Isopin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISOPTINâ (ISOPTINâ)

Composition:

Active substance: verapamil hydrochloride;

1 tablet contains verapamil hydrochloride 80 mg;

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium croscarmellose, magnesium stearate, hypromellose, sodium lauryl sulfate, macrogol, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, biconvex, film-coated tablets. On one side there is an embossing "ISOPTIN 80", on the other side "KNOLL" above the break line.

Pharmacotherapeutic group. Selective calcium channel blockers with direct effects on the heart. Phenylalkylamine derivatives. ATC code C08DA01.

Pharmacological Properties

Pharmacodynamics

Verapamil blocks the transmembrane influx of calcium ions into cardiac myocytes and vascular smooth muscle cells. It directly reduces myocardial oxygen demand by affecting energy-consuming metabolic processes in myocardial cells and indirectly reduces afterload. By blocking calcium channels in smooth muscle cells of coronary arteries, verapamil enhances blood flow to the myocardium, even in post-stenotic areas, and relieves coronary artery spasm. The antihypertensive effect of verapamil is due to reduced peripheral vascular resistance without reflex tachycardia. No undesirable changes in physiological blood pressure values are observed. Verapamil exerts a pronounced antiarrhythmic effect, particularly in supraventricular arrhythmias. It slows impulse conduction through the atrioventricular node, thereby restoring sinus rhythm and/or normalizing ventricular rate, depending on the type of arrhythmia. Normal heart rate is either unchanged or slightly reduced.

Pharmacokinetics

Verapamil hydrochloride is a racemic mixture consisting of equal parts of the R-enantiomer and S-enantiomer. Verapamil is extensively metabolized. Norverapamil is one of 12 metabolites identified in urine, possessing 10–20% of the pharmacological activity of verapamil and accounting for 6% of the excreted drug. Steady-state plasma concentrations of norverapamil and verapamil are similar. Steady-state concentration is achieved within 3–4 days after repeated once-daily administration.

Absorption

More than 90% of verapamil is rapidly and almost completely absorbed in the small intestine after oral administration. The average bioavailability of unchanged compound in healthy volunteers after a single dose is approximately 22%, due to extensive first-pass hepatic metabolism. Bioavailability doubles with repeated dosing.

Maximum plasma concentration of verapamil is reached within 1–2 hours after administration of immediate-release tablets; for norverapamil, peak concentration occurs within 1 hour. Food intake does not affect the bioavailability of verapamil.

Distribution

Verapamil is widely distributed in body tissues. In healthy volunteers, the volume of distribution ranges from 1.8 to 6.8 L/kg. Plasma protein binding of verapamil is approximately 90%.

Metabolism

Verapamil is extensively metabolized. In vitro metabolism studies have shown that verapamil is metabolized primarily by cytochrome P450 enzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. After oral administration to healthy male volunteers, verapamil hydrochloride undergoes extensive hepatic metabolism, producing 12 metabolites, most of which are present in trace amounts. The major metabolites are various N- and O-dealkylated derivatives of verapamil. Among these, only norverapamil exhibits pharmacological activity (approximately 20% of the parent compound), as demonstrated in studies in dogs.

Elimination

The elimination half-life of verapamil is 3–7 hours after oral administration. Approximately 50% of the administered dose is excreted by the kidneys within 24 hours and 70% within 5 days. Up to 16% of the dose is excreted in feces. About 3–4% of the drug excreted by the kidneys is eliminated unchanged. Total clearance of verapamil is nearly as high as hepatic blood flow and averages approximately 1 L/h/kg (range: 0.7–1.3 L/h/kg).

Special Patient Groups

Children. Pharmacokinetic data on verapamil in children are limited. After oral administration, steady-state plasma concentrations are slightly lower in children compared to adults.

Elderly patients. Age may affect the pharmacokinetics of verapamil in patients with arterial hypertension. The elimination half-life may be prolonged in elderly patients. However, the antihypertensive effect of verapamil is independent of age.

Patients with renal impairment. Renal function impairment does not affect the pharmacokinetics of verapamil, as demonstrated in comparative studies in patients with end-stage renal disease and individuals with normal renal function. Verapamil and norverapamil are not removed by hemodialysis.

Patients with hepatic impairment. The elimination half-life of verapamil increases in patients with impaired liver function due to reduced clearance and increased volume of distribution.

Clinical characteristics.

Indications.

