Chronovera (Verapamil HCl)

CHRONOVERA®

Searle

Verapamil HCl

Antihypertensive – Antianginal Agent

System Components and Performance: Chronovera is a formulation designed to initiate the release of verapamil approximately 4 to 5 hours after ingestion by means of a delay coating and thereafter to provide a constant rate of release over 12 hours. The tablet is comprised of a semipermeable membrane surrounding a drug core that is osmotically active. The core itself is divided into 2 layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert, but osmotically active, components.

Delay in release of verapamil after ingestion is accomplished by the introduction of a coating between the active drug core and outer semipermeable membrane. As water from the gastrointestinal tract enters the tablet, this delay coating is solubilized and released. As tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing drug through precision laser-drilled orifices in the outer membrane at a constant rate. This controlled rate of drug delivery in the gastrointestinal lumen is independent of posture, pH, gastrointestinal motility, and fed or fasting conditions.

The biologically inert components of the delivery system remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell (see Warnings, Patients With Pre-existing Gastrointestinal Narrowing or Transit Disorders).

Action And Clinical Pharmacology: Verapamil is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist) that exerts its pharmacological effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conducting and contractile myocardial cells.

Verapamil exerts antihypertensive effects by inducing vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. Verapamil does not blunt hemodynamic response to isometric or dynamic exercise.

Verapamil depresses AV nodal conduction and prolongs functional refractory periods. Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibres.

Verapamil may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see Warnings, Accessory Bypass Tract). Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis.

Verapamil is a potent smooth muscle relaxant with vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences.

Compared to baseline, verapamil does not affect electrolytes, glucose and creatinine. The hypotensive effect of verapamil is not blunted by an increase in sodium intake.

In hypertensive normolipidemic patients, verapamil had no effects on plasma lipoprotein fractions.

Pharmacodynamics: In a study in 5 healthy males, the S enantiomer of verapamil was found to be 8 to 20 times more active than the R enantiomer in slowing AV conduction. In another study using septal strips isolated from the left ventricle of 5 patients with mitral disease, the S enantiomer was 8 times more potent than the R enantiomer in reducing myocardial contractility.

Pharmacokinetics: Upon oral administration of verapamil, rapid stereoselective biotransformation occurs during the first pass through the portal circulation. The systemic concentrations of R and S enantiomers are dependent upon the route administration and the rate and extent of release from the dosage form.

The following bioavailability information was obtained from healthy volunteers and not from the populations most likely to be treated with verapamil.

In a study in 5 healthy volunteers with oral immediate-release verapamil, the systemic bioavailability varied from 33 to 65% for the R enantiomer and from 13 to 34% for the S enantiomer. The S enantiomer is pharmacologically more active than the R enantiomer (see Pharmacology, Pharmacodynamics).

There is a nonlinear correlation between the verapamil dose administered and verapamil plasma levels. In early dose titration with verapamil, a relationship exists between total verapamil (R and S combined) plasma concentration and prolongation of the PR interval. The mean elimination half-life in single-dose studies of immediate release verapamil ranged from 2.8 to 7.4 hours. In these same studies, after steady-state was reached, the half-life increased to a range from 4.5 to 12 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. Aging decreases the clearance and elimination of verapamil.

In healthy men, orally administered verapamil undergoes extensive metabolism by the cytochrome P450 system in the liver. The particular isoenzymes involved are CYP 3A4, CYP 1A2, CYP 2C family. Thirteen metabolites have been identified in urine. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3 to 4% is excreted in the urine as unchanged drug. R-verapamil is 94% bound to plasma albumin, while S-verapamil is 88% bound. In addition, R-verapamil is 92% and S-verapamil 86% bound to alpha-1 acid glycoprotein. The degree of biotransformation during the first pass of verapamil may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours. (See Warnings – Hepatic Insufficiency and Dosage).

Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil is excreted in human milk.

Formulation Specific Information: Racemic verapamil is released from Chronovera at a constant rate following solubilization of the delay coat (see System Components and Performance). This process produces a lag period in drug release of approximately 4 to 5 hours, followed by prolonged drug release over 12 hours. Peak plasma concentration (Cmax) occurs in the morning hours approximately 11 hours after administration, to coincide with the normal circadian rise in blood pressure and heart rate, when Chronovera is administered at bedtime. Trough concentrations occur approximately 4 hours after bedtime dosing while the patient is sleeping.

The clinical benefit of presenting peak, rather than trough, plasma levels of verapamil in the morning has not been established.

