditab CR

US Brand Name

  1. Adalat CC
  2. Afeditab CR
  3. Nifediac CC
  4. Nifedical XL
  5. Procardia
  6. Procardia XL

How supplied

Afeditab® CR, 30 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 30, and are supplied in bottles of 100 and 500.

Afeditab® CR, 60 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 60, and are supplied in bottles of 100 and 500.

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

Manufactured by: Alkermes Pharma Ireland Limited, Athlone, Co. Westmeath, Ireland. Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA. Revised: September 2014

Side Effects of Afeditab CR

Serious side effects have been reported with nifedipine. See the “Drug Precautions” section.

Common side effects of nifedipine include:

  • swelling
  • headache
  • fatigue
  • dizziness
  • constipation
  • nausea
  • flushing
  • weakness

This is not a complete list of nifedipine side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Afeditab CR Interactions

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • beta blockers such as metoprolol (Lopressor, Toprol XL), atenolol (Tenormin), propranolol (Inderal, Inderal LA), and carvedilol (Coreg)
  • digoxin (Lanoxin)
  • quinidine (Cardioquine, Quinact, Duraquin)
  • warfarin (Coumadin, Jantoven)
  • cimetidine (Tagamet)
  • medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, and nimodipine (Nimotop)

This is not a complete list of nifedipine drug interactions. Ask your doctor or pharmacist for more information.

Afeditab CR and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Nifedipine falls into category C. There are no well-controlled studies in pregnant women. Nifedipine should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

What should I discuss with my healthcare provider before taking Afeditab CR (nifedipine)?

You should not use this medicine if you are allergic to nifedipine, if you have severe coronary artery disease, or if you have had a heart attack within the past 2 weeks.

To make sure nifedipine is safe for you, tell your doctor if you have:

  • severe COPD (chronic obstructive pulmonary disease);

  • kidney disease;

  • congestive heart failure; or

  • if you take other medications, especially an antibiotic or antifungal medicine, an antidepressant, heart or blood pressure medicine, or drugs to treat HIV/AIDS or hepatitis C.

It is not known whether nifedipine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Nifedipine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

The nifedipine extended-release tablet may contain lactose. Talk to your doctor before using this form of nifedipine if you have galactose intolerance, or severe problems with lactose (milk sugar).

Afeditab CR 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, C17H18N2O6, 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.

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.

Afeditab CR - 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.

Hemodynamics:

Like other slow-channel blockers, nifedipine 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, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5 to 10 mm Hg systolic), but sometimes larger. With nifedipine extended-release tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies of the immediate release nifedipine formulation 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.

Electrophysiologic Effects:

Although, like other members of its class, nifedipine causes a slight depression of 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 electro-physiologic studies, predominantly in patients with normal conduction systems, nifedipine administered as the immediate release capsule has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Afeditab CR Dosage and Administration

Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablets be administered orally once daily on an empty stomach. Afeditab® CR is an extended release dosage form and tablets should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7 to 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 Afeditab® CR 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 CLINICAL PHARMACOLOGY and PRECAUTIONS).

Care should be taken when dispensing Afeditab® CR to assure that the extended-release dosage form has been prescribed.

How is Afeditab CR Supplied

Afeditab® CR, 30 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 30, and are supplied in bottles of 100 and 500.

Afeditab® CR, 60 mg, is available as round, brownish-red, film-coated, unscored tablets, imprinted with ELN 60, and are supplied in bottles of 100 and 500.

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

Manufactured by:
Alkermes Pharma Ireland Limited
Athlone, Co. Westmeath, Ireland

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Revised: September 2014

40-9252

Side effects

Adverse Experiences

The incidence of adverse events during treatment with nifedipine extended-release tablets 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 nifedipine extended-release tablets and in 64 of the 126 patients on placebo. All adverse events reported during nifedipine extended-release tablets therapy were tabulated independently of their causal relationship to medication.

The most common adverse event reported with nifedipine extended-release tablets was peripheral edema. This was dose related and the frequency was 18% on nifedipine extended-release tablets 30 mg daily, 22% on nifedipine extended-release tablets 60 mg daily and 29% on nifedipine extended-release tablets 90 mg daily versus 10% on placebo.

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

Adverse Event NIFEDIPINE EXTENDED-RELEASE TABLETS(%)
(n=370)
PLACEBO (%)
(n=126)
Headache 19 13
Flushing/heat 4 0
Dizziness 4 2
Fatigue/asthenia 4 4
Nausea 2 1
Constipation 1 0

Where the frequency of adverse events with nifedipine extended-release tablets 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:

Body as a Whole/Systemic: chest pain, leg pain

Central Nervous System: paresthesia, vertigo

Dermatologic: rash

Gastrointestinal: constipation

Musculoskeletal: leg cramps

Respiratory: epistaxis, rhinitis

Urogenital: impotence, urinary frequency

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

Body as a Whole/Systemic: allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction

Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases

Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence

Dermatologic: angioedema, petechial rash, pruritus, sweating

Gastrointestinal: abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting

Hematologic: eosinophilia, lymphadenopathy

Metabolic: gout, weight loss

Musculoskeletal: arthralgia, arthritis, joint disorder, myalgia, myasthenia

Respiratory: dyspnea, increased cough, rales, pharyngitis, stridor

Special Senses : abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus

Urogenital/Reproductive: dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder

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.

Read the entire FDA prescribing information for Afeditab CR (Nifedipine Extended-Release Tablets)

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