Darob

Darob 40mg Tablets are indicated for:

1. Ventricular arrhythmias:

- Treatment of life-threatening ventricular tachyarrhythmias;

- Treatment of symptomatic non-sustained ventricular tachyarrhythmias

2. Supraventricular arrhythmias:

- Prophylaxis of paroxysmal atrial tachycardia, paroxysmal atrial fibrillation, paroxysmal A-V nodal re-entrant tachycardia, paroxysmal A-V re-entrant tachycardia using accessory pathways, and paroxysmal supraventricular tachycardia after cardiac surgery;

- Maintenance of normal sinus rhythm following conversion of atrial fibrillation or atrial flutter

Oral administration in adults:

As with other antiarrhythmic agents, it is recommended that Darob 40mg Tablets be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualized and based on the patient's response. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

In view of its β-adrenergic blocking properties, treatment with Darob 40mg Tablets should not be discontinued suddenly, especially in patients with ischaemic heart disease (angina pectoris, prior acute myocardial infarction) or hypertension, to prevent exacerbation of the disease (see 4.4 Warnings).

The initiation of treatment or changes in dosage with Darob should follow an appropriate medical evaluation including ECG control with measurement of the corrected QT interval, and assessment of renal function, electrolyte balance and concomitant medications (See 4.4 Warnings and precautions).

The following dosing schedule can be recommended:

The initial dose is 80 mg, administered either singly or as two divided doses.

Oral dosage of Darob should be adjusted gradually allowing 2-3 days between dosing increments in order to attain steady-state, and to allow monitoring of QT intervals. Most patients respond to a daily dose of 160 to 320 mg administered in two divided doses at approximately 12 hour intervals. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480 - 640 mg/day. These doses should be used under specialist supervision and should only be prescribed when the potential benefit outweighs the increased risk of adverse events, particularly proarrhythmias (see 4.4 Warnings).

Children

Darob is not intended for administration to children.

Dosage in renally impaired patients

Because Darob is excreted mainly in urine, the dosage should be reduced when the creatinine clearance is less than 60 ml/min according to the following table:

Creatinine clearance (ml/min)

Adjusted doses

The creatinine clearance can be estimated from serum creatinine by the Cockroft and Gault formula:

When serum creatinine is given in μmol/l, divide the value by 88.4 (1mg/dl = 88.4 μmol/l).

Dosage in hepatically impaired patients

No dosage adjustment is required in hepatically impaired patients.

Darob should not be used where there is evidence of:

- sick sinus syndrome

- second and third degree AV heart block unless a functioning pacemaker is present

- congenital or acquired long QT syndromes

- torsades de pointes

- symptomatic sinus bradycardia

- uncontrolled congestive heart failure

- cardiogenic shock

- anaesthesia that produces myocardial depression

- untreated phaeochromocytoma

- hypotension (except due to arrhythmia)

- Raynaud's phenomenon and severe peripheral circulatory disturbances

- history of chronic obstructive airway disease or bronchial asthma

- hypersensitivity to Darob, other betablockers or any of the excipients in the formulation.

- metabolic acidosis

- renal failure (creatinine clearance < 10 ml/min).

- Contraindicated Combination: Darob should not be administered in combination with drugs like class Ia antiarrhythmics, class II antiarrhythmics such as amiodarone, dofetilide, Ibutilide etc; neuroleptics such as trimipramine, phenobarbitone, chlorpromazine etc; and antibiotics such as erythromycin IV and moxifloxacin.

Abrupt Withdrawal

Hypersensitivity to catecholamines is observed in patients withdrawn from beta-blocker therapy.).

Psoriasis

Beta-blocking drugs have been reported rarely to exacerbate the symptoms of psoriasis vulgaris.

There are no data available, but the occasional occurrence of side effects such as dizziness and fatigue should be taken into account (see

The most frequent adverse effects of Darob arise from its beta-blockade properties. Adverse effects are usually transient in nature and rarely necessitate interruption of, or withdrawal from treatment. If they do occur, they usually disappear when the dosage is reduced. The most significant adverse effects, however, are those due to proarrhythmia, including torsades de pointes (see Warnings).

The following are adverse events considered related to therapy, occurring in 1% or more of patients treated with Darob.

