RiteMED Verapamil

Verapamil hydrochloride.

Each sustained release tablet contains 240 mg Verapamil hydrochloride.

ATC code: C08DA01. Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.
Pharmacology: Pharmacodynamics: Verapamil hydrochloride belongs to the group of calcium antagonists. These substances have an inhibitory effect on the calcium influx via muscle cell membranes. Verapamil hydrochloride also acts as a calcium antagonist on smooth musculature, particularly in the area of vessels and gastrointestinal tract. The effect on the smooth vascular muscles is manifested as vasodilation. As a calcium antagonist, verapamil hydrochloride also exerts a marked effect on the myocardium. The effect on the AV node is seen in the form of prolonged conduction time.
A negative-inotropic effect can occur on the working myocardium.
In humans, verapamil hydrochloride causes a decrease in total peripheral resistance due to vasodilation; no increase in cardiac output by reflex action occurs. The result is a corresponding fall in blood pressure.
Pharmacokinetics: Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-enantiomer and the S-enantiomer. Verapamil is extensively metabolised. 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 the small intestine after oral administration. Mean systemic availability of the unchanged compound after a single dose of non-retarded verapamil is 22% and that of retarded verapamil 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 one to two hours after non-retarded administration, and four to five hours after retarded administration. The peak plasma concentration of norverapamil is attained approximately one and five hours after non-retarded or retarded administration, respectively.
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 0-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 intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours).
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 active substance is excreted unchanged. 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).
There are large inter-individual differences in clearance.
Special populations: Paediatric patients: Limited information on the pharmacokinetics in the paediatric population is available. After intravenous dosing, the mean half-life of verapamil was 9.17 hours and the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70-kg adult. Steady-state plasma concentrations appear to be somewhat lower in the paediatric population after oral dosing compared to those observed in adults.
Geriatric patients: 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.
Toxicology: Preclinical safety data: In vitro and in vivo studies gave no evidence that verapamil hydrochloride exerts mutagenic effects.
A long-term study in rats gave no evidence that verapamil hydrochloride has a tumorigenic potential.
Embryotoxicity studies in rabbits and rats gave no evidence of a teratogenic potential employing daily doses of up to 15 mg/kg and 60 mg/kg, respectively. However, in the maternal-toxic range, embryolethality and growth retardation occurred in rats.

Symptomatic coronary heart disease: Chronic stable angina pectoris (exertion angina), unstable angina pectoris (crescendo angina, angina at rest), vasospastic angina pectoris (Prinzmetal angina, variant angina), angina pectoris in conditions after myocardial infarction in patients without cardiac insufficiency if beta-adrenergic blocking agents are not indicated.
Disorders in the heart beat rate in cases of: Paroxysmal supraventricular tachycardia, atrial fibrillation/atrial flutter with rapid AV conduction (except in case of WPW syndrome, see Contraindications).
Hypertension.

Verapamil hydrochloride is to be dosed on an individual basis, adapted to the severity of the disease. According to long-standing clinical experience, the mean dose is between 240 and 360 mg per day in almost all indications.
A daily dose of 480 mg should not be exceeded as long-term therapy, short-term increase is possible.
As far as not otherwise prescribed, the following dose guidelines apply: See Table 1.

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Children and adolescents: The safety and efficacy of verapamil prolonged release tablets in children and adolescents have not been established. No data are available.
Impaired hepatic function: Depending on the severity of the disease in patients with impaired hepatic function, the effect of verapamil hydrochloride is increased and prolonged, due to a decelerated degradation of the medicinal product. For this reason, the dose should be adjusted with special care in these cases and be started with low doses (e.g. in patients with hepatic dysfunctions first 40 mg verapamil hydrochloride 2-3 times daily, equivalent to 80-120 mg verapamil hydrochloride per day).
The tablets are to be taken without sucking and chewing together with a sufficient quantity of liquid (e.g. a glass of water, no grapefruit juice) preferably with or shortly after meals.
Method and duration of administration: Do not take Verapamil hydrochloride in lying position.
Verapamil hydrochloride must not be used in patients with angina pectoris after myocardial infarction until 7 days after the acute infarction.
The duration of treatment is not limited.
After longer-term treatment, Verapamil hydrochloride should generally not be discontinued abruptly, but gradually.

