Isoptin 40mg Film-coated Tablets

  • Name:

    Isoptin 40mg Film-coated Tablets

  • Company:
    info
  • Active Ingredients:

    verapamil hydrochloride

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 20/03/20

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Summary of Product Characteristics last updated on medicines.ie: 20/3/2020

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Mylan IRE Healthcare Limited

Mylan IRE Healthcare Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 20 March 2020 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 20 March 2020 PIL

Reasons for updating

  • Change to section 2 - excipient warnings
  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects
  • Change to section 5 - how to store or dispose
  • Change to section 6 - date of revision

Updated on 19 June 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to MA holder contact details

Updated on 2 June 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 2 June 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited
Unit 35/36
Grange Parade
Baldoyle Industrial Estate
Dublin 13
Ireland
BGP Products Ireland Limited
4051 Kingswood Drive
Citywest Business Campus
Dublin 24
Ireland



10. DATE OF REVISION OF THE TEXT

October 2016May 2017

Updated on 2 June 2017 PIL

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited
Unit 35/36
Grange Parade
Baldoyle Industrial Estate
Dublin 13
Ireland
BGP Products Ireland Limited
4051 Kingswood Drive
Citywest Business Campus
Dublin 24
Ireland



10. DATE OF REVISION OF THE TEXT

October 2016May 2017

Updated on 31 May 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 27 October 2016 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

- Section 4.1: Addition of LGL syndrome
- Section 4.3: Addition of note regarding pacemakers in sick-sinus syndrome. Addition of ivabradine contraindication
- Section 4.4: Addition of Antiarrhythmics, Beta-blockers text. Deletion of hypotension text.
- Section 4.5: Addition of Dabigatran and Ivabradine to table. Typographical corrections to table. Addition of Dabigatran text.
- Section 4.6: Correction of location of Lactation heading.
- Section 4.8: Correction of typographical error. 

Updated on 27 October 2016 PIL

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company

- Section 4.1: Addition of LGL syndrome
- Section 4.3: Addition of note regarding pacemakers in sick-sinus syndrome. Addition of ivabradine contraindication
- Section 4.4: Addition of Antiarrhythmics, Beta-blockers text. Deletion of hypotension text.
- Section 4.5: Addition of Dabigatran and Ivabradine to table. Typographical corrections to table. Addition of Dabigatran text.
- Section 4.6: Correction of location of Lactation heading.
- Section 4.8: Correction of typographical error. 

Updated on 7 August 2015 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

- In section 4.8, hyperkalaamia, dyspnoea and renal failure have been added
- In section 4.8, the details for reporting a side effect have been updated

Updated on 7 August 2015 PIL

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Free text change information supplied by the pharmaceutical company

- In section 4.8, hyperkalaamia, dyspnoea and renal failure have been added
- In section 4.8, the details for reporting a side effect have been updated

Updated on 10 April 2015 PIL

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number

Free text change information supplied by the pharmaceutical company

Section 7: Marketing authorisation holder changed from Abbott Laboratories Ireland Ltd. to BGP Products Ireland Limited
Section 8: PA number updated

Updated on 10 April 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 7: Marketing authorisation holder changed from Abbott Laboratories Ireland Ltd. to BGP Products Ireland Limited
Section 8: PA number updated

Updated on 23 April 2014 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Free text change information supplied by the pharmaceutical company

Significant changes in:-
Section 4.2: Posology and method of administration
Section 4.3: Contraindications
Section 4.4: Special warnings and precautions for use
Section 4.5: Interactions with other medicinal products and other forms of interaction
Section 4.6: Fertility, pregnancy and lactation
Section 4.7: Effects on ability to drive and use machines
Section 4.8: Undesirable effects
Section 4.9: Overdose
Section 5.1: Pharmacodynamic properties
Section 5.2: Pharmacokinetic properties
Section 5.3: Preclinical safety data

Updated on 23 April 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Significant changes in:-
Section 4.2: Posology and method of administration
Section 4.3: Contraindications
Section 4.4: Special warnings and precautions for use
Section 4.5: Interactions with other medicinal products and other forms of interaction
Section 4.6: Fertility, pregnancy and lactation
Section 4.7: Effects on ability to drive and use machines
Section 4.8: Undesirable effects
Section 4.9: Overdose
Section 5.1: Pharmacodynamic properties
Section 5.2: Pharmacokinetic properties
Section 5.3: Preclinical safety data

Updated on 12 February 2013 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications

Free text change information supplied by the pharmaceutical company

SPC Section 4.2 Posology and method of administration

- addition of the statement: Isoptin 40mg tablets should be used for patients likely to display a satisfactory response to low doses (e.g., patients with hepatic dysfunction or elderly patients).


