Domina

Composition:

Each 1ml solution contains 2.5mg Verapamil Hydrochloride (equivalent to 2.31mg Verapamil Base).

Mechanism of Action:

Verapamil inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductible and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of verapamil appears to be due to its effect on the slow channel in cells of the cardiac conduction system. The vasodilatory effect of verapamil appears to be due to its effect on blockage of calcium channels as well as α receptors.

Electrical activity in the SA and AV nodes depends, to a large degree, upon calcium influx through the slow channel. By inhibiting this influx, verapamil slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response.

By interrupting re-entry at the AV node, verapamil can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including (PSVT) associated with Wolff-Parkinson-White syndrome.

Verapamil does not induce peripheral arterial spasm.

Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in human. Verapamil does not alter total serum calcium levels.

Pharmacokinetics:

Intravenously administered verapamil has been shown to be rapidly metabolized.

Following intravenous infusion in human, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2 to 5 hours). Approximately 70% of an administered dose is excreted in the urine and 16% more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug.

Aging may affect the pharmacokinetics of verapamil given to hypertensive patients.

Elimination half-life may be prolonged in the elderly.

Indications:

Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia, including those associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong- Levine [L-G-L] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride administration.
Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White (W-P-W) and Lown-Ganong-Levine (L-G-L) syndromes).

Contraindications:

Severe hypotension or cardiogenic shock.
Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy).
Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction.
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes) are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation.
Ventricular tachycardia: Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting.
Known hypersensitivity to verapamil hydrochloride.

Dosage:

Adults:

The recommended intravenous doses of Docalpam are as follows:

Initial dose: 5mg initially, given slowly (over approximately 2 minutes), keeping the patient under constant observation and if possible, under ECG and blood pressure monitoring.

Repeat dose: If the therapeutic effect is not achieved, a further 5mg may be injected after 5 to 10 minutes. Drip infusion to maintain the therapeutic effect: 5-10 mg/hour in physiological saline, glucose, laevulose or similar solutions (pH≤6.5) on average up to a total dose of 100mg/day.

Pediatric population:

The safety and efficacy of Docalpam injection have been established in neonates, infants, children and adolescents:

Newborn 0.75 - 1mg (= 0.3-0.4 ml).

Infants 0.75 - 2mg (= 0.3-0.8 ml).

If there are any signs of tachycardia-induced heart failure (energetic exhaustion of the myocardium), digitalization is necessary before administering Verapamil intravenously.

Children aged 1-5 years, 2-3 mg (0.8-1.2 ml), aged 6-14 years, 2.5-5 mg (1-2 ml) of Docalpam. The injection should be given only until the onset of action.

Elderly patients:

The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects.

Intravenous infusion in hypertensive crisis:

Initial treatment with 0.05-0.1 mg/kg/hour and, if the effect proves to be insufficient, increase the dose at 30–60minutes intervals until twice the dose or more is reached. Average total dose up to 1.5 mg/kg/day.

Method of administration:

For intravenous use only.

Docalpam should be given as a slow intravenous injection over at least a two-minute period of time under continuous electrocardiographic and blood pressure monitoring.

Docalpam is physically compatible and chemically stable for at least 24 hours at 25° C protected from light in most common large volume parenteral solutions. Use only if solution is clear.

Unused amount of solution should be discarded immediately following withdrawal of any portion of contents.

For stability reasons this product is not recommended for dilution with sodium lactate injection in polyvinyl chloride bags.

Admixing intravenous verapamil hydrochloride with albumin, amphotericin B, hydralazine hydrochloride or trimethoprim and sulfamethoxazole should be avoided.

Verapamil hydrochloride will precipitate in any solution with a pH above 6.

Verapamil should not be taken with grapefruit juice.

Warnings and Precautions:

Hypotension:

Verapamil hydrochloride often produces a decrease in blood pressure below baseline levels which is usually transient and asymptomatic but may result in dizziness.

Extreme Bradycardia/Asystole:

Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second - or third-degree AV block, bradycardia, and in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately.

Heart Failure:

When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before verapamil is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen.

Heart Block:

Verapamil prolongs AV conduction time.

Hepatic and Renal Failure:

Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil hydrochloride but may prolong its duration. Repeated injections of verapamil hydrochloride in such patients may lead to accumulation and an excessive pharmacologic effect of the drug.

Premature Ventricular Contractions:

During conversion to normal sinus rhythm, or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with Verapamil hydrochloride.

Duchenne’s Muscular Dystrophy:

Verapamil hydrochloride can precipitate respiratory muscle failure. Therefore, it should be used with caution.

Increased Intracranial Pressure:

Verapamil hydrochloride has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed.

Side Effects:

Cardiovascular: Symptomatic hypotension, bradycardia, severe tachycardia.

Central Nervous System Effects: Dizziness, headache, Occasional cases of seizures.

Gastrointestinal: Nausea, abdominal discomfort.

In rare cases of hypersensitive patients: broncho/laryngeal spasm accompanied by itch and urticaria has been reported.

The low frequency: Emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, diaphoresis, and respiratory failure.

Drug Interactions:

Quinidine: Verapamil hydrochloride has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However, three patients have been described in whom the combination resulted in an exaggerated hypotensive presumably from the combined ability of both drugs to antagonize the effects of catecholamines on α-adrenergic receptors. Caution should therefore be used when employing this combination of drugs.
Beta-Adrenergic Blocking Drugs: The concomitant administration of intravenous beta-blockers and intravenous verapamil has resulted in serious adverse reactions, (an exaggerated hypotensive response) especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.
Disopyramide: Disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide: The concomitant administration of flecainide and verapamil may have additive effects, reducing myocardial contractility, prolonging AV conduction, and prolonging repolarization.
Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. The addition of verapamil, however, has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.
Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Phenobarbital: Phenobarbital therapy may increase verapamil clearance.
Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin.
Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists (such as verapamil) should be titrated carefully to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents: It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Pregnancy:

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Therefore, Verapamil hydrochloride be used during pregnancy only if clearly needed.

Breast-feeding:

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:

In rare instances, severe hemodynamic side effects - some of them fatal - have occurred following the intravenous administration of verapamil to neonates and infants. Caution should therefore be used when administering verapamil to pediatric patients.

Overdosage:

Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or administration of calcium injections may increase calcium ions flux across the slow channel. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation.