LUNAR
Flunarizine Hydrochloride Tablets
PRESENTATION
Each Uncoated Tablet Contains Flunarizine Dihydrochloride Flunarizine 5/10 mg.
Packing: 10*10 Blister
CLINICAL PARTICULARS
Therapeutic Indications
FLUNARIZINE (flunarizine hydrochloride) is indicated for prophylaxis of migraine (with and without aura) in patients with frequent and severe attacks, who have not responded satisfactorily to other treatment and/or in whom other therapy has resulted in unacceptable side effects. Flunarizine is not indicated for the treatment of acute attacks.
POSOLOGY AND METHOD OF ADMINISTRATION
Posology
Adults The recommended dose is 10 mg daily (at night) for patients younger than 65 years of age. If, during this treatment, depressive, extrapyramidal or other unacceptable adverse experiences occur, administration should be discontinued. If, after 3 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should also be discontinued. If treatment goes beyond 6 months, patients should continue to be closely monitored for side effects, in particular CNS related events, and therapy should be discontinued at the first sign of adverse reactions (see WARNINGS). Although there are no long-term controlled clinical trials with flunarizine, clinical experience suggests that 2 successive drug-free days per week may decrease the potential for adverse reactions. However, it should be noted that a brief interruption in therapy will not significantly reduce the exposure to FLUNARIZINE, given its long half-life (19 days).
Method of Administration
Always take flunarizine after a meal whenever possible to avoid stomach irritation. Swallow the tablets whole with water.
CONTRAINDICATIONS
FLUNARIZINE (flunarizine hydrochloride) is contraindicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders (See WARNINGS and ADVERSE REACTIONS). Flunarizine is contraindicated in patients with known hypersensitivity to the drug.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Extrapyramidal Symptoms Clinical studies indicate that flunarizine treatment, even at recommended doses, can produce motor disturbances in subjects who did not show previous neurological deficits. Elderly patients appear to be particularly at risk. The clinical symptoms resemble Parkinson's disease, however, they do not improve with antiparkinson medication. Experience to date suggests that in most instances the extrapyramidal symptoms tend to be reversible following discontinuation of flunarizine treatment. Depression Clinical studies indicate that flunarizine can, even at recommended doses, precipitate depression, mostly in younger patients. Fatigue In rare cases, fatigue may increase progressively during flunarizine treatment: in this event, therapy should be discontinued. The recommended dose should not be exceeded. Patients should be followed closely and monitored at regular intervals so that extrapyramidal and/or depressive symptoms and/or fatigue may be detected early, and treatment discontinued. If the therapeutic effects diminish during treatment, flunarizine should be discontinued (for duration of treatment see also DOSAGE AND ADMINISTRATION).
PRECAUTIONS ON SPECIAL POPULATIONS
Since sedation and/or drowsiness occur in some patients during treatment with FLUNARIZINE (flunarizine hydrochloride) (see ADVERSE REACTIONS), 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.
Use in the Elderly
The safety and efficacy of flunarizine in the prophylaxis of migraine has not been established in elderly subjects.
Use in Children
The safety and efficacy of flunarizine in the prophylaxis of migraine has not been established in patients younger than 18 years of age.
Endocrine Effects Galactorrhea has been reported in a few female patients, some of whom were also on oral contraceptives, within the first two months of flunarizine treatment. Discontinuation of flunarizine therapy resolved the galactorrhea in most cases. Flunarizine therapy caused a mild but significant elevation of serum prolactin levels while GH, LH, FSH and TSH levels did not show significant variation. Two cases of menstrual irregularities have been reported.
INTERACTION WITH OTHER MEDICINAL PRODUCTS
Evidence from therapeutic trials in epileptic patients indicates that whereas flunarizine does not affect the kinetics of phenytoin, carbamazepine and valproic acid, it does decrease the plasma levels of mephenytoin. Furthermore, steady state levels of flunarizine are reduced by
Co- administration of two or more anticonvulsants. This is considered to be a result of enhanced first pass metabolism of flunarizine as a consequence of liver enzyme induction by the anticonvulsant medications. In other studies, flunarizine was shown not to affect the anticoagulant effect of warfarin sodium or the hypoglycemic effect of glibenclamide and insulin. Excessive sedation can occur when alcohol, hypnotics or tranquilizers are taken simultaneously with FLUNARIZINE
FERTILITY, PREGNANCY AND LACTATION
Pregnancy
To date, there are no data to support the use of flunarizine during pregnancy. It should therefore not be administered to pregnant women unless the anticipated benefits outweigh the potential risks.
