Ikacor

2) For the management and prophylaxis of angina pectoris (including variant angina).

3) The treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of the ventricular rate in atrial fibrillation/flutter. Ikacor should not be used for atrial fibrillation/flutter in patients with Wolff-Parkinson-White syndrome.

CALAN tablets are indicated for the treatment of the following:

Angina

1. Angina at rest including:
   • Vasospastic (Prinzmetal’s variant) angina
   • Unstable (crescendo, pre-infarction) angina
2. Chronic stable angina (classic effort-associated angina)

Arrhythmias

1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract)
2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia

Essential Hypertension

CALAN is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Ikacor is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Ikacor tablets are indicated for the treatment of the following:

Angina

1. Angina at rest including:
   • Vasospastic (Prinzmetal’s variant) angina
   • Unstable (crescendo, pre-infarction) angina
2. Chronic stable angina (classic effort-associated angina)

Arrhythmias

1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract)
2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia

Essential Hypertension

Ikacor is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

ISOPTIN SR (verapamil HCl) is indicated for the management of essential hypertension.

Posology

Adults:

Angina: 120mg three times daily is recommended. 80mg three times daily may be completely satisfactory in some patients with angina of effort. Less than 120mg three times daily is unlikely to be effective in variant angina.

Supraventricular tachycardias: 40-120mg three times daily depending on the severity of the condition.

Paediatric population:

A paradoxical increase in the rate of arrhythmias in children has been noted. Therefore, Ikacor should only be used under expert supervision.

Up to 2 years: 20mg 2-3 times a day.

2 years and above: 40-120mg 2-3 times a day according to age and effectiveness.

Elderly: The adult dose is recommended unless liver or renal function is impaired.

Method of Administration

For oral administration.

The dose of verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed.

Angina

Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (eg, decreased hepatic function, elderly, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (eg, patients with unstable angina) or weekly intervals until optimum clinical response is obtained.

Arrhythmias

The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS) ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy.

Essential Hypertension

Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of CALAN are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

Essential Hypertension

The dose of Ikacor should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, Ikacor, given in the morning. Lower initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (eg, the elderly or small people). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of Ikacor are evident within the first week of therapy.

If adequate response is not obtained with 180 mg of CALAN SR, the dose may be titrated upward in the following manner:

1. 240 mg each morning,
2. 180 mg each morning plus
   180 mg each evening; or
   240 mg each morning plus
   120 mg each evening,
3. 240 mg every 12 hours.

When switching from immediate-release CALAN to Ikacor, the total daily dose in milligrams may remain the same.

The dose of verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed.

Angina

Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (eg, decreased hepatic function, elderly, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (eg, patients with unstable angina) or weekly intervals until optimum clinical response is obtained.

Arrhythmias

The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS) ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy.

Essential Hypertension

Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of Ikacor are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

Essential Hypertension

The dose of ISOPTIN SR should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, ISOPTIN SR, given in the morning. Lower, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of ISOPTIN SR are evident within the first week of therapy.

If adequate response is not obtained with 180 mg of ISOPTIN SR, the dose may be titrated upward in the following manner:

1. 240 mg each morning,
2. 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening
3. 240 mg every twelve hours.

When switching from immediate release ISOPTIN to ISOPTIN SR, the total daily dose in milligrams may remain the same.

Ikacor may affect left ventricular contractility as a result of its mode of action. The effect is small and not normally important. However, cardiac failure may be aggravated or precipitated if it exists. In cases with poor ventricular function, Ikacor should therefore only be administered after appropriate therapy for cardiac failure such as digitalis, etc.

Ikacor may affect impulse conduction and should be administered with caution in patients with first degree atrioventricular block. The effects of Ikacor and beta-blockers or other drugs may be additive both in respect of conduction and contraction, therefore care should be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.

Caution should be observed in the acute stage of myocardial infarction.

Patients with atrial fibrillation/flutter and an accessory pathway (eg Wolff-Parkinson-White syndrome) may rarely develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

Since Ikacor is extensively metabolised in the liver, careful dose titration of Ikacor is required in patients with liver disease. The disposition of Ikacor in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Ikacor is not removed during dialysis.

