Interaction between flunarizine and oral contraceptives./nThe question concerns a 23 years old ment

Fråga: Interaction between flunarizine and oral contraceptives.

The question concerns a 23 years old mentally retarded woman with a special form of epilepsy. She is being treated with Tegretol (carbamazepine) 200 mg daily, Sibelium (flunarizine) (dose unknown) and creatinine monohydrate 2 gx2. Contraceptives are now considered, ie oral contraceptives, Depo-Provera (medroxiprogesteron) or Levonova (levonorgestrel). Her menstuations are normal. Is there an interaction between flunarizine and oral contraceptives?

Sammanfattning: No documentation of an interaction between flunarizine and oral contraceptives has been found and is not primarily expected.

Concerning the other medication of the patient, there is clear evidence of an interaction between Levonova (levonorgestrel) and Tegretol (carbamazepine). In order to acieve an adequate contraceptive effect, an increased dose of steroids is often needed. However, there is no indication of an interaction between Depo-Provera (medroxiprogesteron) and Tegretol.

Svar: Flunarizine, a drug not available on the Swedish market, is a difluorinated piperazine derivate with a histamine H1-receptor and calcium channel blocking activity. It is used in vertigo, prophylactic treatment of migraine and as "add-on" therapy in patients with severe epilepsy. It is extensively metabolised in animals by oxidative N-dealkylation, aromatic hydroxylation and glucuronidation. The main route of metabolite elimination appears to be biliary. Similar patterns of metabolism and elimination are believed to occur in humans although detailed studies have not been reported. Flunarizine has a very long elimination half-life of about 18 days, which is probably due to its high affinity to tissue and slow redistribution. The metabolism of flunarizine appears to be enhanced by enzyme inducers like carbamazepine. In order to achieve a therapeutic plasma concentration, a dosage of 15-20 mg daily is recommended to patients with concomitant antiepileptic medication (1, 2).

It has been shown that anticonvulsants, such as carbamazepine, phenytoin and primidone, induce hepatic enzymes involved in the metabolism of oral contraceptives. This in turn causes an increase in the rate of their metabolism and a reduction of their concentration to below the therapeutic minimum steroid plasma concentration. This is followed by menstrual irregularities and unplanned pregnancies (3, 4). Based on pharmacokinetic studies and case reports it has been shown that the area under the plasma concentration curve (AUC) and plasma concentrations of ethinyloestradiol and levonorgestrel (eg Levonova) decreased when oral contraceptives were given together with enzyme inducing anticonvulsants. No changes in the plasma concentration of progestogens (eg Depo-Provera) were seen (4, 5, 6, 7). Spotting or breakthrough bleeding in patients who are taking oral contraceptives and enzyme inducing anticonvulsants could indicate that the drugs are interacting although lack of breakthrough bleeding does not ensure contraceptive protection (4).

No documentation has been found in the literature concerning a possible interaction between flunarizine and oral contraceptives. However, a mechanism of such kind could not be excluded as flunarizine is metabolised in the liver to a major extent. 1 Martindale, The extra pharmcopoeia, 1993; 30th ed: 939 2 Todd PA, Benfield P: Flunarizine. A Reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs 1989; 38: 481-499 3 Dollery, Therapeutic drugs, 1991; page L15-L20, M27-M31 4 Hansten, Horn, Drug interactions & updates, 1971-; page 333-334 5 Klosterskov Jensen P, Saano V, Haring P, Svenstrup B, Menge GP: Possible interaction between oxcarbazepine and an oral contraceptive. Epilepsia 1992; 33: 1149-1152 6 Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M: The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990; 30: 892-896 7 Drugline nr 02076 (år 1980)