Abbott Healthcare Products Limited

Isoptin 120 mg Film-coated Tablets.

One tablet contains 120 mg of Verapamil Hydrochloride.

For a full list of excipients, see section 6.1

Film-Coated Tablets

Circular, white, biconvex, film-coated tablet, embossed 'Isoptin 120' on one side and 'Knoll' above the scoreline on the other side.

The scoreline is to allow breaking for ease of swallowing.

Prophylaxis and/or treatment of:-

– Angina pectoris, including Prinzmetal's angina (coronary spasm, vasospastic angina).

– Supraventricular tachycardias such as paroxysmal supraventricular tachycardia, atrial fibrillation/flutter with rapid ventricular response (except in WPW syndrome, see “Contraindications”).

– Mild to moderate essential hypertension.

Verapamil should not be taken with grapefruit juice (see Section 4.5, Interactions).

The tablets should be taken with or shortly after meals together with some liquid.

Adults only:

For the treatment of angina, including Prinzmetal's angina, the usual dose is 120 mg 3 to 4 times daily. Although 80 mg 3 times daily may be adequate in many patients with angina of effort, doses below 120 mg 3 times daily are unlikely to be effective in angina of rest and Prinzmetal's angina.

In cases of supraventricular tachycardia the usual dose is 40 mg to 120 mg 3 to 4 times daily according to the severity of the patient's condition.

For the treatment of essential hypertension the usual dose is 40 mg to 120 mg 3 to 4 times daily. In long-term treatment, a total daily dose of 480 mg should not be exceeded; short-term dose increases are possible only when directed by the physician.

Isoptin should not be given in the following cases:

Cardiovascular shock, complicated acute myocardial infarction (bradycardia, hypotension, left ventricular failure), severe conduction disorders (second and third degree AV block, sino-atrial block); sick-sinus syndrome (bradycardia-tachycardia syndrome); manifest heart failure; simultaneous intravenous administration of beta-adrenergic blockers; atrial fibrillation/flutter with simultaneous pre-excitation syndrome, e.g. WPW syndrome (risk of provoking ventricular tachycardia).

Use in patients who are hypersensitive to the active ingredient.

Use in pregnancy unless considered essential by the physician.

Patients with heart failure or those who are susceptible to heart failure should be fully digitalised before verapamil therapy as it may aggravate or precipitate cardiac failure.

Great care should be taken in:

First degree AV block, bradycardia < 50 beats/min, hypotension < 90 mmHg systolic and ventricular tachycardias (QRS complex > 0.12 sec).

Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.

In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending on the severity of the liver disease, due to diminished drug metabolism. In these patients, dosage interval should be prolonged and low doses used.

Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)

If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdosage).

Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis.

Colchicine:

There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended. (see Section 4.5, Drug Interactions).

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

The following table provides a list of potential drug interactions with verapamil:

Potential Drug Interactions associated with Verapamil

Other Drug Interactions and Additional Drug Interaction Information

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. (See Section 4.4, Special Warnings and Special Precautions for Use).

Antiarrhythmics, beta-blockers: Mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension)

Antihypertensives, diuretics, vasodilators: Potentiation of the hypotensive effect

Prazosin, terazosin: Additive hypotensive effect

HIV antiviral agents: Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.

Quinidine: Hypotension. Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

Carbamazepine: Increased carbamazepine levels. This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness.

Lithium: Increased lithium neurotoxicity

Rifampin: Blood pressure lowering effect may be reduced.

Sulfinpyrazone: Blood pressure lowering effect may be reduced.

Neuromuscular blockers: The effect of neuromuscular blocking agents may be potentiated.

Aspirin: Increased tendency to bleed

Ethanol (alcohol): Elevation of ethanol plasma levels

HMG Co-A Reductase Inhibitors (“Statins”): Treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin orlovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin 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.

During pregnancy (especially in the first trimester), Isoptin should only be used if considered essential by the physician.

Verapamil is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.

Depending on the individual susceptibility, the patient's ability to drive a vehicle or operate machinery may be impaired. This is particularly true in the initial stages of treatment, when changing over from another drug, and also with respect to the consumption of alcohol.