Steady-state pharmacokinetics were reached by the third or fourth day of dosing, as determined in healthy volunteers

In older subjects (65 to 80 years), the Cmax for S-verapamil increased by 1.7-fold and for R-verapamil increased by 1.45-fold, in comparison to values in younger subjects (19 to 53 years) when studied at 180 mg. The AUC for S-verapamil increased by 2-fold and for R-verapamil increased by 1.65-fold. Lean body weight also affects its pharmacokinetics inversely, but no gender difference was observed to date with Chronovera.

Consumption of a high fat meal just prior to dosing at night had no significant effect on the pharmacokinetics of Chronovera. The pharmacokinetics were also not affected by whether the volunteers were supine or ambulatory for the 8 hours following dosing. Administering Chronovera in the morning led to a slower rate of absorption and/or elimination, but did not affect the extent of absorption or extent of metabolism to norverapamil.

Indications And Clinical Uses: In the treatment of mild to moderate essential hypertension. Verapamil should normally be used in those patients in whom treatment with diuretics or b-blockers has been associated with unacceptable response or adverse effects.

Chronovera can be tried as an initial agent in those patients in whom the use of diuretics and/or b-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

Verapamil should not be used concurrently with b-adrenoreceptor blockers in the treatment of hypertension (see Precautions, Drug Interactions).

Chronovera is also indicated in the treatment of chronic stable angina pectoris.

Contra-Indications: Complicated myocardial infarction (patients who have ventricular failure manifested by pulmonary congestion); severe congestive heart failure and/or severe left ventricular systolic dysfunction.

Manufacturers’ Warnings In Clinical States: General: In hypertensive patients also using antianginal or antiarrhythmic agents, the additional hypotensive effect of verapamil should be taken into consideration.

Heart Failure: Because of the drug’s negative inotropic effect, verapamil should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by a dysrhythmia. If verapamil is used in such patients, they must be digitalized prior to treatment.

It has been reported that digoxin plasma levels may increase with chronic verapamil administration (see Precautions, Drug Interactions). The use of verapamil in the treatment of hypertension is not recommended in patients with heart failure caused by systolic dysfunction.

Patients with Pre-existing Gastrointestinal Narrowing or Transit Disorders: Since the Chronovera delivery system contains a nondeformable material, which is to be excreted, in general, its use should be avoided in patients with pre-existing gastrointestinal narrowing (pathologic or iatrogenic) or significant gastrointestinal motility disorders. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of Chronovera tablets.

Hypotension: Hypotensive symptoms of lethargy and weakness with faintness have been reported following single oral doses and even after some months of treatment. In some patients it may be necessary to reduce the dose.

Conduction Disturbance: Verapamil slows conduction across the AV node and rarely may produce second or third degree AV block, bradycardia and in extreme cases, asystole.

Verapamil causes dose-related suppression of the SA node. In some patients, sinus bradycardia may occur, especially in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients (see Contraindications and Precautions, Geriatrics).

Bradycardia: The total incidence of bradycardia (ventricular rate less than 50 beats/min) was 1.4% in controlled studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see Overdose: Symptoms and Treatment).

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Verapamil may result in significant acceleration of ventricular response during atrial fibrillation or atrial flutter in the Wolff-Parkinson-White (WPW) or Lown-Ganong-Levine syndromes after receiving i.v. verapamil. 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).

Concomitant use with b-blockers: Generally, oral verapamil should not be given to patients receiving b-blockers since the depressant effects on myocardial contractility, heart rate and AV conduction may be additive. If combined therapy is used, close surveillance of vital signs and clinical status should be carried out and the need for continued concomitant treatment periodically assessed.

Verapamil gives no protection against the dangers of abrupt b-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of b-blocker. Then verapamil may be started with the usual dose.

Patients with Hypertrophic Cardiomyopathy: In 120 patients with hypertrophic cardiomyopathy 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 past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mmHg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Precautions, Drug Interactions) 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%. 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 use have to be discontinued.

Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge. Clinical symptoms of malaise, fever, and/or right upper quadrant pain, in addition to elevation of AST, ALT, and alkaline phosphatase have been reported. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Hepatic Insufficiency: Because verapamil is extensively metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function, since the elimination half-life of verapamil in these patients is prolonged 4-fold (from 3.7 to 14.2 hours). A decreased dosage should be used in patients with hepatic insufficiency and careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect should be carried out (see Pharmacology – Pharmacokinetics and Dosage).

