VERAPAMIL 40 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Verapamil 40mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains verapamil hydrochloride 40 mg

Excipients with known effect

Lactose

Sunset yellow E110

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Pale yellow, convex, film-coated tablets, diameter approximately 6.5 mm, engraved MP68 on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1. The prophylaxis and treatment of angina pectoris.

2. Prophylaxis and treatment of supraventricular paroxysmal tachycardia; atrial fibrillation and premature supraventricular contractions; atrial fibrillation and flutter and supraventricular paroxysmal tachycardia of the reciprocating type, associated with the Wolff-Parkinson-White Syndrome.

3. Treatment either alone or in conjunction with other anti-hypertensive therapy of mild to moderate hypertension (including renal hypertension).

4.2 Posology and method of administration

Posology:

Adults:

120 mg three times a day is recommended. 80 mg three times a day can be completely satisfactory in some patients with angina of effort. Less than 120 mg three times a day is not likely to be effective in angina at rest and variant angina.

Children:

Not applicable

Elderly: As for adults, unless liver or renal function is impaired.

Adults:

40–120 mg three times a day according to the severity of the condition. Children:

Up to 2 years: 20 mg 2–3 times daily.

2 years and above: 40–120 mg 2–3 times daily.

Elderly:

It is recommended to commence with lowest dose and adjust as required.

Adults:

The usual dose range is 80–160 mg three times a day. The dose should be increased from 80 mg three times a day at weekly intervals according to response, either alone or in conjunction with other antihypertensive therapy. A further reduction in blood pressure may be obtained by combining verapamil with other antihypertensive agents, e.g. thiazide diuretics.

Children:

Up to 10 mg per kilo bodyweight per day in divided doses, according to severity of disease.

Elderly:

It is recommended to commence with the lowest dose and adjust as required.

Method of administration:

Oral

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Sick sinus syndrome (except in patients with a functioning artificial pacemaker); second or third degree atrioventricular block (except in patients with a functioning artificial pacemaker), cardiogenic shock, acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; sino-atrial block;

uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mmHg systolic.

Patients with atrial flutter or fibrillation in the presence of an accessory pathway (e.g. Wolff-Parkinson-White syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction)

4.4 Special warnings and precautions for use

Since Verapamil is extensively metabolised in the liver, careful dose titration is required in patients with liver disease. Although the disposition of verapamil in patients with renal impairment are not affected, caution should be exercised and careful patient monitoring is recommended. Verapamil is not removed during dialysis.

Verapamil may affect impulse conduction and should therefore be used with caution in patients with bradycardia or first degree atrioventricular block. Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated. In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.

When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.

Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) for patients taking verapamil.

These patients should be started at the lowest possible dose of verapamil 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), refer to advice in the respective statin product information. Use with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).

Verapamil contains lactose and sunset yellow

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose/galactose malabsorption should not take this medicine.

Sunset yellow (E110) may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro metabolic studies indicate that verapamil hydrochloride is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9

and CYP2C18.

Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and Pglycoprotein (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 are potential drug interactions associated with verapamil:

Acetylsalicylic acid

Concomitant use of verapamil with aspirin may increase the risk of bleeding

Alcohol

Increase in blood alcohol has been reported.

Alpha blockers

Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.

Antiarrhythmics

Verapamil may slightly decrease the plasma clearance of flecainide whereas flecainide has no effect on the verapamil plasma clearance. Verapamil may increase the plasma concentrations of quinidine. Pulmonary oedema may occur in patients with hypertrophic cardiomyopathy. The combination of verapamil and antiarrhythmic agents may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Anticonvulsants

Verapamil may increase the plasma concentrations of carbamazepine. This may produce side effects such as diplopia, headache, ataxia or dizziness. Verapamil may also increase the plasma concentrations of phenytoin.

Antidepressants

Verapamil may increase the plasma concentrations of imipramine.

Antidiabetics

Verapamil may increase the plasma concentrations of glibenclamide (glyburide).

Antihypertensives, diuretics, vasodilators Potentiation of the hypotensive effect.