Adverse reactions have been spontaneously reported during the post-approval use of oral verapamil. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.

Significant adverse events reported with verapamil are listed below by system organ class:

The usual intensive care measures should be taken. Fatalities have occurred as a result of overdose.

Verapamil hydrochloride cannot be removed by haemodialysis.

The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour). The following measures may also be necessary:

In the case of 2^nd or 3^rd degree AV block, sinus bradycardia, asystole: Atropine, isoprenaline, orciprenaline or pacemaker therapy.

In the case of hypotension: Dopamine, dobutamine, norepinephrine.

If there are any signs of continuing myocardial failure: Dopamine, dobutamine, if necessary repeated calcium injections, and possibly other medication that increases cardiac contractility combined with isoprenaline.

Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives ATC Code: C08DA01.

Verapamil inhibits the transmembrane influx of calcium ions into the heart and vascular smooth muscle cell. The myocardial oxygen demand is lowered directly as a result of the effect on the energy consuming metabolic processes of the myocardial cell and indirectly due to a reduction of the afterload.

Due to its effect on coronary vascular smooth muscle, Isoptin enhances myocardial blood flow, even in post-stenotic areas, and relieves coronary spasms.

These properties contribute to the anti-ischaemic and antianginal efficacy of Isoptin in all types of coronary artery disease.

Isoptin has a marked antiarrhythmic effect, particularly in supraventricular arrhythmias. It delays impulse conduction in the AV node. Owing to this, sinus rhythm is restored and/or ventricular rate is normalised, depending on the type of arrhythmia. Normally, the rate is either not affected or only minimally lowered.

The antihypertensive effect of Isoptin stems from a decrease in peripheral vascular resistance, without an increase in heart rate as a reflex response. As early as day 1 of treatment, blood pressure falls; the effect is found to persist also in long-term therapy.

Verapamil is absorbed rapidly and almost exclusively in the small intestine. The absorption rate is 90-92%. Half-life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration. On multiple administration, the half-life of verapamil can be prolonged to about double the value measured after single administration. Peak verapamil hydrochloride plasma levels are reached one to two hours after IR administration.

Verapamil is metabolised almost completely. The main metabolites are norverapamil and the primary and secondary amines. In animal studies, only norverapamil showed any appreciable pharmacological activity, while the other metabolites were practically ineffective.

Verapamil and its metabolites are excreted primarily in the urine; only 3 to 4% is excreted as unchanged drug. Within 24 hours 50%, within 48 hours 55-60% and within 5 days 70% of the administered dose is excreted in the urine. Up to 16% is excreted in the faeces. Recent findings have shown that there are no differences between the pharmacokinetics of verapamil in persons with healthy kidneys and in patients with terminal renal failure.

In coronary heart disease and hypertension, no correlation was found between the therapeutic effect and the plasma concentration; a definite correlation with the plasma level was determined only for the effect on the PR interval. The concentration curve of verapamil in the plasma is protracted after administration of the sustained-release formulations, and is also flatter and more homogenous than after administration of the instant release formulations. Plasma protein binding is about 90%.

Transfer across the placenta: Verapamil passes the placental barrier; the concentration in the plasma of the umbilical vein blood was between 20 and 92% of the plasma concentration of the mother.

Transfer into human milk: Although verapamil is excreted in human milk, the concentrations are so low at therapeutic dose levels that no appreciable pharmacological effect is to be expected in infants.

The cardiovascular findings and the diffuse gingival hyperplasia seen in the chronic toxicity of verapamil hydrochloride are taken into account in Section 4.8 (Undesirable Effects).

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Isoptin 120 mg tablets are packed in PVC blister strips in cartons.

Pack size: 100 tablets.

No special requirements.

Abbott Laboratories Ireland Limited

4051 Kingswood Drive

Citywest Business Campus

Dublin 24

Ireland

PA 38/85/3

Date of first authorisation: 01 April 1980

Date of last renewal: 01 April 2010

29 July 2011