•         Symptomatic coronary heart disease:

               -        chronic stable angina pectoris (angina of effort)

               -        unstable angina pectoris (crescendo angina, angina at rest)

               -        vasospastic angina pectoris (Prinzmetal’s angina, variant angina)

               -        angina pectoris post myocardial infarction in patients without heart failure, when beta receptor blockers are not indicated.

•          Arrhythmias in the case of:

               -        paroxysmal supraventricular tachycardia

               -        atrial fibrillation/atrial flutter with rapid AV conduction [except in WPW (Wolff-Parkinson-White) syndrome or Lown-Ganong-Levine syndrome, see under section 4.3]

•        Hypertension

Posology

The dose of verapamil hydrochloride, the active substance contained in Isoptin, should be adjusted on an individual basis, depending on the severity of the disease. Long-standing clinical experience shows that the average daily dose in almost all indications is between 240 mg and 360 mg.

A daily dose of 480 mg should not be exceeded in long-term therapy. It may be increased for a short period.

Unless otherwise prescribed, the following dosing guidelines apply:

·           Adults and adolescents weighing over 50 kg:

Coronary heart disease

The recommended dose is 240 mg – 480 mg verapamil hydrochloride per day in 2 divided doses, equivalent to:

½ to 1 Isoptin SR sustained-release tablet twice daily (equivalent to 240 mg – 480 mg verapamil hydrochloride per day).

Isoptin SR is used if lower doses (e.g. 240 mg verapamil hydrochloride, sustained-release, per day) have proved inadequate.

Hypertension

The recommended dose is 240 mg – 480 mg verapamil hydrochloride per day in 1 to 2 divided doses, equivalent to:

1 Isoptin SR sustained-release tablet every morning (equivalent to 240 mg verapamil hydrochloride per day).

If this dose is not sufficiently effective, an additional ½ to 1 Isoptin SR sustained-release tablet can be administered in the evening (equivalent to 360 mg – 480 mg verapamil hydrochloride per day).

Paroxysmal, supraventricular tachycardia, atrial fibrillation/atrial flutter

The recommended dose is 240 mg – 480 mg verapamil hydrochloride daily in 2 divided doses, equivalent to:

½ to 1 Isoptin SR sustained-release tablet twice daily (equivalent to 240 mg – 480 mg verapamil hydrochloride per day).

Isoptin SR is used if lower doses (e.g. 240 mg verapamil hydrochloride, sustained-release, per day) have proved inadequate.

Impaired renal function

The information currently available is described in section 4.4.

Verapamil hydrochloride should be used with caution and under close monitoring in patients with renal impairment.

Impaired hepatic function

Depending on the severity of the condition, the effect of verapamil hydrochloride is potentiated and prolonged in patients presenting impaired hepatic function because of slower drug decomposition. In such cases, the dosage should therefore be adjusted with particular caution, starting with lower doses (e.g. in patients with hepatic impairment, initially 40 mg verapamil hydrochloride, 2 to 3 times a day, corresponding to 80 mg – 120 mg verapamil hydrochloride per day) (see also section 4.4).

Method and duration of administration

The medicinal product should be taken whole and unchewed, with sufficient fluid intake (e.g. a glass of water, no grapefruit juice) preferably with or shortly after food.

Verapamil should not be taken in the supine position.

In patients presenting Angina pectoris post myocardial infarction, verapamil should not be taken until 7 days after acute infarction.

The duration of administration is not limited.

Following long-term therapy, verapamil should not, in principle, be discontinued abruptly but gradually decreased.