Renal Insufficiency: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. In one study in healthy volunteers, the total body clearance after i.v. administration of verapamil was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33 mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil in patients with renal disease is decreased. In 2 studies with oral verapamil no difference in pharmacokinetics could be demonstrated. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see Overdose: Symptoms and Treatment).

Precautions: Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Geriatrics: Caution should be exercised when verapamil is administered to elderly patients (³ 65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency (see Dosage and Pharmacology – Pharmacokinetics). Serious adverse events associated with heart block have occurred in the elderly.

Pregnancy: Teratology and reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity or impaired fertility. In rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats.

There are no studies in pregnant women. However, verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil is not recommended for use in pregnant women unless the potential benefits outweigh potential risks to mother and fetus.

Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.

Lactation: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Children: The safety and dosage regimen of verapamil in children has not yet been established.

Information for the Patient: Chronovera tablets should be swallowed whole; do not break, crush, or chew. The medication in the Chronovera tablet is released slowly through an outer shell that does not dissolve. The patient should not be concerned if they occasionally observe this outer shell in their stool as it passes from the body.

Chronovera should be taken at bedtime.

Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of verapamil with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered verapamil to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.

Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects.

b-adrenergic Blockers: The concomitant administration of verapamil with b-blockers can result in severe adverse effects (see Warnings, Concomitant use with b-blockers).

Digoxin: Verapamil treatment increases serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29% respectively. Maintenance and digitalization doses should be reduced when verapamil is administered and the patient should be reassessed to avoid over- or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of verapamil use, the patient should be reassessed to avoid underdigitalization.

Antihypertensive: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, and diuretics) may have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Verapamil should not be combined with b-blockers for the treatment of hypertension. Concomitant use of agents that attenuate a-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine and AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Nitrates, Diuretics: No cardiovascular adverse effects have been attributed to any interaction between these agents and verapamil.

Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Carbamazepine: The concomitant oral administration of verapamil and carbamazepine may potentiate the effects of carbamazepine neurotoxicity. Symptoms include, diplopia, headache, ataxia or dizziness.

Cimetidine: Two clinical trials have shown a lack of significant verapamil interaction with cimetidine. A third study showed cimetidine reduced verapamil clearance and increased elimination half-life.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital: Phenobarbital therapy may increase verapamil clearance.

Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.

Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium channel blocking agents, such as verapamil should each be titrated carefully to avoid excessive cardiovascular depression.

Sulfinpyrazone: Increased clearance and decreased bioavailability of verapamil may occur.

Antineoplastic Agents: Verapamil inhibits P-glycoprotein mediated transport of antineoplastic agents out of tumor cells, resulting in their decreased metabolic clearance. Dosage adjustments of antineoplastic agents should be considered when verapamil is administered concomitantly.

ASA: In a few reported cases, coadministration of verapamil with ASA uses led to an increased bleeding time.

Adverse Reactions: Verapamil immediate release tablets have been studied in 4 826 patients in controlled and uncontrolled trials. The most common adverse reactions were: constipation, dizziness and nausea. The most serious adverse reactions reported with verapamil are heart failure (1.8%), 2° and 3° AV block (0.8%), hypotension (2.5%) and rapid ventricular response (see Warnings).

The following adverse reactions have been reported in controlled or uncontrolled clinical trials with immediate release verapamil.

Cardiovascular: hypotension 2.5%, edema 2.1%, CHF/Pulmonary Edema 1.9%;
CNS: dizziness 3.2%, headache 2.2%, fatigue 1.7%;
Gastrointestinal: constipation 7.3%, nausea 2.7%;
Other: rash 1.2%.

The following reactions to verapamil controlled-onset extended-release occurred at rates greater than 2% or occurred at lower rates but appeared drug-related in clinical trials in hypertension and angina.

See Warnings for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response.

Reversible (upon discontinuation of verapamil) nonobstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulties.

The following reactions, reported with orally administered verapamil in 2% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, AV dissociation, pulmonary edema, chest pain, claudication, myocardial infarction, palpitations, syncope.

Gastrointestinal: dry mouth, gastrointestinal distress, gingival hyperplasia, vomiting, hepatitis.

Hematologic: purpura, petechiae, ecchymosis or bruising.

CNS: cerebrovascular accident, confusion, equilibrium disorders, insomnia, psychotic symptoms, shakiness, somnolence.

Dermatologic: arthralgia, exanthema, hair loss, sweating, pruritus, urticaria, Stevens-Johnson syndrome, erythema multiforme, and vasculitis.

Special Senses: blurred vision.

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

Other: allergy aggravated, dyspnea, myalgia.