Anti-infectives

Rifampicin may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect. Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.

Antineoplastics

Verapamil may increase the plasma concentrations of doxorubicin.

Barbiturates

Phenobarbital may reduce the plasma concentrations of verapamil.

Benzodiazepines and other anxiolytics

Verapamil may increase the plasma concentrations of buspirone and midazolam.

Beta blockers

Verapamil may increase the plasma concentrations of metoprolol and propranolol which may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Intravenous beta-blockers should not be given to patients under treatment with verapamil.

Cardiac glycosides

Verapamil may increase the plasma concentrations of digitoxin and digoxin.

Verapamil has been shown to increase the serum concentration of digoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, Pglycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine.

Combined use is not recommended.

H2 Receptor antagonists

Cimetidine may increase the plasma concentrations of verapamil.

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.

Immunosuppressants

Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus.

Inhaled anaesthetics

When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil hydrochloride, should each be titrated carefully to avoid additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Lipid lowering agents

Verapamil may increase the plasma concentrations atorvastatin, lovastatin and simvastatin. Treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) 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. Atorvastatin has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered. Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.

Lithium

Serum levels of lithium may be reduced. However, there may be increased sensitivity to lithium causing enhanced neurotoxicity.

Neuromuscular blocking agents employed in anaesthesia The effects may be potentiated.

Serotonin receptor agonists

Verapamil may increase the plasma concentrations of almotriptan.

Theophylline

Verapamil may increase the plasma concentrations of theophylline.

Uricosurics

Sulfinpyrazone may reduce the plasma concentrations of verapamil which may produce a reduced blood pressure lowering effect.

Anticoagulants

When oral verapamil was co-administered with dabigatran etexilate (150 mg), a P- gp substrate, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on time between administration and the formulation of verapamil. Co- administration of verapamil 240 mg extended-release at the same time as dabigatran etexilate resulted in increased dabigatran exposure (increase of Cmax by about 90 % and AUC by about 70%).

Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Other Cardiac therapy

Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of verapamil to ivabradine (see section 4.3).

Other

St. John’s Wort may reduce the plasma concentrations of verapamil, whereas grapefruit juice may increase the plasma concentrations of verapamil.

Co-administration of verapamil with metformin may reduce the efficacy of metformin.

4.6 Fertility, pregnancy and lactation

There are no adequate and well-controlled study data in pregnant women. Although animal studies have not shown any teratogenic effects (see section 5.3), verapamil should not be given during the first trimester of pregnancy unless, in the clinician's jud­gement, it is essential for the welfare of the patient.

Verapamil hydrochloride 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 breast-feeding. 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.

4.7 Effects on ability to drive and use machines

Depending on individual susceptibility, the patient's ability to drive a vehicle, operate machinery or work under hazardous conditions may be impaired. This is particularly true in the initial stages of treatment, when changing over from another drug or when the dose is raised or when taken in conjunction with alcohol. Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Undesirable effects

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

Immune system disorders: allergic reactions (e.g. erythema, pruritis, urticaria) are very rarely seen.

Nervous system disorders: headache, dizziness, paraesthesia, tremor and extrapyramidal syndrome.

Ear and labyrinth disorders: vertigo and tinnitus.

Cardiac disorders/vascular disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2nd and 3rd degree AV block, bradyarrhythmia in atrial fibrillation, peripheral oedema, palpitations, tachycardia, development or aggravation of heart failure and hypotension.

There have been rare reports of flushing.

Gastrointestinal disorders: nausea and vomiting, constipation, ileus and abdominal pain/discomfort. On rare occasions gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods and is fully reversible when the drug is discontinued.

Skin and subcutaneous tissue disorders: ankle oedema, Quincke's oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, alopecia and purpura.

Musculoskeletal and connective tissue disorders: muscular weakness, myalgia, arthralgia.

Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia may occur in older male patients under long-term verapamil treatment, and is fully reversible in all cases when the drug was discontinued.

General disorders and administration site conditions: fatigue.

Investigations: A reversible impairment of liver function characterised by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction. Rises in prolactin concentrations have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.