Isoptin SR should not be used in the case of: • hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • cardiovascular shock • pronounced cardiac conduction disorders (e.g. IInd and IIIrd degree SA or AV block; except for patients fitted with a pacemaker) • sick sinus syndrome (except for patients fitted with a pacemaker) • heart failure with a reduced ejection fraction of less than 35% and/or wedge pressure exceeding 20 mmHg (unless secondary to supraventricular tachycardia responding to verapamil) • atrial fibrillation/flutter and the concomitant presence of accessory pathways (e.g. WPW or Lown-Ganong-Levine syndrome). In these patients, verapamil therapy poses an increased risk of ventricular tachycardia, including ventricular fibrillation • concomitant administration of ivabradine (see also section 4.5) Beta receptor blockers should not be administered intravenously in conjunction with verapamil (except in intensive care medicine; see also section 4.5).

Acute myocardial infarction

Verapamil should only be used with caution in the case of acute myocardial infarction with complications (bradycardia, hypotension, left-sided ventricular heart failure).

Conduction disorder/Ist degree AV block/bradycardia/asystole

Verapamil affects AV and sinus nodes and delays AV conduction. It should be used with caution since IInd or IIIrd degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block warrants discontinuation of treatment and the initiation of appropriate therapy, if required.

It affects AV and sinus nodes and, in rare cases, may trigger IInd or IIIrd degree AV block, bradycardia or, in extreme cases, asystole. This is more likely to occur in patients with sick sinus syndrome, which is more common in older patients.

 

In patients not suffering from sick sinus syndrome, asystole is normally of short duration (a few seconds or less), with a spontaneous return to AV-node or normal sinus rhythm. If this does not occur immediately, appropriate treatment should be initiated without delay (see also section 4.8).

Antiarrhythmics, beta blockers and inhalation anaesthetics

Antiarrhythmics (e.g. flecainide, disopyramide), beta receptor blockers (e.g. metoprolol, propranolol) and inhalation anaesthetics may mutually potentiate cardiovascular effects (severe AV block, severe drop in heart rate, onset of heart failure, marked hypotension) if administered concomitantly with verapamil (see also section 4.5).

Asymptomatic bradycardia (36 beats per minute) with a migrating atrial pacemaker was observed in one patient using eye drops containing timolol (a beta blocker) and taking verapamil concomitantly.

Digoxin

The digoxin dose should be reduced if taken concomitantly with verapamil (see also section 4.5).

Heart failure

Heart failure patients with an ejection fraction of over 35% should be compensated before treatment begins. Adequate therapy should also be administered during treatment.

HMG-CoA reductase inhibitors (“statins”)

See section 4.5.

Disorders with impaired neuromuscular transmission

Caution should be exercised when prescribing verapamil for patients previously diagnosed with impaired neuromuscular transmission (Myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy).

Hypotension

Particularly strict monitoring is required in the case of hypotension (less than 90 mmHg systolic).

Further information

Special patient groups

Impaired renal function

Although comparative studies have reliably shown that impaired renal function in patients presenting end-stage renal failure has no effect on the pharmacokinetic profile of verapamil, individual case reports suggest that caution should be exercised and strict monitoring implemented (ECG, blood pressure) when administering verapamil to patients with renal impairment.

Verapamil cannot be removed through haemodialysis.

 

Impaired hepatic function

Use with caution in patients with severely compromised hepatic function (see also information on impaired hepatic function in section 4.2).

Sodium

This medicinal product contains 37.1 mg sodium per sustained-release tablet, equivalent to 1.9% of the WHO’s 2 g maximum recommended dietary allowance for adults.

In-vitro studies have shown that verapamil is metabolised by cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18.

Clinically significant interactions have been reported with CYP3A4 inhibitors responsible for increased verapamil hydrochloride plasma levels; contrastingly, inducers of CYP3A4 lower verapamil hydrochloride plasma levels. Patients should therefore be monitored for interactions.

Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp). Concomitant administration of verapamil and another medicinal product, mainly metabolised via CYP3A4 or representing a P-gp substrate, can increase the active substance concentration of the concomitant medicinal product, thus potentiating or prolonging the therapeutic effect and increasing the adverse events associated with the concomitant medication.

