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

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

- Section 4.1: Addition of LGL syndrome
- 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.

- Section 4.1: Addition of LGL syndrome
- 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.

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

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

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

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

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

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

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."

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."

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."

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."

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

 

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 or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.

 

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

 

4.6       Pregnancy and lactation

 

During pregnancy (especially in the first trimester), Isoptin 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

 

 

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

 

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 or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.

 

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

 

4.6       Pregnancy and lactation

 

During pregnancy (especially in the first trimester), Isoptin 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

 

 

4.5       Interactions with other medicinal products and other forms of interaction

 

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp).  Clinically significant  interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

 

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

 

 

Potential Drug Interactions associated with Verapamil

 

Concomitant drug	Potential effect on verapamil or concomitant drug	Comment
Alpha blockers
Prazosin	↑ prazosin Cmax (~40%) with no effect on half-life	Additional information follows
Terazosin	↑ terazosin AUC (~24%) and Cmax (~25%)
Antiarrhythmics
Flecainide	Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance	Additional information follows
Quinidine	↓oral quinidine clearance (~35%)
Antiasthmatics
Theophylline	↓oral and systemic CL by ~20%	Reduction of CL was lessened in smokers (~11%)
Anticonvulsants
Carbamazepine	↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients	Additional information follows
Antidepressants
Imipramine	↑ imipramine AUC (~15%)	No effect on level of active metabolite, desipramine
Antidiabetics
Glyburide	↑ glyburide Cmax (~28%), AUC (~26%)
Anti-gout agents
Colchicine	Possible ↑ colchicine levels	Additional information follows
Anti-infectives
Erythromycin	Possible ↑ in verapamil levels
Rifampin	↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)	Additional information follows
Telithromycin	Possible ↑in verapamil levels
Antineoplastics
Doxorubicin	­ doxorubicin AUC (89%) and Cmax (61%) with oral verapamil administration	In patients with small cell lung cancer
	No significant change in doxorubicin PK with intravenous verapamil administration	In patients with advanced neoplasms
Barbiturates
Phenobarbital	↑ oral verapamil clearance (~5-fold)
Benzodiazepines and other anxiolytics
Buspirone	↑ buspirone AUC, Cmax by ~3.4-fold
Midazolam	↑ midazolam AUC (~3-fold) and Cmax (~2-fold)
Beta blockers
Metoprolol	↑ metoprolol AUC (~32.5%) and Cmax (~41%) in angina patients	Additional information follows
Propranolol	↑ propranolol AUC (~65%) and Cmax (~94%) in angina patients
Cardiac glycosides
Digitoxin	↓digitoxin total body clearance (~27%) and extrarenal clearance (~29%)
Digoxin	Healthy subjects: ↑ Cmax by ~45-53% ↑ Css by ~42% and ↑ AUC by ~52%
H2 Receptor antagonists
Cimetidine	↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance
Immunologics
CyclosporineCiclosporin	↑ cyclosporineciclosporin AUC, Css, Cmax by ~45%
Everolimus	Possible ↑ everolimus levels
Sirolimus	Possible ↑ sirolimus levels
Tacrolimus	Possible ↑ tacrolimus levels
Lipid lowering agents
Atorvastatin	Possible ↑ atorvastatin levels Increase verapamil AUC (~42.8%)	Additional information follows
Lovastatin	Possible ↑ lovastatin levels
Simvastatin	↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)
Serotonin receptor antagonists
Almotriptan	↑ almotriptan AUC (~20%) ↑ Cmax (~24%)
Uricosurics
Sulfinpyrazone	↑ verapamil oral clearance (~3-fold) ↓ bioavailability (~60%)	Additional information follows
Other
Grapefruit juice	↑ R- (~49%) and S- (~37%) verapamil AUC ↑ R- (~75%) and S- (~51%) verapamil Cmax	Elimination half life and renal clearance not affected
St. John’s Wort	↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

Other Drug Interactions and Additional Drug Interaction Information

 

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

 

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

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

HIV antiviral agents:  due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.

 

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

 

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

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

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

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or /lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or/ lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.

 

There is no direct in vivo clinical evidence for an interaction between atorvastatin and verapamil, however, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin and lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.

