Zinepra

Uses

Flunarizine is used for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Propranolol is used for:

• essential and renal hypertension
• angina pectoris
• long term prophylaxis after recovery from acyte myocardial infarction
• cardiac dysrhythmia
• prophylaxis of migraine
• essential tremor
• anxiety and anxiety tachycardia
• adjunctive management of thyrotoxicosis and thyrotoxic crisis
• hypertrophic obstructive cardiomyopathy
• phaeochromocytoma (with α-blocker)

Zinepra is also used to associated treatment for these conditions: Severe MigraineAkathisia caused by antipsychotic use, Angina Pectoris, Atrial Fibrillation, Cardiovascular Mortality, Gastroesophageal variceal hemorrhage prophylaxis, Hemangiomas, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Obstructive Hypertrophic Cardiomyopathy, Performance Anxiety, Pheochromocytomas, Proliferating Infantile Hemangioma, Supraventricular Arrhythmias, Tachyarrhythmia caused by Digitalis intoxication, Tachyarrhythmia caused by catecholamine excess, Thyroid Crisis, Thyrotoxicosis, Tremor caused by lithium, Tremor, Essential, Ventricular Tachycardia (VT)

How Zinepra works

Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.

Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system.

Dosage

Zinepra dosage

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Tablet:

Adults:

• Hypertension: A starting dose of 80 mg twice a day may increased at weekly intervals according to response. The usual dose range is 160-320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
• Angina, anxiety, migraine and essential tremor: A staring dose of 40 mg two or three times daily may be increased by the same amount at weekly intervals according to patients response. An adequate response in anxiety, migraine and essential tremor is usually seen in the range 80-160 mg/day and an angina in the range 120-240 mg/day.
• Situational and generalized anxiety: A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalized anxiety require long term therapy, usually responds adequately to 40 mg twice daily which ,which individual cases, may be increased to 40 mgthree times daily. Treatment should be continued according to responses. Patients should reviewed after 6 to 12 months treatment.
• Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: A dosage range of 10-40 mg three or four times a day usually achieves the required response.
• Post myocardial infarction: Treatment should be started between days 5 and after 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily doses three after be given as 80 mg twice a day. Phaeochromocytoma (Used only with an alpha receptor blocking drug).
• Pre-operative: 60 mg daily for three days.
• Non-operable malignant cases: 30 mg daily.
• Migraine: Under 12 years: 20 mg two or three times daily.Over 12 years : The adult dose.

Children:

• Sysrhythmias, Phaeochromocytoma, Thyrotoxicisis: Dosage should be individually determined and the following is only a guide 0.25-0.5 mg/kg three or four times daily as required.

Sustained Release Capsule:

Adult:

• Hypertension: The usual initial dose is 80mg Propranolol SR once daily, whether used alone or added to a diuretic. The usual maintenance dosage is 120 to 160 mg once daily.
• Angina pectoris: Starting with 80mg Propranolol SR once daily, dosage should be gradually increased three to seven day intervals until optimum response is obtained.
• Migraine: The initial oral dose is 80 mg Propranolol SR once daily. T he usual effective dose range is 160 to 240 mg once daily. It may be advisable to withdraw the drug gradually over a period of several weeks.
• Hypertrophic subaortic stenosis: 80 mg Propranolol SR once daily

Injection:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The usual dose is 1 to 3 mg administered under careful monitoring, such as electrocardiography and central venous pressure. The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of loweringblood pressureand causing cardiac standstill.

Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after two minutes. Thereafter, additional drug should not be given in less than four hours. Additional propranolol hydrochloride should not be given when the desired alteration in rate or rhythm is achieved.

Transfer to oral therapy as soon as possible.

Side Effects

Flunarizine is well tolerated and seldom causes serious side effects. The main adverse effects experienced by the patients are as follows:

Central nervous system: Depression, drowsiness, sedation, and anxiety.

Gastrointestinal: Heart burn, nausea, emesis, dry mouth, gastralgia.

Miscellaneous: Weight gain, and/or increased appetite, asthenia, muscle aches, skin rash, and galactorrhea in female patients on oral contraceptives.

Propranolol is usually well tolerated. Minor side effects such as cold extremities, nausea, diarrhea, sleep disturbances and lassitude are often transient. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs.

Toxicity

-Flunarizine should be used with care in patients with depression or those being prescribed other agents, such as phenothiazines, concurrently, which may cause extrapyramidal side-effects. -Acute overdosage has been reported and the observed symptoms were sedation, agitation and tachycardia. -Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known.

Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound.

Precaution

Since sedation or drowsiness occur in some patients during treatment with flunarizine hydrochloride, patients should be cautioned against activities which require alertness or rapid, precise responses (e.g. operating machinery or a motor vehicle) until the response to the drug has been determined.

Beta-adrenoceptor blocking drugs should be avoided in over heart failure. Propranolol modifies the tachycardia of hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Interaction

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Flunarizine treatment. Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with flunarizine by increasing its metabolism. So an increase in dosage of flunarizine may be required.

Beta-adrenoceptor blocking drugs interact with clonidine.If beta-adrenoceptor blocking drugs and clonidine are given concurrently, clonidine should be discontinued until several days after withdrawal of beta-adrenoceptor blocking drug. Care should be taken in prescribing a beta-adrenoceptor blocking drugs with class 1 antidysrhythmic agents (disopyramide).Beta-adrenoceptor blocking drugs should be used with caution in combination with verapamil in patients with impaired ventricular function.

Volume of Distribution

The volume of distribution of propranolol is approximately 4L/kg or 320L.

Elimination Route

85% following oral administration.

Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced C_max values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a T_max of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase T_max but does increase bioavailability.

Half Life

18 days

The elimination half life of propranolol is approximately 8 hours. The plasma half life of propranolol is 3 to 6 hours.

Clearance

The clearance of propranolol is 2.7±0.03L/h/kg in infants 90 days. Propranolol clearance increases linearly with hepatic blood flow. Propanolol has a clearance in hypertensive adults of 810mL/min.

Elimination Route

91% of an oral dose of propranolol is recovered as 12 metabolites in the urine.

Pregnancy & Breastfeeding use

Safety in pregnancy and lactation has not been established.

There are no adequate and controlled studies in pregnant women. Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing mother.

Contraindication

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Propranolol Hydrochloride is contraindicated in patients with known Hypersensitivity to any component of the formulation. If there is a history of bronchial asthma of bronchospasm.

Acute Overdose

The symptoms of over dosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm. Treatment of over dosage include close supervision, treatment in an intensive care ward, he use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Storage Condition

Store at a cool & dry place, protected from light and moisture. Keep out of reach of the children.

Store in a cool dry place. Protect from light.

Innovators Monograph

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