Potential pharmacokinetic interactions are highlighted in the following table:

Potential interactions
Concomitant medication	Potential effect on verapamil or the concomitant medication	Comment
Alpha blockers
Prazosin	cmax of prazosin ­ (~ 40%), no effect on half-life	Additive antihypertensive effect
Terazosin	­ in the AUC (~ 24%) and (25%) of terazosin
Antiarrhythmics
Flecainide	Minimal effect on plasma clearance of flecainide (< ~ 10%); no effect on verapamil plasma clearance	Further information (see under section 4.4 - Antiarrhythmics, beta receptor blockers and inhalation anaesthetics)
Quinidine	Clearance of oral quinidine ¯ (~ 35%)	Hypotension.   Pulmonary oedema may occur in patients with hypertrophic obstructive cardiomyopathy.
Amiodarone	Increase in amiodarone plasma levels
Antiasthmatics
Theophylline	Oral and systemic clearance ¯ by ~ 20%	The reduction in clearance was less pronounced in smokers (~ 11%)
Anticonvulsives/Antiepileptics
Carbamazepine	AUC of carbamazepine ­ (~ 46%) in patients with refractory partial epilepsy	Increased carbamazepine levels.   This may trigger adverse events such as diplopia, headaches, ataxia or dizziness/vertigo
	Reduction in verapamil hydrochloride plasma levels
Phenytoin	Verapamil plasma concentrations ¯
Antidepressants
Imipramine	AUC of imipramine ­ (~ 15%)	No effect on the levels of the active metabolite desipramine.
	Increased verapamil hydrochloride plasma levels
Antidiabetics
Glibenclamide	cmax (~ 28%) and AUC of glibenclamide ­ (~ 26%)
	Increased verapamil hydrochloride plasma levels
Gout treatments
Colchicine	­ of AUC (~ 2.0-fold) and cmax (~ 1.3-fold) of colchicine	Reduction in the dose of colchicine (concomitant use of colchicine with verapamil hydrochloride is not recommended).
Anti-infectives
Clarithromycin	Potential ­ in verapamil levels
Erythromycin	Potential ­ in verapamil levels
Rifampicin	With oral administration of verapamil ¯ in AUC (~ 97%), cmax (~ 94%) and oral bioavailability (~ 92%) of verapamil	Potential reduction in anti-hypertensive effect.
	No change in the PC with intravenous administration of verapamil
Telithromycin	Possible ­ in verapamil levels
Antineoplastics
Doxorubicin	With oral administration of verapamil ­ in AUC (104%) and cmax (61%) of doxorubicin	In patients with small-cell lung cancer.
	No significant changes in the PC of doxorubicin with intravenous use of verapamil	In patients with advanced tumours.
Azole fungistatics
Clotrimazole	Increased verapamil hydrochloride plasma levels
Ketoconazole	Increased verapamil hydrochloride plasma levels
Itraconazole	Increased verapamil hydrochloride plasma levels
Barbiturates
Phenobarbital	Clearance of oral verapamil ­ (~ 5-fold)
Benzodiazepines and other anxiolytics
Buspirone	AUC and cmax of buspirone ­ (~ 3.4-fold)
	Increased verapamil hydrochloride plasma levels
Midazolam	AUC (~ 3-fold) and cmax (~ 2-fold) of Midazolam ­
	Increased verapamil hydrochloride plasma levels
Beta blockers
Metoprolol	In patients with angina pectoris ­ in the AUC (~ 32.5%) and cmax (~ 41%) of metoprolol	See Section 4.4.
	Increased verapamil hydrochloride plasma levels
Propranolol	In patients with angina pectoris ­ in AUC (~ 65%) and cmax (~ 94%) of propranolol
	Increased verapamil hydrochloride plasma levels
Cardiac glycosides
Digitoxin	¯ in total clearance of digitoxin (~ 27%) and in extrarenal clearance (~ 29%)
Digoxin	In healthy subjects: cmax of digoxin ­ (~ 44%), c12 h of digoxin ­ (~ 53%), cSS of digoxin ­ (~ 44%) and AUC of digoxin ­ (~ 50%)	Reduction in digoxin dose (see also section 4.4.)
H2-receptor antagonists
Cimetidine	AUC of R- (~ 25%) and S-verapamil (~ 40%) with corresponding ¯ in the clearance of R- and S-verapamil	Cimetidine reduces verapamil clearance after intravenous administration of verapamil.
Immunological agents/Immunosuppressants
Cyclosporine	AUC, cSS, cmax of cyclosporine ­ (~ 45%)
Everolimus	Everolimus-AUC ­ (~ 3.5-fold), cmax ­ (~ 2.3-fold), verapamil: ctrough ­ (~ 2.3-fold)	Potential determination of concentration and dose adjustment of everolimus required.
Sirolimus	Sirolimus-AUC ­ (~ 2.2-fold); S-verapamil-AUC ­ (~ 1.5-fold)	Potential determination of concentration and dose adjustment of sirolimus necessary.
Tacrolimus	Tacrolimus levels possibly ­
Lipid-lowering/HMG-CoA reductase inhibitors
Atorvastatin	Possible ­ in atorvastatin levels AUC of verapamil ­ (~ 43%)	Further information see below.
Lovastatin	Possible ­ in lovastatin levels AUC (~ 63%) and cmax (~ 32%) of verapamil ­
Simvastatin	AUC (~ 2.6-fold) and cmax (~ 4.6-fold) of simvastatin ­
Serotonin receptor agonists
Almotriptan	AUC (~ 20%) and cmax (~ 24%) of almotriptan ­
	Increased verapamil hydrochloride plasma levels
Uricosuric agents
Sulfinpyrazone	Oral clearance of verapamil ­ (~ 3-fold), bioavailability ¯ (~ 60%)	Potential reduction in antihypertensive effect
	No change in the PC with intravenous use of verapamil
Other cardiac treatments
Ivabradine	Concomitant use with ivabradine is contraindicated due to the additional heart rate-reducing effect of verapamil on ivabradine.	See section 4.3
Other
Grapefruit juice	­ in AUC of R- (~ 49%) or S-verapamil (~ 37%) ­ in the cmax of R- (~ 75%) or S-verapamil (~ 51%)	Elimination half-life and renal clearance not affected. Food and drink containing grapefruit should be avoided whilst taking Isoptin.
St. John’s wort	¯ in the AUC of R- (~ 78%) or S-verapamil (~ 80%) with corresponding reduction in cmax

Other interactions and additional information

HIV antiviral drugs

Verapamil plasma concentrations may increase due to the inhibiting potential of some HIV antiviral drugs, such as ritonavir. They should therefore be used with caution and the dose of verapamil should be reduced if necessary.

Similarly, verapamil may increase the plasma levels of these medicinal products by influencing degradation.

Lithium

Increased sensitivity to the effects of lithium (neurotoxicity) have been reported following concomitant administration with lithium; lithium levels were unchanged or increased during treatment.

The administration of verapamil has, however, also led to a reduction in serum lithium levels in patients receiving long-term oral lithium therapy. Patients receiving both active substances should therefore be closely monitored.

Muscle relaxants

Both clinical and experimental animal data show that verapamil may potentiate the effects of muscle relaxants (both curare and depolarising). It may therefore be necessary to reduce the verapamil dose and/or the dose of the muscle relaxant, if both are administered concomitantly.

 

Acetylsalicylic acid
Increased propensity to bleed.

 Dabigatran

Elevated dabigatran Cmax and AUC levels were recorded following concomitant administration of oral verapamil and dabigatran etexilate (150 mg), a substrate of P-gp. The extent of these changes depends on the time of administration and the verapamil formulation used.

Concomitant administration of Verapamil 240 mg sustained-release tablets and dabigatran etexilate led to increased dabigatran exposure (increase of Cmax and AUC by approximately 90% and 70%, respectively).

