Isoptin SR 240mg Prolonged Release Tablets

  • Name:

    Isoptin SR 240mg Prolonged Release 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

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 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 MA holder contact details
  • Change to 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 be renewed (B)

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 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 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 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 3 - how to take/use
  • Change to section 4 - possible side effects

Updated on 27 October 2016 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 4.8 - 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

- Section 4.2: Correction of typographical error
- Section 4.3: 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. 
- Section 4.9: Addition of additional symptoms of overdose

Updated on 13 May 2016 PIL

Reasons for updating

  • Change to date of revision

Updated on 7 April 2016 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 4 April 2016 PIL

Reasons for updating

  • Change of manufacturer

Updated on 11 September 2015 SPC

Reasons for updating

  • Correction of spelling/typing errors

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

Free text change information supplied by the pharmaceutical company

Correction of error in section 6.3

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 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 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 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 31 March 2015 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 5 January 2015 SPC

Reasons for updating

  • Change to section 6.3 - Shelf life

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

Free text change information supplied by the pharmaceutical company

In section 6.3, the shelf-life has been reduced to 3 years

Updated on 20 June 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 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 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 29 April 2013 PIL

Reasons for updating

  • Change to name of manufacturer

Updated on 13 October 2011 PIL

Reasons for updating

  • Change due to user-testing of patient information

Updated on 21 December 2010 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 18 August 2010 SPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • 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

In section 4.4 (Special warnings and special precautions for use), a statement has been included regarding the use of verapamil in patients with impaired renal function.

Updated on 17 August 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 15 April 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to drug interactions

Updated on 24 February 2010 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 4.6 - 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 special precautions for use

 

            When treating hypertension, the patient’s blood pressure should be monitored at regular intervals. Care should be taken in patients with:

1st degree AV block

Broad complex ventricular tachycardia

Progressive muscular dystrophy

Bradycardia less than 50 beats/minute

Systolic blood pressure less than 90 mmHg

Atrial fibrillation/flutter

Simultaneous pre-excitation syndrome, e.g. Wolff-Parkinson-White syndrome (risk of inducing ventricular tachycardia)

Uncompensated heart failure (to be treated by the physician before initiating treatment).

Severe hepatic impairment (See Section 4.2)

Intravenous beta-blockers should not be co-administered to patients on sustained release verapamil (except in ICU settings).

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

 

            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 medicaments 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

 

            Isoptin SR 240mg Prolonged-Release Tablets should not be given during pregnancy (especially in the first trimester) unless, in the physician’s judgement, it is essential for the patient’s well-being.

           

There are no adequate data from the use of verapamil hydrochloride in pregnant women.

 

Verapamil crosses the placenta and has been measured in umbilical cord blood.

 

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

Metabolism and nutrition disorders

Glucose tolerance impaired

Psychiatric disorders

Nervousness

Nervous system disorders

Headache

Dizziness

 Paraesthesia
Tremor

Hypoesthesia

Somnolence

Neuropathy peripheral

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

Flushing

Erythromelalgia

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Ileus

Gingival hyperplasia

Abdominal pain

Abdominal discomfort 

Abdominal distension

Skin and subcutaneous tissue disorders

Angioedema

Stevens-Johnson syndrome

Erythema multiforme

Rash maculopapular
Alopecia

Urticaria

Purpura

Pruritus

Photosensitivity reaction

Erythema

Rash

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

Blood prolactin increased

 

Injury, poisoning and procedural complications

Elevated pacing threshold *

 

* This has been reported in patients with pacemakers while on verapamil hydrochloride treatment.

 

Updated on 27 July 2009 PIL

Reasons for updating

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

Updated on 6 July 2009 SPC

Reasons for updating

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

4.5       Interactions with other medicaments 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

 

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

 

System Organ Class

Adverse Event

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Glucose tolerance impaired

Psychiatric disorders

Nervousness

Nervous system disorders

Headache

Dizziness

Paresthesia

Tremor

Hypoesthesia

Somnolence

Neuropathy

Extrapyramidal disorder

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Atrioventricular block (1°, 2°, 3°)

Sinus bradycardia

Sinus arrest

Cardiac arrest

Bradyarrhythmia

Palpitations

Tachycardia

Heart failure may develop or existing heart failure may be exacerbated

Vascular disorders

Hypotension

Flushing

Erythromelalgia

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Ileus

Gingival hyperplasia

Abdominal pain/discomfort 

Abdominal distension

Skin and subcutaneous tissue disorders

Angioedema

Stevens-Johnson syndrome

Erythema multiforme Maculopapular rash

Alopecia

Urticaria

Purpura

Pruritus

Photosensitivity reaction

Erythema

Rash

Musculoskeletal and connective tissue disorders

Muscular weakness

Myalgia

Arthralgia

Reproductive system and breast disorders

Impotence

Gynecomastia

Galactorrhea

General disorders and administration site conditions

Peripheral edema

Fatigue

Investigations

Hepatic enzyme increased

Blood prolactin increased

 

Injury, poisoning and procedural complications

Elevated pacing threshold *

 

* This has been reported in patients with pacemakers while on verapamil hydrochloride treatment.

