Isoptin 40 Mg Film-Coated Tablets

Angina pectoris (acute and chronic coronary insufficiency), supraventricular tachydysrhythmia.

Posology
The average daily dose is 120 mg u2013 360 mg in three divided doses where possible.
Method of administration
The doses of ISOPTIN 40 mg as prescribed by the physician, are to be taken regularly, preferably half an hour before meals together with some liquid.

ISOPTIN 40 mg is contraindicated in patients with:
u2022 Hypersensitivity to verapamil hydrochloride or any of the excipients listed in section 6.1.
u2022 Retarded atrioventricular (AV) conduction (second- and third-degree AV block).
u2022 Acute stage of myocardial infarction.
u2022 Sick sinus syndrome.
u2022 Cardiovascular shock.
u2022 Pronounced sinoatrial (SA) conduction disorder (second- and third-degree SA block), except for patients fitted with a pacemaker.
u2022 Heart failure with a reduced ejection fraction of less than 35 % and/or wedge pressure exceeding 20 mmHg (unless secondary to supraventricular tachycardia responding to verapamil hydrochloride).
u2022 Atrial fibrillation/flutter and the concomitant presence of accessory pathways (e.g. Wolff-Parkinson-White (WPW) or Lown-Ganong-Levine syndrome). In these patients, ISOPTIN 40 mg therapy poses an increased risk of ventricular tachycardia, including ventricular fibrillation.
u2022 Concomitantly receiving ivabradine (see section 4.5). Beta blockers should not be administered intravenously in conjunction with ISOPTIN 40 mg (except in intensive care medicine; see section 4.5).

Conduction disorder/first degree AV block/bradycardia/asystole : ISOPTIN 40 mg affects AV and sinus nodes and delays AV conduction. It should be used with caution since second- or third-degree AV block (see section 4.3) or unifascicular, bifascicular or trifascicular bundle branch block warrants discontinuation of treatment and the initiation of appropriate therapy, if required.
It affects AV and sinus nodes and, in rare cases, may trigger second- or third-degree AV block, bradycardia or, in extreme cases, asystole. This is more likely to occur in patients with sick sinus syndrome, which is more common in older patients.
In patients not suffering from sick sinus syndrome, asystole is normally of short duration (a few seconds or less), with a spontaneous return to AV-node or normal sinus rhythm. If this does not occur immediately, appropriate treatment should be initiated without delay (see also section 4.8).
Anti-dysrhythmics, beta blockers and inhalation anaesthetics: Anti-dysrhythmics (e.g. flecainide, disopyramide), beta receptor blockers (e.g. metoprolol, propranolol) and inhalation anaesthetics may mutually potentiate cardiovascular effects (severe AV block, severe drop in heart rate, onset of heart failure, marked hypotension) if administered concomitantly with ISOPTIN 40 mg (see section 4.5).
Asymptomatic bradycardia (36 beats per minute) with a migrating atrial pacemaker was observed in one patient using eye drops containing timolol (a beta blocker) and taking verapamil hydrochloride, as contained in ISOPTIN 40 mg, concomitantly.
Digoxin: The digoxin dose should be reduced if taken concomitantly with verapamil hydrochloride, as contained in ISOPTIN 40 mg (see section 4.5).
Heart failure: ISOPTIN 40 mg has a negative inotropic effect, which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4 954 patients, 87 (1,8 %) developed congestive heart failure or pulmonary oedema. Where heart failure is present, full compensation with cardiac glycosides must be achieved before administration of ISOPTIN 40 mg. Adequate therapy should also be administered during treatment. ISOPTIN 40 mg should be avoided in patients with severe left ventricular dysfunction (e.g. ejection fraction less than 30 %, pulmonary wedge pressure above 20 mmHg, or severe symptoms of heart failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see section 4.3). Patients with milder ventricular dysfunction should, if possible, be controlled with optimal doses of digitalis and/or diuretics before ISOPTIN 40 mg treatment.
HMG-CoA reductase inhibitors (u201cstatinsu201d): See section 4.5.
Hypotension: ISOPTIN 40 mg may occasionally produce symptomatic hypotension in normotensive patients. Particularly strict monitoring is required in the case of hypotension (less than 90 mmHg systolic). In hypertensive patients, decreases in blood pressure below normal values are unusual.
Elevated liver enzymes: Elevation of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin has been reported. Such elevations are normally transient and may disappear even in the face of continued ISOPTIN 40 mg treatment.
Special populations
Impaired renal function: Although comparative studies have reliably shown that impaired renal function in patients presenting end-stage renal failure has no effect on the pharmacokinetic profile of ISOPTIN 40 mg, individual case reports suggest that caution should be exercised and strict monitoring implemented (ECG, blood pressure) when administering ISOPTIN 40 mg to patients with renal impairment. ISOPTIN 40 mg cannot be removed through haemodialysis.
Impaired hepatic function: In patients with diminished hepatic function (parenchymal loss/reduced blood supply) the effect of ISOPTIN 40 mg is intensified and prolonged depending on the severity of the disease due to impaired drug metabolism. In these cases dosage should be adjusted with special care.
Accessory bypass tract (Wolff-Parkinson-White or Low-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed an increased anterograde conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil hydrochloride, as contained in ISOPTIN 40 mg has not been established, such patients receiving oral ISOPTIN 40 mg may be at risk (see section 4.3).
Patients with hypertrophic cardiomyopathy (IHSS): A variety of serious adverse effects can occur in patients with hypertrophic cardiomyopathy - pulmonary oedema and/or severe hypotension, sinus bradycardia, AV block and sinus arrest. Most adverse effects respond well to dose reduction and discontinuation of therapy is rarely necessary.
Use in patients with disorders with impaired neuromuscular transmission: Caution should be exercised when prescribing ISOPTIN 40 mg for patients previously diagnosed with impaired neuromuscular transmission (Myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy).
Excipient warning ISOPTIN 40 mg contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially sodium free.

