Isoptin 80mg Film-coated 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
ie-pl-isoptin-40mg-80mg-maht-clean.pdf
Reasons for updating
- Change to section 6 - marketing authorisation holder
- Change to section 6 - marketing authorisation number
Updated on 08 July 2024
File name
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Reasons for updating
- 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 07 September 2021
File name
ie-pl-isoptin-40mg-80mg-art613-07Sep2021-clean.pdf
Reasons for updating
- Removal of one or more presentations from joint PIL
Updated on 06 May 2021
File name
ie-pl-isoptin-40mg-80mg-120mg-TIA-delete AbbVie-clean.pdf
Reasons for updating
- Change to section 6 - manufacturer
- Change to section 6 - date of revision
Updated on 28 January 2021
File name
ie-spc-isoptin-80mg-TIB-PRAC-clean.pdf
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
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 28 January 2021
File name
ie-spc-isoptin-80mg-TIB-PRAC-clean.pdf
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 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 28 January 2021
File name
ie-pl-isoptin-40mg-80mg-120mg-TIB-PRAC-clean.pdf
Reasons for updating
- 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
ie-spc-isoptin-80mg-crn009F2M-clean.pdf
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 5.3 - Preclinical safety data
- Change to section 6.6 - Special precautions for disposal and other handling
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 20 March 2020
File name
ie-pl-isoptin-40mg-80mg-120mg-crn009F2M-clean.pdf
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
File name
IE-PIL-Isoptin 40mg 80mg 120mg-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 02 June 2017
Reasons for updating
- Change to section 7 - Marketing authorisation holder
- Change to section 10 - Date of revision of the text
Free text change information supplied by the pharmaceutical company
7. MARKETING AUTHORISATION HOLDER
Mylan IRE Healthcare Limited
Unit 35/36
Grange Parade
Baldoyle Industrial Estate
Dublin 13
Ireland
BGP Products Ireland Limited
4051 Kingswood Drive
Citywest Business Campus
Dublin 24
Ireland
10. DATE OF REVISION OF THE TEXT
October 2016May 2017
Updated on 31 May 2017
File name
PIL_11991_802.pdf
Reasons for updating
- New PIL for new product
Updated on 27 October 2016
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- 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
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 text regarding using other formulations for higher doses.
- Section 4.3: Addition of note regarding pacemakers in sick-sinus syndrome. Addition of ivabradine contraindication
- Section 4.4: Addition of Antiarrhythmics, Beta-blockers text. Deletion of hypotension text.
- Section 4.5: Addition of Dabigatran and Ivabradine to table. Typographical corrections to table. Addition of Dabigatran text.
- Section 4.6: Correction of location of Lactation heading.
Updated on 27 October 2016
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- 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
Free text change information supplied by the pharmaceutical company
- Section 4.2: Correction of text regarding using other formulations for higher doses.
- Section 4.3: Addition of note regarding pacemakers in sick-sinus syndrome. Addition of ivabradine contraindication
- Section 4.4: Addition of Antiarrhythmics, Beta-blockers text. Deletion of hypotension text.
- Section 4.5: Addition of Dabigatran and Ivabradine to table. Typographical corrections to table. Addition of Dabigatran text.
- Section 4.6: Correction of location of Lactation heading.
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 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
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 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 10 April 2015
Reasons for updating
- Change to section 7 - Marketing authorisation holder
- Change to section 8 - MA number
Free text change information supplied by the pharmaceutical company
Section 7: Marketing authorisation holder changed from Abbott Laboratories Ireland Ltd. to BGP Products Ireland Limited
Section 8: PA number updated
Updated on 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)
Free text change information supplied by the pharmaceutical company
Section 4.2: Posology and method of administration
Section 4.3: Contraindications
Section 4.4: Special warnings and precautions for use
Section 4.5: Interactions with other medicinal products and other forms of interaction
Section 4.6: Fertility, pregnancy and lactation
Section 4.7: Effects on ability to drive and use machines
Section 4.8: Undesirable effects
Section 4.9: Overdose
Section 5.1: Pharmacodynamic properties
Section 5.2: Pharmacokinetic properties
Section 5.3: Preclinical safety data
Updated on 23 April 2014
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 4.9 - Overdose
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 5.3 - Preclinical safety data
Free text change information supplied by the pharmaceutical company
Section 4.2: Posology and method of administration
Section 4.3: Contraindications
Section 4.4: Special warnings and precautions for use
Section 4.5: Interactions with other medicinal products and other forms of interaction
Section 4.6: Fertility, pregnancy and lactation
Section 4.7: Effects on ability to drive and use machines
Section 4.8: Undesirable effects
Section 4.9: Overdose
Section 5.1: Pharmacodynamic properties
Section 5.2: Pharmacokinetic properties
Section 5.3: Preclinical safety data
Updated on 12 February 2013
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
Legal category:Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
SPC Section 4.2 Posology and method of administration
- addition of the statement: Isoptin 40mg tablets should be used for patients likely to display a satisfactory response to low doses (e.g., patients with hepatic dysfunction or elderly patients).
