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1. Verapamil Hydrochloride Bp Tablets 120 Mg
2. Verapamil Hydrochloride Bp Tablets 120 Mg

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Verapamil Hydrochloride BP Tablets 120mg. Hypaneze 120 (Opus Pharmaceuticals only).

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 120mg tablet contains verapamil hydrochloride BP 120mg

3    PHARMACEUTICAL FORM

Tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Verapamil hydrochloride is useful in:

1.    the treatment and prophylaxis of angina pectoris, and variant angina;

2.    the treatment and prophylaxis of paroxysmal supraventricular tachycardia and atrial flutter/fibrillation (verapamil should not be used when atrial flutter/fibrillation complicates Wolff-Parkinson-White syndrome); and

3.    the treatment of mild to moderate hypertension.

4.2 Posology and method of administration

Elderly or patients with impaired liver or kidney function, or cardiac conduction problems may require a reduced dosage.

Angina:

Adults:	120mg, 3 times daily is recommended.
	Some patients with angina of effort may respond to 80mg, 3 times daily, but this dose is not likely to be effective in angina at rest and variant angina.

Supraventricular tachycardias:

Adults:	40mg to 120mg, 3 times daily according to the severity of the condition.
Children, 2 years and above:	40mg to 120mg, 2 to 3 times daily, according to age and effectiveness.

Hypertension:

Adults:	160mg twice daily. A small number of patients may be controlled successfully on 120mg twice daily, whereas others may require up to 480mg daily, given in divided doses. A further reduction in blood pressure may be obtained by combining Verapamil Tablets with other antihypertensive agents, eg thiazide diuretics. Verapamil hydrochloride and beta-blockers may be additive, both with respect to conduction and contraction. Verapamil hydrochloride should, therefore, be given with care to those who are receiving beta-blockers.
Children:	Up to 10mg/kg/day, in divided doses, according to the severity of the condition.
Method of administration:	Oral.

4.3 Contraindications

Hypersensitivity to verapamil or any of the other excipients in the product. Hypotension (of less than 90mmHg systolic), cardiogenic shock, marked bradycardia (less than 50 beats/minute), second or third degree atrioventricular block, sino-atrial block, sick sinus syndrome (except in patients with a functioning artificial pacemaker), uncompensated heart failure.

Combination with beta-blockers is contraindicated in patients with poor ventricular function.

Concomitant ingestion of grapefruit juice.

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

Acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure.

4.4 Special warnings and special precautions for use

Verapamil hydrochloride may affect impulse conduction and should be administered with caution in patients with first degree atrioventricular block. The effects of verapamil and beta-blockers or other drugs may be additive both in respect of conduction and contraction, therefore care should be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.

Caution should be observed in the acute phase of myocardial infarction.

Verapamil hydrochloride may affect left ventricular contractility as a result of its mode of action. This effect is small and not normally important, however, cardiac failure may be aggravated or precipitated if it exists. In cases with poor ventricular function, verapamil hydrochloride should only be administered after appropriate therapy for cardiac failure such as digitalis, etc.

Patients with atrial fibrillation/flutter and an accessory pathway (eg Wolff-

Parkinson-White syndrome) may rarely develop increased conduction across the    anomalous pathway and ventricular tachycardia may be

precipitated.

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).

Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil is required in patients with liver disease.

The disposition of verapamil in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Verapamil is not removed during dialysis.

4.5 Interactions with other medicaments and other forms of interaction

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 are potential drug interactions associated with verapamil:

Acetylsalicylic acid

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

Alcohol

Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

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 offlecainide 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

Verapamil may have an additive effect when given with other antihypertensive drugs, and a reduction in the dosage of the other antihypertensive drug could be    possible.

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. Anaesthesia

Long-term verapamil therapy may give rise to potentiation of neuromuscular blocking agents during anaesthesia.

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 on verapamil.

Cardiac glycosides

Verapamil hydrochloride has been shown to increase the serum concentration of digitoxin and digoxin, therefore care should be exercised with regard to digitalis toxicity.

The digitalis level should be determined and the glycoside dose reduced, if required.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-

glycoprotein (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.

Digoxin

Verapamil has been shown to increase the serum concentration of

digoxin and caution should therefore be exercised with regard to digitalis toxicity.

Dantrolene

Concomitant use of verapamil with intravenous dantrolene may cause hypotension, myocardial depression, and hyperkalaemia. This combination should be avoided.

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, which could lead to increased side-effects.

