Isoptin® sr

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

Composition:

Active ingredient: verapamil hydrochloride;

1 tablet contains verapamil hydrochloride 240 mg;

Excipients: microcrystalline cellulose, sodium alginate, povidone, magnesium stearate, purified water, hypromellose, polyethylene glycol 400, polyethylene glycol 6000, talc, titanium dioxide (E 171), quinoline yellow (E 104) + indigotine (E 132) (aluminium lake E104 + E132), glycol montanic wax.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: film-coated tablets, light green in colour, elongated shape, with transverse grooves on both sides; on one side – embossed with two company logos.

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 myocardial cells 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 the 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 undergoes extensive metabolism. 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. Plasma steady-state concentrations of norverapamil and verapamil are equivalent. 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 mean bioavailability after a single dose of prolonged-release verapamil is approximately 33%, due to extensive first-pass metabolism in the liver. Bioavailability increases twofold after repeated dosing.

After administration of prolonged-release verapamil, maximum plasma concentration of verapamil is reached within 4–5 hours and of norverapamil within 5 hours. Food intake does not affect verapamil bioavailability.

Distribution

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

Metabolism

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

Elimination

After oral administration, the elimination half-life is 3–7 hours. 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 systemic clearance of verapamil is nearly as high as hepatic blood flow, averaging 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 influence verapamil pharmacokinetics in patients with arterial hypertension. The elimination half-life may be prolonged in elderly patients. However, the antihypertensive effect of verapamil has been shown to be independent of age.

Patients with renal impairment. Renal function impairment does not affect verapamil pharmacokinetics, as demonstrated in comparative studies between 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 increases in patients with impaired liver function due to reduced clearance and increased volume of distribution.

Clinical characteristics.

Indications.

• Ischemic heart disease, including: stable angina pectoris; unstable angina (progressive angina, rest angina); vasospastic angina (variant angina, Prinzmetal's angina); post-infarction angina in patients without heart failure when β-adrenoblockers 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 cardiac pacemaker).
• Sick sinus syndrome (except in patients with a functioning artificial cardiac pacemaker).
• Heart failure with reduced ejection fraction below 35% and/or pulmonary capillary 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). In such patients, administration of verapamil hydrochloride may lead to the development 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-adrenoblockers concomitantly during treatment with Isoptinâ SR (except under intensive care conditions).

Interaction with other medicinal products and other forms of interaction.

In vitro studies of verapamil hydrochloride metabolism have shown that it is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil is an inhibitor of CYP3A4 enzymes and P-glycoproteins (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 substrates of P-gp 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 oral clearance of quinidine (~35%). Risk of arterial hypotension; in patients with hypertrophic obstructive cardiomyopathy, pulmonary edema may occur.

Flecainide: minimal effect on plasma clearance of flecainide (<~10%); no effect on plasma clearance of verapamil (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.

Glibenclamide: increased Cmax of glibenclamide by approximately 28%, AUC by 26%.

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

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 fivefold.

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

Midazolam: increases AUC of midazolam threefold and Cmax twofold.

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 necessary.

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

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 a patient already receiving an HMG-CoA reductase inhibitor requires initiation of verapamil, consideration should be given to reducing the statin dose, with dosage adjustments 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, Cmax by 4.6-fold.

Fluvastatin, pravastatin, and rosuvastatin are not metabolized by cytochrome CYP3A4 and are less likely to interact with verapamil.

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

Sulfinpyrazone: increased oral clearance of verapamil (approximately 3-fold), reduced bioavailability by 60%. Hypotensive effect may be diminished.

Dabigatran: verapamil in the form of prolonged-release tablets increases Cmax (up to 90%) and AUC (up to 70%) of dabigatran. Risk of bleeding is increased. When used concomitantly with oral verapamil, dose reduction of dabigatran 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 possible increased risk of bleeding, especially in patients with additional risk factors. Dose reduction of DOACs may be required when used concomitantly with oral verapamil (see DOAC prescribing information for dosing recommendations).

Ivabradine: concomitant use with ivabradine is contraindicated due to additive effects in reducing heart rate by verapamil in addition to the effect of ivabradine (see section "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 certain 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 administration of verapamil hydrochloride and lithium, with or without increased plasma lithium levels. However, in patients who were chronically 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 activity of neuromuscular blocking agents (curare-like and 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, marked arterial hypotension, or left ventricular dysfunction.

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

Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and prolongs atrioventricular conduction time. Use with caution, as development of second- or third-degree atrioventricular block (which are contraindications), or single-, dual-, 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 occurrence 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 common in elderly patients.

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

Antiarrhythmic agents, β-adrenoblockers

Mutual enhancement of cardiovascular effects (increased degree of atrioventricular block, marked reduction in heart rate, onset of heart failure, significant decrease in arterial pressure). Asymptomatic bradycardia (36 beats/min) with wandering atrial pacemaker rhythm has been observed in patients receiving concomitant therapy with timolol eye drops (a β-adrenoblocker) 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 treatment in patients with an ejection fraction greater than 35%, and adequate control must be maintained throughout the treatment period.

HMG-CoA reductase inhibitors (statins)

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

Neuromuscular conduction disorders

Verapamil hydrochloride should be used with caution in patients with disorders affecting 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 eliminated by hemodialysis.

Hepatic impairment

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

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 on reproductive toxicity. Since data obtained from reproductive studies in animals 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 amount of verapamil transferred to the newborn is low (0.1–1% of the dose received by the mother). Therefore, verapamil use may be compatible with breastfeeding; however, the risk to the newborn cannot be excluded. Due to the potential for serious adverse reactions in breastfed newborns, verapamil may be used during breastfeeding only if clearly needed for the mother.

Ability to influence reaction speed when driving or operating machinery.

Due to the antihypertensive effect of verapamil hydrochloride, depending on individual response, the ability to drive vehicles, operate machinery, or work under hazardous conditions may be impaired, particularly during the initial phase of treatment, when increasing the dose, when changing antihypertensive medication, and when taking the drug concomitantly with alcohol. Verapamil may increase plasma alcohol levels and slow its elimination, thereby potentiating the effects of alcohol.

Administration and Dosage

Dosage must be individually adjusted for each adult patient. Long-term clinical experience shows that the average daily dose for all indications ranges from 240 to 360 mg. During prolonged treatment, the average daily dose should not exceed 480 mg; only short-term dose increases are permissible. The tablets should be taken whole, 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. The tablet is divisible, and a half-dose may be administered without altering pharmacokinetic properties.

Ischemic Heart Disease

Recommended dose: 240–480 mg daily, divided into two doses: 0.5–1 tablet of Isoptin® SR twice daily. Isoptin® SR should be used when lower doses do not achieve the desired effect.

Arterial Hypertension

Recommended dose: 240–480 mg daily, divided into two doses. For example: 1 tablet of Isoptin® SR once daily in the morning (equivalent to 240 mg verapamil hydrochloride per day). If the response is inadequate, add an additional 0.5–1 tablet of Isoptin® SR in the evening (equivalent to 360–480 mg verapamil hydrochloride per day).

Paroxysmal Supraventricular Tachycardia, Atrial Flutter/Fibrillation

Recommended dose: 240–480 mg daily, divided into two doses:
0.5–1 tablet of Isoptin® SR twice daily. Isoptin® SR should be used when lower doses do not produce a satisfactory response.

Renal Impairment

Available data are provided in the section "Special Populations". 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 intensified and prolonged due to slowed drug metabolism, depending on the severity of impairment. Therefore, dosage should be initiated with particular caution, starting with low doses (e.g., initially 2–3 times daily 40 mg (in appropriate dosage form, e.g., Isoptin® 40 mg tablets), corresponding to 80–120 mg daily). See "Special Populations".

Do not administer the drug while lying down.

Verapamil hydrochloride must not be administered within 7 days following myocardial infarction.

After long-term 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

There are no data on the use of Isoptin® SR in children.

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 calcium preparations (calcium chloride) are effective in counteracting symptoms of intentional overdose after oral administration of verapamil hydrochloride.

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

Due to the potential for delayed absorption of sustained-release tablets, hospitalization and medical supervision for at least 48 hours are recommended. 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 during 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, hypotension, flushing, peripheral edema, and fatigue.

Immune system disorders: not known – hypersensitivity.

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

Metabolism and nutritional disorders: not known – hyperkalemia.

Psychiatric disorders: rare – somnolence.

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

Cardiac disorders: common – bradycardia, flushing, hypotension; uncommon – palpitations, tachycardia; not known – first-, second-, or third-degree atrioventricular block, heart failure, sinus 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 increased serum prolactin levels.

* Paralysis (tetraparesis) has been reported once during post-marketing surveillance in association with concomitant use of verapamil and colchicine. This may be due to increased penetration of colchicine across the blood-brain barrier as a result of verapamil’s 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 out of reach of children at a temperature not exceeding 25 °C.

Packaging. 15 tablets per blister, 2 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 place of business. Knollstrasse, 67061 Ludwigshafen, Germany or Anthousa Avenue 7, Anthousa Attiki, 15349, Greece.