• Ischemic heart disease, including stable exertional angina; unstable angina (progressive angina, rest angina); vasospastic angina (variant angina, Prinzmetal's angina); post-infarction angina in patients without heart failure when β-blockers are not indicated.
• Arrhythmias: paroxysmal supraventricular tachycardia; atrial flutter/fibrillation with rapid atrioventricular conduction [except in Wolff-Parkinson-White (WPW) syndrome].
• Arterial hypertension.

Contraindications.

• Hypersensitivity to verapamil or to any other component of the medicinal product.
• Cardiogenic shock.
• Second- or third-degree atrioventricular block (except in patients with a functioning artificial pacemaker).
• Sick sinus syndrome (except in patients with a functioning artificial pacemaker).
• Heart failure with reduced ejection fraction below 35% and/or pulmonary artery wedge pressure above 20 mmHg (except when these conditions are secondary to supraventricular tachycardia responsive to verapamil therapy).
• Atrial fibrillation/flutter in the presence of accessory conduction pathways (e.g., WPW syndrome or LGL syndrome (Lown-Ganong-Levine syndrome)). In such patients, administration of verapamil hydrochloride carries a risk of ventricular tachyarrhythmias, including ventricular fibrillation.
• Concomitant use with ivabradine (see "Interaction with other medicinal products and other forms of interaction").
• Do not administer intravenous β-blockers concomitantly during treatment with Isoptin® (except in intensive care settings).

Interaction with other medicinal products and other forms of interaction.

In vitro metabolism studies of verapamil hydrochloride have shown that it is metabolized by cytochrome P450 enzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Clinically significant interactions have been reported with CYP3A4 inhibitors, which were associated with increased plasma levels of verapamil, whereas CYP3A4 inducers caused decreased plasma levels of verapamil hydrochloride. Therefore, monitoring for interactions with other medicinal products is necessary. Concomitant administration of verapamil and drugs that are primarily metabolized by CYP3A4 or are P-gp substrates may lead to increased concentrations, potentially enhancing or prolonging both therapeutic and adverse effects of the co-administered drug.

Potential pharmacokinetic interactions

Prazosin: increased Cmax of prazosin (~40%) without affecting elimination half-life. Additive hypotensive effect.

Terazosin: increased AUC (~24%) and Cmax (~25%) of terazosin. Additive hypotensive effect.

Quinidine: reduced quinidine clearance (~35%) with oral administration. Risk of arterial hypotension; pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.

Flecainide: minimal effect on flecainide plasma clearance (<~10%); no effect on verapamil plasma clearance (see section "Special precautions for use").

Theophylline: reduced oral and systemic clearance by approximately 20%; in smokers, by 11%.

Carbamazepine: increased AUC of carbamazepine (~46%) in patients with refractory partial epilepsy; elevated carbamazepine levels may cause adverse effects such as diplopia, headache, ataxia, or dizziness.

Phenytoin: decreased plasma concentration of verapamil.

Imipramine: increased AUC (~15%) of imipramine without affecting the active metabolite desipramine.

Gliburide: increased Cmax of gliburide by approximately 28% and AUC by 26%.

Metformin: concomitant administration of verapamil with metformin may reduce metformin efficacy.

Colchicine: increased AUC (approximately 2-fold) and Cmax (approximately 1.3-fold) of colchicine. Dose reduction of colchicine is recommended (see colchicine prescribing information).

Clarithromycin, erythromycin, telithromycin: possible increase in verapamil levels.

Rifampicin: possible reduction in antihypertensive effect. Decreased AUC (~97%), Cmax (~94%), and oral bioavailability (~92%) of verapamil.

Doxorubicin: concomitant oral administration of doxorubicin and verapamil increases AUC (~104%) and Cmax (~61%) of doxorubicin in patients with small cell lung cancer.

Phenobarbital: increases oral clearance of verapamil 5-fold.

Buspirone: increases AUC and Cmax of buspirone by 3.4-fold.

Midazolam: increases AUC of midazolam 3-fold and Cmax 2-fold.

Metoprolol: increased AUC (~32.5%) and Cmax (~41%) of metoprolol in patients with angina (see section "Special precautions for use").

Propranolol: increased AUC (~65%) and Cmax (~94%) of propranolol in patients with angina (see section "Special precautions for use").

Digoxin: in healthy volunteers, increased Cmax (~44%), C12h (~53%), Css (~44%), and AUC (~50%) of digoxin. Dose reduction of digoxin is recommended (see also section "Special precautions for use").

Digitoxin: reduced total clearance of digitoxin (~27%) and extrarenal clearance (~29%).