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, and 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 metabolized 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

Long term verapamil treatment may give rise to potentiation of neuromuscular blocking agents during anaesthesia.

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.

Other

St. John's Wort may reduce the plasma concentrations of verapamil.

It has been reported that the concomitant administration of verapamil and grapefruit juice can lead to an increase in verapamil serum level.

4.6 Pregnancy and lactation

Verapamil is excreted in breast milk in small amounts. Although animal studies have not shown any teratogenic effects, verapamil hydrochloride should not be administered during pregnancy or lactation, unless in the clinician’s judgement it is considered essential for the patient’s welfare.

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 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.

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. 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

Reactions from Postmarketing Surveillance or Phase IV Clinical Trials

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

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

Nervous system disorders: headaches occur rarely, dizziness, paresthesia, tremor and extrapyramidal syndrome (e.g. parkinsonism), dystonia.

Ear and labyrinth disorders: vertigo and tinnitus.

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

Vascular disorders: flushing, peripheral oedema.

Gastrointestinal disorders: nausea, vomiting, constipation is not uncommon, ileus and abdominal pain/discomfort. Gingival hyperplasia may occur rarely when the drug is administered over prolonged periods, and is reversible when the drug is discontinued.

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

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

Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare    occasions, gynaecomastia has been observed in elderly 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 characterized 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 blood prolactin levels 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

4.9 Overdosage

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 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, 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 a modified release preparation 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% 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 case of 2nd or 3rd degree AV block, sinus bradycardia, asystole - atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension - dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure - dopamine, dobutamine, if necessary repeated calcium injections.

5.1 Pharmacodynamic properties

Verapamil a calcium antagonist has a balanced profile of cardiac and peripheral effects and is classified as a IV anti-arrhythmic agent.

It lowers heart rate, increases myocardial perfusion and reduces coronary spasm. In a clinical study in patients after myocardial infarction, verapamil reduced total mortality, sudden cardiac death and reinfarction rate. Verapamil inhibits the entry of calcium into smooth muscle cells of the systemic and coronary arteries and in the cells of cardiac muscle and the intracardiac conduction system.

Due to the effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.

Verapamil reduces total peripheral resistance and lowers high blood pressure by vasodilation, without reflex tachycardia. Because of its use ^- dependent action on the voltage-operated calcium channel, the effects of verapamil are more pronounced on high than on normal blood pressure.

As early as day one of treatment, blood pressure falls; the effect is found to persist also in long term therapy. Verapamil is suitable for the treatment of all types of hypertension: for monotherapy in mild to moderate hypertension; combined with other antihypertensives (in particular with diuretics and, according to more recent findings, with ACE inhibitors) in more severe types of hypertension. In hypertensive diabetic patients with nephropathy, verapamil in combination with ACE inhibitors led to a marked reduction of albuminuria and to an improvement of creatinine clearance.

5.2 Pharmacokinetic properties

Absorption: More than 90% of an orally-administered dose of verapamil is absorbed. Due to an intensive hepatic first^- pass metabolism, the absolute bioavailability is about 22% with a variability of about 10 ~ 35%. Under multiple dosing, bioavailability increases by about 30%. Bioavailability is not affected by food consumption.

Distribution, biotransformation and elimination: Plasma concentrations reach their peak 4-8 hours after drug intake. Plasma protein binding of verapamil is about 90%. The elimination half ^- life is about 5 ^_ 8 hours. The mean residence time of modified-release verapamil is 13 hours. After repeated single daily doses, steady-state conditions are reached between 3 - 4 days.

Within 5 days, approximately 70% of an orally-administered dose is excreted in the urine and about 16% with the faeces. Only 3 - 4 % is eliminated renally as unchanged drug. The drug is extensively metabolized. A number of metabolites are generated in humans (twelve have been identified). 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). Norverapamil represents about 6% of the dose eliminated in urine. Norverapamil can reach steady ~ state plasma concentrations approximately equal to those of verapamil itself. Renal insufficiency does not affect the kinetics of verapamil.

At-risk patients: In patients with liver cirrhosis, bioavailability is increased and elimination half ^- life is prolonged. In patients with compensated hepatic insufficiency, no influence on the kinetics of verapamil was observed.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose, lactose, methylcellulose, maize starch, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose (E464), quinoline yellow (E104), FD&C No.2 Lake (E132) and titanium dioxide (E171).

6.2 Incompatibilities

None stated.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store in a cool dry place.

6.5 Nature and contents of container

Securitainers. Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112, 120 and 500.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS