Adverse reactions : תופעות לוואי

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.

Drug Interactions
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.

Potential drug interactions
Verapamil/Prazosin/Terazosin (Alpha Blockers):
Prazosin: Increase of about 40% in Cmax with no effect on half-life.
Terazosin: Increase of about 24% in AUC and 25% in Cmax.
In both cases there is additive hypotensive effect.


Ikacor Tablets-          27 3. 2014 RH                          Page 8 of 13 Verapamil/Colchicine:
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Colchicine levels may rise , AUC (approximately 2 fold) as well as Cmax (approximately 1.3 fold). Reduce colchicine dose.
Verapamil/Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Effect on flecainide plasma clearance is minimal; no effect on verapamil clearance.
Verapamil/Quinidine: Pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy (IHSS). Elevation of quinidine plasma level may occur. In a small number of patients with IHSS, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. Oral quinidine clearance decreases by about 35%.
Verapamil/Theophylline: Concomitant use of verapamil in patients receiving theophylline has resulted in decreased oral and systemic clearance of theophylline by about 20% , elevated serum theophylline concentrations, and a prolonged serum half- life of the bronchodilator.
In smokers, the reduction in theophylline clearance was lessened (about 11%).
Patients receiving theophylline should be closely monitored for signs of theophylline toxicity when verapamil is administered concomitantly; serum theophylline levels should be monitored and dosage of the bronchodilator reduced if indicated.
Verapamil/Carbamazepine/Antiepileptics:((e.g. Phenytoin)         Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia or dizziness Carbamazepine AUC may increase by about 46% in refractory partial epilepsy patients.
Verapamil plasma concentrations may be decreased upon combination with phenytoin.
Verapamil/Antidepressants: Imipramine AUC may increase by about 15%.There was no effect on the level of the active metabolite, desipramine.
Verapamil/Antidiabetics: Glibenclamide Cmax increases by about 28%, and Glibenclamide AUC increases by about 26%.
Verapamil/Erythromycin: Verapamil levels may possibly rise.
Verapamil/Clarithromycin: Concomitant administration may lead to a possible rise in verapamil levels.
Verapamil/Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability by about 92%, verapamil AUC by about 97%, and verapamil Cmax by about 94%.The blood pressure lowering effect may be reduced.
Verapamil/Telithromycin: Verapamil levels may possibly rise.
Verapamil/Doxorubicin: In patients with small cell lung cancer doxorubicin AUC rose by 104% and doxorubicin Cmax by 61% with oral verapamil administration. In patients with advanced neoplasma there was no significant change in doxorubicin PK with intravenous verapamil administration
Verapamil/Phenobarbital: Phenobarbital therapy may increase oral verapamil clearance by about 5 fold.
Verapamil/Buspirone: Buspirone AUC and Cmax may increase by 3.4 fold.
Verapamil/Midazolam: Elevation of midazolam AUC by about 3 fold and its Cmax by about 2 fold.


Ikacor Tablets-          27 3. 2014 RH                          Page 9 of 13 Verapamil/Beta Blockers: Controlled studies in a small number of patients suggest that the concomitant use of Ikacor and oral beta- blocker agents may be beneficial in certain patients with chronic stable angina or hypertension but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractibility. Induction of heart failure and potentiated hypotension may also occur.
Metoprolol AUC increased by about 32.5%, metoprolol Cmax increased by about 41% in angina patients.
Propranolol AUC increased by about 65% and propranolol Cmax increased by about 94% in angina patients.
Verapamil/Digoxin/Digitoxin: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Digoxin Cmax increases by about 44%, digoxin C12h (about 53%) in healthy subjects, Css increases by about 44% and AUC increases by about 50%. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified.
Digitoxin total body clearance and extrarenal clearance are reduced by about 27% and 29%, respectively.
Maintenance digitalization doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or underdigitalization.
Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or the drug temporarily discontinued. Upon discontinuation of verapamil the patient should be monitored to avoid underdigitalization.
Verapamil/Cimetidine: Possible elevation of verapamil hydrochloride plasma levels AUC of R-verapamil increases by about 25%, that of the S-verapamil by about 40% with corresponding decrease in R-and S-verapamil clearance.
Verapamil/Immunologics/Immunosuppressives:
Verapamil/Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine (AUC, Css, Cmax by ~45%).
Verapamil/Sirolimus/Tacrolimus/Everolimus: Possible increase in sirolimus, tacrolimus, or everolimus levels.
Everolimus: AUC increase (about 3.5 fold), Cmax (about 2.3 fold); verapamil: Ctrough increases by about 2.3 fold). Concentration determinations and dose adjustments of everolimus may be necessary.
Sirolimus: increased sirolimus AUC (about 2.2 fold); S-verapamil AUC increases by about 1.5 fold). Concentration determinations and dose adjustments of sirolimus may be necessary.
Tacrolimus: possible increase in tacrolimus levels.