Symptoms And Treatment Of Overdose: Symptoms: Based on reports of intentional overdosage of verapamil, the following symptoms have been observed. Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolongation of AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole.

Treatment: Treatment of overdosage should be supportive. Gastric lavage should be undertaken, even later than 12 hours after ingestion, if no gastrointestinal motility is present. b-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion influx across the slow channel.

These pharmacologic interventions have been effectively used in treatment of overdosage with verapamil. Clinically significant hypotensive reactions should be treated with vasopressor agents. AV block is treated with atropine and cardiac pacing. Asystole should be handled by the usual Advanced Cardiac Life Support measures including the use of vasopressor agents, e.g., isoproterenol HCl. Verapamil is not removed by hemodialysis.

In case of overdosage with large amounts of verapamil, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Depending on the time of ingestion, capsules may be present along the entire length of the gastrointestinal tract which function as active drug depots. Extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage and high enemas.

Suggested Treatment of Acute Cardiovascular Adverse Reactions: Actual treatment and dosage should depend on the severity of the clinical situation and the judgement of the treating physician. Patients with hypertrophic cardiomyopathy treated with verapamil should not be administered positive inotropic agents).

Dosage And Administration: Chronovera is a dosage form designed to deliver peak verapamil levels in the morning. Accordingly, Chronovera should be administered once daily at bedtime.

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

Dosing should be individualized by titration.

Chronovera tablets should be swallowed whole and not chewed, broken or crushed.

Hypertension: Initiate therapy with 180 mg.

If an adequate response is not obtained with 180 mg, the dose may be titrated upward in the following manner: 240 mg each evening; 360 mg each evening (2´180 mg); 480 mg each evening (2´240 mg).

Chronic Stable Angina: Initiate therapy with 180 mg.

If an adequate response is not obtained with 180 mg, the dose may be titrated upward in the following manner: 240 mg each evening; 360 mg each evening (2´180 mg).

The majority of patients who will respond to therapy, will do so at a dosage of 180 to 360 mg once daily. However, some patients may respond to 480 mg once daily.

Geriatrics: In general, bioavailability of Chronovera is higher in the elderly and they tend to respond at lower dosages than those under 65. Dosage should be carefully individualized by titration (see Pharmacology – Pharmacokinetics and Precautions – Geriatrics).

Patients With Impaired Liver and Renal Function: Verapamil should be administered cautiously to patients with liver or renal function impairment. The dosage should be carefully and gradually adjusted depending on patient tolerance and response. These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage. Verapamil should not be used in severe hepatic dysfunction (see Warnings, Hepatic Insufficiency and Renal Insufficiency).

Availability And Storage: 180 mg: Each controlled-onset extended-release, blue, round, film-coated tablet, with SEARLE 2011 printed on one side, contains: verapamil HCl 180 mg. Nonmedicinal ingredients: black ferric oxide, butylated hydroxytoluene, cellulose acetate, FD&C Blue No. 2 Lake, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate, povidone, sodium chloride and titanium dioxide. HDPE bottles of 100.

240 mg: Each controlled-onset extended-release, white, round, film-coated tablet with SEARLE 2021 printed on one side, contains: verapamil HCl 240 mg. Nonmedicinal ingredients: black ferric oxide, butylated hydroxytoluene, cellulose acetate, hydroxethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate, povidone, sodium chloride and titanium dioxide. HDPE bottles of 100.

Protect contents from light and high humidity. HDPE bottles should be stored at controlled room temperature (15 to 25°C).

CHRONOVERA® Searle Verapamil HCl Antihypertensive – Antianginal Agent System Components and Performance: Chronovera is a formulation designed to initiate the release of verapamil approximately 4 to 5 hours after ingestion by means of a delay coating and thereafter to provide a constant rate of release over 12 hours. The tablet is comprised of a semipermeable membrane surrounding a drug core that is osmotically active. The core itself is divided into 2 layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert, but osmotically active, components. Delay in release of verapamil after ingestion is accomplished by the introduction of a coating between the active drug core and outer semipermeable membrane. As water from the gastrointestinal tract enters the tablet, this delay coating is solubilized and released. As tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing drug through precision laser-drilled orifices in the outer membrane at a constant rate. This controlled rate of drug delivery in the gastrointestinal lumen is independent of posture, pH, gastrointestinal motility, and fed or fasting conditions. The biologically inert components of the delivery system remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell (see Warnings, Patients With Pre-existing Gastrointestinal Narrowing or Transit Disorders).

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