SPC Section 4.3 Contraindications
- amendment of the statement "Use in patients who are hypersensitive to the active ingredient." to read "Hypersensitivity to the active substance or to any of the inactive ingredients."
Updated on 12 February 2013
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
Free text change information supplied by the pharmaceutical company
SPC Section 4.2 Posology and method of administration
- addition of the statement: Isoptin 40mg tablets should be used for patients likely to display a satisfactory response to low doses (e.g., patients with hepatic dysfunction or elderly patients).
SPC Section 4.3 Contraindications
- amendment of the statement "Use in patients who are hypersensitive to the active ingredient." to read "Hypersensitivity to the active substance or to any of the inactive ingredients."
Updated on 12 August 2011
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 6.3 - Shelf life
- Change to section 6.4 - Special precautions for storage
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
Section 2: "For excipients, see 6.1" has been changed to "For a full list of excipients, see section 6.1."
Section 3: The following has been added "embossed "80" on one side and 'Knoll' above the scireline on the other side. The scoreline is to allow breaking for ease of swallowing"
Section 4.4: The following has been added:
"Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis."
Section 5.1: Pharmacotherapeutic group has been added.
Section 6.1: "Sodium Lauryl Sulphate" has been changed to "Sodium Laurilsulfate"
Section 6.3: The shelf life has bben changed from 5 to 3 years.
Section 6.4: "None necessary" has been changed to "This medicinal product does not require any special storage conditions."
Updated on 12 August 2011
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 6.3 - Shelf life
- Change to section 6.4 - Special precautions for storage
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
Free text change information supplied by the pharmaceutical company
Section 2: "For excipients, see 6.1" has been changed to "For a full list of excipients, see section 6.1."
Section 3: The following has been added "embossed "80" on one side and 'Knoll' above the scireline on the other side. The scoreline is to allow breaking for ease of swallowing"
Section 4.4: The following has been added:
"Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis."
Section 5.1: Pharmacotherapeutic group has been added.
Section 6.1: "Sodium Lauryl Sulphate" has been changed to "Sodium Laurilsulfate"
Section 6.3: The shelf life has bben changed from 5 to 3 years.
Section 6.4: "None necessary" has been changed to "This medicinal product does not require any special storage conditions."
Updated on 22 February 2010
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
Legal category:Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
Patients with heart failure or those who are susceptible to heart failure should be fully digitalised before verapamil therapy as it may aggravate or precipitate cardiac failure.
Great care should be taken in:
First degree AV block, bradycardia < 50 beats/min, hypotension < 90 mmHg systolic and ventricular tachycardias (QRS complex > 0.12 sec).
Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.
In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending on the severity of the liver disease, due to diminished drug metabolism. In these patients, dosage interval should be prolonged and low doses used.
Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)
If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdosage).
Colchicine:
There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended. (see Section 4.5, Drug Interactions).
4.5 Interactions with other medicinal products and other forms of interaction
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following table provides a list of potential drug interactions with verapamil:
Potential Drug Interactions associated with Verapamil
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 |
||
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 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.
During pregnancy (especially in the first trimester), Isoptin should only be used if considered essential by the physician.
Verapamil is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother’s oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.
4.8 Undesirable effects
Adverse reactions have been spontaneously reported during the post-approval use of oral verapamil. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.