Cimetidine: increased AUC of R-verapamil (~25%) and S-verapamil (~40%), with corresponding reduction in clearance of R- and S-verapamil.

Cyclosporine: increased AUC, Cmax, and Css of cyclosporine by approximately 45%.

Everolimus: increased AUC (approximately 3.5-fold) and Cmax (approximately 2.3-fold) of everolimus; increased Ctrough of verapamil (approximately 2.3-fold). Precise monitoring and dose adjustment of everolimus may be required.

Sirolimus: increased AUC (approximately 2.2-fold) of sirolimus and increased AUC (approximately 1.5-fold) of S-verapamil. Monitoring and dose adjustment of sirolimus may be necessary.

Tacrolimus: possible increase in plasma levels of this drug.

Lipid-lowering agents [HMG-CoA reductase inhibitors (statins)]: treatment with HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, lovastatin) in patients taking verapamil should be initiated at the lowest possible doses and gradually increased. If verapamil is initiated in a patient already receiving an HMG-CoA reductase inhibitor, a reduction in statin dose should be considered, with dosage adjustment based on plasma cholesterol levels.

Atorvastatin: possible increase in atorvastatin levels. Atorvastatin increases AUC of verapamil by approximately 43%.

Loxastatin: possible increase in lovastatin levels. Increased AUC (~63%) and Cmax (~32%) of verapamil.

Simvastatin: increased AUC of simvastatin by approximately 2.6-fold and Cmax by 4.6-fold.

Fluvastatin, pravastatin, and rosuvastatin: not metabolized by cytochrome CYP3A4; likelihood of interaction with verapamil is low.

Almotriptan: increased AUC (~20%) and Cmax (~24%) of almotriptan.

Sulfinpyrazone: increased oral clearance of verapamil by approximately 3-fold, reduced bioavailability by 60%. Reduced antihypertensive effect may occur.

Dabigatran: verapamil in immediate-release tablets increases Cmax (up to 180%) and AUC (up to 150%) of dabigatran. Risk of bleeding is increased. When used concomitantly with oral verapamil, a reduction in dabigatran dose may be required (see dabigatran prescribing information for dosing recommendations).

Other direct oral anticoagulants (DOACs):

Increased absorption of DOACs, as they are P-gp substrates, and, where applicable, reduced elimination of DOACs metabolized by CYP3A4, may lead to increased systemic bioavailability of DOACs.

Some data suggest a potential increased risk of bleeding, particularly in patients with additional risk factors. Dose reduction of DOACs may be required when used with oral verapamil (see DOAC prescribing information for dosing recommendations).

Ivabradine: concomitant use with ivabradine is contraindicated due to additive effects on heart rate reduction by verapamil and ivabradine (see "Contraindications").

Grapefruit juice: increased AUC of R-verapamil (~49%) and S-verapamil (~37%), increased Cmax of R-verapamil (~75%) and S-verapamil (~51%), without changes in elimination half-life or renal clearance. Grapefruit juice should be avoided with verapamil.

Hypericum perforatum (St. John’s wort): decreased AUC of R-verapamil (~78%) and S-verapamil (~80%), with corresponding reduction in Cmax.

Other interactions

Antiviral agents (HIV): due to the ability of some antiviral agents, such as ritonavir, to inhibit metabolism, plasma concentrations of verapamil may increase. Use with caution; dose reduction of verapamil may be necessary.

Lithium: increased neurotoxicity of lithium has been reported with concomitant use of verapamil hydrochloride and lithium, with or without increased plasma lithium levels. However, in patients receiving a constant oral dose of lithium, addition of verapamil hydrochloride led to decreased plasma lithium levels. Patients receiving both medicinal products should be closely monitored.

Neuromuscular blocking agents: clinical data and animal studies indicate that verapamil hydrochloride may potentiate the effects of neuromuscular blocking agents (both depolarizing and non-depolarizing). Dose reduction of verapamil hydrochloride and/or the neuromuscular blocking agent may be necessary when used concomitantly.

Acetylsalicylic acid: increased risk of bleeding.

Ethanol (alcohol): increased plasma ethanol levels.

Antihypertensive agents, diuretics, vasodilators: enhanced hypotensive effect.

Special precautions for use.

Acute myocardial infarction

The drug should be used with caution in patients with acute myocardial infarction complicated by bradycardia, severe arterial hypotension, or left ventricular dysfunction.