SPC Section 4.3 Contraindications

- amendment of the statement "Use in patients who are hypersensitive to the active ingredient." to read "Hypersensitivity to the active substance or to any of the inactive ingredients."

Updated on 12 February 2013 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

SPC Section 4.2 Posology and method of administration

- addition of the statement: Isoptin 40mg tablets should be used for patients likely to display a satisfactory response to low doses (e.g., patients with hepatic dysfunction or elderly patients).


SPC Section 4.3 Contraindications

- amendment of the statement "Use in patients who are hypersensitive to the active ingredient." to read "Hypersensitivity to the active substance or to any of the inactive ingredients."

Updated on 12 August 2011 PIL

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Section 2:  "For excipients, see 6.1" has been changed to "For a full list of excipients, see section 6.1."
Section 3: The following has been added "embossed "40" on one side and embossed with a triangle on the other side."
Section 4.4:  The following has been added:
"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."
Section 5.1: Pharmacotherapeutic group has been added.
Section 6.1: "Sodium Lauryl Sulphate" has been changed to "Sodium Laurilsulfate"
Section 6.3: The shelf life has bben changed from 5 to 3 years.
Section 6.4: "None necessary" has been changed to "This medicinal product does not require any special storage conditions."

Updated on 12 August 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 2:  "For excipients, see 6.1" has been changed to "For a full list of excipients, see section 6.1."
Section 3: The following has been added "embossed "40" on one side and embossed with a triangle on the other side."
Section 4.4:  The following has been added:
"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."
Section 5.1: Pharmacotherapeutic group has been added.
Section 6.1: "Sodium Lauryl Sulphate" has been changed to "Sodium Laurilsulfate"
Section 6.3: The shelf life has bben changed from 5 to 3 years.
Section 6.4: "None necessary" has been changed to "This medicinal product does not require any special storage conditions."

Updated on 22 February 2010 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

4.4       Special warnings and precautions for use

 

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). 

 

Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.

 

In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending on the severity of the liver disease, due to diminished drug metabolism.  In these patients, dosage interval should be prolonged and low doses used.

 

Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)

 

 

If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdose).

 

Colchicine:

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).

4.5       Interactions with other medicinal products and other forms of interaction

 

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 table provides a list of potential drug 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

Additional information follows

Terazosin

↑ terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmics

Flecainide

Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance

Additional information follows

Quinidine

↓oral quinidine clearance (~35%)

Antiasthmatics

Theophylline

↓oral and systemic CL by ~20%

Reduction of CL was lessened in smokers (~11%)

Anticonvulsants

Carbamazepine

↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients

Additional information follows

Antidepressants

Imipramine

↑ imipramine AUC (~15%)

No effect on level of active metabolite, desipramine

Antidiabetics

Glyburide

↑ glyburide Cmax (~28%), AUC (~26%)

 

Anti-gout agents

Colchicine

Possible ↑ colchicine levels

Additional information follows

Anti-infectives

Clarithromycin

Possible ↑ in verapamil levels

 

Erythromycin

Possible ↑ in verapamil levels

 

Rifampin

↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)

Additional information follows

Telithromycin

Possible ↑in verapamil levels

 

Antineoplastics

Doxorubicin

­ doxorubicin AUC (89%) 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

Additional information follows

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 by ~45-53%

↑ Css by ~42% and ↑ AUC by ~52%

 

H2 Receptor antagonists

Cimetidine

↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance

 

Immunologics

Ciclosporin

↑ ciclosporin AUC, Css, Cmax by ~45%

 

Everolimus

Possible ↑ everolimus levels

 

Sirolimus

Possible ↑ sirolimus levels

 

Tacrolimus

Possible ↑ tacrolimus levels

 

Lipid lowering agents

Atorvastatin

Possible ↑ atorvastatin levels

Increase verapamil AUC (~42.8%)

Additional information follows

 

Lovastatin

Possible ↑ lovastatin levels

Simvastatin

↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)

Serotonin receptor antagonists

Almotriptan

↑ almotriptan AUC (~20%)

↑ Cmax (~24%)

 

Uricosurics

Sulfinpyrazone

↑ verapamil oral clearance (~3-fold)

↓ bioavailability (~60%)

Additional information follows

 

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

 

St. John’s Wort

↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

 

 

 

 

Other Drug Interactions and Additional Drug Interaction Information

 

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. (See Section 4.4, Special Warnings and Special Precautions for Use).

