Special Warning : אזהרת שימוש

Warnings
Acute Myocardial infarction
Use with caution in acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.


Ikacor Tablets-           27 3. 2014 RH                            Page 3 of 13 Heart failure
Verapamil 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. Verapamil should be avoided in patients with severe left ventricular dysfunction and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see Drug Interactions).
Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (see Drug Interactions).
Heart failure patients with ejection fraction higher than 35% should be compensated before starting verapamil treatment and should be adequately treated throughout.

Hypotension
Occasionally, the pharmacological action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. Hypotensive is usually asymptomatic, orthostatic, mild and can be controlled by a decrease in the Ikacor dose.

HMG-CoA Reductase Inhibitors (“Statins”)
See Drug Interactions.

Elevated Liver Enzymes
Occasional elevations of transaminases and alkaline phosphatases have been reported. Patients receiving verapamil should have liver enzymes monitored periodically. Use verapamil with caution in patients with severe hepatic impairment.

Atrial Flutter/Fibrillation with Accessory Bypass Tract
Patients with atrial flutter or fibrillation and an accessory AV pathway (e.g. Wolff- Parkinson-White or Lown-Ganong-Levine syndromes) may develop increased antegrade conduction across the aberrant pathway bypassing the AV node, producing a very rapid ventricular response after receiving intravenous verapamil (or digitalis).
Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. Treatment is usually direct current cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Heart Block/ 1st Degree AV block/Bradycardia/Asystole
Verapamil hydrochloride affects the AV and SA nodes and prolongs AV conduction time. Use with caution as development of second-or third-degree AV block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation in subsequent doses of verapamil hydrochloride and institution of appropriate therapy, if needed.

Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients.

Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. See Adverse Reactions.


Ikacor Tablets-          27 3. 2014 RH                         Page 4 of 13 Patients with Hypertrophic Cardiomyopathy (IHSS)
In a total of 120 patients referred to the National Institute of Health (USA) because of hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) a variety of serious adverse effects were observed following therapy with verapamil at doses up to 720 mg/day. Three patients died in pulmonary edema: all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction.
Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients.
Concomitant administration of quinidine (see Drug Interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema).
Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%.
It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

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).
Asymptomatic bradycardia (36 beats/minute) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eye drops and oral verapamil hydrochloride.

Digoxin
If verapamil is administered concomitantly with digoxin, reduce digoxin dosage. See Drug Interactions

Other Neuromuscular transmission disorders
Verapamil should be used with caution in patients with diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy).

Use in Pregnancy
There are no adequate and well-controlled studies in pregnant women. Verapamil crosses the placenta and has been measured in umbilical cord blood. This drug should be used during pregnancy only if clearly needed.
Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Use in Breastfeeding
Verapamil is excreted in human 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.

Special Populations
Renal impairment
Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with end-stage 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.
Ikacor Tablets-          27 3. 2014 RH                           Page 5 of 13 Liver impairment
Use with caution in patients with severely impaired liver function (see Dosage) 
Preclinical safety data
Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats.
There are, however, no adequate and well-controlled studies in pregnant women.

Adverse Reactions

The following adverse reactions have been reported with verapamil from clinical studies, postmarketing surveillance or Phase IV clinical trials and are listed below by system organ class. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

The most commonly reported ADRs were headache, dizziness, gastrointestinal disorders: nausea, constipation and abdominal pain, as well as bradycardia, tachycardia, palpitations, hypotension, flushing, edema peripheral and fatigue.

Adverse reactions reported from clinical studies with verapamil and post- marketing surveillance activities

MedDRA              Common            Uncommon        Rare                 Unknown System Organ
Class
Immune system                                                              Hypersensitivity disorders
Nervous system      Dizziness,                        Paresthesia          Extrapyramidal disorders           Headache                          Tremor               disorder, paralysis
1
(tetraparesis) ,
Seizures
Psychiatric                                           Somnolence disorders
Ear and labyrinth                                     Tinnitus             vertigo disorders

Cardiac             Bradycardia       Palpitations,                        Atrioventricular disorders                             Tachycardia                          block (1°, 2°, 3°), Cardiac failure,
Sinus arrest, Sinus bradycardia;
asystole

Vascular            Flushing,
disorders           Hypotension


Ikacor Tablets-            27 3. 2014 RH                         Page 6 of 13 MedDRA               Common                Uncommon             Rare                  Unknown System Organ
Class
Respiratory,                                                                          Bronchospasm thoracic and mediastinal disorders

Gastrointestinal     Constipation,         Abdominal pain       vomiting              Abdominal disorders            Nausea                                                           discomfort, Gingival hyperplasia,
Ileus
Skin and                                                        Hyperhidrosis         Angioedema, subcutaneous                                                                          Stevens- tissue disorders                                                                      Johnson syndrome,
Erythema multiforme,
Alopecia,
Itching, Pruritus,
Purpura, Rash maculopapular,
Urticaria
Musculoskeletal                                                                       Arthralgia, and connective                                                                        Muscular tissue disorders                                                                      weakness, Myalgia

Reproductive                                                                          Erectile system and                                                                            dysfunction, breast disorders                                                                      Galactorrhea, Gynecomastia
General              Edema                 Fatigue disorders and        peripheral administration site conditions

Investigations                                                                        Blood prolactin increased,
Hepatic enzymes increased

1
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. See Drug Interactions 
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product.


Ikacor Tablets-              27 3. 2014 RH                                  Page 7 of 13 Precautions
Treatment of Acute Cardiovascular Adverse Reactions
The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g. intravenously administered isoproterenol HCl; levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha- adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure and isoproterenol and levarterenol should be avoided.
If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
Use in Patients with Impaired Hepatic Function
Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see Overdosage) should be carried out.
Use in Patients with Impaired Renal Function
About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function.
These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see Overdosage).
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Effects on Driving