NOVO-VERAMIL TABLET

Canada - English - Health Canada

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Active ingredient:
VERAPAMIL HYDROCHLORIDE
Available from:
TEVA CANADA LIMITED
ATC code:
C08DA01
INN (International Name):
VERAPAMIL
Dosage:
80MG
Pharmaceutical form:
TABLET
Composition:
VERAPAMIL HYDROCHLORIDE 80MG
Administration route:
ORAL
Units in package:
100/500/1000
Prescription type:
Prescription
Therapeutic area:
MISCELLANEOUS CALCIUM-CHANNEL BLOCKING AGENTS
Product summary:
Active ingredient group (AIG) number: 0113846002; AHFS: 24:28.92
Authorization status:
APPROVED
Authorization number:
00812331
Authorization date:
2013-06-03

Documents in other languages

PRODUCT MONOGRAPH

Pr

NOVO-VERAMIL

(verapamil hydrochloride)

80 mg, 120 mg tablets

Antiarrhythmic/Antianginal/Antihypertensive Agent

Pr

NOVO-VERAMIL SR

(verapamil hydrochloride)

240 mg sustained release tablets

Antihypertensive Agent

Teva Canada Limited

Date of Preparation:

30 Novopharm Court

May 28, 2013

Toronto, Ontario

M1B 2K9

Submission Control No: 164741

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3

SUMMARY PRODUCT INFORMATION ................................................................................... 3

INDICATIONS AND CLINICAL USE ......................................................................................... 3

CONTRAINDICATIONS .............................................................................................................. 4

WARNINGS AND PRECAUTIONS ............................................................................................. 5

ADVERSE REACTIONS ............................................................................................................... 9

DRUG INTERACTIONS ............................................................................................................. 12

DOSAGE AND ADMINISTRATION ......................................................................................... 18

OVERDOSAGE ........................................................................................................................... 20

ACTION AND CLINICAL PHARMACOLOGY ....................................................................... 21

STORAGE AND STABILITY ..................................................................................................... 26

DOSAGE FORMS, COMPOSITION AND PACKAGING ........................................................ 26

PART II: SCIENTIFIC INFORMATION ............................................................................... 28

PHARMACEUTICAL INFORMATION ..................................................................................... 28

CLINICAL TRIALS ..................................................................................................................... 29

DETAILED PHARMACOLOGY ................................................................................................ 31

TOXICOLOGY ............................................................................................................................ 31

REFERENCES ............................................................................................................................. 35

PART III: CONSUMER INFORMATION .............................................................................. 38

Pr

NOVO-VERAMIL

(verapamil hydrochloride)

80 mg, 120 mg tablets

Pr

NOVO-VERAMIL SR

(verapamil hydrochloride)

240 mg sustained release tablets

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form

/ Strength

All Nonmedicinal Ingredients

Oral

Film-coated

tablet 80 mg,

120 mg

Sustained-

release tablets

240 mg

3A Alcohol, Colloidal Silicon Dioxide, D&C yellow #10,

FD&C Blue #1, FD&C yellow #6, Hydroxypropyl Cellulose,

Hypromellose, Magnesium Stearate, Methanol,

Microcrystalline Cellulose, Polydextrose, Polyethylene Glycol,

Polysorbate, Povidone, Pregelatinized Starch, Sodium

Alginate, Sodium Lauryl Sulfate, Sodium Starch Glycolate,

Talc, Titanium Dioxide, Triacetin, Triethyl Citrate.

For a complete listing see Dosage Forms, Composition and

Packaging section.

INDICATIONS AND CLINICAL USE

NOVO-VERAMIL Tablets

NOVO-VERAMIL (verapamil hydrochloride) tablets may be used in the treatment of:

Chronic stable angina of effort.

Angina resulting from coronary artery spasm.

Obstructive hypertrophic cardiomyopathy where surgery is not otherwise indicated.

Atrial fibrillation or flutter with rapid ventricular response not otherwise controllable

with digitalis preparations.

Follow–up treatment to the use of injectable verapamil in paroxysomal supraventricular

tachycardia.

Mild to moderate essential hypertension. It should be used in those patients in whom

treatment with diuretics or beta blockers produced unacceptable adverse effects.

NOVO-VERAMIL can be tried as an initial agent in those patients in whom the use of diuretics

and/or beta blockers is contraindicated or in patients with medical conditions in which these

drugs frequently cause serious adverse effects.

Concomitant use of NOVO-VERAMIL with a diuretic has been shown to be compatible and

showed additive antihypertensive effect. Concomitant use of NOVO-VERAMIL with an

angiotensin converting enzyme inhibitor has been shown to be compatible and to have additive

blood pressure lowering effects.

NOVO-VERAMIL should not be concurrently used with beta blockers in the treatment of

hypertension (see PRECAUTIONS - Drug Interactions).

Safety of concurrent use of NOVO-VERAMIL with other antihypertensive agents has not been

established and such use cannot be recommended at this time.

NOVO-VERAMIL SR Tablets

NOVO-VERAMIL SR (verapamil hydrochloride) sustained release tablets is indicated for:

the treatment of mild to moderate essential hypertension. Verapamil hydrochloride should

normally be used in those patients in whom treatment with diuretics or beta-blockers has

been associated with unacceptable adverse effects.

Verapamil hydrochloride can be tried as an initial agent in those patients in whom the use of

diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which

these drugs frequently cause serious adverse effects.

Concomitant use of verapamil hydrochloride with a diuretic or an angiotensin converting enzyme

(ACE) inhibitor has been shown to be compatible and to have additive blood pressure lowering

effects.

Verapamil hydrochloride should not be used concurrently with beta-adrenoreceptor blockers in

the treatment of hypertension. See (DRUG INTERACTIONS – Table 2).

Geriatrics (≥ 65 years of age):

Caution should be exercised when verapamil hydrochloride is administered to elderly patients.

See [WARNINGS AND PRECAUTIONS -Special Populations, Geriatrics (≥ 65 years of

age)].

Pediatrics (<18 years of age):

NOVO-VERAMIL SR has not been studied in children and therefore use in this age group is not

recommended.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or

component of the container. For a complete listing, see the DOSAGE FORMS,

COMPOSITION AND PACKAGING section of the Product Monograph.

Complicated myocardial infarction (patients who have ventricular failure manifested by

pulmonary congestion).

Severe congestive heart failure and/or severe left ventricular dysfunction (i.e. ejection

fraction <40%), unless secondary to a supraventricular tachycardia amenable to oral

verapamil therapy.

Cardiogenic shock.

Severe hypotension.

Second- or third-degree atrioventricular (A-V) block.

Sick sinus syndrome. See (WARNINGS AND PRECAUTIONS – Cardiovascular,

Conduction Disturbance).

Marked bradycardia.

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 – Cardiovascular, Accessory Bypass Tract).

WARNINGS AND PRECAUTIONS

General

In patients with angina or arrhythmias using antihypertensive drugs, the additional

hypotensive effect of NOVO-VERAMIL and NOVO-VERAMIL SR (verapamil

hydrochloride) sustained-release tablets should be taken into consideration.

Verapamil hydrochloride does not alter total serum calcium levels. However, one report

suggested that calcium levels above the normal range may decrease the therapeutic effect of

verapamil hydrochloride.

Patients with Neuromuscular Diseases

Due to Verapamil hydrochloride’s neuromuscular blocking action, Verapamil hydrochloride

should be used with caution in the presence of diseases in which neuromuscular transmission is

affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular

dystrophy). The decision to administer Verapamil hydrochloride should be based on the

physician’s assessment of the risk and benefit to the patient. It may be necessary to decrease the

dose. Ventilation support should be available if required. See (DRUG INTERACTIONS, Drug-

Drug Interaction, Use in Patients with Attenuated (Decreased) Neuromuscular

Transmission).

Carcinogenesis and Mutagenesis

There was no evidence of a carcinogenic effect when verapamil hydrochloride was administered

orally (diet) to male and female rats at doses up to 112.2 and 102.5 mg/kg/day, respectively, for

24 months.

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five

different strains of Salmonella typhimurium, nor in studies on chromosomal aberrations and

sister chromatid exchanges (SCE) in human lymphocytes, nor in the hypoxanthine guanine

phosphoribosyltransferase (HGPRT) test with V-79 Chinese hamster cells, and also not in the

cell transformation assay with Syrian hamster embryo cells. In addition verapamil did not show

any SCE-inducing activity in vivo (Chinese hamster). See (TOXICOLOGY – Carcinogenicity

and Mutagenicity).

Cardiovascular

Heart Failure

Because of the drug's negative inotropic effect, verapamil hydrochloride 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 hydrochloride 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

hydrochloride administration. See (DRUG INTERACTIONSTable 2). The use of verapamil

hydrochloride in the treatment of hypertension is not recommended in patients with heart failure

caused by systolic dysfunction.

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 of verapamil hydrochloride.

Conduction Disturbance

Verapamil hydrochloride slows conduction across the A-V node and rarely may produce second

or third degree A-V block, bradycardia and in extreme cases, asystole. Verapamil hydrochloride

should be used with caution in the presence of first degree AV block. Patients with first degree

A-V block may progress to second or third-degree A-V block; they require a reduction in the

dose or discontinuation of Verapamil hydrochloride, and the institution of appropriate therapy

depending upon the patient’s clinical condition.

Verapamil hydrochloride causes dose-related suppression of the sinoatrial (S-A) node. In some

patients, sinus bradycardia may occur, especially in patients with a sick sinus syndrome (S-A

nodal disease), which is more common in older patients. See (CONTRAINDICATIONS).

Bradycardia

The total incidence of bradycardia (ventricular rate less than 50 beats/minute) 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 A-V nodal or normal sinus

rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately.