Cardiovascular

Bradycardia, dyspnoea, chest pain, palpitations, oedema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope

Dermatologic

Rash

Gastro-intestinal

Nausea/vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence

Musculoskeletal

Cramps

Nervous/psychiatric

Fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paresthesia, mood changes, anxiety

Urogenital

Sexual dysfunction

Special Senses

Visual disturbances, taste abnormalities, hearing disturbances

Body as a whole

Fever

In trials of patients with cardiac arrhythmia, the most common adverse events leading to discontinuation of Darob were fatigue 4%, bradycardia (<50 bpm) 3%, dyspnoea 3%, proarrhythmia 2%, asthenia 2%, and dizziness 2%.

Cold and cyanotic extremities, Raynaud's phenomenon, increase in existing intermittent claudication and dry eyes have been seen in association with other beta-blockers.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal products is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Intentional or accidental overdose with Darob has rarely resulted in death. Haemodialysis results in a large reduction of plasma levels of Darob.

Symptoms and treatment of overdose: The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycaemia. In cases of massive intentional overdose (2-16 g) of Darob the following clinical findings were seen: hypotension, bradycardia, prolongation of QT-interval, premature ventricular complexes, ventricular tachycardia, torsades de pointes.

If overdose occurs, therapy with Darob should be discontinued and the patient observed closely. In addition, if required, the following therapeutic measures are suggested:

Bradycardia

Atropine (0.5 to 2 mg IV), another anticholinergic drug, a beta-adrenergic agonist (isoprenaline, 5 microgram per minute, up to 25 microgram, by slow IV injection) or transvenous cardiac pacing

Heart Block (second and third degree)

Transvenous cardiac pacing

Hypotension

Adrenaline rather than isoprenaline or noradrenaline may be useful, depending on associated factors

Bronchospasm

Aminophylline or aerosol beta-2-receptor stimulant

Torsades de pointes

DC cardioversion, transvenous cardiac pacing, adrenaline, and/or magnesium sulphate

ATC Code - C70A A07

D,l-Darob is a non-selective hydrophilic β-adrenergic receptor blocking agent, devoid of intrinsic sympathomimetic activity or membrane stabilizing activity.

Darob has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Darob has no known effect on the upstroke velocity and therefore no effect on the depolarisation phase.

Darob uniformly prolongs the action potential duration in cardiac tissues by delaying the repolarisation phase. Its major effects are prolongation of the atrial, ventricular and accessory pathway effective refractory periods.

The Class II and III properties may be reflected on the surface electrocardiogram by a lengthening of the PR, QT and QTc (QT corrected for heart rate) intervals with no significant alteration in the QRS duration.

The d- and l-isomers of Darob have similar Class III antiarrhythmic effects while the l-isomer is responsible for virtually all of the beta-blocking activity. Although significant beta-blockade may occur at oral doses as low as 25 mg, Class III effects are usually seen at daily doses of greater than 160 mg.

Its β-adrenergic blocking activity causes a reduction in heart rate (negative chronotropic effect) and a limited reduction in the force of contraction (negative inotropic effect). These cardiac changes reduce myocardial oxygen consumption and cardiac work. Like other β-blockers, Darob inhibits renin release. The renin-suppressive effect of Darob is significant both at rest and during exercise. Like other beta adrenergic blocking agents, Darob produces a gradual but significant reduction in both systolic and diastolic blood pressures in hypertensive patients. Twenty-four-hour control of blood pressure is maintained both in the supine and upright positions with a single daily dose.

The bioavailability of oral Darob is essentially complete (greater than 90%). After oral administration, peak levels are reached in 2.5 to 4 hours, and steady-state plasma levels are attained within 2-3 days. The absorption is reduced by approximately 20% when administered with a standard meal, in comparison to fasting conditions. Over the dosage range 40-640 mg/day Darob displays dose proportionality with respect to plasma levels. Distribution occurs to a central (plasma) and a peripheral compartment, with an elimination half-life of 10-20 hours. Darob does not bind to plasma proteins and is not metabolised. There is very little inter-subject variability in plasma levels. Darob crosses the blood brain barrier poorly, with cerebrospinal fluid concentrations only 10% of those in plasma. The primary route of elimination is renal excretion. Approximately 80 to 90% of a dose is excreted unchanged in the urine, while the remainder is excreted in the faeces. Lower doses are necessary in conditions of renal impairment (see Dosage and Administration in patients with renal dysfunction). Age does not significantly alter the pharmacokinetics, although impaired renal function in geriatric patients can decrease the excretion rate, resulting in increased drug accumulation.

No further particulars.

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