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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Univer 120 mg Prolonged-release Hard Capsules

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Verapamil hydrochloride 120 mg.

Excipients:    Univer 120 mg capsules contain 31.32 mg Sucrose per capsule

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release capsule, hard.

Capsules are blue and yellow and printed with V120.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Mild to moderate hypertension. Angina pectoris.

4.2    Posology and method of administration

For oral administration only. The capsules should be swallowed not chewed.

The bioequivalence of Univer to other prolonged release formulations may not have been evaluated. As such, this product be directly substituted for other non-identical formulations of verapamil and vice-versa.

Adults:

Mild to moderate hypertension: Initial dose in adult patients new to verapamil therapy should be 120 mg once daily. This can be increased to 240 mg once daily which is the normal maintenance dosage. The dose may be further increased to a maximum of 480 mg once daily if required.

Angina: The usual adult dose is 360 mg once daily. Dosage may be increased to a maximum of 480 mg daily if required.

Elderly: The adult dose is recommended unless renal or hepatic function is impaired (see Section 4.4)

Elderly patients show enhanced bioavailability of verapamil and therapeutic control may be achieved with lower doses in this patient population.

Paediatric population

The safety and efficacy of verapamil prolonged release tablets in children and adolescents have not been established. No data are available.

Hepatic impairment: Verapamil is extensively metabolised in the liver and for those patients with impaired liver function, the dose should be reduced and carefully titrated.

Renal impairment: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil should be prescribed cautiously when renal function is impaired. Careful patient monitoring is recommended.

4.3 Contraindications

•    Acute myocardial infarction with complications such as bradycardia,

•    Marked hypotension, left ventricular failure

•    Second or third degree atrioventricular (AV) block (except in patients with functioning artificial pacemaker)

•    Sino-atrial block

•    Sick sinus syndrome (except in patients with functioning artificial pacemaker)

•    Bradycardia of less than 50 beats/minute

•    Uncompensated heart failure

•    Atrial flutter or atrial fibrillation associated with an accessory pathway (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated

•    Porphyria

•    Hypotension (systolic pressure <90    mm Hg)

•    Cardiogenic shock

•    Intravenous dantrolene (see section    4.5)

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

•    Concomitant ingestion of grapefruit juice

•    Combination with ivabradine (see section 4.5).

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, as plasma levels of verapamil may be increased (see section 4.2). Although the pharmacokinetics 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 AV block. The effects of verapamil and beta blockers or other drugs with a cardio-depressive action may be additive both with respect to conduction and contraction, therefore care must be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.

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

If there are signs of tachycardia-induced heart failure (energetic exhaustion of the myocardium) digitalisation is necessary before intravenous administration of verapamil.

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.

Special care should be taken in hypotension (see section 4.3), especially in acute myocardial infarction as this is a condition where atrioventricular conduction defects may develop and contractility may be impaired.

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 (see section 4.5 Interaction with other medicinal products and other forms of interaction).

There have been reports of calcium-channel blockers exacerbating muscle weakness in patients with myasthenia gravis. Verapamil 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).

Owing to the presence of sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products 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-gly coprotein (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:

Concomitant use contra-indicated

Muscle relaxants

Dantrolene: the association of this muscle relaxant given intravenously and verapamil is potentially dangerous (can cause fatal ventricular fibrillation in animals) and is contraindicated.

Verapamil taken with intravenous dantrolene may cause hypotension, myocardial depression and hyperkalaemia.

Other relevant interactions

Acetvlsalicvlic 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). With verapamil taken with either disopyramide or flecainide there is an increased risk of myocardial depression and asystole.

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. Ketoconozole, 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.

A period between stopping beta-blocking therapy and starting therapy with this product may be advisable. Concomitant use of verapamil and beta-blockers or antiarrhythmics, if necessary, should only be administered to patients in a closely monitored clinical setting.

The effects of verapamil may be additive to other hypotensive agents.

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, 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.

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).

Ivabradine

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

Lipid lowering agents

Verapamil may increase the plasma concentrations of 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. Lithium can enhance neuromuscular block during anaesthesia and hence verapamil with lithium may potentiate the neuromuscular blocking effect.

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.

Other

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies have shown no teratogenic effects and data on a limited number of exposed pregnancies showed no adverse effects on the health of the foetus or newborn child.

Caution should be exercised, however, when prescribing to pregnant women and verapamil should be avoided in the first trimester unless the benefits clearly outweigh the risks. However, verapamil can cause uterine muscle relaxation and this possibility should be considered at term.

Lactation

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.

4.7 Effects on ability to drive and use machines

Depending on individual susceptibility, the patient’s ability to drive a vehicle or 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: headache, dizziness, paresthesia, 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, 2^nd and 3^rd 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, vomiting, constipation, ileus and abdominal pain/discomfort. 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 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 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 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 with 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% 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    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel blockers, Phenylalkylamine derivatives, ATC code: C08D A01.

Verapamil is a phenylalkylamine calcium antagonist with effects upon arterial smooth muscle, myocardial cells and cells of the cardiac conduction system. It lowers heart rate, increases myocardial perfusion and reduces coronary spasm. It decreases vascular peripheral resistance and lowers blood pressure by vasodilation without reflex tachycardia. The effects are more pronounced on high blood pressure than on normal pressure because of its use-dependent action on the voltage-operated calcium channel.

5.2    Pharmacokinetic properties

Approximately 90% of verapamil is absorbed following oral administration and is subject to extensive first pass metabolism in the liver. There is considerable interindividual variation in plasma concentrations. About 70% of the oral dose is excreted by the kidneys and 16% with the faeces.

Where liver damage exists plasma levels of verapamil may be increased. Renal failure does not significantly alter the kinetics of the drug. Elderly subjects show enhanced bioavailability of verapamil.

Univer provides prolonged release of verapamil in the gastrointestinal tract and a pharmacokinetic profile consistent with a prolonged release formulation. A study in healthy volunteers compared the pharmacokinetics of Univer 240 mg administered once daily and immediate-release verapamil 80 mg administered three times daily. The comparative steady state kinetic data are shown below:

5.3 Preclinical safety data

There is no evidence of teratogenicity or carcinogenicity with verapamil. There are no additional preclinical safety data of relevance to the prescriber.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule contents:

Fumaric acid

Sugar spheres (containing sucrose and maize starch) Talc

Povidone

Shellac

Capsule shell:

Gelatin

Titanium dioxide (E171)

Erythrosine (E127)

Indigotine (E132)

Yellow iron oxide (E172)

Printing ink:

Titanium dioxide (E171)

Black iron oxide (E172)

Shellac

Propylene glycol (E1520)

Simethicone

Incompatibilities

None stated.

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5    Nature and contents of container

PVC/aluminium blister packs of 4, 8, 28 or 56 capsules. Not all pack sizes may be marketed

6.6    Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Cephalon UK Limited Ridings Point Whistler Drive Castleford West Yorkshire WF10 5HX United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16260/0025

22^nd March 2010

10 DATE OF REVISION OF THE TEXT

20/01/2016