See (OVERDOSAGE).

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

Verapamil hydrochloride may result in significant acceleration of ventricular response during

atrial fibrillation or atrial flutter in the Wolff-Parkinson-White (WPW) or Lown-Ganong-Levine

(LGL) syndromes after receiving intravenous verapamil hydrochloride. Although a risk of this

occurring with oral verapamil hydrochloride has not been established, such patients receiving

oral verapamil hydrochloride may be at risk and its use in these patients is contraindicated. See

(CONTRAINDICATIONS).

Concomitant Use with Beta-Blockers

Generally, oral verapamil hydrochloride should not be given to patients receiving beta-blockers

since the depressant effects on myocardial contractility, heart rate and A-V conduction may be

additive. However, in exceptional cases when in the opinion of the physician concomitant use in

angina and arrhythmias is considered essential, such use should be instituted gradually under

careful supervision. 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 hydrochloride gives no protection against the dangers of abrupt beta-blocker

withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-

blocker. Then verapamil hydrochloride may be started with the usual dose.

Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy who received therapy with verapamil

hydrochloride 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 mm Hg) pulmonary wedge pressure and a marked

left ventricular outflow obstruction were present in most of these patients. Concomitant

administration of quinidine (see 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 A-V 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, but in some cases, verapamil hydrochloride use

had to be discontinued.

Hepatic/Biliary/Pancreatic

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and

bilirubin have been reported. Several published cases of hepatocellular injury produced by

verapamil hydrochloride have been proven by rechallenge. Clinical symptoms of malaise, fever,

and/or right upper quadrant pain, in addition to elevation of serum glutamic-oxaloacetic

transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) and alkaline phosphatase

have been reported. Periodic monitoring of liver function in patients receiving verapamil

hydrochloride is therefore prudent.

Hepatic Insufficiency

Because verapamil hydrochloride is extensively metabolized by the liver, it should be

administered cautiously to patients with impaired hepatic function, since the elimination half-life

of verapamil hydrochloride 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 (ACTION AND CLINICAL PHARMACOLOGY,

Pharmacokinetics) and (DOSAGE AND ADMINISTRATION).

Ophthalmologic

Atypical lens changes and cataracts were observed in beagle dog studies at high doses. This has

been concluded to be species-specific for the beagle dog. (These ophthalmological changes were

not seen in a second study.) No similar changes have been observed in long-term prospective

human ophthalmological trials.

Renal

Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the

urine. In one study in healthy volunteers, the total body clearance after intravenous

administration of verapamil hydrochloride 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 hydrochloride in patients with renal disease is decreased. In two

studies with oral verapamil hydrochloride no difference in pharmacokinetics could be

demonstrated.

Therefore, until further data are available, verapamil hydrochloride should be used with caution

in patients with impaired renal function. These patients should be carefully monitored for

abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect. See

(DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women

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 hydrochloride crosses the

placental barrier and can be detected in umbilical vein blood at delivery. Verapamil

hydrochloride is not recommended for use in pregnant women unless the potential benefits

outweigh potential risks to mother and fetus.

Labour and Delivery - It is not known whether the use of verapamil hydrochloride during labour

or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the

duration of labour or increases the need for forceps delivery or other obstetric intervention.

Nursing Women

Verapamil hydrochloride is excreted in human breast milk. Because of the potential for adverse

reactions in nursing infants from verapamil hydrochloride, nursing should be discontinued while

verapamil hydrochloride is administered.

Pediatrics (< 18 years of age)

The safety and dosage regimen of verapamil hydrochloride in children below the age of 18 has

not yet been established. Therefore, use in this group is not recommended.

Geriatrics ( 65 years of age)

Caution should be exercised when verapamil hydrochloride is administered to elderly patients

(≥ 65 years) especially those prone to developing hypotension or those with a history of

cerebrovascular insufficiency. See (DOSAGE AND ADMINISTRATION). The incidence of

adverse reactions is approximately 4% higher in the elderly. The adverse reactions occurring

more frequently include dizziness and constipation. Serious adverse events associated with heart

block have occurred in the elderly.

Monitoring and Laboratory Tests

Patients should be monitored by measuring the blood pressure response.

Concomitant Use with Beta-Blockers

In exceptional cases, when in the opinion of the physician concomitant use in angina and

arrhythmias is considered essential, such use should be instituted gradually under careful

supervision. 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.

Elevated Liver Enzymes

Periodic monitoring of liver function in patients receiving verapamil hydrochloride is prudent.

Hepatic Insufficiency

Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive

pharmacologic effect should be carried out.

Renal Insufficiency

Patients with renal insufficiency should be carefully monitored for abnormal prolongation of the

PR interval or other signs of excessive pharmacologic effect.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In 4,826 patients treated with verapamil hydrochloride immediate release tablets for arrhythmias,

angina or hypertension, the overall adverse reaction rate in these patients was 37.1% and the

dropout rate was 10.2%. The majority of these patients were seriously ill and treated under

emergency drug regulations.

In controlled pivotal studies with 128 patients treated with verapamil hydrochloride sustained-

release tablets for hypertension, the overall adverse reaction rate was 21.7% and the dropout rate

was 3.9%.

The most common adverse reactions were: constipation (7.3%), dizziness (3.2%), and nausea

(2.7%). In hypertension studies, constipation occurred in 18.5% of patients on verapamil

hydrochloride immediate release tablets and 4.7% of patients on verapamil hydrochloride

sustained release tablets.

The most serious adverse reactions reported with verapamil hydrochloride are heart failure

(1.8%), hypotension (2.5%), A-V block (1.2%) and rapid ventricular response. See

(WARNINGS AND PRECAUTIONS).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

The following adverse reactions divided by body system have been reported in clinical trials or

marketing experience. When incidences are shown, they are calculated based on the 4,954 (4,826

+ 128) patient base.

Table 1

Adverse Reactions Reported in Clinical Trials

Verapamil Hydrochloride

N = 4,954

Cardiovascular

Hypotension

Edema

CHF/Pulmonary Edema

Bradycardia

A-V Block

Total (1º, 2º, 3º)

2º and 3º

2.5%

2.1%

1.9%

1.4%

1.2%

0.8%

Central Nervous System

Dizziness

Headache

Fatigue

3.2%

2.2%

1.7%

Gastrointestinal

Constipation

Nausea

7.3%

2.7%

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following reactions were reported in 1.0% or less of patients in clinical trials:

Cardiovascular Disorders:

angina pectoris, atrioventricular dissociation, cardiac failure,

chest pain, claudication, development of rhythm disturbances,

myocardial infarction, painful coldness and numbness of

extremities, palpitations,syncope, severe tachycardia,

ventricular dysrhythmias.

Ear and Labyrinth Disorders: vertigo

Eye Disorders:

blurred vision, diplopia

Nervous System Disorders:

cerebrovascular accident, confusion, equilibrium disorders,

excitation, extrapyramidal disorders, hyperkinesis, paresthesia,

rotary nystagmus, shakiness, somnolence, tremor

Gastrointestinal Disorders:

abdominal discomfort, diarrhea, dry mouth, gastrointestinal

distress, gingival hyperplasia, vomiting

Musculoskeletal and

Connective Tissue Disorders:

arthralgia, muscle cramps, muscle fatigue

Psychiatric Disorders:

depression, insomnia, psychotic symptoms

Renal and Urinary Disorders: increased frequency of urination

Respiratory, Thoracic and

Mediastinal Disorders:

bronchospasm, dyspnea

Reproductive System and

Breast Disorders:

erectile dysfunction, gynecomastia, oligomenorrhea, spotty

menstruation

Skin and Subcutaneous

System Disorders:

alopecia, ecchymosis or bruising, erythema multiforme,

exanthema, hyperkeratosis, macules, pruritus, purpura, rash,

Stevens-Johnson syndrome, sweating, urticaria

Vascular Disorders:

flushing

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

breathing difficulty.

In clinical trials related to the control of ventricular response in digitalized patients who had

atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and

asymptomatic hypotension occurred in 5% of patients.

Abnormal Hematologic and Clinical Chemistry Findings

Hepatotoxicity with elevated enzymes (SGOT, SGPT, alkaline phosphatase) and bilirubin levels,

jaundice and associated symptoms of hepatitis with cholestasis have been reported. See

(WARNINGS AND PRECAUTIONS). Elevated prolactin levels have also been reported.

Post-Market Adverse Drug Reactions

The following adverse events have been reported with verapamil hydrochloride from post-

marketing surveillance or Phase 4 clinical trials.

Cardiac Disorders:

sinus arrest, sinus bradycardia

Ear and Labyrinth Disorders:

tinnitus

Gastrointestinal Disorders:

abdominal pain, ileus

General Disorders and

Administration Site Conditions:

edema peripheral

Immune System Disorders:

hypersensitivity

Musculoskeletal and Connective

Tissue Disorders:

muscle weakness, myalgia

Skin and Subcutaneous

System Disorders:

rash maculopapular

Reproductive System and

Breast Disorders:

galactorrhea.

There has been a single post-marketing report of paralysis (tetraparesis) associated with the

combined use of verapamil hydrochloride and colchicine. This may have been caused by

colchicine crossing the blood-brain barrier due to CYP3A4 and P-glycoprotein (P-gp) inhibition

by verapamil hydrochloride. Combined use of verapamil hydrochloride and colchicine is not

recommended.

DRUG INTERACTIONS

Drug-Drug Interactions

As with all drugs, care should be exercised when treating patients with multiple medications.