Heart block / first-degree atrioventricular block / bradycardia / asystole

Verapamil hydrochloride affects both the atrioventricular and sinoatrial nodes and prolongs atrioventricular conduction time. Use with caution, as development of second- or third-degree atrioventricular block (which is a contraindication), or single, double, or triple bundle branch block of the His bundle requires discontinuation of subsequent verapamil hydrochloride doses and initiation of appropriate therapy if necessary.

Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and very rarely may provoke the development of second- or third-degree atrioventricular block, bradycardia, and extremely rarely asystole. Such symptoms are more likely to occur in patients with sick sinus syndrome (sinoatrial nodal disease), which is more commonly observed in elderly patients.

Asystole in patients without sick sinus syndrome is usually transient (a few seconds or less), with spontaneous return to atrioventricular nodal or normal sinus rhythm. If this phenomenon is not fleeting, appropriate therapy should be initiated immediately (see section "Adverse reactions").

Antiarrhythmic agents, β-adrenergic blockers

Mutual enhancement of cardiovascular effects (increased degree of high-grade atrioventricular block, significant reduction in heart rate, onset of heart failure, significant decrease in blood pressure). Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in patients receiving concomitant therapy with ophthalmic timolol (a β-adrenergic blocker) during verapamil hydrochloride treatment.

Digoxin

When verapamil is used concomitantly with digoxin, the digoxin dose should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure

Heart failure must be compensated prior to initiating verapamil therapy in patients with ejection fraction greater than 35%, and adequately controlled throughout the entire treatment period.

HMG-CoA reductase inhibitors (statins)

See section "Interaction with other medicinal products and other forms of interaction".

Neuromuscular transmission disorders

Verapamil hydrochloride should be used with caution in the presence of diseases involving impaired neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy).

Renal impairment

Although data from confirmed comparative studies have shown that renal impairment does not affect verapamil pharmacokinetics in patients with end-stage renal disease, there have been several reports suggesting that verapamil should be used with caution and under close monitoring in patients with renal impairment. Verapamil is not removed by hemodialysis.

Hepatic impairment

Verapamil should be used with caution in patients with significantly impaired liver function (see section "Method of administration and dosage").

Use during pregnancy or breastfeeding.

Well-controlled and clearly established data on the use of the drug in pregnant women are lacking. Animal studies have not revealed any direct or indirect harmful effects regarding reproductive toxicity. Since data obtained from reproductive animal studies cannot always be extrapolated to humans, the drug should be used during pregnancy only if clearly needed.

Verapamil crosses the placenta and is detectable in umbilical cord blood.

Verapamil and its metabolites are excreted into breast milk. Limited human data on oral administration indicate that the dose of verapamil transferred to the newborn is low (0.1–1% of the dose taken by the mother); therefore, verapamil use may be compatible with breastfeeding, but the risk to the newborn cannot be excluded. Due to the risk of serious adverse reactions in breastfed infants, verapamil may be used during breastfeeding only if clearly needed for the mother.

Ability to affect reaction speed when driving or operating machinery.

Due to the antihypertensive effect of verapamil hydrochloride, the ability to drive vehicles, operate machinery, or work under hazardous conditions may be impaired depending on individual response. This is particularly relevant during the initial phase of treatment, dose escalation, changes in antihypertensive therapy, and concomitant use of the drug with alcohol. Verapamil may increase plasma alcohol levels and slow its elimination, thereby potentiating the effects of alcohol.

Dosage and Administration

The dosage is determined individually by a physician for each patient. The drug should be taken without chewing or sucking, with sufficient fluid (e.g., one glass of water; grapefruit juice must not be used under any circumstances), preferably during or immediately after a meal.

Adults and adolescents with body weight over 50 kg

Ischemic heart disease, paroxysmal supraventricular tachycardia, atrial flutter/fibrillation

The recommended daily dose is 120–480 mg, divided into 3–4 doses. The maximum daily dose is 480 mg.

Arterial hypertension

The recommended daily dose is 120–360 mg, divided into 3 doses.

Preschool children older than 6 years up to 6 years of age (only for cardiac rhythm disorders): the recommended dose is 80–120 mg per day, divided into 2–3 doses.

Children aged 6–14 years (only for cardiac rhythm disorders): the recommended dose is 80–360 mg per day, divided into 2–4 doses.

Renal impairment

Available data are provided in the section "Special instructions". Verapamil hydrochloride should be used with caution and under close medical supervision in patients with renal insufficiency.