Close clinical monitoring is recommended if verapamil is combined with dabigatran etexilate, especially in the event of bleeding and particularly in patients with mild to moderate renal impairment.

Other direct oral anticoagulants (DOACs)

Both CYP3A4 and P-gp inhibitors such as verapamil can increase DOAC plasma concentrations to a clinically relevant extent. Some data suggest a potential increase in the risk of bleeding, particularly in patients presenting risk factors. The DOAC dose should be reduced during concomitant administration of verapamil, if required (see dosing instructions in the DOAC package leaflet/smPC).

Ethanol (Alcohol)

Delayed ethanol degradation and elevated ethanol plasma levels, thus potentiating the effect of alcohol.

HMG-CoA reductase inhibitors (statins)

In patients receiving verapamil, HMG-CoA reductase inhibitor treatment (e.g. simvastatin, atorvastatin or lovastatin) should be started at the lowest possible dose and up-titrated. If verapamil is added to existing HMG-CoA reductase inhibitor therapy (e.g. simvastatin, atorvastatin or lovastatin), a statin dose reduction should be considered, with back-titration against the serum cholesterol concentration.

The risk of myopathy/rhabdomyolysis is increased following concomitant administration of higher doses of verapamil and simvastatin. The simvastatin dose should be adjusted accordingly (see the manufacturer’s production information; see also section 4.4).

Fluvastatin, pravastatin and rosuvastatin are not metabolised via cytochrome P450 isoenzyme 3A4. An interaction with verapamil is less likely.

Antihypertensives, diuretics, vasodilators:

Potentiation of the antihypertensive effect with the risk of excessive hypotension.

Antiarrhythmics (e.g. flecainide, disopyramide), beta receptor blockers (e.g. metoprolol, propranolol), inhalation anaesthetics:

Mutual potentiation of cardiovascular effects (severe AV block, severe drop in heart rate, onset of heart failure, exacerbated hypotension).

Intravenous beta receptor blockers should not be administered concomitantly to patients receiving intravenous verapamil therapy (except in intensive care; see also section 4.3). Concomitant administration of intravenous verapamil and anti-adrenergic agents may lead to excessive hypotension. Simultaneous administration of intravenous beta blockers or disopyramide with intravenous verapamil increased the risk of adverse events, particularly in patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, since both substance classes suppress myocardial contractility and AV conduction (see also section 4.8).

Pregnancy

Verapamil can cross the placenta. The plasma concentration in umbilical vein blood amounts to 20 - 92% of the plasma concentration in the maternal blood. There is inadequate experience of the use of this medicinal product during pregnancy. However, data on a limited number of orally treated pregnant women do not suggest teratogenic effects. Animal studies have highlighted reproduction toxicity (see section 5.3.).

Therefore, verapamil should not be taken during the first and second trimesters of pregnancy. It should only be administered in the third trimester of pregnancy if strictly indicated, taking into account the risk for mother and child.

Breast-feeding

Verapamil diffuses into breast milk (milk concentration approx. 23% of maternal plasma concentration). Limited human data following oral administration have shown that the nursing infant absorbs only a small quantity of active substance (0.1 to 1% of the maternal dose). Treatment may therefore be compatible with breast-feeding.

A risk to the new-born/nursing infant cannot be ruled out. Hence, given the risk of serious adverse events in the nursing infant, verapamil should only be administered during breast-feeding if deemed absolutely essential for the mother’s well-being.

There is evidence to suggest that verapamil may cause hyperprolactinaemia and galactorrhoea in individual cases.

Patients must be monitored regularly during verapamil therapy. Given the variation in individual reactions, the ability to react may be changed to such an extent that the ability to drive, use machines or work without secure footing is adversely affected. This applies in particular at the start of treatment, if the dosage is increased or the preparation changed, and in combination with alcohol. Blood alcohol levels may be increased and the elimination of alcohol slowed down, thus potentially enhancing the effects of alcohol.