WARNINGS

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. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure 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. (Note interactions with digoxin under PRECAUTIONS)

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even with continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White Or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade 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 has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral CALAN.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending on the clinical situation.

Patients With Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. 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 (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS, 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 use have to be discontinued.

PRECAUTIONS

General

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 OVERDOSE) should be carried out.

Use In Patients With Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

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 OVERDOSE).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Reproduction studies have been performed in rabbits and rats at oral 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 no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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.

Labor And Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

WARNINGS

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. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a betaadrenergic blocker (see PRECAUTIONS: DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. (Note interactions with digoxin under PRECAUTIONS)

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White Or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade 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 has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral CALAN.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked firstdegree block or progressive development to second- or third-degree AV block, requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending upon the clinical situation.

Patients With Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. 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 (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS: 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 use have to be discontinued.

PRECAUTIONS

General

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 immediate-release 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 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.

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).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rabbits and rats at oral 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 no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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.

Labor And Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and efficacy of Ikacor in pediatric patients below the age of 18 years have not been established.

WARNINGS

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. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure 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. (Note interactions with digoxin under PRECAUTIONS)

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Accessory Bypass Tract (Wolff-Parkinson-White Or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade 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 has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral Ikacor.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending on the clinical situation.

Patients With Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. 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 (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS, 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 use have to be discontinued.

PRECAUTIONS

General

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 OVERDOSE) should be carried out.

Use In Patients With Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

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 OVERDOSE).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Reproduction studies have been performed in rabbits and rats at oral 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 no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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.

Labor And Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

WARNINGS

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. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, or moderate to severe symptoms of cardiac failure) 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 (Note interactions with digoxin under: PRECAUTIONS).

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade 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 has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCI and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. 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 (greater than 20 mmHg) pulmonary 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.

PRECAUTIONS

General

Use in Patients with Impaired Hepatic Functions

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 immediate release 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 Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

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).

Carcinogenesis, Mutagenesis, Impairment of Fertility

An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral 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 the reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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.

Labor and Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and efficacy of ISOPTIN tablets in pediatric patients below the age of 18 years have not been established.

Disturbi del sistema immunitario: reazioni allergiche (ad es. eritema, prurito, orticaria) sono visti molto raramente.

Disturbi del sistema nervoso : il mal di testa si verifica raramente, vertigini, parestesia, tremore, sindrome extrapiramidale (ad es. parkinsonismo), distonia.

Patologie dell'orecchio e del labirinto : vertigini, acufeni.

Disturbi cardiaci : aritmie bradicardiche come bradicardia sinusale, arresto sinusale con asistolia, blocco AV di 2 ° e 3 ° grado, bradiaritmia nella fibrillazione atriale, palpitazioni, tachicardia, sviluppo o aggravamento dell'insufficienza cardiaca, ipotensione.

Disturbi vascolari : rossore, edema periferico.

Disturbi gastrointestinali : nausea, vomito, costipazione non sono rari, ileo e dolore / disagio addominale. L'iperplasia gengivale può verificarsi molto raramente quando il farmaco viene somministrato per periodi prolungati. Questo è completamente reversibile quando il farmaco viene sospeso.

Patologie della cute e del tessuto sottocutaneo : alopecia, edema alla caviglia, edema di Quincke, sindrome di Steven-Johnson, eritema multiforme, eritromelalgia, porpora.

Patologie del sistema muscoloscheletrico e del tessuto connettivo : debolezza muscolare, mialgia e artralgia.

Patologie dell'apparato riproduttivo e della mammella: l'impotenza (disfunzione erettile) è stata segnalata raramente e casi isolati di galattorrea. La ginecomastia è stata osservata in occasioni molto rare in pazienti di sesso maschile anziano con trattamento Ikacor a più lungo termine che era completamente reversibile in tutti i casi in cui il farmaco è stato sospeso.