Symptoms: The symptoms of intoxication after intoxications with verapamil hydrochloride depend on the quantity supplied, the time of detoxification measures and myocardial contractility (age-dependent).
The following symptoms are observed in case of severe intoxication with verapamil: Considerable fall in blood pressure, cardiac insufficiency, bradycardiac or tachycardiac arrhythmias (e.g. junctional rhythm with AV dissociation and higher-degree AV block) which can lead to cardiovascular shock and cardiac arrest.
Depression of consciousness up to coma, hyperglycaemia, hypokalaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema, impaired renal function and convulsions, deaths have uncommonly been reported.
Therapeutic measures: Elimination of the noxae and restoration of stable cardiovascular conditions have therapeutic priority.
The therapeutic measures depend on the time and mode of administration as well as on the type and severity of the intoxication symptoms.
In case of intoxications with higher amounts of retard preparations, it has to be taken into account that the substance may still be released and absorbed in the intestine for more than 48 hours after intake.
Gastric lavage is to be recommended after oral intoxication with verapamil hydrochloride, even later than 12 hours after intake if no gastrointestinal motility (bowel sounds) can be detected. In case of suspected intoxication with retard preparations, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of stomach and small intestine via suction while monitoring endoscopically, intestinal lavage, laxation, high enema.
Haemodialysis is not useful, since verapamil hydrochloride is not dialysable; however, haemofiltration and possibly plasmapheresis are recommended (high plasma protein binding of calcium antagonists).
Usual intensive care resuscitative measures, such as extrathoracic cardiac massage, ventilation, defibrillation or pace-maker therapy.
Specific measures: Removal of cardiodepressive effects, of hypotension and bradycardia; Bradycardiac arrhythmias are to be treated symptomatically with atropine and/or beta-sympathomimetics (isoprenaline, orciprenaline); alarming cases of bradycardiac arrhythmias require temporary pace-maker therapy. Asystole should be handled by the usual measures including beta adrenergic stimulation (e.g., isoprenaline).
Calcium is a specific antidote, e.g. 10-20 ml of a 10% calcium gluconate solution administered intravenously (2.25 to 4.5 mmol), if necessary repeated or as continuous insulation (e.g. 5 mmol/hour).
Hypotension resulting from cardiogenic shock and arterial vasodilation is to be treated with dopamine (up to 25 μg per kg bodyweight per minute), dobutamine (up to 15 μg per kg bodyweight per minute), epinephrine or norepinephrine, respectively. The dose of these medicinal agents is orientated solely to the achieved effect. The serum calcium level should be maintained at a highly normal to slightly elevated level. Due to arterial vasodilation, liquid is additionally substituted in the early phase (Ringers solution or sodium chloride solution).

Verapamil must not be used in cases of: Hypersensitivity (allergy) to the active substance verapamil hydrochloride or to any of the excipients; Cardiovascular shock; Pronounced conduction disturbances (such as SA or AV block degrees II and III; except in patients with an artificial pacemaker); Sick sinus syndrome (except in patients with an artificial pacemaker); Cardiac insufficiency with reduced ejection fraction of less than 35%, and/or pulmonary wedge pressure above 20 mmHg (unless secondary to a supraventricular tachycardia amenable to verapamil therapy); Atrial fibrillation/flutter in the presence of an accessory bypass tract (e.g., WPW or Lown-Ganong-Levine syndrome). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil hydrochloride is administered. Combination with ivabradine (see Interactions).
Beta-blockers must not be used concurrently intravenously in patients treated with verapamil (exception intensive care medicine) (see also Interactions).

Myocardial infarction: Use with caution in acute myocardial infarction with complications (bradycardia, hypotension, left ventricular dysfunction).
Conduction disturbance/AV block degree I/bradycardia/asystole: Verapamil hydrochloride affects the AV and sinus nodes and prolongs AV conduction time. Use with caution as development of second- or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation of verapamil hydrochloride and institution of appropriate therapy, if needed.
Verapamil hydrochloride affects the AV and sinus nodes and rarely may produce second- or third-degree AV block, bradycardia, or, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome, which is more common in older patients.
Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see Adverse Reactions).
Anti-arrhythmics, beta-blockers and inhalation anaesthetics: Anti-arrhythmics (e.g. flecainide, disopyramide), beta-receptor blockers (e.g. metoprolol, propranolol) and inhalation anaesthetics may cause mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension) (see Interactions).
Asymptomatic bradycardia (36 beats/minute) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blacker) eye drops and oral verapamil hydrochloride.
Digoxin: If verapamil is administered concomitantly with digoxin, digoxin dose is to be reduced (see Interactions).
Cardiac insufficiency: Cardiac insufficiency patients with ejection fraction higher than 35% should be compensated before starting verapamil treatment and should be adequately treated throughout.
HMG-CoA reductase inhibitors ("statins"): See Interactions.
Neuromuscular transmission disorders: Verapamil hydrochloride 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).
Hypotension: In hypotension (less than 90 mmHg systolical blood pressure), extra careful monitoring is required.
Special populations: Impaired renal function: Although comparison studies have reliably shown that impaired renal function in patients with end-stage renal failure has no effect on the pharmacokinetics of verapamil, isolated case reports have suggested that verapamil should only be used with caution and with careful monitoring (ECG, blood pressure) in patients with impaired renal function.
Verapamil cannot be removed via haemodialysis.
Impaired liver function: Use with caution in patients with severely impaired liver function (see Dosage & Administration).
Effects on ablity to drive and use machines: Treatment with verapamil requires regular medical monitoring. Due to inter-individually different reactions, reactivity may be impaired to such an extent that the ability to drive, to operate machinery or to work in an unsafe posture is impaired. This applies to a higher degree when starting therapy, increasing the dose and changing the preparation as well as in conjunction with alcohol.
Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