Lactation
Studies in lactating dogs have shown that flunarizine is excreted in milk. The concentration of flunarizine in milk is much greater than that in plasma. No data are available on the excretion in human breast milk. Women taking flunarizine should not breast feed.
UNDESIRABLE EFFECTS
In clinical trials with flunarizine hydrochloride in migraine patients, drowsiness (also described as sedation or fatigue) as well as weight gain (and/or increased appetite) occurred fairly frequently, in the order of 20 and 15%, respectively. Of 840 migraine patients, 23 (2.7%) and 9 (1.1%) required withdrawal from flunarizine therapy due to drowsiness and weight gain, respectively. The most serious side effect encountered in migraines’ during clinical trials was depression of 840 migraine patients, 11 (1.3%) were withdrawn due to depression. International postmarketing experience suggests that patients between 20 and 54 years of age with a personal or familial history of depression are particularly at risk (see CONTRAINDICATIONS and WARNINGS). Clinical experience in other indications and epidemiologic surveys suggest that extrapyramidal symptoms may develop during flunarizine therapy. Elderly patients are particularly at risk (see CONTRAINDICATIONS and WARNINGS). Other side effects encountered in clinical trials for migraine prophylaxis included the following: Gastrointestinal: Heartburn, nausea, emesis, gastralgia; Central Nervous System: Insomnia and sleep change, anxiety, dizziness/vertigo; Miscellaneous: Dry mouth, asthenia, muscle aches, skin rash.
OVERDOSE
Symptoms
On the basis of the pharmacological properties of the drug, sedation and asthenia may be expected to occur. A few cases of acute over dosage (up to 600 mg in one intake) have been reported and the observed symptoms included central nervous system effects (e.g. sedation, confusion and agitation) and cardiovascular effects (e.g. tachycardia).
Treatment There is no specific antidote. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics Properties
Pharmacotherapeutic Group: Anti-vertigo Preparations
Mechanism of Action
Flunarizine hydrochloride is a selective calcium antagonist. It prevents cellular calcium overload by reducing excessive trans membrane calcium influx. Flunarizine does not interfere with normal cellular calcium homeostasis. Flunarizine also has antihistaminic properties. The effects of flunarizine in the prophylaxis of migraine are most pronounced with regards to the reduction of the frequency of attacks. The severity of migraine attacks improves to a lesser extent, while little or no effect is seen on the duration of migraine episodes.
Pharmacokinetic
The drug is well absorbed reaching peak plasma concentrations within 2-4 hours, and reaching steady state at 5-6 weeks.
Absorption
Flunarizine is well absorbed (>80%) from the gastrointestinal tract, reaching peak plasma concentrations within 2 to 4 hours after oral dosing. Under conditions of reduced gastric acidity (higher gastric pH), bioavailability may be moderately lower.
Distribution
Flunarizine is >99% bound to plasma proteins. It has a large volume of distribution of approximately 78 L/kg in healthy subjects and approximately 207 L/kg in epileptic patients indicating extensive distribution into extravascular tissue. The drug quickly crosses the blood brain barrier; concentrations in the brain are approximately 10 times higher than those in plasma.
Metabolism
Flunarizine is metabolized in the liver into at least 15 metabolites. The primary metabolic pathway is CYP2D6.
Elimination
Flunarizine is primarily eliminated as parent drug and metabolites through the faces via bile. Within 24 to 48 hours after administration, approximately 3% to 5% of the administered dose of flunarizine is eliminated in the faces as parent drug and metabolites and <1% is excreted as unchanged drug in urine. Its terminal elimination half-life is highly variable, ranging from 5 to 15 hours in most individual subjects after a single dose. Some subjects show measurable plasma concentrations of flunarizine (>0.5 ng/mL) for a prolonged time period (up to 30 days), possibly due to redistribution of the drug from other tissues. Plasma concentrations of flunarizine reach steady state after approximately 8 weeks of oncedaily multiple dosing and are about 3-fold higher than those observed after a single dose. Steady state flunarizine concentrations are proportional over a dose range of 5 mg to 30 mg.
Preclinical Safety Data
Preclinical effects of a CNS nature (e.g. sedation, salivation, and ataxia) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
SPECIAL PRECAUTIONS FOR STORAGE
Store at room temperature (15-30°C), protected from light and moisture.