 

Antiarrhythmics, beta-blockers:  mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension)

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

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.

 

Quinidine:  hypotension.  Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

 

Carbamazepine:  increased carbamazepine levels.  This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness.

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Neuromuscular blockers:  the effect of neuromuscular blocking agents may be potentiated.

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  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 orlovastatin), 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.

 

 

4.6       Pregnancy and lactation

 

During pregnancy (especially in the first trimester), Isoptin should only be used if considered essential by the physician.

 

Verapamil 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.

 

4.8       Undesirable effects

 

Adverse reactions have been spontaneously reported during the post-approval use of oral verapamil. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.

 

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

 

System Organ Class

Adverse Event

Immune system disorders

Hypersensitivity

Psychiatric disorders

Nervousness

Nervous system disorders

Headache

Dizziness

Paraesthesia

Tremor

Extrapyramidal disorder

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Atrioventricular block (1°, 2°, 3°)

Sinus bradycardia

Sinus arrest

Cardiac arrest

Bradyarrhythmia

Palpitations

Tachycardia

Cardiac failure

Vascular disorders

Hypotension

Vasodilatation

Flushing

Erythromelalgia

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Ileus

Gingival hyperplasia

Abdominal pain

Abdominal discomfort

Skin and subcutaneous tissue disorders

Angioedema

Stevens-Johnson syndrome

Erythema multiforme

Alopecia

Rash maculopapular

Urticaria

Purpura

Pruritus

Rash

Erythema

Musculoskeletal and connective tissue disorders

Muscular weakness

Myalgia

Arthralgia

Reproductive system and breast disorders

Erectile dysfunction

Gynaecomastia

Galactorrhoea

General disorders and administration site conditions

Oedema peripheral

Fatigue

Investigations

Hepatic enzyme increased

Transaminases increased

Blood alkaline phosphatase increased

Blood prolactin increased

 

Updated on 22 February 2010 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company

4.4       Special warnings and precautions for use

 

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). 

 

Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.

 

In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending on the severity of the liver disease, due to diminished drug metabolism.  In these patients, dosage interval should be prolonged and low doses used.

 

Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)

 

 

If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdose).

 

Colchicine:

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).

4.5       Interactions with other medicinal products and other forms of interaction

 

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 table provides a list of potential drug 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

Additional information follows

Terazosin

↑ terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmics

Flecainide

Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance

Additional information follows

Quinidine

↓oral quinidine clearance (~35%)

Antiasthmatics

Theophylline

↓oral and systemic CL by ~20%

Reduction of CL was lessened in smokers (~11%)

Anticonvulsants

Carbamazepine

↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients

Additional information follows

Antidepressants

Imipramine

↑ imipramine AUC (~15%)

No effect on level of active metabolite, desipramine

Antidiabetics

Glyburide

↑ glyburide Cmax (~28%), AUC (~26%)

 

Anti-gout agents

Colchicine

Possible ↑ colchicine levels

Additional information follows

Anti-infectives

Clarithromycin

Possible ↑ in verapamil levels

 

Erythromycin

Possible ↑ in verapamil levels

 

Rifampin

↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)

Additional information follows

Telithromycin

Possible ↑in verapamil levels

 

Antineoplastics

Doxorubicin

­ doxorubicin AUC (89%) 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

Additional information follows

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 by ~45-53%

↑ Css by ~42% and ↑ AUC by ~52%

 

H2 Receptor antagonists

Cimetidine

↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance

 

Immunologics

Ciclosporin

↑ ciclosporin AUC, Css, Cmax by ~45%

 

Everolimus

Possible ↑ everolimus levels

 

Sirolimus

Possible ↑ sirolimus levels

 

Tacrolimus

Possible ↑ tacrolimus levels

 

Lipid lowering agents

Atorvastatin

Possible ↑ atorvastatin levels

Increase verapamil AUC (~42.8%)

Additional information follows

 

Lovastatin

Possible ↑ lovastatin levels

Simvastatin

↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)

Serotonin receptor antagonists

Almotriptan

↑ almotriptan AUC (~20%)

↑ Cmax (~24%)

 

Uricosurics

Sulfinpyrazone

↑ verapamil oral clearance (~3-fold)

↓ bioavailability (~60%)

Additional information follows

 

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

 

St. John’s Wort

↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

 

 

 

 

Other Drug Interactions and Additional Drug Interaction Information

 

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. (See Section 4.4, Special Warnings and Special Precautions for Use).