The following undesirable effects have been reported in clinical trials, post-marketing studies or phase IV clinical trials; they are ranked according to system organ class.

The frequency data are defined as follows:

Very common: may affect more than 1 in 10 patients treated

Common: may affect up to 1 in 10 patients treated

Uncommon: may affect up to 1 in 100 patients treated

Rare: may affect up to 1 in 1,000 patients treated

Very rare: may affect up to 1 in 10,000 patients treated

Unknown: frequency cannot be estimated from the available data

The most commonly reported undesirable effects were headaches, dizziness or giddiness, gastrointestinal disorders (nausea, constipation, abdominal discomfort), as well as bradycardia, tachycardia, palpitations, hypotension, flushes, peripheral oedema and fatigue.

Undesirable effects reported from clinical studies with verapamil and post-marketing observations

MedDRA system organ class	common	uncommon	rare	very rare	unknown
Immune system disorders					Hypersensitivity
Nervous system disorders	Dizziness or giddiness, headaches, neuropathy		Paraesthesia, tremor		Extrapyramidal symptoms, paralysis (tetraparesis)1, cramps
Metabolism and nutrition disorders		Reduced glucose tolerance			Hyperkaliaemia
Psychiatric disorders	Anxiety		Drowsiness
Ear and labyrinth disorders			Tinnitus		Vertigo
Cardiac disorders	Bradycardia, onset of heart failure or exacerbation of pre-existing heart failure, excessive blood pressure reduction and/or orthostatic regulation disorders	Palpitations, tachycardia			AV block (Ist, IInd or IIIrd degree), heart failure, sinus arrest, sinus bradycardia, asystole
Vascular disorders	Flushes, hypotension
Respiratory, thoracic and mediastinal disorders					Bronchospasm, dyspnoea
Gastrointestinal disorders	Constipation, nausea	Abdominal pain	Vomiting		Abdominal discomfort, gingival hyper­plasia, ileus
Hepatobiliary disorders		Probably allergy-induced hepatitis with reversible increase in liver-specific enzymes.
Skin and subcutaneous tissue disorders	Erythromelalgia		Hyperhidrosis	Photodermatitis	Angioedema, Stevens-Johnson syndrome, erythema multiforme, alopecia, itching, pruritus, purpura, maculopapular exanthema, urticaria
Musculoskeletal and connective tissue disorders				Aggravation of Myasthenia gravis, Lambert-Eaton syndrome and progressive Duchenne muscular dystrophy	Arthralgia, muscular weakness, myalgia
Renal and urinary disorders					Renal insufficiency
Reproductive system and breast disorders					Erectile dysfunction, galactorrhoea, gynecomastia
General disorders and administration site conditions	Peripheral oedema	Fatigue
Investigations					Increased blood prolactin levels

¹There was a single post-marketing report on paralysis (tetraparesis) related to the concomitant administration of verapamil and colchicine. This could have been caused by the passage of colchicine through the blood-brain barrier following inhibition of CYP3A4 and P-gp by verapamil (see also section 4.5).

Note

In patients fitted with pacemakers, an increase in the pacing and sensing threshold cannot be ruled out during verapamil therapy.

In patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, concomitant administration of intravenous beta blockers or disopyramide with intravenous verapamil increased the risk of severe side effects as since both substance classes have a cardiodepressive effect (see also section 4.5).

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  : 

To report any side effect(s):

-National Pharmacovigilance Center (NPC)

o Fax: +966-11-205-7662

o SFDA Call Center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

Symptoms of overdose:

Intoxication symptoms following verapamil poisoning progress depending on the amount ingested, the time at which detoxification measures are applied and the contractile functionality of the myocardium (age-dependent).

The following symptoms have been observed with severe poisoning:

Serious hypotension, heart failure, bradycardia or tachycardia arrhythmia (e.g. junctional rhythm with AV dissociation and severe AV block), potentially culminating in cardiovascular shock and cardiac arrest.