Verapamil hydrochloride undergoes biotransformation by the CYP3A4, CYP1A2, CYP2C8,

CYP2C9 and CYP2C18 isoenzymes of the cytochrome P

system. Verapamil hydrochloride

has also been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Co-

administration of verapamil hydrochloride with other drugs which follow the same route of

biotransformation or are inhibitors or inducers of these enzymes may result in altered

bioavailability of verapamil hydrochloride or these drugs. 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 hydrochloride sustained-release tablets to maintain optimum therapeutic

blood levels.

The following table provides a list of potential drug interactions:

Table 2

Potential Drug Interactions Associated with Verapamil

Hydrochloride

Concomitant Drug

Class: Drug Name

Effect on Concentration of

Verapamil

Hydrochloride

Concomitant Drug

Clinical Comment

Alpha-Blockers

Prazosin

↑ prazosin C

(~40%) with no

effect on t

Concomitant use of verapamil hydrochloride and alpha-

adrenoceptor blockers may result in excessive fall in blood

pressure in some patients as observed in one study following

the concomitant administration of verapamil hydrochloride

and prazosin.

Terazosin

↑ terazosin AUC (~24%) and

(~25%)

Antiarrhythmics

Disopyramide

Until data on possible interactions between verapamil

hydrochloride and disopyramide are obtained, disopyramide

should not be administered within 48 hours before or 24 hours

after verapamil hydrochloride administration.

Flecainide

Minimal effect on flecainide

plasma clearance (<~10%); no

effect on verapamil plasma

clearance.

The concomitant administration of flecainide and verapamil

hydrochloride may have additive effects on myocardial

contractility, A-V conduction, and repolarisation. May also

have negative inotropic effect and prolongation of

atrioventricular conduction.

Quinidine

↓ oral quinidine clearance (~35%)

In a small number of patients with hypertrophic

cardiomyopathy, concomitant use of verapamil hydrochloride

and quinidine resulted in significant hypotension and may

result in pulmonary edema. Until further data are obtained,

combined therapy of verapamil hydrochloride and quinidine

in patients with hypertrophic cardiomyopathy should be

avoided.

The electrophysiological effects of quinidine and verapamil

hydrochloride on A-V conduction were studied in 8 patients.

Verapamil hydrochloride significantly counteracted the

effects of quinidine on A-V conduction. There has been a

report of increased quinidine levels during verapamil

hydrochloride therapy.

Antiasthmatics

Theophylline

↓ oral and systemic clearance of

theophylline by ~20%.

Reduction of clearance was

lessened in smokers (~11%).

Caution should be exercised when co-administering

theophylline and verapamil hydrochloride.

Anticonvulsants

Table 2

Potential Drug Interactions Associated with Verapamil

Hydrochloride

Concomitant Drug

Class: Drug Name

Effect on Concentration of

Verapamil

Hydrochloride

Concomitant Drug

Clinical Comment

Carbamazepine

↑ carbamazepine AUC (~46%) in

refractory partial epilepsy patients.

Concomitant oral use may potentiate the effects of

carbamazepine neurotoxicity. Symptoms include nausea,

diplopia, headache, ataxia or dizziness.

Antidepressants

Imipramine

↑ imipramine AUC (~15%).

No effect on level of active

metabolite desipramine.

As with all antihypertensive agents, there is an elevated risk

of orthostatic hypotension when combining verapamil

hydrochloride with major tranquilizers or tricyclic

antidepressants, such as imipramine.

Antidiabetics

Glyburide

↑ glyburide C

(~28%), AUC

(~26%)

Antihypertensive Agents

Verapamil hydrochloride administered concomitantly with

antihypertensive agents such as vasodilators, ACE inhibitors,

and diuretics may have an additive effect on lowering blood

pressure. In patients with angina or arrhythmias using

antihypertensive drugs, this additional hypotensive effect

should be taken into consideration. Verapamil should not be

combined with beta-blockers for the treatment of

hypertension. Concomitant use of verapamil and alpha-

adrenoceptor blockers may result in excessive fall in blood

pressure in some patients as observed in one study following

the concomitant administration of verapamil and prazosin.

Anti-infectives

Clarithromycin

Possible ↑ in verapamil when

used in combination with

clarithromycin

Erythromycin

Possible ↑ in verapamil when

used in combination with

erythromycin

Rifampin

↓ verapamil AUC (~97%),

(~94%) oral bioavailability

(~92%)

Blood pressure lowering effect of verapamil hydrochloride

may be reduced when used concomitantly with rifampin.

Telithromycin

Possible ↑ in verapamil when

used in combination with

telithromycin.

Antimanic Agents

Lithium

Increased sensitivity to the effects of lithium (neurotoxicity)

has been reported during concomitant verapamil

hydrochloride-lithium therapy with either no change or an

increase in serum lithium levels.

Lithium based drugs should be administered with caution, and

frequent monitoring of serum lithium levels is recommended.

If a diuretic is also used, the risk of lithium toxicity may be

further increased.

Antineoplastics

Doxorubicin

↑ doxorubicin AUC (89%) and

(61%) with oral verapamil

Verapamil hydrochloride inhibits P-glycoprotein (P-gp)-

mediated transport of anti-neoplastic agents out of tumour

Table 2

Potential Drug Interactions Associated with Verapamil

Hydrochloride

Concomitant Drug

Class: Drug Name

Effect on Concentration of

Verapamil

Hydrochloride

Concomitant Drug

Clinical Comment

administration in patients with

small cell lung cancer.

In patients with advanced

neoplasm, intravenous verapamil

administration did not change

significantly doxorubicin PK.

cells, resulting in their decreased metabolic clearance. Dosage

adjustments of anti-neoplastic agents should be considered

when verapamil hydrochloride is administered concomitantly.

Barbiturates

Phenobarbital

↑ oral verapamil clearance (~5-

fold)

Benzodiazepines and Other Anxiolytics

Buspirone

↑ buspirone AUC, C

by ~3.4-

fold

Midazolam

↑ midazolam AUC (~3-fold) and,

(~2-fold)

Beta-Blockers

Atenolol

A variable increase in atenolol

plasma concentration at steady

state has been reported in patients

with angina pectoris.

Metoprolol

↑ metoprolol AUC (~32.5%) and

Cmax (~41%) in patients with

angina pectoris.

Concomitant therapy may result in additive negative effects

on heart rate, atrioventricular conduction and/or cardiac

contractility. See (

WARNINGS AND

PRECAUTIONS

Verapamil Hydrochloride should not be combined with beta-

blockers for the treatment of hypertension.

Propranolol

↑ propanolol AUC (~65%), C

(~94%) in patients with angina

pectoris

Timolol

Asymptomatic bradycardia (<36 beats/min) with a wandering

atrial pacemaker has been observed in a patient receiving

concomitant timolol (a beta-adrenergic blocker) eye drops and

oral verapamil hydrochloride.

Cardiac Glycosides

Digitoxin

↓ digitoxin total body clearance

(~27%) and extrarenal clearance

(~29%)

The increase in digoxin levels can result in digoxin toxicity.

Maintenance digoxin doses should be reduced when

verapamil hydrochloride is administered, and the patient

should be carefully monitored to avoid over- or under-

digitalization. Whenever overdigitalization is suspected, the

daily dose of digoxin should be reduced or temporarily

discontinued. Upon discontinuation of verapamil

hydrochloride, the patient should be reassessed to avoid

underdigitalization. See (

WARNINGS AND

PRECAUTIONS

Digoxin

digoxin C

(~45% to 53%),

by ~42% and ↑ AUC by

~52% in healthy subjects

Diuretics

Concomitant use with diuretics may cause a potentiation of

the hypotensive effect.

Dispoypramide

Until data on possible interactions between verapamil

hydrochloride and disopyramide are obtained, disopyramide

should not be administered within 48 hours before or 24 hours

Table 2

Potential Drug Interactions Associated with Verapamil

Hydrochloride

Concomitant Drug

Class: Drug Name

Effect on Concentration of

Verapamil

Hydrochloride

Concomitant Drug

Clinical Comment

after verapamil hydrochloride administration.

H2-Receptor Antagonists

Cimetidine

In healthy subjects, ↑ AUC of R-

(~25%) and S-(~40%) verapamil

with corresponding ↓ in R- and S-

verapamil clearance

HIV antiviral agents

Due to the metabolic inhibitory potential of some of the HIV

antiviral agents, such as ritonavir, plasma concentrations of

verapamil hydrochloride may increase. Caution should be

used or the dose of verapamil hydrochloride may be

decreased.

Immunologics

Cyclosporine

↑ cyclosporine AUC, C

45% in renal transplant

patients

The co-administration of verapamil and immunosuppressive

agents both known substrates and inhibitors for CYP 3A4

may increase the plasma levels of these drugs. Dose

adjustment should be considered when these drugs are

concomitantly administered, which may be assessed by blood

levels, blood pressure monitoring and clinical monitoring of

other patient symptoms.

Sirolimus

Possible ↑ sirolimus levels

Tacrolimus

Possible ↑ tacrolimus levels

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 antagonists, such as

verapamil hydrochloride, should be titrated carefully to avoid

excessive hemodynamic effects.

Lipid metabolism regulators

Atorvastatin

Possible ↑ atorvastatin levels

↑ verapamil AUC by ~42.8%

Treatment with HMG-CoA reductase inhibitors (e.g.

atorvastatin, simvastatin or lovastatin) in a patient taking

verapamil hydrochloride should be started at the lowest

possible dose and titrated upwards. If verapamil

hydrochloride treatment is to be added to patients already

taking and HMG-CoA reductase inhibitor (e.g. atorvastatin,

simvastatin or lovastatin), consider a reduction in the statin

dose and retitrate against serum cholesterol concentrations.

Fluvastatin, pravastatin and rosuvastatin are not metabolized

by CYP3A4 and are less likely to interact with verapamil

hydrochloride.