Patologie sistemiche e condizioni relative alla sede di somministrazione : fatica.

Indagini: In occasioni molto rare, durante il trattamento con Ikacor può verificarsi un deterioramento reversibile della funzionalità epatica caratterizzato da un aumento delle transaminasi e / o della fosfatasi alcalina ed è probabilmente una reazione di ipersensibilità.

Segnalazione di sospette reazioni avverse

È importante segnalare sospette reazioni avverse dopo l'autorizzazione del medicinale. Consente il monitoraggio continuo del rapporto rischi / benefici del medicinale. Agli operatori sanitari viene chiesto di segnalare eventuali sospette reazioni avverse tramite il sistema della carta gialla; sito web: www.mhra.gov.uk/yellowcard

Le reazioni avverse gravi non sono comuni quando la terapia con CALAN viene iniziata con titolazione della dose verso l'alto entro la dose giornaliera singola e totale raccomandata. Vedere AVVERTENZE per la discussione di insufficienza cardiaca, ipotensione, elevati enzimi epatici, blocco AV e risposta ventricolare rapida. Ileo paralitico reversibile (dopo l'interruzione del verapamil) è stato riportato di rado in associazione con l'uso del verapamil. Le seguenti reazioni al verapamil somministrato per via orale si sono verificate a tassi superiori all'1,0% o si sono verificate a tassi più bassi ma sono comparse chiaramente correlate al farmaco negli studi clinici su 4.954 pazienti :

Negli studi clinici relativi al controllo della risposta ventricolare nei pazienti digitalizzati che presentavano fibrillazione atriale o flutter, si sono verificate percentuali ventricolari inferiori a 50 a riposo nel 15% dei pazienti e si è verificata ipotensione asintomatica nel 5% dei pazienti.

Le seguenti reazioni, riportate nell'1,0% o meno dei pazienti, si sono verificate in condizioni (studi aperti, esperienza di marketing) in cui una relazione causale è incerta; sono elencati per avvisare il medico di una possibile relazione :

Cardiovascolare: angina pectoris, dissociazione atrioventricolare, dolore toracico, claudicatio, infarto del miocardio, palpitazioni, porpora (vasculite), sincope.

Sistema digestivo : diarrea, secchezza delle fauci, angoscia gastrointestinale, iperplasia gengivale.

Emico e linfatico : ecchimosi o lividi.

Sistema nervoso : incidente cerebrovascolare, confusione, disturbi dell'equilibrio, insonnia, crampi muscolari, parestesia, sintomi psicotici, tremore, sonnolenza, sintomi extrapiramidali.

Pelle: artralgia ed eruzione cutanea, esantema, perdita di capelli, ipercheratosi, macule, sudorazione, orticaria, sindrome di Stevens-Johnson, eritema multiforme.

Sensi speciali: visione offuscata, acufeni.

Urogenitale: ginecomastia, galattorrea / iperprolattinemia, aumento della minzione, mestruazioni chiazze, impotenza.

Trattamento delle reazioni avverse cardiovascolari acute

La frequenza delle reazioni avverse cardiovascolari che richiedono terapia è rara; pertanto, l'esperienza con il loro trattamento è limitata. Ogni volta che si verificano ipotensione grave o blocco AV completo dopo somministrazione orale di verapamil, devono essere applicate immediatamente le misure di emergenza appropriate; ad esempio, noradrenalina bitartrato somministrata per via endovenosa, atropina solfato, isoproteenolo HCl (tutti nelle dosi abituali) o gluconato di calcio (soluzione al 10%). Nei pazienti con cardiomiopatia ipertrofica (IHSS), gli agenti alfa-adrenergici (fenilefrina HCl, metaraminolo bitartrato o metossamina HCl) devono essere usati per mantenere la pressione sanguigna e si devono evitare isoproteenolo e noradrenalina. Se è necessario ulteriore supporto, è possibile somministrare dopamina HCl o dobutamina HCl. Il trattamento e il dosaggio effettivi dovrebbero dipendere dalla gravità della situazione clinica e dal giudizio e dall'esperienza del medico curante.

