Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
Use with caution in acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.
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 reduction in subsequent doses or discontinuation 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. Patients with heart failure or those who are susceptible to heart failure should be fully digitalised before verapamil therapy as it may aggravate or precipitate cardiac failure.
Great care should be taken in:
First degree AV block, bradycardia <50 beats/min, hypotension <90 mmHg systolic and ventricular tachycardias (QRS complex >0.12 sec).
If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdose).
Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function.
Mutual potentiation of cardiovascular effects (higher‐grade AV block, higher‐grade lowering of heart rate, induction of heart failure and potentiated hypotension). Asymptomatic bradycardia (36 beats/minute) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta‐adrenergic blocker) eye drops and oral verapamil hydrochloride.
There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood‐brain barrier due to CYP3A4 and P‐gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended. (see Section 4.5, Drug Interactions).
If verapamil is administered concomitantly with digoxin, reduce digoxin dosage. See Interactions with other medicinal drug products and other forms of interaction section.
Heart failure patients with ejection fraction higher than 35% should be compensated before starting verapamil treatment and should be adequately treated throughout.
See Interaction with other medicinal products and other forms of interaction section
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). Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.
Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis.
Use with caution in patients with severely impaired liver function (see also Posology section on liver impairment).
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium‐free’.
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. Coadministration of verapamil with a drug known to be primarily metabolized by CYP3A4 or known to be a P‐gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
With the simultaneous administration of Isoptin and drugs with a cardiodepressive action and/or inhibitory effects on impulse generation or conduction, e.g. beta‐receptor blockers, antiarrhythmics and inhalation anaesthetics, watch should be kept for possible additive effects (AV blockade, bradycardia, hypotension, heart failure). Above all, Isoptin should not be administered intravenously if the patient is on beta‐receptor blockers (except in intensive care).
The blood pressure lowering effect of Isoptin must be borne in mind in patients on antihypertensive drugs.
The following table provides a list of potential interactions with verapamil:
Potential Drug Interactions associated with Verapamil
| Concomitant drug | Potential effect on verapamil or concomitant drug | Comment |
|---|---|---|
| Alpha blockers | ||
| Prazosin | ↑ prazosin Cmax (~40%) with no effect on half‐life | Additive hypotensive effect. |
| Terazosin | ↑ terazosin AUC (~24%) and Cmax (~25%) | |
| Antiarrhythmics | ||
| Flecainide | Minimal effect on flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance | See section 4.4 |
| Quinidine | ↓ oral quinidine clearance (~35%) | Hypotension. Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy. |
| Antiasthmatics | ||
| Theophylline | ↓ oral and systemic clearance by ~20% | Reduction of clearance was lessened in smokers (~11%) |
| Anticonvulsants/Anti-epileptics | ||
| Carbamazepine | ↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients | Increased carbamazepine levels. This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness. |
| Phenytoin | ↓ verapamil plasma concentrations | |
| Antidepressants | ||
| Imipramine | ↑ imipramine AUC (~15%) | No effect on level of active metabolite, desipramine |
| Antidiabetics | ||
| Glyburide | ↑ glyburide Cmax (~28%), AUC (~26%) | |
| Metformin | Co‐administration of verapamil with metformin may reduce the efficacy of metformin. | |
| Anti-gout agents | ||
| Colchicine | Possible ↑ colchicine levels ↑ colchicine AUC (~2.0-fold) and Cmax (~1.3‐fold) | Reduce colchicine dose (see colchicine label) |
| Anti-infectives | ||
| Clarithromycin | Possible ↑ in verapamil levels | |
| Erythromycin | Possible ↑ in verapamil levels | |
| Rifampicin | ↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%) with oral verapamil administration | Blood pressure lowering effect may be reduced. |
| Telithromycin | Possible ↑ in verapamil levels | |
| Antineoplastics | ||
| Doxorubicin | ↑ doxorubicin AUC (104%) and Cmax (61%) with oral verapamil administration | In patients with small cell lung cancer |
| No significant change in doxorubicin PK with intravenous verapamil administration | In patients with advanced neoplasms | |
| Barbiturates | ||
| Phenobarbital | ↑ oral verapamil clearance (~5‐fold) | |
| Benzodiazepines and other anxiolytics | ||
| Buspirone | ↑ buspirone AUC, Cmax by ~3.4‐fold | |
| Midazolam | ↑ midazolam AUC (~3-fold) and Cmax (~2‐fold) | |
| Beta blockers | ||
| Metoprolol | ↑ metoprolol AUC (~32.5%) and Cmax (~41%) in angina patients | See Special warnings and precautions for use section |
| Propranolol | ↑ propranolol AUC (~65%) and Cmax (~94%) in angina patients | |
| Cardiac glycosides | ||
| Digitoxin | ↓ digitoxin total body clearance (~27%) and extrarenal clearance (~29%) | |
| Digoxin | Healthy subjects: ↑ Cmax (~44%) ↑ digoxin C12h (~53%) ↑ Css (~44%) and ↑ AUC (~50%) | Reduce digoxin dosage. Also see Special Warnings and Precautions for Use Section |
| H2 Receptor Antagonists | ||
| Cimetidine | ↑ AUC of R(~25%) and S(~40%) verapamil with corresponding ↓ in R‐and Sverapamil clearance | Cimetidine reduces verapamil clearance following intravenous verapamil administration. |
| Immunologics/Immuno-suppres sives | ||
| Ciclosporin | ↑ ciclosporin AUC, Css, Cmax by ~45% | |
| Everolimus | Everolimus: ↑ AUC (~3.5-fold) and ↑ Cmax (~2.3-fold) Verapamil: ↑ Ctrough (~2.3‐fold) | Concentration determinations and dose adjustments of everolimus may be necessary. |