Significant adverse events reported with verapamil are listed below by system organ class:
System Organ Class |
Adverse Event |
Immune system disorders |
Hypersensitivity |
Psychiatric disorders |
Nervousness |
Nervous system disorders |
Headache Dizziness Paraesthesia Tremor Extrapyramidal disorder |
Ear and labyrinth disorders |
Vertigo Tinnitus |
Cardiac disorders |
Atrioventricular block (1°, 2°, 3°) Sinus bradycardia Sinus arrest Cardiac arrest Bradyarrhythmia Palpitations Tachycardia Cardiac failure |
Vascular disorders |
Hypotension Vasodilatation Flushing Erythromelalgia |
Gastrointestinal disorders |
Nausea Vomiting Constipation Ileus Gingival hyperplasia Abdominal pain Abdominal discomfort |
Skin and subcutaneous tissue disorders |
Angioedema Stevens-Johnson syndrome Erythema multiforme Alopecia Rash maculopapular Urticaria Purpura Pruritus Rash Erythema |
Musculoskeletal and connective tissue disorders |
Muscular weakness Myalgia Arthralgia |
Reproductive system and breast disorders |
Erectile dysfunction Gynaecomastia Galactorrhoea |
General disorders and administration site conditions |
Oedema peripheral Fatigue |
Investigations |
Hepatic enzyme increased Transaminases increased Blood alkaline phosphatase increased Blood prolactin increased |
Updated on 22 February 2010
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
Patients with heart failure or those who are susceptible to heart failure should be fully digitalised before verapamil therapy as it may aggravate or precipitate cardiac failure.
Great care should be taken in:
First degree AV block, bradycardia < 50 beats/min, hypotension < 90 mmHg systolic and ventricular tachycardias (QRS complex > 0.12 sec).
Respiratory standstill has been reported for one patient with progressive muscular dystrophy following administration of Isoptin.
In patients with impaired hepatic function, the effect of verapamil is intensified and prolonged, depending on the severity of the liver disease, due to diminished drug metabolism. In these patients, dosage interval should be prolonged and low doses used.
Diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)
If acute cardiovascular side effects arise, treat as for overdose (see Section 4.9, Overdosage).
Colchicine:
There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended. (see Section 4.5, Drug Interactions).
4.5 Interactions with other medicinal products and other forms of interaction
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following table provides a list of potential drug interactions with verapamil:
Potential Drug Interactions associated with Verapamil
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 |
||
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 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.
During pregnancy (especially in the first trimester), Isoptin should only be used if considered essential by the physician.
Verapamil is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1 – 1% of the mother’s oral dose) and that verapamil use may be compatible with breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.
4.8 Undesirable effects
Adverse reactions have been spontaneously reported during the post-approval use of oral verapamil. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.
Significant adverse events reported with verapamil are listed below by system organ class:
System Organ Class |
Adverse Event |
Immune system disorders |
Hypersensitivity |
Psychiatric disorders |
Nervousness |
Nervous system disorders |
Headache Dizziness Paraesthesia Tremor Extrapyramidal disorder |
Ear and labyrinth disorders |
Vertigo Tinnitus |
Cardiac disorders |
Atrioventricular block (1°, 2°, 3°) Sinus bradycardia Sinus arrest Cardiac arrest Bradyarrhythmia Palpitations Tachycardia Cardiac failure |
Vascular disorders |
Hypotension Vasodilatation Flushing Erythromelalgia |
Gastrointestinal disorders |
Nausea Vomiting Constipation Ileus Gingival hyperplasia Abdominal pain Abdominal discomfort |
Skin and subcutaneous tissue disorders |
Angioedema Stevens-Johnson syndrome Erythema multiforme Alopecia Rash maculopapular Urticaria Purpura Pruritus Rash Erythema |
Musculoskeletal and connective tissue disorders |
Muscular weakness Myalgia Arthralgia |
Reproductive system and breast disorders |
Erectile dysfunction Gynaecomastia Galactorrhoea |
General disorders and administration site conditions |
Oedema peripheral Fatigue |
Investigations |
Hepatic enzyme increased Transaminases increased Blood alkaline phosphatase increased Blood prolactin increased |
Updated on 06 July 2009
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 4.9 - Overdose
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Legal category:Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
4.5 Interactions with other medicinal products and other forms of interaction
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following table provides a list of potential drug interactions with verapamil:
Potential Drug Interactions associated with Verapamil
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
Cardiovascular
Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1st, 2nd or 3rd degree AV block or bradyarrhythmia in atrial fibrillation), tachycardia, palpitations, hypotension, development or aggravation of heart failure. Vasodilation may result in flushing, headache and peripheral oedema.
