Isoptin 2.5mg/ml soIution for injection or infusion

  • Name:

    Isoptin 2.5mg/ml soIution for injection or infusion

  • Company:
    info
  • Active Ingredients:

    verapamil hydrochloride

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

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

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

Updated on 20 March 2020 PIL

Reasons for updating

  • Change to section 2 - excipient warnings
  • 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 2 June 2017

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 2 June 2017 SPC

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 not be renewed (A)

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 31 May 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 27 October 2016 SPC

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

Legal category: Product subject to medical prescription which may not be renewed (A)

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 intravenous beta-adrenergic blocking drugs. Addition of ivabradine contraindication
- Section 4.4: Addition of Antiarrhythmics, Beta-blockers text. Addition of text regarding life-threatening adverse responses.
- Section 4.5: Addition of Dabigatran and Ivabradine to table. Typographical corrections to table. Addition of Antihypertensives, diuretics, vasodilators text
- Section 4.6: Correction of location of Lactation heading.

Updated on 27 October 2016 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 4 - possible side effects

Updated on 24 October 2016 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 7 August 2015 SPC

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 not be renewed (A)

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 4 August 2015 PIL

Reasons for updating

  • Change to side-effects
  • Addition of information on reporting a side effect.

Updated on 10 April 2015 SPC

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 not be renewed (A)

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 9 April 2015 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 23 April 2014 SPC

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 not be renewed (A)

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 16 April 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions
  • Addition of manufacturer
  • Addition of information on reporting a side effect.

Updated on 26 March 2013 SPC

Reasons for updating

  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 6.1 - Addition of detail 10% after Hydrochloric acid
Section 6.3 - Shelf life reduced from 5 years to 36 months
Section 6.4 - Storage condition change to Do not store above 30C.

Updated on 20 March 2013 PIL

Reasons for updating

  • Change of inactive ingredient
  • Change of manufacturer
  • Change to storage instructions

Updated on 11 February 2013 SPC

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

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

SPC Section 4.2 Posology and method of administration - addition of the following statements:

- Elderly: The dose should be administered over at least 3 minutes to minimise the risk of untoward drug effects.

- The Isoptin ampoule should be checked visually prior to use and must not be used if it does not match the product description (see section 3).


SPC Section 4.3 Contraindications
- addition of the following statement:

- Hypersensitivity to the active substance or to any of the other ingredients.


SPC Section 4.4 Special warnings and precautions for use
- addition of the following statements:

- This medicinal product contains less than 1 mmol sodium (23mg) per 2ml ampoule, i.e. essentially ‘sodium-free’.      

Updated on 7 February 2013 PIL

Reasons for updating

  • Change to dosage and administration

Updated on 13 October 2011 PIL

Reasons for updating

  • Change due to user-testing of patient information

Updated on 12 August 2011 SPC

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 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.2 - Incompatibilities
  • 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 not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 1: The name of the product has been updated to "Isoptin 2.5mg/ml Solution for Injection or Infusion".
Section 2:  The following has been added "Each ampoule contains 2ml of solution containing 5ml of verapamil hydrochloride. "
"For excipients, see 6.1" has been changed to "For a full list of excipients, see section 6.1."
Section 3: Solution for injection" has been updated to "Solution for injection or infusion".
Section 4.4:  The following has been added:

"Renal Failure

Although impaired renal function has been shown in robust comparatorstudies 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.

Other

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)."

Section 5.1: Pharmacotherapeutic group has been added.
Section 6.4: "Keep the ampoules in the outer carton" has been updated to "Keep the ampoules in the outer carton in order to protect from light."

Updated on 19 April 2010 PIL

Reasons for updating

  • Change to side-effects
  • Change to drug interactions

Updated on 24 February 2010 SPC

Reasons for updating

  • 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 not be renewed (A)

Free text change information supplied by the pharmaceutical company



4.5.      Interactions with other medicinal products and other forms of interaction

 

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.

 

When given in combination with quinidine to patients with hypertrophic obstructive cardiomyopathy, single cases of hypotension and pulmonary oedema have been observed under treatment with oral Isoptin.  Also after intravenous administration of Isoptin, hypotensive reactions have been observed in individual patients receiving quinidine therapy. 

