1 INDICATIONS AND USAGE

Verelan® PM (verapamil hydrochloride extended-release capsules) for oral use is indicated for the management of essential hypertension.

2 DOSAGE AND ADMINISTRATION

THE CONTENTS OF THE Verelan PM CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan PM CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE.

2.1 Essential Hypertension

Administer Verelan PM once daily at bedtime. Clinical trials studied doses of 100 mg, 200 mg, 300 mg and 400 mg. The usual daily dose of extended-release Verelan PM in clinical trials has been 200 mg given by mouth once daily at bedtime. In rare instances, initial doses of 100 mg a day may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. (see Use in Specific Populations (8.5, 8.6, 8.7))]. Base upward titration on therapeutic efficacy and safety eva luated approximately 24 hours after dosing. The antihypertensive effects of Verelan PM are evident within the first week of therapy.

If an adequate response is not obtained with 200 mg of Verelan PM, the dose may be titrated upward in the following manner:

a) 300 mg each evening b) 400 mg each evening (2 × 200 mg)

When Verelan PM is administered at bedtime, office eva luation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual eva luation of trough effect, which sometimes might be needed to eva luate the appropriateness of any given dose of Verelan PM, would be just prior to bedtime.

2.2 Sprinkling the Capsule Contents on Food

Verelan PM capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verelan PM capsule is not recommended.

3 DOSAGE FORMS AND STRENGTHS

Extended-release capsules controlled onset: 100 mg, 200 mg, 300 mg.

100 mg: white opaque cap imprinted SCHWARZ/4085 and amethyst body imprinted 100 mg.

200 mg: amethyst opaque cap imprinted SCHWARZ/4086 and amethyst body imprinted 200 mg.

300 mg: lavender opaque cap imprinted SCHWARZ/4087 and amethyst body imprinted 300 mg.

4 CONTRAINDICATIONS

Verapamil is contraindicated in:

• Severe left ventricular dysfunction [see Warnings and Precautions (5.1)].
• Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.
• Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
• Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
• Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Heart Failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 87 (1.8%) developed congestive heart failure or pulmonary edema. Avoid verapamil in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker [see Drug Interactions (7.3)]. Control patients with milder ventricular dysfunction, if possible, with optimum doses of digitalis and/or diuretics before verapamil treatment is started [see Drug Interactions (7.4)].

5.2 Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. In hypertensive patients, decreases in blood pressure below normal are unusual. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials of other verapamil formulations was 2.5% [see Adverse Reactions (6.1)]. In clinical studies of Verelan PM, 1.7% of the patients developed significant hypotension. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

5.3 Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment.

Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

5.4 Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong Levine)

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated [see Contraindications (4)]. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

5.5 Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed in previous verapamil clinical trials [see Adverse Reactions (6.1)].

Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil and institution of appropriate therapy depending upon the clinical situation.

5.6 Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis (IHSS) (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) pulmonary capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine [see Drug Interactions (7.9)] preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2% [see Adverse Reactions (6)]. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5) for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.

The following reactions (Table 1) to orally administered Verelan PM occurred at rates of 2.0% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension.

In previous experience with other formulations of verapamil (N=4,954) the following reactions (Table 2) have occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients.

In clinical trials related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

6.2 Open Trials / Postmarketing Experience

The following reactions, reported with orally administered verapamil in 2.0% or less of patients, occurred under conditions (open verapamil trials, postmarketing experience [reactions added since the initial US approval of Verelan PM in 1998 are marked with an asterisk]) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, atrioventricular dissociation, ECG Abnormal*, chest pain, claudication, hypertension*, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive System: diarrhea, dry mouth, elevated liver enzymes* [see Warnings and Precautions (5.3)], gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic: ecchymosis or bruising.

Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.

Respiratory: dyspnea.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special Senses: blurred vision, tinnitus.

Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, impotence, increased urination, spotty menstruation.

Other: allergy aggravated, asthenia*.

6.3 Treatment of Acute Cardiovascular Adverse Reactions

The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, apply the appropriate emergency measures immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy, use alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) to maintain blood pressure, and isoproterenol and avoid norepinephrine. If further support is necessary, inotropic agents (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage depends on the severity of the clinical situation and the judgment and experience of the treating physician.

7 DRUG INTERACTIONS

7.1 CYP3A4 Inhibitors and Inducers

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil.

7.2 Grapefruit Juice

Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the pharmacokinetics of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

7.3 Beta Blockers

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of extended-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

7.4 Digitalis

Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor d