Flunarizine

Summary

Synopsis: Flunarizine¹ is a ‘selective’ calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day.

The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria.

A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening.

Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.

Pharmacodynamic Studies: Flunarizine reduces the transmembrane fluxes of calcium in situations where calcium is stimulated to enter the cell in excess, thus preventing the deleterious consequences of ‘calcium overload’ within the cell. It does not interfere with normal cellular calcium homeostasis, having little negative inotropic effect on heart muscle and has no action on the myogenic tone of blood vessels.

Potent and long lasting inhibition of calcium-related contraction of vascular smooth muscle induced by a variety of agents has been observed with flunarizine, the degree of inhibition varying with the origin of the blood vessel, the species and the nature of the stimulus. Electron microscopic studies strongly support the concept that the drug exerts its calcium-blocking effects at the level of the plasma membrane. In vitro and in vivo studies of flunarizine in animals demonstrate protection of endothelial cells against damage from calcium overload, whilst it has also been shown to inhibit in a dose-dependent way echinocyte formation and the concomitant membrane rigidity induced by calcium ion loading with a calcium ion ionophore in red blood cells. The effects of flunarizine on the tolerance of the brain to oxygen deprivation have been demonstrated in various animal models. Essentially, brain cell survival after hypoxia or anoxia is increased after acute as well as chronic treatment with flunarizine, the beneficial action of the drug again thought to be operating through prevention of cellular calcium overload.

Flunarizine has also demonstrated vestibular depressive effect in animals and humans. Studies in animals have revealed an antihistaminic action whilst promising anticonvulsant properties in animal studies led to preliminary trials of flunarizine in epileptic patients. An antiarrhythmic effect has been demonstrated in dogs, and an apparent antiserotonin effect is thought likely to be due to a direct action of the drug on the vascular smooth muscle cell.

Pharmacokinetic Studies: Peak plasma levels occur 2 to 4 hours after oral administration of flunarizine in healthy subjects. With repeated administration of 10mg daily, plasma concentrations increase very gradually, reaching a steady-state after about 5 to 6 weeks of drug administration. Steady-state plasma levels remain constant during prolonged treatment with 10 mg/day and range between 39 and 115 ng/ml. No correlation between plasma levels and therapeutic effect has been determined.

Flunarizine pharmacokinetics are characterised by a very large volume of distribution (apparent volume of distribution in healthy subjects 43.2 L/kg), and in animal studies drug concentrations in various tissues were several times higher than plasma levels, particularly in adipose tissue and skeletal muscle in which flunarizine accumulates. Flunarizine enters the central nervous system, but brain levels in animals are very low. Small amounts of radioactivity have been recovered from the placenta and fetuses of rats, and relatively large amounts from the breast milk of dogs, after maternal administration of radiolabeled drug.

0.8% of flunarizine was present as free drug in plasma, 90% being bound to plasma proteins and 9% in blood cells. Only a negligible amount of flunarizine is excreted unchanged in the urine. Metabolism in animals involves oxidative-N-dealkylation, aromatic hydroxylation and glucuronidation, but metabolic studies in man have yet to be reported. Biliary excretion in rats accounted for between 40 and 80% of a dose. In healthy subjects flunarizine was removed from the body with a long elimination half-life of around 18 days.

Therapeutic Trials: Flunarizine has undergone trials in several therapeutic areas, particularly migraine prophylaxis, peripheral vascular disease and vertigo, sometimes involving cerebral blood flow disturbances. In the areas studied to date, flunarizine shows a progressive onset of effect often over several months.

In open studies of both classical and common migraine, flunarizine 10mg demonstrated a reduction in attack frequency in patients with a previous attack rate of less than 8 per month. Frequency of attacks was significantly reduced by flunarizine 10mg compared with placebo, and patients evaluated flunarizine therapy as being significantly better than placebo, but no consistent suppression of severity nor duration of attacks was reported. Results of 3 comparative trials found flunarizine 10mg to be at least as effective as pizotifen (2 to 3mg daily), with flunarizine improving some evaluation criteria more than pizotifen.

The majority of trials of flunarizine 10mg in patients with peripheral venous insufficiency have been placebo-controlled and have resulted in significant improvements of subjective and objective symptoms, together with the patient’s or physician’s global evaluation. Flunarizine 10mg daily produced equivalent improvements in subjective symptoms to the venotropic drug troxerutin 900mg daily over a 2-month therapy period; whilst both drugs reduced leg diameter measurements in patients to a similar extent in the first month of treatment, but the effect of flunarizine improved in the second month whilst that of troxerutin remained stable. Doses of flunarizine 20mg daily for initial periods of 1 to 3 months, reducing to 15 or 10mg thereafter, have resulted in significant increases in walking distance in patients with intermittent claudication compared with placebo. Other symptoms of occlusive and obliterative arterial disease have not shown such consistent improvements on flunarizine therapy. Flunarizine 75mg as a single initial dose produced a significantly better effect than the related compound cinnarizine (150mg), but after 1 week’s therapy the improvements in symptoms were comparable. Similarly, in a longer term trial, flunarizine 10mg daily was reported to produce equivalent improvement of symptoms of peripheral arteriosclerosis to cinnarizine 150mg daily.

Trials in patients with vertigo of peripheral or central origin frequently included an initial open stage in which flunarizine 20 to 60mg daily was administered for periods ranging from 1 week to 2 months. This led into a double-blind phase, where the doses were gradually reduced to a maintenance level of 10mg daily. Significant improvements were seen in both classes of vertigo when flunarizine was compared with placebo. Flunarizine 60mg was reported to be as effective as cinnarizine 150mg in a short term study in patients with vertigo of peripheral origin. A longer term study (4 months) in vertigo of central origin, comparing flunarizine 10mg with cinnarizine 200mg, again demonstrated equivalent effects for both drugs on the subjective system scores, but flunarizine was rated as significantly better in the patients’ global evaluation of treatment.

Side Effects: Flunarizine has been well tolerated, and has seldom caused important side effects. The main adverse effect experienced by patients is that of drowsiness, which can often be avoided by taking the dose at night or reducing the dose. Weight gain, mainly in migraine patients, may also occur and is sometimes a reason for reducing the dose.

Dosage: A maintenance dose of flunarizine 10mg daily is recommended in adults. Due to the long half-life of flunarizine, this dose may be taken once daily in the evening in an attempt to minimise the side effect of drowsiness. Since the onset of maximum effect may be gradual, possibly related to the gradual onset of steady-state plasma concentrations with usual doses, in cases where full efficacy is required as quickly as possible the 10mg daily dose may be doubled during the first 2 weeks, but it should be reduced to 10mg thereafter. Doses of 5mg may be used in patients in whom side effects are a problem, and 5mg daily is recommended for children weighing less than 40kg.