 

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.

 



 

5.2       Pharmacokinetic properties

 

           

About 92% of verapamil is absorbed rapidly from the small intestine. Mean systemic availability of the unchanged compound after a single dose is 22% owing to an extensive hepatic first pass metabolism. Bioavailability is about 2 times higher with repeated administration.

 

Peak verapamil hydrochloride plasma levels are reached one to two hours after IR administration. The elimination half-life is 3 to 7 hours. Verapamil hydrochloride in plasma is approximately 90% protein bound. The drug is extensively metabolized. A number of metabolites are generated in humans (twelve have been identified). Of these metabolites, only norverapamil has any appreciable pharmacological effect (approximately 20% that of the parent compound), which was observed in a study with dogs.

 

Verapamil hydrochloride and its metabolites are primarily eliminated by the renal route. Only 3 to 4% of the renally excreted drug is eliminated as the unchanged drug. About 50% of the dose is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the faeces. Impaired renal function has no effect on verapamil hydrochloride pharmacokinetics, as shown by comparative studies in patients with end-stage renal failure and subjects with healthy kidneys. The half-life of verapamil is prolonged in patients with impaired liver function owing to lower oral clearance and a higher volume of distribution.

10.       DATE OF REVISION OF THE TEXT

 

            August 2008 June 2009

 

Updated on 5 September 2008 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions

Updated on 5 September 2008 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 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

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

Free text change information supplied by the pharmaceutical company

Section 4.2: added the following
In patients with impaired liver function, metabolism of the drug is delayed to a greater or lesser extent depending on the severity of hepatic dysfunction, thus potentiating and prolonging the effects of verapamil hydrochloride. Therefore, the dosage needs to be adjusted with special caution in patients with impaired liver function and low doses should be given initially.
 
Section 4.3 Added the following
, atrial fibrillation/flutter, concomitant Wolff-Parkinson-White syndrome, untreated decompensated heart failure and sick sinus syndrome
 
Isoptin SR 240mg Prolonged-Release Tablets are contra-indicated for use in patients within 7 days of an acute MI.
 
Section 4.4 Added the following

Broad complex ventricular tachycardia

Progressive muscular dystrophy
Severe hepatic impairment (See Section 4.2)Intravenous beta-blockers should not be co-administered to patients on sustained release verapamil (except in ICU settings).
 
Section 4.6 Added the following
There are no adequate data from the use of verapamil hydrochloride in pregnant or lactating women.Verapamil crosses the placenta and has been measured in umbilical cord blood. 
Verapamil is excreted into breast milk and therefore, breast-feeding should be discontinued while taking verapamil.
 
Section 4.8 Added the following
Glucose tolerance impaired

                        Somnolence

                        Neuropathy

Extrapyramidal disorder
Tinnitus

                        Cardiac arrest

Bradyarrhythmia
Bronchospasm
Vomiting
Abdominal distension,
                        Maculopapular rash
                       Photosensitivity reaction

                        Muscular weakness

                        Myalgia

                        Arthralgia
                        Elevated pacing threshold *
 
Section 4.9 Added the following
Due to the potential for delayed absorption of the sustained release product, patients may require observation and hospitalization for up to 48 hours.
Fatalities have occurred as a result of overdose.
 
Section 5.1 Added the following
ATC Code:  C08DA01
 
Section 5.2 Added description on aborsption of verapamil
 

Updated on 3 June 2008 SPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • 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 3: To add statement' The tablets can be divided into equal halves but must not be crushed or chewed.
Section 10: Date of revison changed to May 2008

Updated on 22 January 2008 SPC

Reasons for updating

  • Change to section 6.4 - Special precautions for storage

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

Free text change information supplied by the pharmaceutical company

Section 6.4 Addition of storage condition

Updated on 22 January 2008 PIL

Reasons for updating

  • Change to storage instructions

Updated on 8 January 2008 SPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 9 - Date of renewal of authorisation

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

Free text change information supplied by the pharmaceutical company

Change to section 1, 2, 4.1,4.3,4.6, 5.1, 5.2: Trade name changed to Isoptin SR 240mg Prolonged Release Tablets.
Change to section 2 : Excipients: Each Prolonged release tablet contains up to 32mg (1.39mmol) Sodium.
Change to section 10:Date of last renewal 07 May 2007
Change to section 9: November 2007

Updated on 18 April 2007 PIL

Reasons for updating

  • Change to drug interactions

Updated on 13 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 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 23 March 2007 SPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

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

Free text change information supplied by the pharmaceutical company

Change to 6.5: Nature and Contents of Container

Updated on 23 March 2007 PIL

Reasons for updating

  • Change to packaging

Updated on 23 March 2007 PIL

Reasons for updating

  • New PIL for new product

Updated on 16 December 2004 SPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 6.1 - List of excipients
  • Change to section 6.5 - Nature and contents of container
  • 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)

Updated on 27 June 2003 SPC

Reasons for updating

  • New SPC for medicines.ie

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