Le reazioni avverse gravi non sono comuni quando la terapia con verapamil viene iniziata con titolazione della dose verso l'alto entro la dose giornaliera singola e totale raccomandata. Vedere AVVERTENZE per la discussione di insufficienza cardiaca, ipotensione, elevati enzimi epatici, blocco AV e risposta ventricolare rapida. Ileo paralitico reversibile (dopo l'interruzione del verapamil) è stato riportato di rado in associazione con l'uso del verapamil. Le seguenti reazioni al verapamil somministrato per via orale si sono verificate a tassi superiori all'1,0% o si sono verificate a tassi più bassi ma sono comparse chiaramente correlate al farmaco negli studi clinici su 4.954 pazienti :

Negli studi clinici relativi al controllo della risposta ventricolare nei pazienti digitalizzati con fibrillazione atriale o flutter, si sono verificate velocità ventricolari inferiori a 50 / min a riposo nel 15% dei pazienti e si è verificata ipotensione asintomatica nel 5% dei pazienti.

Le seguenti reazioni, riportate nell'1% o meno dei pazienti, si sono verificate in condizioni (studi aperti, esperienza di marketing) in cui una relazione causale è incerta; sono elencati per avvisare il medico di una possibile relazione :

Cardiovascolare: angina pectoris, dissociazione atrioventricolare, dolore toracico, claudicatio, infarto del miocardio, palpitazioni, porpora (vasculite), sincope.

Sistema digestivo : diarrea, secchezza delle fauci, angoscia gastrointestinale, iperplasia gengivale.

Emico e linfatico : ecchimosi o lividi.

Sistema nervoso : incidente cerebrovascolare, confusione, disturbi dell'equilibrio, insonnia, crampi muscolari, parestesia, sintomi psicotici, tremore, sonnolenza.

Pelle: artralgia ed eruzione cutanea, esantema, perdita di capelli, ipercheratosi, macule, sudorazione, orticaria, sindrome di Stevens-Johnson, eritema multiforme.

Sensi speciali: visione offuscata, acufeni.

Urogenitale: ginecomastia, galattorrea / iperprolattinemia, aumento della minzione, mestruazioni chiazze, impotenza.

Trattamento delle reazioni avverse cardiovascolari acute

La frequenza delle reazioni avverse cardiovascolari che richiedono terapia è rara; pertanto, l'esperienza con il loro trattamento è limitata. Ogni volta che si verificano ipotensione grave o blocco AV completo dopo somministrazione orale di verapamil, devono essere applicate immediatamente le misure di emergenza appropriate; ad esempio, noradrenalina bitartrato somministrata per via endovenosa, atropina solfato, isoproteenolo HCl (tutti nelle dosi abituali) o gluconato di calcio (soluzione al 10%). Nei pazienti con cardiomiopatia ipertrofica (IHSS), gli agenti alfa-adrenergici (fenilefrina HCl, metaraminolo bitartrato o metossamina HCl) devono essere usati per mantenere la pressione sanguigna e si devono evitare isoproteenolo e noradrenalina. Se è necessario ulteriore supporto, è possibile somministrare dopamina HCl o dobutamina HCl. Il trattamento e il dosaggio effettivi dovrebbero dipendere dalla gravità della situazione clinica e dal giudizio e dall'esperienza del medico curante.

Le reazioni avverse gravi non sono comuni quando la terapia con Ikacor viene iniziata con titolazione della dose verso l'alto entro la dose giornaliera singola e totale raccomandata. Vedere AVVERTENZE per la discussione di insufficienza cardiaca, ipotensione, elevati enzimi epatici, blocco AV e risposta ventricolare rapida. Ileo paralitico reversibile (dopo l'interruzione del verapamil) è stato riportato di rado in associazione con l'uso del verapamil. Le seguenti reazioni al verapamil somministrato per via orale si sono verificate a tassi superiori all'1,0% o si sono verificate a tassi più bassi ma sono comparse chiaramente correlate al farmaco negli studi clinici su 4.954 pazienti :

Negli studi clinici relativi al controllo della risposta ventricolare nei pazienti digitalizzati che presentavano fibrillazione atriale o flutter, si sono verificate percentuali ventricolari inferiori a 50 a riposo nel 15% dei pazienti e si è verificata ipotensione asintomatica nel 5% dei pazienti.

