Isoptin SR 240mg Prolonged Release Tablets
*Company:
Mylan IRE Healthcare LtdStatus:
No Recent UpdateLegal Category:
Product subject to medical prescription which may be renewed (B)Active Ingredient(s):
*Additional information is available within the SPC or upon request to the company
Updated on 08 July 2024
File name
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- Change to section 7 - Marketing authorisation holder
- Change to section 8 - Marketing authorisation number(s)
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 08 July 2024
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- Change to section 6 - marketing authorisation holder
- Change to section 6 - marketing authorisation number
Updated on 11 October 2022
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- Change to section 6 - manufacturer
Updated on 28 January 2021
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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 - how to report a side effect
- Change to section 4.9 - Overdose
- Change to section 10 - Date of revision of the text
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Updated on 28 January 2021
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- 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 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 28 January 2021
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- Change to section 2 - interactions with other medicines, food or drink
- Change to section 4 - how to report a side effect
- Change to section 6 - date of revision
Updated on 20 March 2020
File name
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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
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Updated on 20 March 2020
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- 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
File name
IE-PIL-Isoptin SR 240mg-Famar address-08Jun2018_CRN2207894-emc.pdf
Reasons for updating
- Change to MA holder contact details
- Change to date of revision
Updated on 02 June 2017
Reasons for updating
- New SPC for new product
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 02 June 2017
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
File name
PIL_11932_567.pdf
Reasons for updating
- New PIL for new product
Updated on 31 May 2017
Reasons for updating
- Change to section 6 - marketing authorisation holder
- Change to section 6 - date of revision
Updated on 27 October 2016
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 4.3: 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 27 October 2016
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 13 May 2016
Reasons for updating
- Change to date of revision
Updated on 07 April 2016
Reasons for updating
- Correction of spelling/typing errors
Updated on 04 April 2016
Reasons for updating
- Change of manufacturer
Updated on 11 September 2015
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
Updated on 07 August 2015
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, the details for reporting a side effect have been updated
Updated on 04 August 2015
Reasons for updating
- Change to side-effects
- Addition of information on reporting a side effect.
Updated on 10 April 2015
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
Reasons for updating
- Change to marketing authorisation holder
Updated on 05 January 2015
Reasons for updating
- Change to section 6.3 - Shelf life
Legal category:Product subject to medical prescription which may be renewed (B)
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Updated on 20 June 2014
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
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)
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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
Reasons for updating
- Change to name of manufacturer
Updated on 13 October 2011
Reasons for updating
- Change due to user-testing of patient information
Updated on 21 December 2010
Reasons for updating
- Improved electronic presentation
Updated on 18 August 2010
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
Updated on 17 August 2010
Reasons for updating
- Change to warnings or special precautions for use
- Change to date of revision
Updated on 15 April 2010
Reasons for updating
- Change to warnings or special precautions for use
- Change to drug interactions
Updated on 24 February 2010
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 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 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
Reasons for updating
- Change to side-effects
- Change to date of revision
Updated on 06 July 2009
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
Concomitantdrug |
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 |
||
|
|
↑ |
|
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 05 September 2008
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
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Free text change information supplied by the pharmaceutical company
Broad complex ventricular tachycardia
Somnolence
Neuropathy
Cardiac arrest
Muscular weakness
Myalgia
Updated on 05 September 2008
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to drug interactions
Updated on 03 June 2008
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
Updated on 22 January 2008
Reasons for updating
- Change to section 6.4 - Special precautions for storage
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Updated on 22 January 2008
Reasons for updating
- Change to storage instructions
Updated on 08 January 2008
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
Updated on 18 April 2007
Reasons for updating
- Change to drug interactions
Updated on 13 April 2007
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
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)
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Updated on 23 March 2007
Reasons for updating
- New PIL for new product
Updated on 23 March 2007
Reasons for updating
- Change to packaging
Updated on 16 December 2004
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
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Updated on 27 June 2003
Reasons for updating
- New SPC for medicines.ie
Legal category:Product subject to medical prescription which may be renewed (B)