Lovastatin

Possible ↑ lovastatin levels

Simvastatin

↑ simvastatin AUC (~2.6-fold),

(~4.6-fold) in healthy subjects

Neuromuscular Blocking Agents

Clinical data and animal studies suggest that verapamil

hydrochloride may potentiate the activity of neuromuscular

blocking agents (curare-like and depolarizing). It may,

therefore, be necessary to decrease the dose of verapamil

hydrochloride and/or the dose of the neuromuscular blocking

agent when the drugs are used concomitantly.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs)

Table 2

Potential Drug Interactions Associated with Verapamil

Hydrochloride

Concomitant Drug

Class: Drug Name

Effect on Concentration of

Verapamil

Hydrochloride

Concomitant Drug

Clinical Comment

Acetylsalicylic acid

Potential adverse reactions in terms of bleeding due to

synergistic antiplatelet effects of acetylsalicylic acid and

verapamil hydrochloride should be taken into consideration in

patients taking the two agents concomitantly.

Serotonin receptor agonists

Almotriptan

↑ almotriptan AUC (~20%)

↑ C

(~24%)

Uricosurics

Colchicine

Colchicine is a substrate for both CYP3A and the efflux

transporter P-gp. Verapamil hydrochloride is known to inhibit

CYP3A and P-gp. When verapamil hydrochloride and

colchicine are administered together, inhibition of P-gp and/or

CYP3A by verapamil hydrochloride may lead to increased

exposure to colchicine. Combined use is not recommended.

Sulfinpyrazone

↑ verapamil oral clearance (~3-

fold)

↓ bioavailability (~60%)

The blood pressure lowering effect of verapamil

hydrochloride may

be reduced

Vasodilators

Concomitant use with vasodilators may cause a potentiation

of the hypotensive effect.

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil hydrochloride decreases neuromuscular transmission in

patients with Duchenne’s muscular dystrophy, and that verapamil hydrochloride prolongs

recovery from the neuromuscular blocking agent vecuronium. Accordingly, it may be necessary

to decrease the dosage of verapamil hydrochloride when it is administered to patients with

attenuated neuromuscular transmission.

Drug-Food Interactions

In healthy volunteers, multiple high doses of grapefruit juice increased the AUC for R-verapamil

and S-verapamil by up to 49% and 37%, respectively. The increase in Cmax for R-verapamil and

S-verapamil were up to 75% and 51%, respectively. Elimination half-life and renal clearance of

both S- and R-verapamil were not affected.

Drug-Herb Interactions

In healthy volunteers, multiple doses of St John’s Wort decreased the AUC for R- and S-

verapamil hydrochloride by 78% and 80%, respectively, with similar decreases in Cmax.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been evaluated.

Drug-Lifestyle Interactions

Verapamil hydrochloride may increase blood alcohol (ethanol) concentrations and prolong its

effects.

Depending on the individual response, verapamil hydrochloride may affect the ability to react to

the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous

conditions. This applies all the more at the start of treatment, when the dose is raised, when

switching from another drug and in conjunction with alcohol.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The antihypertensive effects of verapamil hydrochloride sustained-release tablets are evident

within the first week of therapy. Optimal doses are usually lower in patients also receiving

diuretics since additive antihypertensive effects can be expected.

Patients with Hepatic and Renal Impairment - Verapamil hydrochloride 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 hydrochloride should not be used in severe hepatic dysfunction. See (WARNINGS

AND PRECAUTIONS – Hepatic/Billiary/Pancreatic, Hepatic Insufficiency).

Switching from NOVO-VERAMIL Tablets to NOVO-VERAMIL SR Tablets.

When switching from NOVO-VERAMIL (verapamil hydrochloride) Tablets to NOVO-

VERAMIL SR (verapamil hydrochloride) sustained-release tablets, the total daily dose in

milligrams may remain the same.

Recommended Dose and Dosage Adjustment

NOVO–VERAMIL TABLETS

Verapamil should be taken with food (see ACTION AND CLINICAL PHARMACOLOGY -

Pharmacokinetics: Influence of Food).

1. Angina Pectoris

Usual starting dose in adults is 80 mg of NOVO-VERAMIL (verapamil hydrochloride) Tablets 3

to 4 times daily. This may be increased to 120 mg 3 to 4 times daily until optimum response is

obtained. Do not increase the dose beyond 480 mg/day. In some cases the dose may be

decreased following clinical improvement.

2. Paroxysmal Supraventricular Tachycardias

Replace i.v. therapy with oral treatment as soon as possible. In adults, use the same dosage

schedule as for angina pectoris. Duration of treatment will depend on the underlying cause and

history of recurrence. At this time there is insufficient data to establish a safe and effective dose

for children.

3. Atrial Fibrillation and Flutter with Rapid Ventricular Response

NOVO-VERAMIL Tablets may be administered to adults not completely controlled with

digitalis preparations. The same dosage as for angina pectoris can be used but the physician

should be aware that digoxin plasma levels may increase with verapamil administration and the

reduction of digoxin dose may be necessary (see PRECAUTIONS - Drug Interactions).

4. Obstructive Hypertrophic Cardiomyopathy

Usual starting dose is 80 to 120 mg 3 to 4 times daily, and occasionally patients may require up

to 600 to 720 mg/day.

5. Mild to Moderate Essential Hypertension

NOVO-VERAMIL should be individually titrated, depending on patient tolerance and

responsiveness.

Initial dose is usually 80 mg three times a day. The dose may be increased up to 160 mg three

times a day. The daily dose should not exceed 480 mg.

Antihypertensive effects will be evident within the first week of therapy. In patients also taking

diuretics, the optimal doses should be lower due to additive antihypertensive effects.

Use in the Elderly: Lower dosages of NOVO-VERAMIL may be warranted in elderly patients

(i.e.  65 years) (see PRECAUTIONS). The dosage should be carefully and gradually adjusted

depending on patient tolerance and response. Elderly patients may be more sensitive to the

effects of the usual adult dose. Consideration can be given to beginning titration using one-half

of an NOVO-VERAMIL SR Tablet (120 mg) once a day since no suitable strength of standard

tablet is available.

Use in Patients with Impaired Hepatic Function: NOVO-VERAMIL should be administered

cautiously to patients with impaired hepatic function. The dosage should be carefully and

gradually adjusted depending on patient tolerability and response. Careful monitoring for

abnormal prolongation of the PR interval or other signs of overdosage should be carried out. At

this time, NOVO-VERAMIL should not be used in patients with severe hepatic dysfunction (see

WARNINGS - Hepatic Insufficiency).

Use in Patients with Impaired Renal Function: NOVO-VERAMIL should be administered

cautiously to patients with impaired renal function. The dosage should be carefully and

gradually adjusted depending on patient tolerability and response. These patients should also be

monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage.

NOVO–VERAMIL SR TABLETS

Mild to Moderate Essential Hypertension

The dosage should be individualized by titration depending on patient tolerance and

responsiveness to NOVO-VERAMIL SR. Titration should be based on therapeutic efficacy and

safety, evaluated weekly and approximately 24 hours after the previous dose.

The usual initial adult dose is 180 to 240 mg/day. If required, the dose may be increased up to

240 mg twice a day. NOVO-VERAMIL SR Tablets are not available as a180 mg strength but

verapamil hydrochloride sustained release tablets are available through other manufacturers. A

maximum daily dose of 480 mg should not be exceeded.

Recommended dosing intervals for specific daily dosages are given in Table 3 below:

Table 3

Recommended Dosing Intervals for Specific Daily Dosages

Total Daily NOVO-VERAMIL SR Dose

Recommended Dosing Intervals

180 mg

Once each morning with food

240 mg

Once each morning with food

360 mg

180 mg each morning plus

180 mg each evening, with food;

240 mg each morning plus

120 mg each evening, with food

480 mg

240 mg each morning plus

240 mg each evening with food

Elderly

Lower dosages of NOVO-VERAMIL SR, i.e. 120 mg a day, may be warranted in elderly

patients (i.e. 65 years and older). See (WARNINGS AND PRECAUTIONS – Special

Populations, Geriatrics). The dosage should be carefully and gradually adjusted depending on

patient tolerability and response.

Administration

Crushing or chewing NOVO-VERAMIL SR (verapamil hydrochloride) sustained-release tablets

is not recommended since the sustained-release effect will be altered by damage to the tablet

structure. The NOVO-VERAMIL SR 240 mg tablet may be split in half.

NOVO-VERAMIL SR Tablets should be taken with food. See (ACTION AND CLINICAL

PHARMACOLOGY –Pharmacokinetics, Influence of Food).

OVERDOSAGE

For management of a suspected drug overdose, contact your regional

Poison Control Centre Immediately.

Based on reports of intentional overdosage of verapamil hydrochloride, the following symptoms

have been observed: Hypotension (varying from transient to severe), bradycardia to high degree

A-V block and sinus arrest, hyperglycemia, stupor and metabolic acidosis. Conduction

disturbances seen included: prolongation of A-V conduction time, A-V dissociation, nodal

rhythm, ventricular fibrillation and ventricular asystole. Fatalities have occurred as a result of

overdose.

Treatment of overdosage should be supportive. Gastric lavage should be undertaken, even later

than 12 hours after ingestion, if no gastrointestinal motility is present. Beta-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 hydrochloride. Clinically significant hypotensive reactions should be treated with

vasopressor agents. A-V 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 hydrochloride. Verapamil is not removed by hemodialysis.

In case of overdosage with large amounts of verapamil hydrochloride sustained-release product,

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, incompletely dissolved tablets 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.

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 hydrochloride should not be administered positive inotropic agents marked by

asterisks in Table 4).