In-vitro studies have shown that verapamil is metabolised by cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant interactions have been reported with CYP3A4 inhibitors responsible for increased verapamil hydrochloride plasma levels; contrastingly, inducers of CYP3A4 lower verapamil hydrochloride plasma levels. Patients should therefore be monitored for interactions.
Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp). Concomitant administration of verapamil and another medicine, mainly metabolised via CYP3A4 or representing a P-gp substrate, can increase the active substance concentration of the concomitant medicine, thus potentiating or prolonging the therapeutic effect and increasing the adverse events associated with the concomitant medicine.
Potential pharmacokinetic interactions are highlighted in the following table:
Potential interactions
Concomitant medicine
Potential effect on ISOPTIN 40 mg or the concomitant medicine
Comment
Alpha blockers
Prazosin C max of prazosin u2191 (~ 40 %), no effect on half-life
Additive antihypertensive effect.
Terazosin u2191 in the AUC (~ 24 %) and (25 %) of terazosin
Anti-dysrhythmics
Flecainide Minimal effect on plasma clearance of flecainide (<~ 10 %); no effect on verapamil plasma clearance
Further information (see section 4.4 u2013 Anti-dysrhythmics, beta receptor blockers and inhalation anaesthetics).
Quinidine Clearance of oral quinidine u2193 (~ 35 %)
Hypotension. Pulmonary oedema may occur in patients with hypertrophic obstructive cardiomyopathy.
Amiodarone Increase in amiodarone plasma levels
Antiasthmatics
Theophylline Oral and systemic clearance u2193 by ~ 20 %
The reduction in clearance was less pronounced in smokers (~ 11 %).
Anticonvulsants/Antiepileptics
Carbamazepine AUC of carbamazepine u2191 (~ 46 %) in patients with refractory partial epilepsy
Increased carbamazepine levels. This may trigger adverse events such as diplopia, headaches, ataxia or dizziness/vertigo.
Reduction in verapamil hydrochloride plasma levels
Phenytoin Verapamil plasma concentrations u2193
Antidepressants
Imipramine AUC of imipramine u2191 (~ 15 %)
No effect on level of active metabolite, desipramine.
Increased verapamil hydrochloride plasma levels
Antidiabetics
Glibenclamide C max (~ 28 %) and AUC of glibenclamide u2191 (~ 26 %)
Increased verapamil hydrochloride plasma levels
Gout treatments
Colchicine u2191 of AUC (~ 2,0-fold) and C max (~ 1,3-fold) of colchicine
Reduction in the dose of colchicine (concomitant use of colchicine with verapamil hydrochloride is not recommended).
Anti-infectives
Clarithromycin Possible u2191 in verapamil levels
Erythromycin Possible u2191 in verapamil levels
Rifampicin With oral administration of verapamil u2193 in AUC (~ 97 %), C max (~ 94%) and oral bioavailability (~ 92 %) of verapamil
Potential reduction in anti-hypertensive effect. No change in the PK with intravenous administration of verapamil
Telithromycin Possible u2191 in verapamil levels
Antineoplastics
Doxorubicin With oral administration of verapamil u2191 in AUC (104 %) and C max (61 %) of doxorubicin
In patients with small-cell lung cancer. No significant changes in the PK of doxorubicin with intravenous use of verapamil in patients with advanced tumours.
Azole fungistatics
Clotrimazole Increased verapamil hydrochloride plasma levels
Ketoconazole Increased verapamil hydrochloride plasma levels
Itraconazole Increased verapamil hydrochloride plasma levels
Barbiturates
Phenobarbital Clearance of oral verapamil u2191 (~ 5-fold)
Benzodiazepines and other anxiolytics
Buspirone AUC and C max of buspirone u2191 (~ 3,4-fold)
Increased verapamil hydrochloride plasma levels
Midazolam AUC (~ 3-fold) and C max (~ 2-fold) of midazolam u2191
Increased verapamil hydrochloride plasma levels
Beta blockers
Metoprolol In patients with angina pectoris u2191 in the AUC (~ 32,5 %) and C max (~ 41 %) of metoprolol
See section 4.4.
Increased verapamil hydrochloride plasma levels
Propranolol In patients with angina pectoris u2191 in AUC (~ 65 %) and C max (~ 94 %) of propranolol
Increased verapamil hydrochloride plasma levels
Cardiac glycosides
Digitoxin u2193 in total clearance of digitoxin (~ 27 %) and in extrarenal clearance (~ 29 %)
Digoxin In healthy subjects: C max of digoxin u2191 (~ 44 %), C12h of digoxin u2191 (~ 53 %), C ss of digoxin u2191 (~ 44 %) and AUC of digoxin u2191 (~ 50 %)
Reduction in digoxin dose (see section 4.4.).
H2 Receptor antagonists
Cimetidine AUC of R- (~ 25 %) and S- verapamil (~ 40 %) with corresponding
Cimetidine reduces verapamil clearance after intravenous administration of verapamil.