 

Antiarrhythmics, beta-blockers:  mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension)

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

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.

 

Quinidine:  hypotension.  Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

 

Carbamazepine:  increased carbamazepine levels.  This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness.

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Neuromuscular blockers:  the effect of neuromuscular blocking agents may be potentiated.

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  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 orlovastatin), 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.

 

 

4.6       Pregnancy and lactation

 

During pregnancy (especially in the first trimester), Isoptin should only be used if considered essential by the physician.

 

Verapamil 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.

 

4.8       Undesirable effects

 

Adverse reactions have been spontaneously reported during the post-approval use of oral verapamil. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.

 

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

 

System Organ Class

Adverse Event

Immune system disorders

Hypersensitivity

Psychiatric disorders

Nervousness

Nervous system disorders

Headache

Dizziness

Paraesthesia

Tremor

Extrapyramidal disorder

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Atrioventricular block (1°, 2°, 3°)

Sinus bradycardia

Sinus arrest

Cardiac arrest

Bradyarrhythmia

Palpitations

Tachycardia

Cardiac failure

Vascular disorders

Hypotension

Vasodilatation

Flushing

Erythromelalgia

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Ileus

Gingival hyperplasia

Abdominal pain

Abdominal discomfort

Skin and subcutaneous tissue disorders

Angioedema

Stevens-Johnson syndrome

Erythema multiforme

Alopecia

Rash maculopapular

Urticaria

Purpura

Pruritus

Rash

Erythema

Musculoskeletal and connective tissue disorders

Muscular weakness

Myalgia

Arthralgia

Reproductive system and breast disorders

Erectile dysfunction

Gynaecomastia

Galactorrhoea

General disorders and administration site conditions

Oedema peripheral

Fatigue

Investigations

Hepatic enzyme increased

Transaminases increased

Blood alkaline phosphatase increased

Blood prolactin increased

 

Updated on 6 July 2009 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

4.5       Interactions with other medicinal products and other forms of interaction

 

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 table provides a list of potential drug 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

Additional information follows

Terazosin

↑ terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmics

Flecainide

Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance

Additional information follows

Quinidine

↓oral quinidine clearance (~35%)

Antiasthmatics

Theophylline

↓oral and systemic CL by ~20%

Reduction of CL was lessened in smokers (~11%)

Anticonvulsants

Carbamazepine

↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients

Additional information follows

Antidepressants

Imipramine

↑ imipramine AUC (~15%)

No effect on level of active metabolite, desipramine

Antidiabetics

Glyburide

↑ glyburide Cmax (~28%), AUC (~26%)

 

Anti-gout agents

Colchicine

Possible ↑ colchicine levels

Additional information follows

Anti-infectives

Erythromycin

Possible ↑ in verapamil levels

 

Rifampin

↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)

Additional information follows

Telithromycin

Possible ↑in verapamil levels

 

Antineoplastics

Doxorubicin

­ doxorubicin AUC (89%) 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

Additional information follows

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 by ~45-53%

↑ Css by ~42% and ↑ AUC by ~52%

 

H2 Receptor antagonists

Cimetidine

↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance

 

Immunologics

CyclosporineCiclosporin

cyclosporineciclosporin AUC, Css, Cmax by ~45%

 

Everolimus

Possible everolimus levels

 

Sirolimus

Possible ↑ sirolimus levels

 

Tacrolimus

Possible ↑ tacrolimus levels

 

Lipid lowering agents

Atorvastatin

Possible ↑ atorvastatin levels

Increase verapamil AUC (~42.8%)

Additional information follows

 

Lovastatin

Possible ↑ lovastatin levels

Simvastatin

↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)

Serotonin receptor antagonists

Almotriptan

↑ almotriptan AUC (~20%)

↑ Cmax (~24%)

 

Uricosurics

Sulfinpyrazone

↑ verapamil oral clearance (~3-fold)

↓ bioavailability (~60%)

Additional information follows

 

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

 

St. John’s Wort

↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

 

 

 

 

Other Drug Interactions and Additional Drug Interaction Information

 

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. (See Section 4.4, Special Warnings and Special Precautions for Use).