Table 4

Overdosage Adverse Reactions and Recommended Treatments

Adverse Reaction

Proven Effective Treatment

Treatment with Good

Theoretical Rationale

Supportive

Treatment

Shock, cardiac failure, severe

hypotension

Calcium salt (e.g. i.v. calcium

gluconate; i.v. metaraminol

bitartrate*)

i.v. dopamine HCl*;

i.v. dobutamine HCl*

i.v. fluids;

Trendelenburg position

Bradycardia, A-V block,

asystole

i.v. isoproterenol HCl*;

i.v. atropine sulphate;

cardiac pacing

i.v. fluids (slow drip)

Rapid ventricular rate (due to

antegrade conduction in

flutter/fibrillation with WPW or

LGL syndrome)

D.C. cardioversion (high

energy may be required);

i.v. procainamide;

i.v. lidocaine HCl

i.v. fluids (slow drip)

* positive inotropic agent

Definition: i.v. = intravenous

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Verapamil hydrochloride 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 hydrochloride exerts antihypertensive effects by inducing vasodilation and reducing

peripheral vascular resistance usually without reflex tachycardia. Verapamil hydrochloride does

not blunt hemodynamic response to isometric or dynamic exercise.

Verapamil hydrochloride depresses A-V nodal conduction and prolongs functional refractory

periods. Verapamil hydrochloride 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 hydrochloride 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 A-V pathway following

administration of verapamil hydrochloride. See (WARNINGS AND PRECAUTIONS –

Cardiovascular, Conduction Disturbance). Verapamil hydrochloride has a local anesthetic

action that is 1.6 times that of procaine on an equimolar basis.

Verapamil hydrochloride 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 hydrochloride does not affect electrolytes, glucose, and

creatinine. The hypotensive effect of verapamil hydrochloride is not blunted by an increase in

sodium intake.

In hypertensive normolipidemic patients, verapamil hydrochloride had no effects on plasma

lipoprotein fractions.

Pharmacodynamics

In a study in five healthy males, the S-enantiomer was found to be 8 to 20 times more active than

the R-enantiomer in slowing A-V conduction. In another study using septal strips isolated from

the left ventricle of five patients with mitral disease, the S-enantiomer was 8 times more potent

than the R-enantiomer in reducing myocardial contractility.

Pharmacokinetics

Absorption

Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer

and the S-enantiomer. More than 90% of the orally administered dose of verapamil

hydrochloride is absorbed from the small intestine. Upon oral administration, there is rapid

stereoselective biotransformation during the first pass of verapamil hydrochloride through the

portal circulation. The systemic concentrations of R- and S-enantiomers are dependent upon the

route and the rate of administration and the rate and extent of release from the dosage forms.

The following bioavailability information was obtained from healthy volunteers and not from the

populations most likely to be treated with verapamil hydrochloride.

In a study in five healthy volunteers with oral immediate-release verapamil hydrochloride, 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

(ACTION AND CLINICAL PHARMACOLOGY –Pharmacodynamics) and (DETAILED

PHARMACOLOGY – Animal Pharmacology, Pharmacodynamics).

There is a nonlinear correlation between the verapamil hydrochloride dose administered and

verapamil hydrochloride plasma levels. In early dose titration with verapamil, a relationship

exists between total verapamil hydrochloride (R- and S-enatiomers combined) plasma

concentration and prolongation of the PR interval. The mean elimination t½ in single-dose

studies of immediate release verapamil hydrochloride ranged from 2.8 to 7.4 hours. In these

same studies, after steady state was reached, the t½ increased to a range from 4.5 to 12.0 hours

(after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil hydrochloride

may increase during titration. Aging decreases the clearance and elimination of verapamil

hydrochloride.

In a randomized, multiple-dose study in 44 healthy young subjects, administration of 240 mg of

verapamil hydrochloride sustained-release tablets with food produced peak plasma

concentrations at approximately 8 hours postdose of 188 and 76 ng/mL and AUC's (0 to 24

hours) of 2,553 and 1,046 ng.hr/mL for the R- and S-enantiomers, respectively. Similar results

were demonstrated for plasma norverapamil.

A study was conducted in which 240 mg single oral doses of verapamil hydrochloride

immediate-release tablets (fasting) and verapamil hydrochloride sustained-release tablets (fed)

were given to 12 young, healthy males (19 to 37 years old) in a randomized, crossover (7-day

washout) study. Serial blood samples for drug determination were taken over a 48-hour period.

The pharmacokinetic data from this study is summarized in the following table.

Table 5

Pharmacokinetic Data Comparing a Single-Dose of Verapamil Hydrochloride Immediate-

Release Tablet vs. Verapamil Hydrochloride Sustained-Release Tablet

Parameter

Verapamil Hydrochloride Immediate-

Release Tablet

(240 mg)

Verapamil Hydrochloride Sustained-

Release Tablet

(240 mg)

R-verapamil

S-verapamil

R-verapamil

S-verapamil

Cmax, ng/mL

59.0

60.1

11.3

Tmax, hr

1.46

1.58

10.8

11.8

AUC 0-48, ng/mL/hr

1250

The steady-state pharmacokinetic data from a study in which 11 volunteers were treated with the

sustained-release formulation twice daily at 12 hourly intervals and with the immediate-release

formulation three time daily at 8 hourly intervals for five days is summarized in the following

table.

Table 6

Steady-State Pharmacokinetic Data Comparing Verapamil Hydrochloride Immediate-Release

Tablet vs. Verapamil Hydrochloride Sustained-Release Tablet

Parameters

Verapamil

Hydrochloride

Immediate-Release 120

mg Tablet**

(360 mg daily)

Verapamil Hydrochloride

Sustained-Release

240 mg Tablet**

(360 mg daily)

Verapamil Hydrochloride

Sustained-Release

240 mg Tablet*

(480 mg daily)

Cmax (ng/mL)

289.4

250.5

298.4

Cmin (ng/mL)

80.1

110.7

152.0

Tmax (hr)

Tl/2 (hr)

AUC0-∞ (ng/mL/hr)

1850

3466

4484

AUC0-36

(ng/mL/hr)

1809

3154

4116

* last dose = 240 mg

** last dose = 120 mg

The data have been calculated from samples taken at frequent intervals for 36 hours after the last dose.

Distribution

Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein

blood at delivery. Verapamil hydrochloride is excreted in human milk.

Metabolism

In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism by

the cytochrome P-450 system in the liver. The particular isoenzymes involved are CYP3A4,

CYP1A2, and CYP2C 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,

which was observed in a study in dogs. 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.

Excretion

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.

Influence of Food

Administration of verapamil hydrochloride sustained-release tablets with food results in marked

prolongation of T

(45 to 75%) and slight decreases in C

(about 15%) and AUC (1 to 8%).

Food thus produces a slight decrease in bioavailability (AUC), but a narrower peak-to-trough

ratio.

Special Populations and Conditions

Geriatrics

The pharmacokinetics of verapamil hydrochloride are significantly different in elderly (≥65

years), compared to younger subjects. AUCs are increased approximately 80% with verapamil

hydrochloride. In the elderly, verapamil hydrochloride clearance is reduced resulting in increases

in elimination t

Gender

The effect of gender on verapamil hydrochloride, when administered as NOVO-VERAMIL SR,

has not been investigated.

Race

The effect of different races on verapamil hydrochloride, when administered as NOVO-

VERAMIL SR, has not been investigated.

Hepatic Insufficiency

The degree of biotransformation during the first pass of verapamil hydrochloride may vary

according to the status of the liver in different patient populations. In patients with hepatic

insufficiency, metabolism is delayed and elimination t½ prolonged up to 14 to 16 hours. See

(WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic, Hepatic Insufficiency)

and (DOSAGE AND ADMINISTRATION).

Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the

urine. In one study in healthy volunteers, the total body clearance after intravenous

administration of verapamil hydrochloride 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 hydrochloride in patients with renal disease is decreased. In two

studies with oral verapamil hydrochloride no difference in pharmacokinetics could be

demonstrated. See (WARNINGS AND PRECAUTIONS – Renal, Renal Insufficiency).

Genetic Polymorphism

The effect of genetic polymorphism on verapamil hydrochloride pharmacokinetics has not been

investigated.

STORAGE AND STABILITY

Store NOVO-VERAMIL tablets and NOVO-VERAMIL SR tablets between 15

C and

protect from light. Unit Dose strips should be stored between 15

C, and protected from high

humidity and light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-VERAMIL 80 mg is available as a round, yellow, sugar-coated tablet containing

verapamil HCl 80 mg. Non-medicinal ingredients: Colloidal Silicon Dioxide, Microcrystalline

Cellulose, Magnesium Stearate, Povidone, Pregelatinized Starch, Sodium Lauryl Sulfate and

Sodium Starch Glycolate. Coating ingredients: 3A Alcohol, D&C yellow #10, FD&C yellow #6,

Hydroxypropyl Cellulose, Hypromellose, Polydextrose, Polyethylene Glycol, Talc, Titanium

Dioxide, Triacetin and Triethyl Citrate

NOVO-VERAMIL 120 mg is available as a round, white, sugar-coated tablet containing

verapamil HCl 120 mg. Non-medicinal ingredients: Colloidal Silicon Dioxide, Microcrystalline

Cellulose, Magnesium Stearate, Povidone, Pregelatinized Starch, Sodium Lauryl Sulfate and

Sodium Starch Glycolate. Coating Ingredients: Hypromellose, Methanol, Polydextrose,

Polyethylene Glycol, Talc, Titanium Dioxide and Triethyl Citrate

NOVO-VERAMIL SR Tablets are available as 240 mg pale green, capsule-shaped, biconvex

scored, film-coated tablets containing 240 mg of verapamil hydrochloride. Non-medicinal

ingredients: Magnesium Stearate, Microcrystalline Cellulose, Sodium Alginate and Povidone.