 

The effect of muscle relaxants may be potentiated.  Rises in digoxin plasma levels under concomitant administration of verapamil have been reported.

 

The following table provides a list of potential interactions with verapamil:

 

 

 

 

Concomitant drug

Potential effect on verapamil or concomitant drug

Comment

Alpha blockers

Prazosin

↑ prazosin Cmax (~40%) with no effect on half-life

 

Terazosin

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

Antiarrhythmics

Flecainide

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

 

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 adminisatration

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

 

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%

 

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).

 

Cimetidine:   Cimetidine reduces verapamil clearance following intravenous verapamil administration.

 

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.

 

Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated.

Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic 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.

 

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

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Aspirin:  increased tendency to bleed

 

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.

 

 

 

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 Injection should only be given if considered essential by the physician.

 

Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

 

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. However, there are currently no reports of verapamil injection or infusion use during 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 verapamil injection. 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

Convulsion

Somnolence

Paraesthesia

Extrapyramidal disorder

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Atrioventricular block (1°, 2°, 3°)

Sinus bradycardia

Sinus arrest

Cardiac arrest

Bradyarrhythmia

Tachycardia

Cardiac failure

Vascular disorders

Hypotension

Vasodilatation

Flushing

Erythromelalgia

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Nausea

Constipation

Gingival hyperplasia

Abdominal discomfort

Hepatobiliary disorders

Hepatitis

Skin and subcutaneous tissue disorders

Angioedema

Stevens-Johnson syndrome

Erythema multiforme

Hyperhidrosis

Urticaria

Pruritus

Rash

Erythema

Musculoskeletal and connective tissue disorders

Myalgia

Arthralgia

Reproductive system and breast disorders

Gynaecomastia

 

General disorders and administration site conditions

Oedema peripheral

Fatigue

Investigations

Transaminases increased

Blood alkaline phosphatase increased

Blood prolactin increased

 

 

 

Updated on 3 August 2009 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 8 July 2009 SPC

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 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 not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.5.      Interactions with other medicinal products and other forms of interaction

 

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.

 

When given in combination with quinidine to patients with hypertrophic obstructive cardiomyopathy, single cases of hypotension and pulmonary oedema have been observed under treatment with oral Isoptin.  Also after intravenous administration of Isoptin, hypotensive reactions have been observed in individual patients receiving quinidine therapy. 

 

The effect of muscle relaxants may be potentiated.  Rises in digoxin plasma levels under concomitant administration of verapamil have been reported.

 

The following table provides a list of potential interactions with verapamil:

 

 

 

 

Concomitant drug

Potential effect on verapamil or concomitant drug

Comment

Alpha blockers

Prazosin

↑ prazosin Cmax (~40%) with no effect on half-life

 

Terazosin

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

Antiarrhythmics

Flecainide

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

 

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 adminisatration

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

 

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%

 

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).

 

Cimetidine:  Cimetidine has no effect on intravenous verapamil hydrochloride kinetics. Cimetidine reduces verapamil clearance following intravenous verapamil administration.

 

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.

 

Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated.

Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic 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.

 

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

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Aspirin:  increased tendency to bleed

 

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), severe tachycardia, 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 and abdominal discomfort have 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 ,  nervousness, diaphoresis, and seizures and extrapyramidal syndrome have been reported.

 

Respiratory

In rare cases of hypersensitivity, bronchospasm (accompanied by pruritus and urticaria) have been reported.

 

Neuromuscular

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

 

Skin

Exanthema, erythema, pruritus, urticaria, Quincke’s oedema and Stevens-Johnson syndrome have 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.



 

4.9.      Overdose

 

The usual intensive care measures should be taken.  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.

 

Fatalities have occurred as a result of overdose.




9.         DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

3 May 2002 April 2005

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

August 2008 June 2009

Updated on 23 April 2007 PIL

Reasons for updating

  • Change to drug interactions

Updated on 20 April 2007 PIL

Reasons for updating

  • New PIL for new product

Updated on 12 April 2007 SPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 12 April 2007 SPC

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 not be renewed (A)

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