Clouding of consciousness progressing to coma, hyperglycaemia, hypokalaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema, impaired renal function and convulsions. Deaths have occasionally been reported.

Therapeutic measures in the event of overdose:

Detoxification and restoration of stable cardiovascular conditions are pre-requisite.

Therapeutic measures depend on the time and method of ingestion, as well as the nature and severity of the intoxication symptoms.

If larger quantities of sustained-release preparations have been ingested, it should be noted that the active substance may be released and absorbed by the intestines even longer than 48 hours after intake.

Gastric lavage is advisable after oral verapamil poisoning, even more than 12 hours after ingestion, if no gastrointestinal motility (bowel sounds) can be detected. If intoxication with sustained-release preparations is suspected, extensive elimination measures are indicated, such as induced vomiting, aspiration of the contents of the stomach and small intestine under endoscopic guidance, intestinal lavage, evacuation, high enema.

As verapamil cannot be dialysed, haemodialysis is not advisable, but haemofiltration and possibly plasmapheresis (high plasma protein binding of calcium channel blockers) are recommended.

Standard intensive care resuscitation measures, such as extrathoracic cardiac massage, ventilation, defibrillation and/or pacemaker therapy.

Specific measures:

Elimination of cardiodepressive effects, hypotension and bradycardia.

Bradycardia arrhythmia is treated symptomatically with atropine and/or beta sympathomimetic agents (isoprenaline, orciprenaline); in the case of life-threatening bradycardia arrhythmia, temporary pacemaker therapy is required. Asystole should be treated by standard methods, including beta adrenergic stimulation (isoprenaline).

Calcium is a specific antidote, e.g. 10 to 20 ml of a 10% intravenous calcium gluconate solution (2.25 to 4.5 mmol), repeated if necessary, or administered as a continuous drip infusion (e.g. 5 mmol/hour).

Hypotension, as a result of cardiogenic shock and arterial vasodilation, is treated with dopamine (up to 25 μg per kg of bodyweight per minute), dobutamine (up to 15μg per kg of bodyweight per minute), epinephrine or norepinephrine. The dosage of these medicinal products is guided solely by the effect achieved. Serum calcium should be maintained at high-normal to slightly elevated levels. Additional fluid replacement therapy is administered in the early stages due to arterial vasodilation (Ringer's or sodium chloride solution).

Pharmacotherapeutic group: selective calcium channel blockers with predominantly cardiac effects, phenyl alkylamine derivatives

ATC code: C08DA01

Mechanism of action and pharmacodynamic effects

Verapamil belongs to the group of calcium channel blockers. These substances inhibit calcium influx through muscle cell membranes.

It also acts as a calcium channel blocker on smooth muscle, particularly in the region of the vessels and gastrointestinal tract. The effect on smooth muscle manifests in vasodilation.

As a calcium channel blocker, verapamil also has a marked effect on the myocardium. The effect on AV nodes is expressed through prolonged conduction time. This can lead to a negative inotropic effect in the working myocardium.

As a result of vasodilation, a decrease in total peripheral resistance is observed in humans. There is no reflex increase in cardiac output. Consequently, blood pressure drops.

Verapamil is a racemic mixture consisting of equal portions of the R and S enantiomers. Verapamil is extensively metabolised. Norverapamil is one of 12 metabolites that can be detected in the urine; it possesses 10 to 20% of the pharmacological activity of verapamil and accounts for 6% of the excreted active substance.

The steady-state plasma concentrations of norverapamil and verapamil are comparable. Steady-state is reached after three to four days with repeated daily dosing.

Absorption

Over 90% of verapamil is quickly absorbed from the small intestine following oral administration. The mean systemic availability of the unchanged substance following a single dose of non-sustained-release verapamil is 22% compared to approximately 32% with sustained-release verapamil. This is due to a significant first-pass effect in the liver.