Le seguenti reazioni, riportate nell'1,0% o meno dei pazienti, si sono verificate in condizioni (studi aperti, esperienza di marketing) in cui una relazione causale è incerta; sono elencati per avvisare il medico di una possibile relazione :

Cardiovascolare: angina pectoris, dissociazione atrioventricolare, dolore toracico, claudicatio, infarto del miocardio, palpitazioni, porpora (vasculite), sincope.

Sistema digestivo : diarrea, secchezza delle fauci, angoscia gastrointestinale, iperplasia gengivale.

Emico e linfatico : ecchimosi o lividi.

Sistema nervoso : incidente cerebrovascolare, confusione, disturbi dell'equilibrio, insonnia, crampi muscolari, parestesia, sintomi psicotici, tremore, sonnolenza, sintomi extrapiramidali.

Pelle: artralgia ed eruzione cutanea, esantema, perdita di capelli, ipercheratosi, macule, sudorazione, orticaria, sindrome di Stevens-Johnson, eritema multiforme.

Sensi speciali: visione offuscata, acufeni.

Urogenitale: ginecomastia, galattorrea / iperprolattinemia, aumento della minzione, mestruazioni chiazze, impotenza.

Trattamento delle reazioni avverse cardiovascolari acute

La frequenza delle reazioni avverse cardiovascolari che richiedono terapia è rara; pertanto, l'esperienza con il loro trattamento è limitata. Ogni volta che si verificano ipotensione grave o blocco AV completo dopo somministrazione orale di verapamil, devono essere applicate immediatamente le misure di emergenza appropriate; ad esempio, noradrenalina bitartrato somministrata per via endovenosa, atropina solfato, isoproteenolo HCl (tutti nelle dosi abituali) o gluconato di calcio (soluzione al 10%). Nei pazienti con cardiomiopatia ipertrofica (IHSS), gli agenti alfa-adrenergici (fenilefrina HCl, metaraminolo bitartrato o metossamina HCl) devono essere usati per mantenere la pressione sanguigna e si devono evitare isoproteenolo e noradrenalina. Se è necessario ulteriore supporto, è possibile somministrare dopamina HCl o dobutamina HCl. Il trattamento e il dosaggio effettivi dovrebbero dipendere dalla gravità della situazione clinica e dal giudizio e dall'esperienza del medico curante.

Le reazioni avverse gravi non sono comuni quando la terapia con verapamil viene iniziata con titolazione della dose verso l'alto entro la dose giornaliera singola e totale raccomandata. Vedere AVVERTENZE per la discussione di insufficienza cardiaca, ipotensione, elevati enzimi epatici, blocco AV e risposta ventricolare rapida. Ileo paralitico reversibile (dopo l'interruzione del verapamil) è stato riportato di rado in associazione con l'uso del verapamil. Le seguenti reazioni al verapamil somministrato per via orale si sono verificate a tassi superiori all'1,0% o si sono verificate a tassi più bassi, ma sono comparse chiaramente correlate al farmaco negli studi clinici su 4.954 pazienti.

Enzimi epatici elevati

(Vedere AVVERTENZE)

Negli studi clinici relativi al controllo della risposta ventricolare in pazienti digitalizzati con fibrillazione atriale o flutter atriale, si sono verificate velocità ventricolari inferiori a 50 / min a riposo nel 15% dei pazienti e si è verificata ipotensione asintomatica nel 5% dei pazienti.

Le seguenti reazioni, riportate nell'1,0% o meno dei pazienti, si sono verificate in condizioni (studi aperti, esperienza di marketing) in cui una relazione causale è incerta; sono elencati per avvisare il medico di una possibile relazione.

