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

- 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

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

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

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

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

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

SPC Section 4.3 Contraindications - addition of the following statement:

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

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

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

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

"Renal Failure

Although impaired renal function has been shown in robust comparatorstudies to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by hemodialysis.

Other

Verapamil hydrochloride should be used with caution in the presence of

diseases in which neuromuscular transmission is affected (myasthenia gravis,

Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy)."

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



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

 

With the simultaneous administration of Isoptin and drugs with a cardiodepressive action and/or inhibitory effects on impulse generation or conduction, e.g. beta-receptor blockers, antiarrhythmics and inhalation anaesthetics, watch should be kept for possible additive effects (AV blockade, bradycardia, hypotension, heart failure). Above all, Isoptin should not be administered intravenously if the patient is on beta-receptor blockers (except in intensive care).  The blood pressure lowering effect of Isoptin must be borne in mind in patients on antihypertensive drugs.

 

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

 

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

 

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

 

 

 

 

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

 

Other Drug Interactions and Additional Drug Interaction Information

 

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

 

Cimetidine:   Cimetidine reduces verapamil clearance following intravenous verapamil administration.

 

Protein-bound drugs:  as verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs.

 

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

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

Prazosin, terazosin:  additive hypotensive effect

 

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

 

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

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Aspirin:  increased tendency to bleed

 

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

 

 

 

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

 

4.6.      Pregnancy and lactation

 

During pregnancy (especially in the first trimester), Isoptin Injection should only be given if considered essential by the physician.

 

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

 

Verapamil is excreted in human breast milk. Limited human data from oral administration has shown that the infant relative dose of verapamil is low (0.1-1% of the mother’s oral dose) and that verapamil use may be compatible with breastfeeding. However, there are currently no reports of verapamil injection or infusion use during breastfeeding. Due to the potential for serious adverse reactions in nursing infants, verapamil should only be used during lactation if it is essential for the welfare of the mother.

4.8.      Undesirable effects

 

Adverse reactions have been spontaneously reported during the post-approval use of verapamil injection. These events are reported voluntarily from a population of an unknown rate of exposure. Therefore, it is not possible to estimate the true incidence of adverse events or establish a causal relationship to verapamil exposure.

 

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

 

System Organ Class	Adverse Event
Immune system disorders	Hypersensitivity
Psychiatric disorders	Nervousness
Nervous system disorders	Headache Dizziness Convulsion Somnolence Paraesthesia Extrapyramidal disorder
Ear and labyrinth disorders	Vertigo
Cardiac disorders	Atrioventricular block (1°, 2°, 3°) Sinus bradycardia Sinus arrest Cardiac arrest Bradyarrhythmia Tachycardia Cardiac failure
Vascular disorders	Hypotension Vasodilatation Flushing Erythromelalgia
Respiratory, thoracic and mediastinal disorders	Bronchospasm
Gastrointestinal disorders	Nausea Constipation Gingival hyperplasia Abdominal discomfort
Hepatobiliary disorders	Hepatitis
Skin and subcutaneous tissue disorders	Angioedema Stevens-Johnson syndrome Erythema multiforme Hyperhidrosis Urticaria Pruritus Rash Erythema
Musculoskeletal and connective tissue disorders	Myalgia Arthralgia
Reproductive system and breast disorders	Gynaecomastia
General disorders and administration site conditions	Oedema peripheral Fatigue
Investigations	Transaminases increased Blood alkaline phosphatase increased Blood prolactin increased

 

 

 

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

 

With the simultaneous administration of Isoptin and drugs with a cardiodepressive action and/or inhibitory effects on impulse generation or conduction, e.g. beta-receptor blockers, antiarrhythmics and inhalation anaesthetics, watch should be kept for possible additive effects (AV blockade, bradycardia, hypotension, heart failure). Above all, Isoptin should not be administered intravenously if the patient is on beta-receptor blockers (except in intensive care).  The blood pressure lowering effect of Isoptin must be borne in mind in patients on antihypertensive drugs.

 

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

 

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

 

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

 

 

 

 

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

 

Other Drug Interactions and Additional Drug Interaction Information

 

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

 

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

 

Protein-bound drugs:  as verapamil hydrochloride is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs.

 

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

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

Prazosin, terazosin:  additive hypotensive effect

 

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

 

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

 

Rifampin:  blood pressure lowering effect may be reduced.

 

Sulfinpyrazone:  Blood pressure lowering effect may be reduced.

 

Aspirin:  increased tendency to bleed

 

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

 

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

 

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

 

4.8.      Undesirable effects

 

Cardiovascular

Particularly when given in high doses or in the presence of previous damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias (sinus bradycardia, sinus arrest with asystole,1^st,  2^nd or 3^rd degree AV block or bradyarrhythmia in atrial fibrillation), severe tachycardia, hypotension, development or aggravation of heart failure.  Vasodilation may result in flushing, headache and peripheral oedema.

 

Gastrointestinal tract and liver

Constipation has been reported frequently.  Nausea and abdominal discomfort have also been reported.  On rare occasions, gingival hyperplasia, which is fully reversible when the drug is discontinued, may occur under long-term treatment. A reversible increase in transaminases and/or alkaline phosphatase, which is probably a sign of allergic hepatitis, has also been reported.

 

Central Nervous System

Vertigo, dizziness, headache, fatigue ,  nervousness, diaphoresis, and seizures and extrapyramidal syndrome have been reported.

 

Respiratory

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

 

Neuromuscular

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

 

Skin

Exanthema, erythema, pruritus, urticaria, Quincke’s oedema and Stevens-Johnson syndrome have been reported.  In rare cases, erythromelalgia and paraesthesia may occur.

 

Endocrine

In very rare cases, gynaecomastia has been observed, which is fully reversible following discontinuation of treatment.  Rises in prolactin levels have been reported.

 

4.9.      Overdose

 

The usual intensive care measures should be taken.  Verapamil hydrochloride cannot be removed by haemodialysis.

 

The specific antidote is calcium, e.g. 10-20 ml in a 10% calcium gluconate solution administered intravenously (2.25-4.5 mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5 mmol/hour).  The following measures may also be necessary:

 

In the case of 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.

 

Fatalities have occurred as a result of overdose.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

 

3 May 2002 April 2005

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

August 2008 June 2009

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