Pregnancy
ISOPTIN 40 mg should be used during pregnancy only if clearly needed. Verapamil hydrochloride, as contained in ISOPTIN 40 mg crosses the placental barrier and can be detected in umbilical vein blood at delivery. The plasma concentration in umbilical vein blood amounts to 20 u2013 92 % of the plasma concentration in the maternal blood.
Breastfeeding
ISOPTIN 40 mg is excreted in human milk (milk concentration approximately 23 % of maternal plasma concentration). Breastfeeding should be discontinued while ISOPTIN 40 mg is administered.

Patients must be monitored regularly during ISOPTIN 40 mg therapy. Given the variation in individual reactions, the ability to react may be changed to such an extent that the ability to drive, use machines or work without secure footing is adversely affected. This applies in particular at the start of treatment, if the dosage is increased or the preparation changed, and in combination with alcohol. Blood alcohol levels may be increased and the elimination of alcohol slowed down, thus potentially enhancing the effects of alcohol.

As ISOPTIN 40 mg inhibits AV conduction, it may cause AV block. ISOPTIN 40 mg may also lead to a transient decrease in blood pressure, even in normotensive patients.
a. Summary of the safety profile
The most commonly reported undesirable effects were headaches, dizziness or giddiness, gastrointestinal disorders (nausea, constipation, abdominal discomfort), as well as bradycardia, tachycardia, palpitations, hypotension, flushes, peripheral oedema and fatigue.
b. Tabulated list of adverse effects:
The following undesirable effects have been reported in clinical trials, post-marketing studies or phase IV clinical trials; they are ranked according to system organ class. The frequency data are defined as follows: Very common: may affect more than 1 in 10 patients treated Common: may affect up to 1 in 10 patients treated Uncommon: may affect up to 1 in 100 patients treated Rare: may affect up to 1 in 1,000 patients treated Very rare: may affect up to 1 in 10,000 patients treated Unknown: frequency cannot be estimated from the available data
Undesirable effects reported from clinical studies with verapamil and post-marketing observations
MedDRA system organ class Undesirable effect Frequency
Immune system disorders Hypersensitivity Unknown
Nervous system disorders Dizziness or giddiness Headaches Neuropathy Common Paraesthesia Shakiness (mild tremor) Rare Extrapyramidal symptoms Paralysis (tetraparesis) 1 Cramps Severe facial pain Unknown
Metabolism and nutrition disorders Reduced glucose tolerance Uncommon Hyperkaliaemia Unknown
Psychiatric disorders Anxiety Common Drowsiness Rare
Ear and labyrinth disorders Tinnitus Rare Vertigo Unknown
Cardiac disorders Bradycardia Onset of heart failure or exacerbation of pre-existing heart failure Excessive blood pressure reduction and/or orthostatic regulation disorders Common Palpitations Tachycardia Uncommon Atrioventricular block (1 st , 2 nd or 3 rd degree) SA block Heart failure Sinus arrest Sinus bradycardia Asystole Unknown
Vascular disorders Flushing Hypotension Common
Respiratory, thoracic and mediastinal disorders Bronchospasm Dyspnoea Unknown
Gastrointestinal disorders Constipation Nausea Common Abdominal pain Uncommon Vomiting Rare Abdominal discomfort Gingival hyperplasia and burning sensations of the gums Ileus Unknown
Hepato-biliary disorders Probably allergy-induced hepatitis with reversible increase in liver-specific enzymes Uncommon
Skin and subcutaneous tissue disorders Erythromelalgia Common Hyperhidrosis Rare Photodermatitis Very rare Temporary skin rash Unknown Angioedema Stevens Johnson syndrome Erythema multiforme Alopecia Itching Pruritus Purpura Maculopapular exanthema Urticaria