Cardiovascolare: angina pectoris, dissociazione atrioventricolare, dolore toracico, claudicatio, infarto del miocardio, palpitazioni, porpora (vasculite), sincope.

Sistema digestivo : diarrea, secchezza delle fauci, angoscia gastrointestinale, iperplasia gengivale.

Emico e linfatico : ecchimosi o lividi.

Sistema nervoso : incidente cerebrovascolare, confusione, disturbi dell'equilibrio, insonnia, crampi muscolari, parastesia, sintomi psicotici, tremore, sonnolenza, sintomi extrapiramidali.

Pelle: artralgia ed eruzione cutanea, esantema, ipercheratosi per la caduta dei capelli, macule, sudorazione, orticaria, sindrome di Stevens-Johnson, eritema multiforme.

Sensi speciali : visione offuscata, acufeni.

Urogenitale: ginecomastia, impotenza, galattorrea / iperprolattinemia, aumento della minzione, mestruazioni chiazze.

Trattamento delle reazioni avverse cardiovascolari acute

La frequenza delle reazioni avverse cardiovascolari che richiedono terapia è rara, quindi l'esperienza con il loro trattamento è limitata. Ogni volta che si verificano ipotensione grave o blocco AV completo dopo somministrazione orale di verapamil, le misure di emergenza appropriate devono essere applicate immediatamente, ad es.isoproteenolo HCl somministrato per via endovenosa, noradrenalina bitartrato, atropina solfato (tutte nelle dosi abituali) o gluconato di calcio (soluzione al 10%). Nei pazienti con cardiomiopatia ipertrofica (IHSS), gli agenti alfa-adrenergici (fenilefrina HCl, metaraminolo bitartrato o metossamina HCl) devono essere usati per mantenere la pressione sanguigna e si devono evitare isoproteenolo e noradrenalina. Se è necessario ulteriore supporto, (dopamina HCl o dobutamina HCl) può essere somministrato. Il trattamento e il dosaggio effettivi dovrebbero dipendere dalla gravità della situazione clinica e dal giudizio e dall'esperienza del medico curante.

Il decorso dei sintomi nell'intossicazione da Ikacor dipende dalla quantità assunta, dal momento in cui vengono prese le misure di disintossicazione e dalla contrattilità miocardica (legata all'età). I sintomi principali sono i seguenti: caduta della pressione sanguigna (a volte a valori non rilevabili) sintomi di shock, perdita di coscienza, Blocco AV di 1 ° e 2 ° grado (spesso come fenomeno di Wenckebach con o senza ritmi di fuga) blocco AV totale con dissociazione AV totale, ritmo di fuga, asistolia, bradicardia fino a blocco AV di alto grado e, arresto del seno, iperglicemia, stupore e acidosi metabolica. Si sono verificate vittime a causa del sovradosaggio.

Le misure terapeutiche da adottare dipendono dal momento in cui è stato adottato Ikacor e dal tipo e dalla gravità dei sintomi di intossicazione. In intossicazioni con grandi quantità di preparati a rilascio lento, va notato che il rilascio del farmaco attivo e l'assorbimento nell'intestino possono richiedere più di 48 ore. L'ikacor cloridrato non può essere rimosso mediante emodialisi. A seconda del tempo di ingestione, si dovrebbe tener conto del fatto che potrebbero esserci alcuni grumi di compresse disciolte in modo incompleto lungo l'intera lunghezza del tratto gastrointestinale, che funzionano come depositi di farmaci attivi.

Misure generali da adottare: lavanda gastrica con le consuete precauzioni, anche dopo 12 ore dall'ingestione, se non è rilevabile alcuna motilità gastrointestinale (suoni peristaltici). Laddove si sospetti un'intossicazione da una preparazione a rilascio modificato, sono indicate ampie misure di eliminazione, come il vomito indotto, la rimozione del contenuto dello stomaco e dell'intestino tenue sotto endoscopia, lavaggio intestinale, lassativo, clisteri alti. Si applicano le consuete misure di rianimazione intensiva, come massaggio cardiaco extratoracico, respirazione, defibrillazione e / o terapia del pacemaker.