| Sirolimus | Sirolimus ↑ AUC (~2.2‐fold); Sverapamil ↑ AUC (~1.5‐fold) | Concentration determinations and dose adjustments of sirolimus may be necessary. |
| Tacrolimus | Possible ↑ tacrolimus levels | |
| Lipid lowering agents (HMG COA reductase inhibitors) | ||
| Atorvastatin | Possible ↑ atorvastatin levels Increase verapamil AUC (~43%) | Additional information follows |
| Lovastatin | Possible ↑ lovastatin levels ↑ verapamil AUC (~63%) and Cmax (~32%) | |
| Simvastatin | ↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold) | |
| Serotonin receptor agonists | ||
| Almotriptan | ↑ almotriptan AUC (~20%) ↑ Cmax (~24%) | |
| Uricosurics | ||
| Sulfinpyrazone | ↑ verapamil oral clearance (~3‐fold) ↓ bioavailability (~60%) | Blood pressure lowering effect may be reduced. |
| No change in PK with intravenous verapamil administration | ||
| Anticoagulants | ||
| Dabigatran | Verapamil immediate release ↑ dabigatran (Cmax up to 180%) and AUC (up to 150%) Verapamil sustained release ↑ dabigatran (Cmax up to 90%) and AUC (up to 70%) | The risk of bleeding may increase. The dose of dabigatran with oral verapamil may need to be reduced. (See dabigatran label for dosing instructions). |
| Other direct oral anticoagulants (DOACs) | Increased absorption of DOACs since they are P‐gp substrates and, if applicable, also reduced elimination of DOACs which are metabolized by Cyp 3A4, may increase the systemic bioavailability of DOACs. | Some data suggest a possible increase of the risk of bleeding, especially in patients with further risk factors (see DOAC label for further information). |
| Other Cardiac therapy | ||
| Ivabradine | Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of verapamil to ivabradine | See section Contraindications |
| Other | ||
| Grapefruit juice | ↑ R‐(~49%) and S‐(~37%) verapamil AUC ↑ R‐(~75%) and S‐(~51%) verapamil Cmax | Elimination half‐life and renal clearance not affected. Grapefruit juice should therefore not be ingested with verapamil. |
| St. John’s Wort | ↓ R‐(~78%) and S‐(~80%) verapamil AUC with corresponding reductions in Cmax | |
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.
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 stable oral lithium. Patients receiving both drugs should be monitored carefully.
Clinical data and animal studies suggest that verapamil hydrochloride may potentiate the activity of neuromuscular blocking agents (curare‐like and depolarizing). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
Increased tendency to bleed.
Elevation of ethanol plasma levels.
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. Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.
Potentiation of the hypotensive effect.
As verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein‐bound drugs.
When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil hydrochloride injection, should each be titrated carefully to avoid excessive cardiovascular depression.
There are no adequate and well‐controlled study data in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Because animal reproduction studies are not always predictive of human response, during pregnancy (especially in the first trimester), verapamil should only be used if considered essential by the physician.
Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Verapamil hydrochloride/metabolites are excreted in human 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.
A risk to the newborns/infants cannot be excluded. 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.
Due to its antihypertensive effect, depending on the individual response, verapamil hydrochloride may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug and in conjunction with alcohol. Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.
The following adverse events reactions have been reported with verapamil from clinical studies, postmarketing surveillance or Phase IV clinical trials and are listed below by system organ class.
Frequencies are defined as: 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, gastrointestinal disorders: nausea, constipation and abdominal pain, bradycardia, tachycardia, palpitations, hypotension, flushing, oedema peripheral, fatigue.
Adverse reactions reported from clinical studies with verapamil and post-marketing surveillance activities:
| MedDRA System Organ Class | Common | Uncommon | Rare | Unknown |
|---|---|---|---|---|
| Immune system disorders | Hypersensitivity | |||
| Nervous system disorders | Dizziness, Headache | Paresthesia, Tremor | Extrapyramidal disorder, paralysis (tetraparesis)1, Seizures | |
| Metabolism and nutrition disorders | Hyperkalaemia | |||
| Psychiatric disorders | Somnolence | Nervousness | ||
| Ear and labyrinth disorders | Tinnitus | Vertigo | ||
| Cardiac disorders | Bradycardia | Palpitations, Tachycardia | Atrioventricular block (1°, 2°, 3°), Cardiac failure, Cardiac arrest, Bradyarrhythmia, Sinus arrest, Sinus bradycardia; asystole | |
| Vascular disorders | Flushing, Hypotension | Vasodilation, Erythromelalgia | ||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm, Dyspnoea | |||
| Gastrointestinal disorders | Constipation, Nausea | Abdominal pain | Vomiting | Abdominal discomfort, Gingival hyperplasia, Ileus |
| Skin and subcutaneous tissue disorders | Hyperhidrosis | Angioedema, Stevens‐Johnson syndrome, Erythema multiforme, Alopecia, Itching, Pruritus, Purpura, Rash maculopapular, Urticaria, Rash, Erythema | ||
| Musculoskeletal and connective tissue disorders | Arthralgia, Muscular weakness, Myalgia | |||
| Renal and urinary disorders | Renal failure | |||
| Reproductive system and breast disorders | Erectile dysfunction, Galactorrhea, Gynecomastia | |||
| General disorders and administration site conditions | Oedema peripheral | Fatigue | ||
| Investigations | Blood prolactin increased, Transaminases increased, Blood alkaline phosphatase increased, Hepatic enzymes increased |
1 There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood‐brain barrier due to CYP3A4 and P‐gp inhibition by verapamil. See Interactions with other medicinal products and other forms of interaction section.
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 HPRA Pharmacovigilance, Website: www.hpra.ie.
Not applicable.
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