Musculoskeletal and connective tissue disorders Aggravation of Myasthenia gravis, Lambert-Eaton syndrome and progressive Duchenne muscular dystrophy Very rare Exacerbation of arthritis Arthralgia Muscular weakness or myalgia (muscle and joint pain) Unknown
Renal and urinary disorders Renal insufficiency Increased urination Unknown
Reproductive system and breast disorders Erectile dysfunction Galactorrhoea Gynaecomastia Unknown
General disorders and administration site conditions Peripheral oedema Common Fatigue Uncommon
Investigations Elevated blood prolactin levels Laboratory abnormalities: Unknown
Reversible increase of transaminases and/or alkaline phosphatase has been observed and is most probably a response of allergic hepatitis 1 There was a single post-marketing report on paralysis (tetraparesis) related to the concomitant administration of verapamil hydrochloride, as contained in ISOPTIN 40 mg and colchicine. This could have been caused by the passage of colchicine through the blood-brain barrier following inhibition of CYP3A4 and P-gp by verapamil (see section 4.5).
Note In patients fitted with pacemakers, an increase in the pacing and sensing threshold under cannot be ruled out during verapamil therapy. In patients with a history of cardiovascular disease, e.g. severe cardiomyopathy, congestive heart failure or recent myocardial infarction, concomitant administration of intravenous beta blockers or disopyramide with intravenous verapamil increased the risk of severe side effects as since both substance classes have a cardiodepressive effect (see section 4.5).

Symptoms of overdose: Intoxication symptoms following ISOPTIN 40 mg poisoning progress depending on the amount ingested, the time at which detoxification measures are applied and the contractile functionality of the myocardium (age-dependent). The following symptoms have been observed with severe poisoning: Serious hypotension, heart failure, bradycardia or tachycardia arrhythmia (e.g. junctional rhythm with AV dissociation and severe AV block), potentially culminating in cardiovascular shock and cardiac arrest. Clouding of consciousness progressing to coma, hyperglycaemia, hypokalaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema, impaired renal function and convulsions. Deaths have occasionally been reported.
Therapeutic measures in the event of overdose: Detoxification and restoration of stable cardiovascular conditions are pre-requisite. Therapeutic measures depend on the time and method of ingestion, as well as the nature and severity of the intoxication symptoms. If larger quantities of sustained-release preparations have been ingested, it should be noted that the active substance may be released and absorbed by the intestines even longer than 48 hours after intake. Gastric lavage is advisable after oral ISOPTIN 40 mg poisoning, even more than 12 hours after ingestion, if no gastrointestinal motility (bowel sounds) can be detected. If intoxication with sustained-release preparations is suspected, extensive elimination measures are indicated, such as induced vomiting, aspiration of the contents of the stomach and small intestine under endoscopic guidance, intestinal lavage, evacuation, high enema. As ISOPTIN 40 mg cannot be dialysed, haemodialysis is not advisable, but haemofiltration and possibly plasmapheresis (high plasma protein binding of calcium channel blockers) are recommended.
Specific counteractive measures: Cardiac arrest: External cardiac massage, artificial respiration, ECG for differentiating between asystole and ventricular fibrillation; then appropriate intensive measures, such as defibrillation or pacemaker therapy, as required. Second- and third-degree AV block: Atropine, isoproterenol, if necessary pacemaker therapy. Development of myocardial insufficiency: Dopamine, dobutamine, cardiac glycosides or calcium. Hypotension: Proper positioning, dopamine, dobutamine norepinephrine.