Misure specifiche da adottare: eliminazione di effetti cardiodepressivi, ipotensione o bradicardia. L'antidoto specifico è il calcio, ad es. 10 20 ml di una soluzione di gluconato di calcio al 10% somministrata per via endovenosa (2,25 - 4,5 mmol), ripetuta se necessario o somministrata come infusione continua di gocciolamento (ad es. 5mmol / ora).

Possono anche essere necessarie le seguenti misure: in caso di blocco AV di 2 ° o 3 ° grado, bradicardia sinusale, asistole - atropina, isoprenalina, orciprenalina o terapia del pacemaker. In caso di ipotensione - dopamina, dobutamina, noradrenalina (noradrenalina). Se ci sono segni di continua insufficienza del miocardio - dopamina, dobutamina, se necessario ripetute iniezioni di calcio.

Trattare tutte le overdose di verapamil come gravi e mantenere l'osservazione per almeno 48 ore (in particolare CALAN SR), preferibilmente in cure ospedaliere continue. Conseguenze farmacodinamiche ritardate possono verificarsi con la formulazione a rilascio prolungato. Verapamil è noto per ridurre il tempo di transito gastrointestinale.

Il trattamento del sovradosaggio deve essere di supporto. La stimolazione beta-adrenergica o la somministrazione parenterale di soluzioni di calcio possono aumentare il flusso di ioni calcio attraverso il canale lento e sono state utilizzate efficacemente nel trattamento del sovradosaggio deliberato con verapamil. In alcuni casi segnalati, il sovradosaggio con bloccanti dei canali del calcio è stato associato a ipotensione e bradicardia, inizialmente refrattario all'atropina ma diventando più sensibile a questo trattamento quando i pazienti hanno ricevuto dosi elevate (vicino a 1 grammo / ora per più di 24 ore) di cloruro di calcio. Verapamil non può essere rimosso dall'emodialisi. Reazioni ipotensive clinicamente significative o blocco AV di alto grado devono essere trattate rispettivamente con agenti vasopressori o stimolazione cardiaca. L'asistolia deve essere gestita con le consuete misure, inclusa la rianimazione cardiopolmonare.

Il sovradosaggio con verapamil può portare a pronunciate ipotensione, bradicardia e anomalie del sistema di conduzione (ad es. Ritmo biennale con dissociazione AV e blocco AV di alto grado, inclusa l'asistola). Altri sintomi secondari all'ipoperfusione (ad es. Acidosi metabolica, iperglicemia, iperkaliemia, disfunzione renale e convulsioni) possono essere evidenti.

Trattare tutte le overdose di verapamil come gravi e mantenere l'osservazione per almeno 48 ore (in particolare Ikacor), preferibilmente in cure ospedaliere continue. Conseguenze farmacodinamiche ritardate possono verificarsi con la formulazione a rilascio prolungato. Verapamil è noto per ridurre il tempo di transito gastrointestinale.

In caso di sovradosaggio, occasionalmente sono state segnalate caplette di Ikacor per formare concrezioni all'interno dello stomaco o dell'intestino. Queste concrezioni non sono state visibili su semplici radiografie dell'addome e nessun mezzo medico per lo svuotamento gastrointestinale è di comprovata efficacia nel rimuoverle. L'endoscopia può essere ragionevolmente considerata in caso di sovradosaggio massiccio quando i sintomi sono insolitamente prolungati.

Il trattamento del sovradosaggio deve essere di supporto. La stimolazione beta-adrenergica o la somministrazione parenterale di soluzioni di calcio possono aumentare il flusso di ioni calcio attraverso il canale lento e sono state utilizzate efficacemente nel trattamento del sovradosaggio deliberato con verapamil. Il trattamento continuato con grandi dosi di calcio può produrre una risposta. In alcuni casi segnalati, il sovradosaggio con bloccanti dei canali del calcio che inizialmente era refrattario all'atropina è diventato più sensibile a questo trattamento quando i pazienti hanno ricevuto dosi elevate (vicino a 1 g / ora per più di 24 ore) di cloruro di calcio. Verapamil non può essere rimosso dall'emodialisi. Reazioni ipotensive clinicamente significative o blocco AV di alto grado devono essere trattate rispettivamente con agenti vasopressori o stimolazione cardiaca. L'asistolia deve essere gestita con le consuete misure, inclusa la rianimazione cardiopolmonare.

