Verapamil 120mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Verapamil 120mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains verapamil hydrochloride 120 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, concave, film-coated tablets engraved MP70 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:
Angina
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.
Supraventricular paroxysmal tachycardia
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.
Hypertension
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 listed in section 6.1.
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; history of heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90 mmHg systolic Patients with atrial flutter or fibrillation complicating Wolff-Parkinson-White syndrome may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated. Porphyria. Concomitant ingestion of grapefruit juice.
Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction)
4.4 Special warnings and precautions for use
Patients with impaired liver function exhibit reduced drug metabolism and therefore careful attention should be paid to dosage in these patients. 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.
Verapamil should be used with caution in patients with bradycardia or first degree atrioventricular block because impulse conduction may be affected. Left ventricular contractility may be affected by verapamil because of its mode of action; cardiac failure may therefore be precipitated or, if it already exists, may be aggravated by verapamil. It is therefore important that verapamil should only be administered after appropriate therapy for cardiac failure has been instituted, e.g. digoxin etc.
Verapamil should not be used in children with arrhythmias without specialist advice; some supraventricular arrhythmias in childhood can be accelerated by verapamil with dangerous consequences.
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).
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorbtion 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.
4.6 Fertility, Pregnancy and lactation
Pregnancy
Verapamil is not recommended for use during the first trimester of pregnancy unless the benefits of the drug outweigh the possible hazards to the foetus.
Breast-feeding
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. 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
Administration of verapamil is commonly associated with constipation. Occasionally the following side-effects may be experienced and are listed below by system organ class:
Immune system disorders: Sensitivity or allergy to verapamil is rare. Symptoms of allergy are erythema, pruritis, urticaria, angioedema and Stevens-Johnson syndrome.
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 after long-term treatment 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.
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 classical measures for cardiovascular side effects should be instituted immediately.
Cardiac arrest should be treated by heart massage and mechanical respiration, and the necessary intensive care appropriate to the condition should be instituted.
In the case of hypotension, dopamine, noradrenaline or dobutamine may be used together with appropriate positioning of the patient. Likewise, in myocardial insufficiency treatment should be either dopamine, dobutamine, cardiac glycosides or 10-20 ml of a 10% solution of calcium gluconate. Second or third degree AV block should be treated with atropine, isoprenaline or orcipenaline and if necessary a pace maker should be used.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.
ATC-Code: C08DA01
Verapamil, a phenylalkylamine calcium antagonist, has a balanced profile of cardiac and peripheral effects. 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 re-infarction rate.
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
Verapamil is almost completely (>90%) absorbed from the gastro-intestinal tract but is subject to very considerable first-pass metabolism in the liver. The plasma half-life is about 7 hours following oral administration and that of its active metabolite which is norverapamil is about nine hours.
Verapamil acts within minutes of intravenous administration but its effects may only last for about half-an-hour. It may require two hours to act after oral administration with peak effect after five hours.
Distribution
Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8-6.8 L/kg in healthy subjects. Verapamil is extensively bound to plasma proteins (approximately 90%).
Biotransformation
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
The drug is mainly excreted by the kidneys in the form of its metabolites, but some is also excreted in the bile and in the faeces.
Special Populations
Elderly:
Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in older people. The antihypertensive effect of verapamil was found not to be age-related.
Renal impairment:
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 impairment:
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
None stated.
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: 2 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
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Genethics Europe Limited 41 - 43 Klimentos Klimentos Tower Nicosia 1061 Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 42976/0040
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14 June 2002 / 13 March 2009
10 DATE OF REVISION OF THE TEXT
26/07/2016