Coating Ingredients: D&C Yellow #10, FD&C Blue #1, FD&C Yellow #6, Hypromellose,

Polyethylene Glycol, Polysorbate and Titanium Dioxide

NOVO-VERAMIL & NOVO-VERAMIL SR tablets are available in bottles of 100 and 500,

1000 and in boxes of 100 (as unit dose strips).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Verapamil hydrochloride

Chemical name:

α-isopropyl-α-[(N-methyl-N-homoveratryl)-γ- aminopropyl]-3,4-

dimethoxyphenylacetonitrile hydrochloride.

Molecular formula:

HCl

Molecular mass:

491.07

Structural formula:

Physicochemical properties:

Verapamil HCl is a white or almost white, odourless or almost

odourless, bitter-tasting, crystalline powder. The compound is

soluble 1 in 20 of water, sparingly soluble in ethanol and freely

soluble in chloroform. It has a melting point of 140

C. Verapamil

hydrochloride should be protected from light.

CLINICAL TRIALS

A comparative two-way, single-dose bioavailability study was performed on Novo-Veramil 80

mg Tablets and Isoptin

80 mg Tablets. The pharmacokinetic plasma data calculated for the

parent compound, verapamil is tabulated below:

Verapamil

(1 x 80 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test*

Reference

% Ratio of

Geometric Means

Confidence

Interval, 90%

(ngh/mL)

272.99

202.51 (74.18)

280.92

172.36 (61.35)

92.88

82.18-104.97

(ngh/mL)

306.47

211.11 (68.88)

309.65

178.66 (57.70)

96.39

86.50-107.42

(ng/mL)

68.23

42.07 (61.65)

74.57

40.74 (54.63)

89..28

78.16-101.98

1.42 (0.64)

1.33 (0.51)

3.30 (1.02)

3.14 (0.83)

*Novo-Veramil 80 mg Tablets (Teva Canada Limited., Canada)

Isoptin® 80 mg Tablets (Abbott Laboratories Ltd., Canada, purchased in Canada)

Expressed as the

arithmetic mean (CV% only).

A comparative, multi-dose study was performed on two 240 mg verapamil hydrochloride

sustained release products in 24 healthy male volunteers. The pharmacokinetic plasma data

calculated for the Novo-Veramil SR and Isoptin

SR tablet formulations is tabulated below.

Verapamil

(1 x 240 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test*

Reference

% Ratio of

Geometric Means

Confidence

Interval, 90%

(ngh/mL)

1339

1417.88 (33)

1394

1530.16 (44)

87-106

(ng/mL)

113.3

124.48 (42)

103.5

115.66 (48)

(ng/mL)

23.1

25.56 (42)

28.49 (46)

5.0 (2.5)

8.0 (2.6)

*Novo-Veramil SR 240 mg Tablets (Teva Canada Limited., Canada)

Isoptin® SR 240 mg Tablets (Abbott Laboratories Ltd., Canada, purchased in Canada)

Expressed as the

arithmetic mean (CV% only).

A comparative two-way, single-dose bioavailability study was performed on Novo-Veramil SR

240 mg tablets and Isoptin

SR 240 mg tablets in 24 healthy normal male volunteers

immediately following a standardized meal. The pharmacokinetic plasma data calculated for

verapamil is tabulated below:

Verapamil

(1 x 240 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test*

Reference

% Ratio of

Geometric Means

Confidence

Interval, 90%

(ngh/mL)

963.1 (47)

925.5 (40)

91-114

(ngh/mL)

1075

1156.45 (39)

1022

1530.16 (31)

(ng/mL)

74.5 (77)

72.4 (45)

78-111

7.0 (4.3)

8.0 (2.6)

10.9 (5.5)

8.9 (5.2)

*Novo-Veramil SR 240 mg Tablets (Teva Canada Limited., Canada)

Isoptin® SR 240 mg Tablets (Abbott Laboratories Ltd., Canada, purchased in Canada)

Expressed as the

arithmetic mean (CV% only).

A comparative two-way, single-dose bioavailability study was performed on Novo-Veramil SR

240 mg tablets and Isoptin

SR 240 mg tablets in 18 fasted, healthy, normal male volunteers.

The pharmacokinetic plasma data calculated for verapamil is tabulated below:

Verapamil

(1 x 240 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test*

Reference

% Ratio of

Geometric Means

Confidence

Interval, 90%

(ngh/mL)

1200

1329.75 (43)

1188

1274.82 (38)

85-120

(ngh/mL)

1287

1417.79 (33)

1287

1373.22 (36)

(ng/mL)

165.22 (49)

144.92 (38)

90-134

4.5 (1.6)

5.0 (4.7)

7.2 (2.9)

7.6 (3.3)

*Novo-Veramil SR 240 mg Tablets (Teva Canada Limited., Canada)

Isoptin® SR 240 mg Tablets (Abbott Laboratories Ltd., Canada, purchased in Canada)

Expressed as the

arithmetic mean (CV% only).

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

Verapamil hydrochloride was initially investigated in experimental animals as a smooth muscle

relaxant, with vasodilator properties. Subsequent studies have demonstrated that verapamil

hydrochloride has significant antiarrhythmic effects when tested in a variety of experimental

arrhythmias. The mechanism of action of verapamil hydrochloride seems to be the blocking of

transmembrane influx of calcium through the slow channels, without affecting to any significant

degree, transmembrane influx of sodium through the fast channels. It does not directly modify

calcium uptake, binding or exchange by cardiac microsomes. Its main locus of action seems to

be the superficially located membrane storage sites for calcium.

In isolated cardiac tissues, at low to moderate concentrations, verapamil exerts little or no effect

on action potential amplitude, but suppresses activity in the sinoatrial (S-A) and atrioventricular

(A-V) nodes. Any activity within the S-A and A-V nodes seems to be particularly sensitive to the

suppressant effects of verapamil because normal impulse formation in the sinus node and

conduction in the A-V node appear to be maintained by operation of slow channel mechanisms.

The depressant effects exerted by verapamil on A-V nodal conduction may in part explain its

effectiveness in treating supraventricular tachycardia.

Verapamil has a marked negative inotropic effect on isolated cardiac muscle. In intact animals,

the depressant effect on cardiac output and stroke volume is dose-dependent.

Although verapamil has local anaesthetic properties, in clinically relevant doses it does not affect

the rate of either the depolarization or the repolarization phase of the cardiac action potential.

Verapamil does not have beta-blocking properties, although it antagonizes beta-adrenergic

influences on the heart by a functional antagonism, due to its basic pharmacodynamic properties

at the level of the conduction system and the myocardium.

In animal studies, the S-enantiomer has 15 and 50 times the activity of the R-enantiomer in

reducing myocardial contractility in isolated blood-perfused dog papillary muscle and isolated

rabbit papillary muscle, respectively, and twice the effect in reducing peripheral resistance.

TOXICOLOGY

Acute Toxicity

Table 7:

Lethal Dose 50 (LD

50

) (mg/kg) of Verapamil

Intravenous

Intraperitoneal

Subcutaneous

Oral

Rat

Mouse

Guinea Pig

Juvenile Rat

93 (M)

113 (F)

Juvenile Rabbit

114.2 (M)

129.8 (F)

Definitions:

M = male

F = female

Symptoms preceding death were similar in both sexes with marked sedation, decreased

excitability, forced respirations, clonic spasms and convulsions.

Subacute Toxicity

Oral Studies

Verapamil was administered orally in doses of 12.5, 25 and 50 mg/kg per day, to rats via food

for 14 weeks (29 animals/group) and to dogs for 6 days/week in capsules, for 15 to 16 weeks (4

animals/ group). Baboons received 2, 4, 8, 16, 32 and 64 mg/kg by mouth daily for 4 weeks (2

animals/group).

In rats, a dose-related increase in heart and lung weights was found. Dogs given 25 to 50 mg/kg

showed slight weight loss and a significant reduction in heart rate up to Week 11, followed by a

gradual return to normal. In one dog on 12.5 mg/kg, one on 25 mg/kg and in all animals on 50

mg/kg, there was emesis during the first two weeks of the study. Serum glutamic-pyruvic

transaminase (SGPT) was elevated for one dog on 25 mg/kg at week 9 and for two animals on 50

mg/kg at the end of the test. Macroscopic examinations at necropsy were negative and there was

no drug-attributal histological changes. The baboons showed no drug-related changes.

Intramuscular Studies

Beagle dogs were given 0, 2 and 10 mg/kg, 5 days/week for 30 days (4 animals/group). Injection

sites in all animals became edematous and a dose-related reduction in heart rate was observed. At

10 mg/kg, hemoglobin and hematocrit values decreased and one animal had a raised SGPT. At

necropsy, edema was noted at injection sites and higher spleen weights were recorded at the 10

mg/kg dose. One dog on this dose also showed increased inflammatory cell infiltration in the

liver, with some hepatic cell degenerative changes.

Intravenous Studies

Verapamil was given to Sprague-Dawley rats at 0.2, 1 and 5.0 mg/kg once daily for 4 weeks (30

animals/group) and similarly to beagle dogs at 0.1, 0.4 and 1.6 mg/kg levels (6 animals/group).

At the highest dose level, all dogs showed some restlessness, salivation and laboured breathing,

along with delayed A-V conduction in one-half of the animals. In 4 of 6 animals at the highest

dose (1.6 mg/kg) sporadic small focal gatherings of Kupffer cells, with death of individual liver

cells (necrobioses and/or necrosis of hepatocytes) were found histopathologically.