Verapamil/Lipid Lowering Agents (HMG Co-A Reductase Inhibitors, i.e. “Statins”, e.g., Atorvastatin, Lovastatin, Simvastatin): Concomitant use of these agents with verapamil hydrochloride may increase the serum levels of atorvastatin (as well as increase in AUC of verapamil by about 43%), simvastatin or lovastatin. For simvastatin: a rise in AUC (about 2.6 fold), Cmax (about 4.6 fold). Lovastatin levels may possibly rise; verapamil AUC may rise (63%), Cmax (32%)
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/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.

Ikacor Tablets-           27 3. 2014 RH                           Page 10 of 13 Verapamil/Almotriptan (Serotonin Receptor Agonist): There is an increase in almotriptan AUC by about 20%, and its Cmax about 24%.
Verapamil/Sulfinpyrazone (Uricosuric): Oral verapamil clearance increases by about 3 fold, with a decrease in of about 60% in its bioavailability. The blood pressure lowering effect may be reduced.
Verapamil/Grapefruit juice: Grapefruit juice may increase the plasma levels of verapamil hydrochloride (AUC for R-verapamil increases by about 49% and for S- verapamil by about 37% verapamil AUC. Cmax for R-verapamil increases by about 75% and for the S-verapamil by about 51%. Elimination half-life and renal clearance not affected. Grapefruit juice should therefore not be ingested with verapamil Verapamil/St.John’s Wort: Verapamil AUC decreases: R-verapamil by about 78% and S-verapamil by about 80% with corresponding reductions in Cmax.

Other Drug Interactions and Additional Drug Interaction Information (see also Potential drug interactions.

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).

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.
Verapamil Protein-Bound Drugs: As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs, such as oral anticoagulants.
Verapamil/Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure.
Patients receiving these combinations should be appropriately monitored.
Concomitant use of agents that attenuate -adrenergic function with verapamil may result in a reduction in blood pressure, which may be excessive in some patients. Such an effect has been observed in one study following the concomitant administration of verapamil and prazosin.
Verapamil/Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Verapamil/Nitrates: Verapamil has been given concomitantly with short- and long- acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Verapamil/Acetylsalicylic acid : Increased tendency to bleed
Verapamil/Ethanol (alcohol): Elevation of ethanol plasma levels
Verapami/ Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil hydrochloride-lithium therapy with either no change or an increase in serum lithium levels. The addition of verapamil hydrochloride, however, has also resulted in the lowering of the serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs should be monitored carefully.
Verapamil/Inhalation Anesthetic Agents/ Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of inhalation anesthetics and neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly..
Ikacor Tablets-           27 3. 2014 RH                          Page 11 of 13 Effects on ability to drive and use machines
Due to its antihypertensive effect, depending on the individual response, verapamil hydrochloride may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug and in conjunction with alcohol. Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

Dosage and Administration
The dose of verapamil must be individualized by titration.
Ikacor should be administered with food.
Ikacor tablets should be taken whole. They should not be crushed, sucked, chewed, or divided.

Angina
120 mg, 3 times daily is recommended.
80 mg, 3 or 4 times daily may be satisfactory in some patients with angina of effort.
The total daily dosage ranges from 240 - 480 mg.
The optimum daily dosage for most patients ranges from 320 - 480 mg.
Dosage may be increased at daily (e.g., patients with unstable angina) or weekly intervals until optimum clinical response is obtained. In general, maximum effects of any given dosage would be apparent during the first 24 to 48 hours of therapy, but note that between 24 to 48 hours the half-life of verapamil increases, hence maximum response may be delayed.

Arrhythmia
40 -120 mg, 3 times daily according to the severity of the condition.

Hypertension
240 - 480 mg daily in divided doses.