Gastrointestinal tract and liver
Constipation has been reported frequently. Nausea, vomiting, ileus and abdominal pain/discomfort has also been reported. On rare occasions, gingival hyperplasia, which is fully reversible when the drug is discontinued, may occur under long-term treatment. A reversible increase in transaminases and/or alkaline phosphatase, which is probably a sign of allergic hepatitis, has also been reported.
Central Nervous System
Vertigo, dizziness, headache, fatigue, tremor and , nervousness, tinnitus and extrapyramidal syndrome have been reported.
Neuromuscular
In very rare cases, there may be muscular weakness or myalgia and arthralgia.
Skin
Hypersensitivity has been reported following treatment. Exanthema, pruritus, urticaria, erythema, purpura, Quincke’s oedema and, Stevens-Johnson syndrome, erythema multiforme and alopecia have also been reported. In rare cases, erythromelalgia and paraesthesia may occur.
Endocrine
In very rare cases, gynaecomastia has been observed, which is fully reversible following discontinuation of treatment. Rises in prolactin levels have been reported and isolated cases of galactorrhoea. Impotence has been rarely reported.
4.9 Overdosage
The usual intensive care measures should be taken. Fatalities have occurred as a result of overdose.
Verapamil hydrochloride cannot be removed by haemodialysis.
The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour). The following measures may also be necessary:
In the case of 2nd or 3rd degree AV block, sinus bradycardia, asystole: Atropine, isoprenaline, orciprenaline or pacemaker therapy.
In the case of hypotension: Dopamine, dobutamine, norepinephrine.
If there are any signs of continuing myocardial failure: Dopamine, dobutamine, if necessary repeated calcium injections, and possibly other medication that increases cardiac contractility combined with isoprenaline.
5.2 Pharmacokinetic properties
Verapamil is absorbed rapidly and almost exclusively in the small intestine. The absorption rate is 90-92%. Half-life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration. On multiple administration, the half-life of verapamil can be prolonged to about double the value measured after single administration Peak verapamil hydrochloride plasma levels are reached one to two hours after IR administration.
Verapamil is metabolised almost completely. The main metabolites are norverapamil and the primary and secondary amines. In animal studies, only norverapamil showed any appreciable pharmacological activity, while the other metabolites were practically ineffective.
Verapamil and its metabolites are excreted primarily in the urine; only 3 to 4% is excreted as unchanged drug. Within 24 hours 50%, within 48 hours 55-60% and within 5 days 70% of the administered dose is excreted in the urine. Up to 16% is excreted in the faeces. Recent findings have shown that there are no differences between the pharmacokinetics of verapamil in persons with healthy kidneys and in patients with terminal renal failure.
In coronary heart disease and hypertension, no correlation was found between the therapeutic effect and the plasma concentration; a definite correlation with the plasma level was determined only for the effect on the PR interval. The concentration curve of verapamil in the plasma is protracted after administration of the sustained-release formulations, and is also flatter and more homogenous than after administration of the instant release formulations. Plasma protein binding is about 90%.
Transfer across the placenta: Verapamil passes the placental barrier; the concentration in the plasma of the umbilical vein blood was between 20 and 92% of the plasma concentration of the mother.
Transfer into human milk: Although verapamil is excreted in human milk, the concentrations are so low at therapeutic dose levels that no appreciable pharmacological effect is to be expected in infants.
10. DATE OF REVISION OF THE TEXT
August 2008 June 2009
Updated on 06 July 2009
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 4.9 - Overdose
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Free text change information supplied by the pharmaceutical company
4.5 Interactions with other medicinal products and other forms of interaction
In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.
The following table provides a list of potential drug interactions with verapamil:
Potential Drug Interactions associated with Verapamil
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
Cardiovascular
Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1st, 2nd or 3rd degree AV block or bradyarrhythmia in atrial fibrillation), tachycardia, palpitations, hypotension, development or aggravation of heart failure. Vasodilation may result in flushing, headache and peripheral oedema.
Gastrointestinal tract and liver
Constipation has been reported frequently. Nausea, vomiting, ileus and abdominal pain/discomfort has also been reported. On rare occasions, gingival hyperplasia, which is fully reversible when the drug is discontinued, may occur under long-term treatment. A reversible increase in transaminases and/or alkaline phosphatase, which is probably a sign of allergic hepatitis, has also been reported.