 

Antiarrhythmics, beta-blockers:  mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension)

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

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.

 

Quinidine:  hypotension.  Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

 

Carbamazepine:  increased carbamazepine levels.  This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness.

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Neuromuscular blockers:  the effect of neuromuscular blocking agents may be potentiated.

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  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.

 

There is no direct in vivo clinical evidence for an interaction between atorvastatin and verapamil, however, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin and 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.

4.8       Undesirable effects

 

Cardiovascular

Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1st, 2nd or 3rd degree AV block or bradyarrhythmia in atrial fibrillation), tachycardia, palpitations, hypotension, development or aggravation of heart failure.  Vasodilation may result in flushing, headache and peripheral oedema.

 

Gastrointestinal tract and liver

Constipation has been reported frequently.  Nausea, vomiting, ileus and abdominal pain/discomfort has also been reported.  On rare occasions, gingival hyperplasia, which is fully reversible when the drug is discontinued, may occur under long-term treatment. A reversible increase in transaminases and/or alkaline phosphatase, which is probably a sign of allergic hepatitis, has also been reported.

 

Central Nervous System

Vertigo, dizziness, headache, fatigue, tremor, and nervousness, tinnitus and extrapyramidal syndrome have been reported.

 

Neuromuscular

In very rare cases, there may be muscular weakness or myalgia and arthralgia.

 

Skin

Hypersensitivity has been reported following treatment.Exanthema, pruritus, urticaria, erythema, purpura, Quincke’s oedema and Stevens-Johnson syndrome, erythema multiforme and alopecia have also been reported.  In rare cases, erythromelalgia and paraesthesia may occur.

 

Endocrine

In very rare cases, gynaecomastia has been observed, which is fully reversible following discontinuation of treatment.  Rises in prolactin levels have been reported and isolated cases of galactorrhoea.  Impotence has been rarely reported.

4.9       Overdose

 

The usual intensive care measures should be taken. Fatalities have occurred as a result of overdose. Verapamil hydrochloride cannot be removed by haemodialysis. 

 

The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour). The following measures may also be necessary:

 

In the case of 2nd or 3rd degree AV block, sinus bradycardia, asystole:  Atropine, isoprenaline, orciprenaline or pacemaker therapy.

 

In the case of hypotension: Dopamine, dobutamine, norepinephrine.

 

If there are any signs of continuing myocardial failure: Dopamine, dobutamine, if necessary repeated calcium injections, and possibly other medication that increases cardiac contractility combined with isoprenaline.

Isoptin has a marked antiarrhythmic effect, particularly in supraventricular arrhythmias.  It delays impulse conduction in the AV node.  Owing to this, sinus rhythm is restored and/or ventricular rate is normalised, depending on the type of arrhythmia. Normally, the rate is either not affected or only minimally lowered.

 

The antihypertensive effect of Isoptin stems from a decrease in peripheral vascular resistance, without an increase in heart rate as a reflex response.  As early as day 1 of treatment, blood pressure falls; the effect is found to persist also in long-term therapy.

 

5.2.      Pharmacokinetic properties

 

Verapamil is absorbed rapidly and almost exclusively in the small intestine.  The absorption rate is 90-92%.  Half-life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration.  On multiple administration, the half-life of verapamil can be prolonged to about double the value measured after single administration. Peak verapamil hydrochloride plas­ma levels are reached one to two hours after IR administration.

 

Verapamil is metabolised almost completely. The main metabolites are norverapamil and the primary and secondary amines. In animal studies, only norverapamil showed any appreciable pharmacological activity, while the other metabolites were practically ineffective.

 

Verapamil and its metabolites are excreted primarily in the urine; only 3 to 4% is excreted as unchanged drug.  Within 24 hours 50%, within 48 hours 55-60% and within 5 days 70% of the administered dose is excreted in the urine.  Up to 16% is excreted in the faeces.  Recent findings have shown that there are no differences between the pharmacokinetics of verapamil in persons with healthy kidneys and in patients with terminal renal failure.