Hepatic impairment

In patients with impaired liver function, the effect of verapamil hydrochloride is enhanced and prolonged due to slowed drug metabolism. Therefore, dosage should be initiated with particular caution and low doses (e.g., initially 2–3 times daily 40 mg, i.e., 80–120 mg daily) should be used in patients with hepatic dysfunction. See "Special instructions".

If verapamil hydrochloride 40 mg dosage is required, verapamil hydrochloride in the appropriate dosage strength (40 mg tablets) should be administered.

Do not take the drug while lying down.

Verapamil hydrochloride must not be administered to patients who have experienced myocardial infarction within the previous 7 days.

After prolonged therapy, the drug should be discontinued gradually by tapering the dose.

The duration of treatment is determined individually by the physician and depends on the patient's condition and disease course.

Children

The drug may be administered to children only for cardiac rhythm disorders (see section "Dosage and Administration").

Overdose

Clinical manifestations: arterial hypotension, bradycardia progressing to high-degree atrioventricular block and sinus node arrest, hyperglycemia, stupor, metabolic acidosis, and acute respiratory distress syndrome. Fatal outcomes have been reported following overdose.

Treatment of verapamil hydrochloride overdose should primarily be supportive and individualized. Beta-adrenergic stimulation and/or intravenous administration of calcium preparations (calcium chloride) are effective in managing symptoms of intentional overdose following oral administration of verapamil hydrochloride.

In cases of severe arterial hypotension or high-degree atrioventricular block, vasopressors or cardiac pacemakers should be used as appropriate. In asystole, standard measures should be applied, including beta-adrenergic stimulation (e.g., isoprenaline hydrochloride), other vasopressors, or cardiopulmonary resuscitation.

Verapamil hydrochloride is not removed by hemodialysis.

Adverse Reactions

The adverse reactions listed below have been reported during clinical trials, post-marketing use of verapamil, or in phase IV clinical studies.

For each organ system, adverse reactions are classified according to frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (frequency cannot be estimated from available data).

The most commonly observed adverse reactions were: headache, dizziness; gastrointestinal disorders: nausea, constipation, and abdominal pain; as well as bradycardia, tachycardia, palpitations, decreased blood pressure, flushing, peripheral edema, and fatigue.

Immune system disorders: not known – hypersensitivity.

Nervous system disorders: common – dizziness, headache; rare – paraesthesia, tremor; not known – extrapyramidal disorders, paralysis (tetraparesis)*, seizures.

Metabolism and nutrition disorders: not known – hyperkalemia.

Psychiatric disorders: rare – somnolence.

Ear and labyrinth disorders: rare – tinnitus; not known – vertigo.

Cardiac disorders: common – bradycardia, flushing, decreased blood pressure; uncommon – palpitations, tachycardia; not known – atrioventricular block (first-, second-, or third-degree), heart failure, sinus node arrest, sinus bradycardia, asystole.

Respiratory, thoracic and mediastinal disorders: not known – bronchospasm, dyspnea.

Gastrointestinal disorders: common – nausea, constipation; uncommon – abdominal pain; rare – vomiting; not known – abdominal discomfort, intestinal obstruction, gingival hyperplasia.

Skin and subcutaneous tissue disorders: rare – hyperhidrosis; not known – angioneurotic edema, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, urticaria, sensation of pruritus, pruritus, purpura.

Musculoskeletal and connective tissue disorders: not known – myalgia, arthralgia, muscle weakness.

Renal and urinary disorders: not known – renal failure.

Reproductive system and breast disorders: not known – erectile dysfunction, gynecomastia, galactorrhea.

General disorders: common – peripheral edema; uncommon – fatigue.

Investigations: not known – increased levels of liver enzymes and serum prolactin.

* One case of paralysis (tetraparesis) has been reported during post-marketing surveillance in association with concomitant use of verapamil and colchicine. This may be due to colchicine penetration through the blood-brain barrier as a result of verapamil-induced inhibition of CYP3A4 and P-gp. See section "Interaction with other medicinal products and other forms of interaction".

Shelf life. 3 years.

Storage conditions.

Store in a place inaccessible to children at a temperature not exceeding 25 °C.

Packaging.

20 tablets per blister pack, 5 blisters per cardboard box; 10 tablets per blister pack, 10 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

AbbVie Deutschland GmbH & Co. KG, Germany or Famar A.V.E. Anthoussa Plant, Greece.

Manufacturer's address and location of operations.

Knollstrasse, 67061 Ludwigshafen, Germany or Anthousa Avenue 7, Anthousa Attiki, 15349, Greece.