Chronic Toxicity

Oral

Rats were given verapamil at 10, 15, 25, 30, 60 and 62.5 mg/kg/day (50 animals/group) and

beagle dogs at 10, 15, 25, 30, 40, 60, 62.5, 70, 81 and 85 mg/kg (6 animals/group) for 12 and 18

months. Clinical signs were observed and changes in food consumption, consistency of stools,

hemograms, clinical chemistry and urinalyses performed. Blood pressure, electrocardiogram

(ECG) and ophthalmoscopic examinations were done on the dogs.

In one 18-month rat study, an increase in weight of the thyroid glands in females on the 62.5 mg

dose was noted. In a later 12-month study, a slight reduction in weight gain was recorded.

In dogs, at doses of 60 mg and greater, toxic signs such as vomiting, salivation, reversible

hyperplasia of the gums, reduced food consumption, slight weight loss and a transitory, slight to

moderate elevation of SGPT were noted and three of the animals died. The 40 mg dose caused

loss of coat colour and hair, and a delay in A-V conduction.

In another study, atypical lens changes (cataracts) were observed in eight beagles receiving toxic

dose levels (62.5 and 70 mg/kg). In a later study, four beagles were given 81 mg/kg for 18

months and none developed cataracts. It was concluded that any changes caused by verapamil in

lens transparency are specific to the beagle. This is supported by the absence of similar lesions in

other species studied, and by the apparent lack of any impairment by verapamil of carbohydrate

or energy metabolism in lenticular tissue. The water-soluble proteins of the canine lens are

known to have differences from those in other species.

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five

different strains of Salmonella typhimurium, nor in studies on chromosomal aberrations and

sister chromatid exchanges (SCE) in human lymphocytes, nor in the hypoxanthine guanine

phosphoribosyltransferase (HGPRT)-test with V-79 Chinese hamster cells, and also not in the

cell transformation assay with Syrian hamster embryo cells. In addition verapamil did not show

any SCE-inducing activity in vivo (Chinese hamster).

Carcinogenicity

In a 24-month carcinogenicity study, verapamil hydrochloride was administered orally to 50

male and 50 female rats in the diet as actual mean doses of 9.3/9.5, 32.6/33.2, and 112.2/102.5

mg/kg/day, respectively. Two hundred animals served as controls.

Drug-related significant reductions in body weight and mortality were seen in males and females

of the high dose group.

Dose-related cardiac lesions (dilatation, atrial thrombi and myocardial metaplasia, combined

with hydrothorax) were seen in the high dose group. These cardiac lesions are considered to be

related to a chronic, exaggerated pharmacologic effect at this high dose level.

At the end of the study, all rats were examined histopathologically with regards to tumorigenesis.

All non-neoplastic and neoplastic lesions were considered to reflect the spectrum of spontaneous

lesions commonly encountered in rats of this age and strain. As compared to the controls, the

type and incidence of these lesions were not increased in treated rats.

Reproduction and Teratology

Studies were carried out in rats and rabbits with verapamil given in food and/or by gastric tube.

These studies included fertility and general reproduction performance in rats, teratogenicity

studies in rats and rabbits and peri- and post-natal studies in rats. Rats were given 2.5, 12.5, 25

and 100 mg/kg body weight, by gastric tube and 1.3, 1.6, 5.2, 7.5, 13.3, 16 and 55 mg/kg body

weight in food. In another teratogenicity study, rats were given 5, 10 and 20 mg/kg body weight

by gavage three times daily at an interval of about 4.5 hours. Rabbits were given 5 and 15 mg/kg

body weight by gastric tube.

There was no evidence of teratogenicity in either species and no embryotoxic effects observed in

the rats dosed via food, or with doses up to 12.5 mg/kg body weight given by gastric tube, or

with doses up to 10 mg/kg three-times a day. The single daily dose of 25 mg/kg body weight or

more, caused a higher resorption rate in the rat. The dose of 20 mg/kg three-times a day. 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 was no difference in resorption rates observed in the rabbit and

no effect on peri- and post-natal development or fertility in the rat.

REFERENCES

Anavekar SN, Christophidis N, Louis WJ, Doyle AE. Verapamil in the Treatment of

Hypertension. J Cardiovasc Pharm 1981; 3:287-92.

Bauer LA, et al. Verapamil Inhibits Ethanol Elimination and Prolongs the Perception of

Intoxication. Clin Pharmacol Ther 1992;52(1):6-10.

Bonow RO, Leon MB, Rosing DR, et al. Effects of Verapamil and Propranolol on Left

Ventricular Systolic Function and Diastolic Filling in Patients with Coronary Artery

Disease: Radionuclide Angiographic Studies at Rest and During Exercise. Circulation

1981; 65:1337-50.

Cubeddu LX, Aranda J, Singh B, et al. A Comparison of Verapamil and Propranolol for

the Initial Treatment of Hypertension - Racial Differences in Response. J Am Med Assoc

l986; 256:2214-21.

Ferlinz J, Easthope JL. Effects of Verapamil on Myocardial Performance in Coronary

Disease. Circulation 1979; 59:313-9.

Ferlinz J, Turbow ME, Aronow WS. Myocardial Metabolism and Anginal Threshold in

Coronary Disease after Verapamil Administration. Clin Invest Med 1980; 3:101-9.

Follath F, Fromer M, Meier P, Vozeh S. Pharmacodynamic Comparison of Oral and

IntravenousVerapamil in Atrial Fibrillation. Clin Invest Med 1980; 3:49-52.

Frishman WH, Klein NA, Klein P, et al. Comparison of Oral Propranolol and Verapamil

for Combined Systemic Hypertension and Angina Pectoris. A Placebo-controlled

Double-blind Randomized Crossover Trial. Amer J Cardiol 1982; 50:1164-1172.

Frishman WH, Klein NA, Strom JA, et al. Superiority of Verapamil to Propranolol in

Stable Angina Pectoris: A Double-blind, Randomized Crossover Trial. Circulation 1982;

65(suppl.I):I51-9.

Gould BA, Mann S, Kieso H, Balasubramanian V, Raftery EB. The Role of a Slow

Channel Inhibitor, Verapamil, in the Management of Hypertension. Clin Exp Pharmacol

Physiol 1982; Suppl 6:113-121

Johnson SM, Mauritson DR, Corbett JR, Woodward W, Willerson JT, Hillis LD. Double-

blind, Randomized, Placebo-controlled Comparison of Propranolol and Verapamil in the

Treatment of Patients with Stable Angina Pectoris. Am J Med 1981; 71:443-51.

Johnson SM, Mauritson DR, Willerson JT, Hillis LD. A Controlled Trial of Verapamil

for Prinzmetal's Variant Angina. New Eng J Med 1981; 304:862-6.

Kaltenbach M, Hopf R, Kober G, Bussmann WD, Keller M, Petersen Y. Treatment of

Hypertrophic Obstructive Cardiomyopathy by Verapamil. Br Heart J 1979; 42:35-42.

Klein HO, Lang R, Weiss E, et al. The Influence of Verapamil in Serum Digoxin

Concentrations. Circulation 1982; 65:998-1003.

Miller MR, Withers R, Bhamra R, Holt DW. Verapamil and Breast-feeding. Eur J Clin

Pharmacol, 1986; 30:125-6.

Nayler WG. Cardioprotective Effects of Calcium Ion Antagonists in Myocardial

Ischemia. Clin Invest Med 1980; 3:91-9.

Packer M, Meller J, Medina N, et al. Hemodynamic Consequences of Combined Beta-

adrenergic and Slow Calcium Channel Blockade in Man. Circulation 1982; 65:660-8.

Perez-Reyes M, et al. Interaction Between Ethanol and Calcium Channel Blockers in

Humans. Alcohol Clin Exp Res 1992;16(4):769-775.

Pozenel H. Plasma Concentration and Blood Pressure Effect of a Sustained Release

Verapamil Preparation. In Calcium Antagonists & Hypertension Current Status, Excerpta

Medica, Amsterdam, 1986, pp 56-65.

Rinkenberger RL, Prystowsky EN, Heger JJ, Troup PJ, Jackman WM, Zipes DP. Effects

of Intravenous and Chronic Oral Verapamil Administration in Patients with

Supraventricular Tachyarrhythmias. Circulation 1980; 62:996-1010.

Rosing DR, Condit JR, Maron BJ, et al. Verapamil Therapy: A New Approach to the

Pharmacologic Treatment of Hypertrophic Cardiomyopathy: III. Effects of Long Term

Administration. Am J Cardiol 1981; 48:545-553.

Schwartz JB, Keefe DL, Kirsten E, Kates RE, Harrison DC. Prolongation of Verapamil

Elimination Kinetics During Chronic Oral Administration. Am Heart J 1982;

104:198203.

Subramanian VB, Bowles MJ, Khurmi NS, Davies AB, Raferty EB. Randomized

Double-blind Comparison of Verapamil and Nifedipine in Chronic Stable Angina. Am J

Cardiol 1982; 50:696-703.

Vohra J, Ross D, Cole P, Hunt D, Sloman G. The Effect of Orally Administered

Verapamil on Atrioventricular Nodal Conduction and Refractoriness. I.R.C.S., Med Sci

1980; 8:45.

Zachariah PK, Sheps SG, Schirger A, Spiekerman RE, O'Brien PC, Simpson KK.

Verapamil & 24-hour Ambulatory Blood Pressure Monitoring in Essential Hypertension.

Am J Cardiol 1986; 57:74D-79D.

Zacny JP, Yajnik S. Effects of Calcium Channel Inhibitors on Ethanol Effects and

Pharmacokinetics in Healthy Volunteers. Alcohol 1993;10(6):505-509.

A comparative two-way, single-dose bioavailability study of verapamil tablets in normal

human volunteers, June 3, 1986.

A comparative two-way, multi-dose bioavailability study of verapamil sustained release

tablets in normal male volunteers. May 20, 1992.