 

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.  The concentration curve of verapamil in the plasma is protracted after administration of the sustained-release formulations, and is also flatter and more homogenous than after administration of the instant release formulations.  Plasma protein binding is about 90%.

 

Transfer across the placenta: Verapamil passes the placental barrier; the concentration in the plasma of the umbilical vein blood was between 20 and 92% of the plasma concentration of the mother.

 

Transfer into human milk: Although verapamil is excreted in human milk, the concentrations are so low at therapeutic dose levels that no appreciable pharmacological effect is to be expected in infants.

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

August 2008 June 2009

 
June 2009

Updated on 6 July 2009 PIL

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

4.5       Interactions with other medicinal products and other forms of interaction

 

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 table provides a list of potential drug 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

Additional information follows

Terazosin

↑ terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmics

Flecainide

Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance

Additional information follows

Quinidine

↓oral quinidine clearance (~35%)

Antiasthmatics

Theophylline

↓oral and systemic CL by ~20%

Reduction of CL was lessened in smokers (~11%)

Anticonvulsants

Carbamazepine

↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients

Additional information follows

Antidepressants

Imipramine

↑ imipramine AUC (~15%)

No effect on level of active metabolite, desipramine

Antidiabetics

Glyburide

↑ glyburide Cmax (~28%), AUC (~26%)

 

Anti-gout agents

Colchicine

Possible ↑ colchicine levels

Additional information follows

Anti-infectives

Erythromycin

Possible ↑ in verapamil levels

 

Rifampin

↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)

Additional information follows

Telithromycin

Possible ↑in verapamil levels

 

Antineoplastics

Doxorubicin

­ doxorubicin AUC (89%) 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

Additional information follows

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 by ~45-53%

↑ Css by ~42% and ↑ AUC by ~52%

 

H2 Receptor antagonists

Cimetidine

↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance

 

Immunologics

CyclosporineCiclosporin

cyclosporineciclosporin AUC, Css, Cmax by ~45%

 

Everolimus

Possible everolimus levels

 

Sirolimus

Possible ↑ sirolimus levels

 

Tacrolimus

Possible ↑ tacrolimus levels

 

Lipid lowering agents

Atorvastatin

Possible ↑ atorvastatin levels

Increase verapamil AUC (~42.8%)

Additional information follows

 

Lovastatin

Possible ↑ lovastatin levels

Simvastatin

↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)

Serotonin receptor antagonists

Almotriptan

↑ almotriptan AUC (~20%)

↑ Cmax (~24%)

 

Uricosurics

Sulfinpyrazone

↑ verapamil oral clearance (~3-fold)

↓ bioavailability (~60%)

Additional information follows

 

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

 

St. John’s Wort

↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

 

 

 

 

Other Drug Interactions and Additional Drug Interaction Information

 

Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. (See Section 4.4, Special Warnings and Special Precautions for Use).

 

Antiarrhythmics, beta-blockers:  mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension)

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

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.

 

Quinidine:  hypotension.  Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

 

Carbamazepine:  increased carbamazepine levels.  This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness.

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Neuromuscular blockers:  the effect of neuromuscular blocking agents may be potentiated.

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  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.

 

There is no direct in vivo clinical evidence for an interaction between atorvastatin and verapamil, however, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin and 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.

4.8       Undesirable effects

 

Cardiovascular

Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1st, 2nd or 3rd degree AV block or bradyarrhythmia in atrial fibrillation), tachycardia, palpitations, hypotension, development or aggravation of heart failure.  Vasodilation may result in flushing, headache and peripheral oedema.

 

Gastrointestinal tract and liver

Constipation has been reported frequently.  Nausea, vomiting, ileus and abdominal pain/discomfort has also been reported.  On rare occasions, gingival hyperplasia, which is fully reversible when the drug is discontinued, may occur under long-term treatment. A reversible increase in transaminases and/or alkaline phosphatase, which is probably a sign of allergic hepatitis, has also been reported.

 

Central Nervous System

Vertigo, dizziness, headache, fatigue, tremor, and nervousness, tinnitus and extrapyramidal syndrome have been reported.

 

Neuromuscular

In very rare cases, there may be muscular weakness or myalgia and arthralgia.

 

Skin

Hypersensitivity has been reported following treatment.Exanthema, pruritus, urticaria, erythema, purpura, Quincke’s oedema and Stevens-Johnson syndrome, erythema multiforme and alopecia have also been reported.  In rare cases, erythromelalgia and paraesthesia may occur.