Bioavailability increases approximately two-fold with repeated dosing. Following the administration of non-sustained-release verapamil, peak plasma concentrations are reached after one to two hours compared to four to five hours after administration of sustained-release verapamil. Norverapamil peak plasma concentrations are reached after one hour (non-sustained-release) or after five hours (sustained-release).

The bioavailability of verapamil is unaffected if the medicinal product is taken with food.

Distribution

Verapamil is widely distributed in the body tissues; the volume of distribution is 1.8 to 6.8 l/kg in healthy subjects. 90% bind to plasma proteins.

Biotransformation

Verapamil is extensively metabolised. In-vitro studies show that verapamil is metabolised by the cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Oral verapamil is extensively metabolised in the liver in healthy men; 12 metabolites have been identified but mostly only in traces. The majority of metabolites consist of various N- and O-dealkylated degradation products of verapamil. Of these, only norverapamil has any notable pharmacological effect (approximately 20% of that of the parent substance); this was seen in a study conducted in dogs.

Elimination

Following intravenous infusion, verapamil is rapidly eliminated bi-exponentially, with a faster early distribution phase (half-life about four minutes) and a slower terminal elimination phase (half-life two to five hours).

The elimination half-life of oral verapamil is three to seven hours post-dose.

About 50% of the dose administered is eliminated via the kidneys within 24 hours, and 70% within five days. Up to 16% are excreted with the faeces. About 3 to 4% of the active substance is excreted unchanged via the kidneys. Total clearance is approximately on par with hepatic blood flow, about 1 l/h/kg (range: 0.7 to 1.3 l/h/kg).

Considerable inter-individual differences are apparent in terms of clearance.

Special patient groups

Paediatric population

Only limited pharmacokinetic data are available regarding use in the paediatric population. Following intravenous administration, the mean half-life was 9.17 hours and the average clearance 30 l/h compared to 70 l/h in an adult weighing 70 kg. Steady-state plasma concentrations after oral administration appear to be lower in children than in adults.

Elderly patients

Age may influence the pharmacokinetic effects in patients with high blood pressure. The elimination half-life may be prolonged in elderly patients. The anti-hypertensive effect of verapamil is not age-dependent.

Impaired renal function

Impaired renal function does not impact the pharmacokinetic profile; this was shown in comparison studies involving end-stage renal failure patients and patients with healthy kidneys.

Verapamil and norverapamil cannot be removed through haemodialysis.

Impaired hepatic function

The half-life is prolonged in patients with impaired hepatic function. This is due to the reduced clearance of the orally administered substance and the increased distribution volume.

Embryonic toxicity studies, not carried out in accordance with current standards, did not reveal any teratogenic effects in rats and rabbits at the highest doses tested (360 mg/m² and 180 mg/m², respectively). Maternal toxicity (reduced feed intake and bodyweight gain) and embryo toxicity manifesting in increased embryonic lethality and growth retardation were reported in rats following administration of the highest dose, equivalent to 300 mg/m² in the human therapeutic dosing range. As the highest dose tested in rabbits was far below the human therapeutic dose, the relevance of the study is unclear.

Quinoline yellow and indigo carmine

 aluminium salts

 purified water

 hypromellose

macrogol 400

 macrogol 6000

magnesium stearate (Ph.Eur.)

microcrystalline cellulose

Montan glycol wax

sodium alginate

 povidone (K-30)

 talcum

 titanium dioxide (E171).

Not applicable.

36 months

Do not store over 25°C

Original packaging with 20 sustained-release tablets

Original packaging with 30 sustained-release tablets

Original packaging with 50 sustained-release tablets

Original packaging with 98 sustained-release tablets

Clinical pack with          40 sustained-release tablets

Clinical pack with        160 (4 x 40) sustained-release tablets

Clinical pack with        200 (5 x 40) sustained-release tablets

 

      Not all pack sizes may be marketed.

No special requirements