Central Nervous System
Vertigo, dizziness, headache, fatigue, tremor and , nervousness, tinnitus and extrapyramidal syndrome have been reported.
Neuromuscular
In very rare cases, there may be muscular weakness or myalgia and arthralgia.
Skin
Hypersensitivity has been reported following treatment. Exanthema, pruritus, urticaria, erythema, purpura, Quincke’s oedema and, Stevens-Johnson syndrome, erythema multiforme and alopecia have also been reported. In rare cases, erythromelalgia and paraesthesia may occur.
Endocrine
In very rare cases, gynaecomastia has been observed, which is fully reversible following discontinuation of treatment. Rises in prolactin levels have been reported and isolated cases of galactorrhoea. Impotence has been rarely reported.
4.9 Overdosage
The usual intensive care measures should be taken. Fatalities have occurred as a result of overdose.
Verapamil hydrochloride cannot be removed by haemodialysis.
The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour). The following measures may also be necessary:
In the case of 2nd or 3rd degree AV block, sinus bradycardia, asystole: Atropine, isoprenaline, orciprenaline or pacemaker therapy.
In the case of hypotension: Dopamine, dobutamine, norepinephrine.
If there are any signs of continuing myocardial failure: Dopamine, dobutamine, if necessary repeated calcium injections, and possibly other medication that increases cardiac contractility combined with isoprenaline.
5.2 Pharmacokinetic properties
Verapamil is absorbed rapidly and almost exclusively in the small intestine. The absorption rate is 90-92%. Half-life values between 3 and 7 hours have been measured for the elimination of unchanged substance from the plasma after single intravenous and oral administration. On multiple administration, the half-life of verapamil can be prolonged to about double the value measured after single administration Peak verapamil hydrochloride plasma levels are reached one to two hours after IR administration.
Verapamil is metabolised almost completely. The main metabolites are norverapamil and the primary and secondary amines. In animal studies, only norverapamil showed any appreciable pharmacological activity, while the other metabolites were practically ineffective.
Verapamil and its metabolites are excreted primarily in the urine; only 3 to 4% is excreted as unchanged drug. Within 24 hours 50%, within 48 hours 55-60% and within 5 days 70% of the administered dose is excreted in the urine. Up to 16% is excreted in the faeces. Recent findings have shown that there are no differences between the pharmacokinetics of verapamil in persons with healthy kidneys and in patients with terminal renal failure.
In coronary heart disease and hypertension, no correlation was found between the therapeutic effect and the plasma concentration; a definite correlation with the plasma level was determined only for the effect on the PR interval. The concentration curve of verapamil in the plasma is protracted after administration of the sustained-release formulations, and is also flatter and more homogenous than after administration of the instant release formulations. Plasma protein binding is about 90%.
Transfer across the placenta: Verapamil passes the placental barrier; the concentration in the plasma of the umbilical vein blood was between 20 and 92% of the plasma concentration of the mother.
Transfer into human milk: Although verapamil is excreted in human milk, the concentrations are so low at therapeutic dose levels that no appreciable pharmacological effect is to be expected in infants.
10. DATE OF REVISION OF THE TEXT
August 2008 June 2009
Updated on 12 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 12 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
Free text change information supplied by the pharmaceutical company
Change to section 4.4
Special Warnings and Precautions for Use
addition of colchicine precaution
Change to section 4.5
Interactions with other medicinal products and other forms of interaction.
Section has been completely revised and potential interactions tabulated. Interaction information for doxorubicin, colchicine and statins have been added.
Change to section 4.8
Undesirable effects
Additional undesirable effects added
Change to section 4.9
Overdose
Statement that verapamil cannot be removed by haemodialysis added
Updated on 21 February 2006
Reasons for updating
- Change to section 1 - Name of medicinal product
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 6.2 - Incompatibilities
- Change to section 6.6 - Special precautions for disposal and other handling
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 21 February 2006
Reasons for updating
- Change to section 1 - Name of medicinal product
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 6.2 - Incompatibilities
- Change to section 6.6 - Special precautions for disposal and other handling
Updated on 27 June 2003
Reasons for updating
- New SPC for medicines.ie
Legal category:Product subject to medical prescription which may be renewed (B)
Updated on 27 June 2003
Reasons for updating
- New SPC for medicines.ie