 

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

 

4.8       Undesirable effects

 

Cardiovascular

Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1^st, 2^nd or 3^rd 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 2^nd or 3^rd 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  

 

 

 

4.5       Interactions with other medicinal products and other forms of interaction

 

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp).  Clinically significant  interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

 

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

 

 

Potential Drug Interactions associated with Verapamil

 

Concomitant drug	Potential effect on verapamil or concomitant drug	Comment
Alpha blockers
Prazosin	↑ prazosin Cmax (~40%) with no effect on half-life	Additional information follows
Terazosin	↑ terazosin AUC (~24%) and Cmax (~25%)
Antiarrhythmics
Flecainide	Minimal affect on  flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance	Additional information follows
Quinidine	↓oral quinidine clearance (~35%)
Antiasthmatics
Theophylline	↓oral and systemic CL by ~20%	Reduction of CL was lessened in smokers (~11%)
Anticonvulsants
Carbamazepine	↑ carbamazepine AUC (~46%) in refractory partial epilepsy patients	Additional information follows
Antidepressants
Imipramine	↑ imipramine AUC (~15%)	No effect on level of active metabolite, desipramine
Antidiabetics
Glyburide	↑ glyburide Cmax (~28%), AUC (~26%)
Anti-gout agents
Colchicine	Possible ↑ colchicine levels	Additional information follows
Anti-infectives
Erythromycin	Possible ↑ in verapamil levels
Rifampin	↓ verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)	Additional information follows
Telithromycin	Possible ↑in verapamil levels
Antineoplastics
Doxorubicin	­ doxorubicin AUC (89%) and Cmax (61%) with oral verapamil administration	In patients with small cell lung cancer
	No significant change in doxorubicin PK with intravenous verapamil administration	In patients with advanced neoplasms
Barbiturates
Phenobarbital	↑ oral verapamil clearance (~5-fold)
Benzodiazepines and other anxiolytics
Buspirone	↑ buspirone AUC, Cmax by ~3.4-fold
Midazolam	↑ midazolam AUC (~3-fold) and Cmax (~2-fold)
Beta blockers
Metoprolol	↑ metoprolol AUC (~32.5%) and Cmax (~41%) in angina patients	Additional information follows
Propranolol	↑ propranolol AUC (~65%) and Cmax (~94%) in angina patients
Cardiac glycosides
Digitoxin	↓digitoxin total body clearance (~27%) and extrarenal clearance (~29%)
Digoxin	Healthy subjects: ↑ Cmax by ~45-53% ↑ Css by ~42% and ↑ AUC by ~52%
H2 Receptor antagonists
Cimetidine	↑ AUC of R- (~25%) and S- (~40%) verapamil with corresponding ↓ in R-and S-verapamil clearance
Immunologics
CyclosporineCiclosporin	↑ cyclosporineciclosporin AUC, Css, Cmax by ~45%
Everolimus	Possible ↑ everolimus levels
Sirolimus	Possible ↑ sirolimus levels
Tacrolimus	Possible ↑ tacrolimus levels
Lipid lowering agents
Atorvastatin	Possible ↑ atorvastatin levels Increase verapamil AUC (~42.8%)	Additional information follows
Lovastatin	Possible ↑ lovastatin levels
Simvastatin	↑ simvastatin AUC (~2.6-fold), Cmax(~4.6-fold)
Serotonin receptor antagonists
Almotriptan	↑ almotriptan AUC (~20%) ↑ Cmax (~24%)
Uricosurics
Sulfinpyrazone	↑ verapamil oral clearance (~3-fold) ↓ bioavailability (~60%)	Additional information follows
Other
Grapefruit juice	↑ R- (~49%) and S- (~37%) verapamil AUC ↑ R- (~75%) and S- (~51%) verapamil Cmax	Elimination half life and renal clearance not affected
St. John’s Wort	↓ R- (~78%) and S- (~80%) verapamil AUC with corresponding reductions in Cmax

 

Other Drug Interactions and Additional Drug Interaction Information

 

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

 

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

 

Antihypertensives, diuretics, vasodilators:  potentiation of the hypotensive effect

 

Prazosin, terazosin:  additive hypotensive effect

 

HIV antiviral agents:  due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or dose of verapamil may be decreased.

 

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

 

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

 

Lithium:  increased lithium neurotoxicity

 

Rifampin:  blood pressure lowering effect may be reduced.

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

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

 

Aspirin:  increased tendency to bleed

 

Ethanol (alcohol):  Elevation of ethanol plasma levels

 

HMG Co-A Reductase Inhibitors (“Statins”):  treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or /lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or/ lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.

 

There is no direct in vivo clinical evidence for an interaction between atorvastatin and verapamil, however, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin and lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.

 

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

 

4.8       Undesirable effects

 

Cardiovascular

Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole, 1^st, 2^nd or 3^rd 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 2^nd or 3^rd 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  

 

 

 

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

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