Trattare tutte le overdose di verapamil come gravi e mantenere l'osservazione per almeno 48 ore (in particolare Ikacor SR), preferibilmente in cure ospedaliere continue. Conseguenze farmacodinamiche ritardate possono verificarsi con la formulazione a rilascio prolungato. Verapamil è noto per ridurre il tempo di transito gastrointestinale.

Il trattamento del sovradosaggio deve essere di supporto. La stimolazione beta-adrenergica o la somministrazione parenterale di soluzioni di calcio possono aumentare il flusso di ioni calcio attraverso il canale lento e sono state utilizzate efficacemente nel trattamento del sovradosaggio deliberato con verapamil. In alcuni casi segnalati, il sovradosaggio con bloccanti dei canali del calcio è stato associato a ipotensione e bradicardia, inizialmente refrattario all'atropina ma diventando più sensibile a questo trattamento quando i pazienti hanno ricevuto dosi elevate (vicino a 1 grammo / ora per più di 24 ore) di cloruro di calcio. Verapamil non può essere rimosso dall'emodialisi. Reazioni ipotensive clinicamente significative o blocco AV di alto grado devono essere trattate rispettivamente con agenti vasopressori o stimolazione cardiaca. L'asistolia deve essere gestita con le consuete misure, inclusa la rianimazione cardiopolmonare.

Il sovradosaggio con verapamil può portare a pronunciate ipotensione, bradicardia e anomalie del sistema di conduzione (ad es., ritmo biennale con dissociazione AV e blocco AV di alto grado, inclusa l'asistola). Altri sintomi secondari all'ipoperfusione (ad es.possono essere evidenti acidosi metabolica, iperglicemia, iperkaliemia, disfunzione renale e convulsioni).

Trattare tutte le overdose di verapamil come gravi e mantenere l'osservazione per almeno 48 ore [in particolare ISOPTIN® SR (verapamil cloridrato)] preferibilmente in cure ospedaliere continue. Conseguenze farmacodinamiche ritardate possono verificarsi con la formulazione a rilascio prolungato. Verapamil è noto per ridurre il tempo di transito gastrointestinale.

In caso di sovradosaggio, occasionalmente sono state riportate compresse di ISOPTIN SR per formare concrezioni all'interno dello stomaco o dell'intestino. Queste concrezioni non sono state visibili su semplici radiografie dell'addome e nessun mezzo medico per lo svuotamento gastrointestinale è di comprovata efficacia nel rimuoverle. L'endoscopia può essere ragionevolmente considerata in caso di sovradosaggio massiccio quando i sintomi sono insolitamente prolungati.

Il trattamento del sovradosaggio deve essere di supporto. La stimolazione beta adrenergica o la somministrazione parenterale di soluzioni di calcio possono aumentare il flusso di ioni calcio attraverso il canale lento e sono state utilizzate efficacemente nel trattamento del sovradosaggio deliberato con verapamil. Il trattamento continuato con grandi dosi di calcio può produrre una risposta. In alcuni casi segnalati, il sovradosaggio con bloccanti dei canali del calcio che inizialmente era refrattario all'atropina è diventato più sensibile a questo trattamento quando i pazienti hanno ricevuto dosi elevate (vicino a 1 grammo / ora per più di 24 ore) di cloruro di calcio. Verapamil non può essere rimosso dall'emodialisi. Reazioni ipotensive clinicamente significative o blocco AV di alto grado devono essere trattate rispettivamente con agenti vasopressori o stimolazione cardiaca. L'asistolia deve essere gestita con le consuete misure, inclusa la rianimazione cardiopolmonare.