 

Endocrine

In very rare cases, gynaecomastia has been observed, which is fully reversible following discontinuation of treatment.  Rises in prolactin levels have been reported and isolated cases of galactorrhoea.  Impotence has been rarely reported.

4.9       Overdose

 

The usual intensive care measures should be taken. Fatalities have occurred as a result of overdose. Verapamil hydrochloride cannot be removed by haemodialysis. 

 

The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour). The following measures may also be necessary:

 

In the case of 2nd or 3rd degree AV block, sinus bradycardia, asystole:  Atropine, isoprenaline, orciprenaline or pacemaker therapy.

 

In the case of hypotension: Dopamine, dobutamine, norepinephrine.

 

If there are any signs of continuing myocardial failure: Dopamine, dobutamine, if necessary repeated calcium injections, and possibly other medication that increases cardiac contractility combined with isoprenaline.

Isoptin has a marked antiarrhythmic effect, particularly in supraventricular arrhythmias.  It delays impulse conduction in the AV node.  Owing to this, sinus rhythm is restored and/or ventricular rate is normalised, depending on the type of arrhythmia. Normally, the rate is either not affected or only minimally lowered.

 

The antihypertensive effect of Isoptin stems from a decrease in peripheral vascular resistance, without an increase in heart rate as a reflex response.  As early as day 1 of treatment, blood pressure falls; the effect is found to persist also in long-term therapy.

 

5.2.      Pharmacokinetic properties

 

Verapamil is absorbed rapidly and almost exclusively in the small intestine.  The absorption rate is 90-92%.  Half-life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration.  On multiple administration, the half-life of verapamil can be prolonged to about double the value measured after single administration. Peak verapamil hydrochloride plas­ma levels are reached one to two hours after IR administration.

 

Verapamil is metabolised almost completely. The main metabolites are norverapamil and the primary and secondary amines. In animal studies, only norverapamil showed any appreciable pharmacological activity, while the other metabolites were practically ineffective.

 

Verapamil and its metabolites are excreted primarily in the urine; only 3 to 4% is excreted as unchanged drug.  Within 24 hours 50%, within 48 hours 55-60% and within 5 days 70% of the administered dose is excreted in the urine.  Up to 16% is excreted in the faeces.  Recent findings have shown that there are no differences between the pharmacokinetics of verapamil in persons with healthy kidneys and in patients with terminal renal failure.

 

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.  The concentration curve of verapamil in the plasma is protracted after administration of the sustained-release formulations, and is also flatter and more homogenous than after administration of the instant release formulations.  Plasma protein binding is about 90%.

 

Transfer across the placenta: Verapamil passes the placental barrier; the concentration in the plasma of the umbilical vein blood was between 20 and 92% of the plasma concentration of the mother.

 

Transfer into human milk: Although verapamil is excreted in human milk, the concentrations are so low at therapeutic dose levels that no appreciable pharmacological effect is to be expected in infants.

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

August 2008 June 2009

 
June 2009

Updated on 12 April 2007 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Change to section 4.4

Special Warnings and Precautions for Use

Addition of colchicine precaution

 

Change to section 4.5

Interactions with other medicinal products and other forms of interaction.

Section has been completely revised and potential interactions tabulated.  Interaction information for doxorubicin, colchicine and statins have been added.

 

Change to section 4.8

Undesirable effects

Additional undesirable effects added

 

Change to section 4.9      

Overdose

Statement that verapamil cannot be removed by haemodialysis added

Updated on 12 April 2007 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose

Free text change information supplied by the pharmaceutical company

Change to section 4.4

Special Warnings and Precautions for Use

Addition of colchicine precaution

 

Change to section 4.5

Interactions with other medicinal products and other forms of interaction.

Section has been completely revised and potential interactions tabulated.  Interaction information for doxorubicin, colchicine and statins have been added.

 

Change to section 4.8

Undesirable effects

Additional undesirable effects added

 

Change to section 4.9      

Overdose

Statement that verapamil cannot be removed by haemodialysis added

Updated on 21 February 2006 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 21 February 2006 PIL

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.6 - Special precautions for disposal and other handling

Updated on 27 June 2003 PIL

Reasons for updating

  • New SPC for medicines.ie

Updated on 27 June 2003 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)