8.9 Overdose

The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related). The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenckebach's phe­nomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and sinus arrest, hyperglycaemia, stupor, acute respiratory distress syndrome and metabolic acidosis. Fatalities have occurred as a result of overdose.

The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. In intoxications with large amounts of slow-release preparations (Verapamil), it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Verapamil hydrochloride cannot be removed by haemodialysis. Depending on the time of ingestion, it should be taken into account that there may be some lumps of incompletely dissolved tablets along the entire length of the gastrointestinal tract, which function as active drug depots.

General measures to be taken: Gastric lavage with the usual precautions, even

later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable. Where intoxication by Verapamil is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures apply, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy.

Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10–20 ml of a 10% solution of calcium gluconate solution administered intraveneously (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 case of second or third degree AV block, sinus bradycardia, asystole – atropine, isoprenaline, orcipenaline or pacemaker therapy. In case of hypotension – dopamine, noradrenaline or dobutamine. If there are signs of continuing myocardial failure – dopamine, dobutamine, if necessary repeated calcium injections.

5 PHARMACOLOGICAL PROPERTIES

5.1.   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Verapamil hydrochloride is a racemic mixture consisting of equal portions of the Renantiomer and the S-enantiomer. Verapamil is extensively metabolized. Norverapamil is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity of verapamil and accounts for 6% of excreted drug. The steady-state plasma concentrations of norverapamil and verapamil are similar.

Steady state after multiple once daily dosing is reached after three to four days.

Absorption

Greater than 90% of Verapamil is rapidly absorbed from small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of Verapamil is approximately 33%, owing to an extensive hepatic first-pass metabolism. Bioavailability is about two times higher with repeated administration. Peak verapamil plasma levels are reached for up to five hours after oral administration. The peak plasma concentration of norverapamil is attained approximately five hours after verapamil administration. The presence of food has no effect on the bioavailability of verapamil.

Distribution

Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of Verapamil is approximately 90%.

Metabolism

Verapamil is extensively metabolised. In vitro metabolic studies indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N and O-dealkylated products of verapamil. Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.

Elimination

Following oral administration, the elimination half-life is three to seven hours. Approximately 50% of an administered dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the faeces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7–1.3 L/h/kg).

Special Populations

Elderly:

Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly. The antihypertensive effect of verapamil was found not to be age-related.

Renal insufficiency:

Impaired renal function has no effect on verapamil pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. Verapamil and norverapamil are not significantly removed by haemodialysis.

Hepatic insufficiency:

The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.

5.3 Preclinical safety data

Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 (180 mg/m2/day) and 1.2 times (360 mg/m2/day) respectively the equivalent maximum recommended human oral daily dose (300 mg/m2/day) and have revealed no evidence of teratogenicity. In the rat the highest dose was embryocidal and retarded foetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and reduced weight gain of dams). This oral dose has also been shown to cause hypotension in rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Maize Starch

Lactose monohydrate

Gelatin

Silica, colloidal anhydrous

Talc

Magnesium stearate

Tablet coat:

Titanium dioxide

Hydroxypropyl cellulose

Quinoline yellow E104

Sunset yellow E110

Hydroxypropyl methylcellulose 2910

Ethylcellulose

Diethyl phthalate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Container: 2 years

Blister pack: 3 years

6.4 Special precautions for storage

Containers: Do not store above 25°C. Keep the container tightly closed.

Blister Packs: Do not store above 25°C. Store in the original package to protect from light.

6.5 Nature and contents of container

Tablets containers: High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane or polythene inserts.

Blister packs: 250 micron PVC and 25 micron aluminium foil coated with heat resistant print primer on one side and heat-seal lacquer on the other.

Containers of 100 and 500 tablets.

Blister packs of 28 and 84 tablets.

6.6 Special precautions for disposal

The tablets should not be chewed or sucked.

Any unused product or waste material should be disposed of in accordance with local requirements.

Genethics Europe Limited 41 – 43 Klimentos Klimentos Tower

Nicosia 1061

Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 42976/0038

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14 June 2002 / 13 March 2009