Pregnancy: Verapamil hydrochloride has placental patency. The plasma concentration in umbilical venous blood is 20-92% of the maternal plasma concentration. No sufficient experience is available regarding use of verapamil hydrochloride during pregnancy. However, data about a limited number of pregnant women treated orally do not suggest teratogenic effects of verapamil hydrochloride. Experimental animal studies have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Verapamil hydrochloride should therefore not be taken in the first and second trimesters of pregnancy. It may be taken in the third trimenon only in case of compelling indication while considering the risk for mother and child.
Lactation: Verapamil is excreted in breast milk (milk concentration is approximately 23% of the maternal plasma concentration). Limited human data after oral ingestion have shown that the infant absorbs only a small amount of the active substance (0.1 to 1% of the maternal dose) so taking verapamil could therefore be compatible with breast-feeding.
A risk for the newborn/infant cannot be excluded.
Due to the risk of severe adverse reactions in infants, verapamil should not be administered during lactation unless it is absolutely necessary for the welfare of the mother.
Evidence exists that verapamil can cause hyperprolactinaemia and galactorrhoea in isolated cases.

The following adverse events reactions have been reported with verapamil from clinical studies, post-marketing surveillance or phase IV clinical trials and are listed as follows by system organ class.
The frequencies are defined as follows: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
The most commonly reported ADRs were headache, dizziness or drowsiness, gastrointestinal disorders (nausea, constipation and abdominal disorders), further bradycardia, tachycardia, palpitations, hypotension, flushing, oedema peripheral, as well as fatigue.

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Note: In patients with a pacemaker, an increase in the pacing and sensing threshold cannot be excluded on verapamil hydrochloride.
In patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, the risk of severe side effect was increased with concomitant administration of intravenous beta-blocker or disopyramide with intravenous verapamil as both substance classes exert a cardiodepressive effect (see Interactions).

In vitro 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 P-glycoprotein (P-gp). Clinically significant interactions hove 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 listing provides a list of potential interactions with verapamil: See Table 3.

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Other drug interactions and additional drug interaction information: 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 and the dose of verapamil may be decreased.
Correspondingly, verapamil hydrochloride may induce increased plasma level of these medicinal agents by influencing degradation.
Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil hydrochloride-lithium therapy with either no change or an increase in serum lithium levels.
The addition of verapamil hydrochloride, however, has also resulted in the lowering of the serum lithium levels in patients receiving chronic oral lithium. Patients receiving both medicinal products should therefore be monitored carefully.
Muscle relaxants: Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the activity of muscle relaxants (curare-like and depolarising). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the medicinal products are used concomitantly.
Acetylsalicylic acid: Increased haemorrhagic diathesis.
Ethanol (alcohol): Delayed ethanol elimination and elevation of ethanol plasma levels, resulting in enhanced effect of alcohol by verapamil.
HMG Co-A reductase inhibitors ("statins"): In patients taking verapamil, treatment with HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) 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), a reduction in the statin dose should be considered, whereby the dose should be re-titrated based on serum cholesterol concentrations.
If verapamil and simvastatin are used concurrently at higher doses, the risk of myopathy/rhabdomyolysis is increased. The dose of simvastatin should be adjusted accordingly (see Precautions).
Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.
Antihypertensives, diuretics, vasodilators: Increase of the antihypertensive effect with risk of accelerated fall in blood pressure.
Anti-arrhythmics (e.g. Flecainide, disopyramide), beta-adrenergic blocking agents (e.g. metoprolol, propranolol), inhalation anaesthetics: Reciprocal increase in cardiovascular effects (higher-degree AV block, higher-degree decrease in the heart rate, occurrence of cardiac insufficiency, potentiated fall in blood pressure).
Beta-blockers must not be used concurrently intravenously in patients treated with verapamil (except intensive care medicine) (see Contraindications).
Concomitant administration of intravenous verapamil hydrochloride with anti-adrenergic substances can result in exaggerated hypotensive response. Especially in patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, the risk of this side effect was increased with concomitant administration of intravenous beta-blocker or disopyramide with intravenous verapamil as both substance classes reduce the myocardial contractility and AV-conduction (see Adverse Reactions).
Concomitant use with ivabradine is contraindicated due to the additional heart rate-lowering effect of verapamil to ivabradine (see Contraindications).

Incompatibilities: Not applicable.

Store at temperatures not exceeding 25°C.

Calcium Antagonists

C08DA01 - verapamil ; Belongs to the class of phenylalkylamine derivative selective calcium-channel blockers with direct cardiac effects. Used in the treatment of cardiovascular diseases.

Rx

SR tab 240 mg (oblong, biconvex, light green film-coated with scores on both sides and smooth, intact surface) x 100's.