A comparative two-way, single-dose bioavailability study of verapamil sustained release

tablets in normal male volunteers immediately following a standardized meal.

Completed May 3, 1993.

A comparative two-way, single-dose bioavailability study of verapamil sustained release

tablets in fasted normal male volunteers. Completed June 10, 1993.

ISOPTIN® SR Product Monograph, Abbott Laboratories limited, Control No.: 131123,

Revision Date: January 5, 2010.

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

NOVO-VERAMIL

(verapamil hydrochloride tablets)

&

Pr

NOVO-VERAMIL SR

(verapamil hydrochloride sustained-release tablets)

This leaflet is part III of a three-part "Product Monograph"

published when NOVO-VERAMIL & NOVO-VERAMIL

SR was approved for sale in Canada and is designed

specifically for Consumers. This leaflet is a summary and

will not tell you everything about NOVO-VERAMIL &

NOVO-VERAMIL SR. Contact your doctor or pharmacist

if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

NOVO-VERAMIL tablets may be used in the treatment of:

1. Chronic stable angina of effort. (Chest pain)

2. Angina resulting from coronary artery spasm. (Chest pain)

3. Obstructive hypertrophic cardiomyopathy where surgery is

not otherwise indicated.

4. Atrial fibrillation or flutter with rapid ventricular response not

otherwise controllable with digitalis preparations. (Irregular

heart beat)

5. Follow-up treatment to the use of injectable verapamil in

paroxysomal supraventricular tachycardia. (Irregular heart

beat)

6. Mild to moderate essential hypertension (high blood

pressure).

NOVO-VERAMIL SR is used to treat hypertension (high blood

pressure).

What it does:

Verapamil hydrochloride is a calcium channel blocker. Calcium

channel blockers change the amount of calcium getting into the

muscle cells of your heart and blood vessels. This can change

the strength and speed at which your heart beats. It also opens

up the blood vessels so that blood can be pumped around your

body more easily. This helps to lower your blood pressure.

When it should not be used:

NOVO-VERAMIL & NOVO-VERAMIL SR should not be

used if:

you are allergic to any component of NOVO-VERAMIL &

NOVO-VERAMIL SR, including the active ingredient or the

nonmedicinal ingredients. See (What the nonmedicinal

ingredients are).

you have certain serious heart disease or problems.

you feel faint when you get up.

you have symptoms such as rapid pulse and breathing,

anxiety, weakness, decreased urine production, cool hands

and feet and loss of alertness. See your doctor immediately.

you have had a heart attack.

You have slow heartbeat or irregular heartbeat.

you are breast-feeding while taking this medication.

Ask your doctor for advice.

What the medicinal ingredient is:

NOVO-VERAMIL & NOVO-VERAMIL SR contains

verapamil hydrochloride.

What the important non-medicinal ingredients are:

NOVO-VERAMIL 80 mg and 120 mg: Colloidal Silicon

Dioxide, Microcrystalline Cellulose, Magnesium Stearate,

Povidone, Pregelatinized Starch, Sodium Lauryl Sulfate and

Sodium Starch Glycolate.

NOVO-VERAMIL 80 mg coating: 3A Alcohol, D&C yellow

#10, FD&C yellow #6, Hydroxypropyl Cellulose,

Hypromellose, Polydextrose, Polyethylene Glycol, Talc,

Titanium Dioxide, Triacetin and Triethyl Citrate.

NOVO-VERAMIL 120 mg coating: Hypromellose, Methanol,

Polydextrose, Polyethylene Glycol, Talc, Titanium Dioxide and

Triethyl Citrate.

NOVO-VERAMIL SR 240 mg: Magnesium Stearate,

Microcrystalline Cellulose, Sodium Alginate and Povidone.

NOVO-VERAMIL SR 240 mg coating: D&C Yellow #10,

FD&C Blue #1, FD&C Yellow #6, Hypromellose, Polyethylene

Glycol, Polysorbate and Titanium Dioxide.

What dosage forms it comes in:

NOVO-VERAMIL is available in tablets in the following

strengths: 80 mg, 120 mg.

NOVO-VERAMIL SR is available as sustained-release tablets

in the following strengths: 240 mg.

WARNINGS AND PRECAUTIONS

BEFORE you use NOVO-VERAMIL & NOVO-VERAMIL

SR talk to your doctor or pharmacist if:

you are pregnant or planning to become pregnant.

you have any heart disease.

you have kidney disease.

you have liver disease.

you are taking beta-blockers. See (Interactions With This

Medication).

you have neuromuscular disease (i.e. myasthenia gravis or

Duchenne muscular dystrophy).

IMPORTANT: PLEASE READ

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with NOVO-VERAMIL & NOVO-

VERAMIL SR include:

beta-blockers (e.g., propranolol, metoprolol, atenolol,

timolol);

any other treatment for hypertension (high blood pressure) or

an arrhythmia (abnormal heart beat) (e.g.,

hydrochlorothiazide, disopyramide, flecainide, quinidine,

prazosin, terazosin);

digoxin, digitoxin, cimetidine, lithium, rifampin, theophylline,

sulfinpyrazone, clarithromycin, erythromycin, telithromycin,

glyburide, almotriptan, colchicine;

carbamazepine and phenobarbital;

any of the group of medicines known as major tranquilizers,

or an antidepressant of the tricyclic group (e.g. imipramine);

any of the group of medicines known as benzodiazepines or

other anti-anxiety treatment (e.g. buspirone, midazolam);

any of the group of medicines known as non-steroidal anti-

inflammatory drugs (e.g. acetylsalicylic acid);

anti-cancer medication (e.g. doxorubicin);

some medication that can affect your immune system (e.g.

cyclosporine, sirolimus, tacrolimus);any neuromuscular

blocking agent (e.g., atracurium);

some anti-cholesterol products (e.g., simvastatin, atorvastatin,

lovastatin);

some HIV-antiviral medication (e.g., ritonavir);

grapefruit juice;

alcohol;

St John’s Wort.

PROPER USE OF THIS MEDICATION

Usual dose:

Angina Pectoris (Chest pain): Usual starting dose in adults is

80 mg of NOVO-VERAMIL Tablets 3 to 4 times daily.

Paroxysmal Supraventricular Tachycardias (Irregular heart

beat): In adults, use the same dosage schedule as for angina

pectoris.

Atrial Fibrillation and Flutter with Rapid Ventricular

Response (Irregular heart beat): The same dosage as for angina

pectoris can be used.

Obstructive Hypertrophic Cardiomyopathy: Usual starting

dose is 80 to 120 mg 3 to 4 times daily.

Mild to Moderate Essential Hypertension (High blood

pressure): Dosage must be individualized.

Initial dose for NOVO-VERAMIL is usually 80 mg three times

a day.

NOVO-VERAMIL SR should be taken once-a-day at the same

time every day. The usual adult dose NOVO-VERAMIL SR is

180 to 240 mg/day.

Take NOVO-VERAMIL & NOVO-VERAMIL SR with food to

help it work better.

NOVO-VERAMIL & NOVO-VERAMIL SR tablets should not

be divided, crushed or chewed.

Overdose:

If you or someone you know accidentally takes more than stated

dose, contact your doctor immediately or go to the nearest

hospital with the tablets.

In case of accidental drug overdose, contact a health care

practitioner, hospital emergency department or regional poison

control centre immediately, even if there are no symptoms. Tell

your doctor or hospital how much was taken. Treat even small

overdoses seriously.

Missed Dose:

If you forget to take one tablet, take another as soon as you

remember, unless it is almost time for your next dose. If it is, do

not take the missed tablet at all.

Never double-up on a missed dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Along with its needed effects, a medicine may cause some

unwanted effects. These are referred to as “side effects”.

Although not all of these side effects may occur, if they do

occur they may need medical attention.

The most common side effects with NOVO-VERAMIL &

NOVO-VERAMIL SR are constipation, dizziness and feeling

sick (nausea). Other less common side effects may include

headache and tiredness.

Check with your physician or pharmacist if you experience any

unexpected effects, or are concerned by the above side effects.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist

Only if

severe

In all

cases

Common

Feeling dizzy and faint or your

blood pressure is too low

Difficulty breathing

Swelling in the arms or legs

Uncommon

IMPORTANT: PLEASE READ

Feeling an irregular heart beat

Rash or other skin irritation

Muscle weak

This is not a complete list of side effects. For any unexpected

effects while taking NOVO-VERAMIL & NOVO-VERAMIL

SR, contact your doctor or pharmacist.

HOW TO STORE IT

Keep NOVO-VERAMIL & NOVO-VERAMIL SR and all other

medicines out of reach of children.

NOVO-VERAMIL & NOVO-VERAMIL SR tablets should be

stored between 15

- 30

C and protected from light. Unit Dose

strips should be stored between 15

- 25

C, and protected from

high humidity and light.

Do not take your tablets after the expiry date shown on the label.

It is important to keep the NOVO-VERAMIL & NOVO-

VERAMIL SR tablets in the original package.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions associated

with the use of health products to the Canada Vigilance

Program by one of the following 3 ways:

Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to 1-866-678-6789, or

- Mail to: Canada Vigilance Program

Health Canada

Postal Locator 0701C

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form

and the adverse reaction reporting guidelines are

available on the MedEffect™ Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the

management of side effects, contact your health

professional. The Canada Vigilance Program does not

provide medical advice.

MORE INFORMATION

This document plus the full Product Monograph, prepared for

health professionals can be obtained by contacting the sponsor,

Teva Canada Limited at:

1-800-268-4127 ext. 5005 (English);

1-877-777-9117 (French)

or druginfo@tevacanada.com

This leaflet was prepared by:

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

Canada, M1B 2K9

Last revised: May 28, 2013

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