Verapamil hydrochloride is indicated in

 

·       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]

 

·       Initial treatment of unstable angina pectoris when nitrates and/or beta receptor blockers are not indicated.

Adults:

Adults and adolescents weighing over 50 kg: Starting dose of 5 mg verapamil hydrochloride (equivalent to 2 ml Verapamil QO solution for injection), and an additional 5 mg verapamil hydrochloride after 5 – 10 minutes, if required.

 

If necessary, a continuous drip solution of 5 – 10 mg verapamil hydrochloride/hour can be administered in isotonic sodium chloride solution, 5% glucose solutions or other appropriate solutions (pH [Bigger than} 6.5), up to an average overall dose of 100 mg verapamil hydrochloride daily. 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 the biological availability of verapamil hydrochloride can increase considerably in patients with impaired hepatic function. Particular caution should therefore be exercised when deciding on the dosage for these patients (see also section 4.4).

 

 

 

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

The biological availability of verapamil hydrochloride can increase considerably in patients with impaired hepatic function. Particular caution should therefore be exercised when deciding on the dosage for these patients (see also section 4.4).

 

Special Populations

 

Pediatric population

Digitalisation is required prior to the intravenous administration of verapamil hydrochloride following signs of tachycardia-induced heart failure (exhaustion of myocardial energy).

 

0 – 1 year:  if strictly indicated and no other alternative is available. Severe interim hemodynamic effects, some of them fatal, have been observed in isolated cases following the intravenous administration of verapamil hydrochloride to new-born babies and infants.

 

Age Dose of verapamil hydrochloride Corresponding to

 

New-born babies 0.75 – 1.0 mg 0.3 – 0.4 ml Verapamil QO solution for injection

 

Infants 0.75 – 2.0 mg 0.3 – 0.8 ml Verapamil QO solution for injection

 

1 – 5 years 2.0 – 3.0 mg 0.8 – 1.2 ml Verapamil QO solution for injection

 

6 – 14 years 2.5 – 5.0 mg 1.0 – 2.0 ml Verapamil QO solution for injection

 

The injection should be carried out up to  of efficacy.

 

 

 

 

 

Method of administration

For intravenous use only.

The intravenous injection should be administered slowly (duration of injection at least 2 minutes) with patient observation and ECG and blood pressure monitoring, if possible.

Parenteral medicinal products should be visually inspected for particles and discoloration prior to administration, solution and containers permitting. The preparation must be used if the solution is clear and the ampoule seal intact.

Any residue left in the ampoule after injection should be discarded.

 

Note:

If unstable angina pectoris is initially treated with Verapamil QO solution for injection, therapy should be switched to oral verapamil hydrochloride as soon as possible.

 

 

 

Hypersensitivity to the active substance or to any of the excipients. Cardiogenic shock; acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure; second or third degree AV block (except in patients with a functioning artificial ventricular pacemaker); sino-atrial block; sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker); uncompensated heart failure; bradycardia of less than 50 beats/minute; hypotension of less than 90mmHg systolic; simultaneous administration of intravenous beta-blockers. Patients with atrial flutter/fibrillation in the presence of an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated. Combination with ivabradine (see section Interactions with other medicinal products and other forms of interaction).

Verapamil hydrochloride injection should be given as a slow intravenous injection over at least a two-minute period of time under continuous ECG and blood pressure monitoring.

 

A small fraction of patients treated with verapamil hydrochloride respond with life-threatening adverse responses including (rapid ventricular rate (in atrial flutter/fibrillation in the presence of an accessaory bypass tract), marked hypotension or extreme bradycardia/asystole).

 

Heart Block/ 1st Degree AV block/Bradycardia/Asystole

 

Verapamil hydrochloride affects the AV and SA 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 in subsequent doses of verapamil hydrochloride and institution of appropriate therapy, if needed.

 

Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), 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 Undesirable Effects Section.

 

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.

 

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).

In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil hydrochloride, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride injection with agents that decrease adrenergic function may result in an exaggerated hypotensive response.

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

The following are potential drug interactions due to pharmacokinetic reasons:

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. Phenytoin may decrease the plasma concentrations of verapamil.

Antidepressants

Verapamil may increase the plasma concentrations of imipramine.

Antidiabetics

Verapamil may increase the plasma concentrations of glibenclamide (glyburide). Co-administration of verapamil with metformin may reduce the efficacy of metformin.

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.When verapermil and rifampicin are administrated together there is no change in PK. 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, 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. Concentration determinations and dose adjustments of everolimus and sirolimus may be necessary.

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 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. Patients receiving both drugs should be monitored carefully.

Neuromuscular blocking agents employed in anaesthesia

The effects may be potentiated.

Protein-bound drugs

As verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs.

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. When verapermil and sulfinpyrazone are administrated together there is no change in PK.

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.

Pregnancy

 

There are no adequate and well-controlled study data in pregnant women. Although animal studies have not shown any teratogenic effects (see section 5.3), verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient.

 

Verapamil hydrochloride is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother's oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.

None stated

Adverse events observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.

 

 

System Organ Class	Frequency	Undesirable Effects
Nervous system disorders
	common	- dizziness - headache
Cardiac disorders/vascular disorders
	common	- bradycardia - hypotension
	uncommon	- tachycardia
Gastrointestinal disorders
	uncommon	- nausea - abdominal pain

Cases of seizures during verapamil hydrochloride injection have been reported.

In rare cases of hypersensitivity, bronchospasm accompanied by pruritis and urticaria has been reported.

Other Reactions from Postmarketing Surveillance or Phase IV Clinical Trials

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

Psychiatric disorders: on rare occasions, nervousness has been reported.

Nervous system disorders: somnolence and extrapyramidal syndrome.

Ear and labyrinth disorders: vertigo.

Cardiac disorders/vascular disorders: decreased myocardial contractility has been reported. On rare occasions, 2^nd and 3^rd block may occur and in extreme cases, this may lead to asystole. The asystole is usually of short duration and cardiac action returns spontaneously after a few seconds, usually in the form of sinus rhythm. If necessary, the procedures for the treatment of overdosage should be followed as described below. On rare occasions, flushing has been reported.

Gastrointestinal disorders: gingival hyperplasia may occur very rarely when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued. On rare occasions, vomiting has also been reported.

Skin and subcutaneous tissue disorders: Steven-Johnson syndrome, erythema and hyperhidrosis.

Reproductive system and breast disorders: On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment; this was fully reversible in all cases when the drug was discontinued.

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.

 

 

 

 

 

 

Reporting of suspected adverse reactions

To report any side effect(s):

 

Saudi Arabia:

- The National Pharmacovigilance Centre (NPC) Toll free phone: 19999 E-mail: npc.drug@sfda.gov.sa   Website: https://ade.sfda.gov.sa/

 

Other GCC States:

Please contact the relevant competent authority.

The symptoms of overdosage include hypotension, shock, loss of consciousness, first and second 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 and acute respiratory distress syndrome.. Fatalities have occurred as a result of overdose.

 

Treatment of overdosage depends on the type and severity of symptoms. The specific antidote is calcium, e.g. 10-20 ml of 10% calcium gluconate solution i.v. (2.25-4.5 mmol) if necessary by repeated injection or continuous infusion (e.g. 5 mmol/hour). The usual emergency measures for acute cardiovascular collapse should be applied and followed by intensive care. Verapamil hydrochloride cannot be removed by haemodialysis. Similarly, in the case of second or third degree AV block, atropine, orciprenaline, isoprenaline and if required, pacemaker therapy should be considered. If there are signs of myocardial insufficiency, dopamine, dobutamine, cardiac glycosides or calcium gluconate (10-20 ml of a 10% solution) can be administered.

 

In the case of hypotension, after appropriately positioning the patient, dopamine, dobutamine or noradrenaline may be given.

Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac effects, phenylalkylamine derivatives.

ATC-Code: C08DA01

Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in cells of the intracardiac conduction system. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period

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.

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 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

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).

Special Populations

Paediatric:

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 70kg adult.

Geriatric:

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 hemodialysis.

Hepatic insufficiency:

Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolised.

 

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 metabolized. In vitro metabolic studies indicate that verapamil is metabolized 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.

In coronary heart disease and hypertension, no correlation was found between the therapeutic effect and the plasma concentration; a definite correlation with the plasma level was determined only for the effect on the PR interval.

 

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 feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug.

 

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).

 

Special Populations

Paediatric:

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:

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 hemodialysis.

 

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.

Verapamil hydrochloride, administered intravenously, has been shown to be rapidly metabolized.

Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 0.6 (180 mg/m²/day) and 1.2 times (360 mg/m²/day) respectively the equivalent maximum recommended human oral daily dose (300 mg/m²/day) and have revealed no evidence of teratogenicity. In the rat the highest dose was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats.

Sodium chloride

Hydrochloric acid

Sodium Hydroxide

Water for Injections

Verapamil QO solution for injection is incompatible with alkaline solutions. In the absence of compatability studies, this medicinal product must not be mixed with other medicinal products.

36 months

Do not store above 25^o C. Protect from Light.

Keep out of the reach of children.

5 x 2 mL Single-Dose Vials

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.