Has a rise in S-Alanine-aminotransferase (ALAT) levels been described for Leponex (clozapine)?/nA 2

Fråga: Has a rise in S-Alanine-aminotransferase (ALAT) levels been described for Leponex (clozapine)? A 20-year-old patient, suffering from schizophrenia, has elevated ALAT levels (1.65 ukat/l down to 1.06 ukat/l (reference <0.7 ukat/l)). The dose of clozapine is 150 mg daily. Other medication: Disipal (orphenadine) tablets 100 mg twice daily, Hibernal (chlorpromazine) 100 mg two tablets twice daily, Stesolid (diazepam) half a tablet of 5 mg twice daily.

Sammanfattning: Hepatotoxicity, revealed by increased aminotransferase concentrations, is a well-known side effect of clozapine and other neuroleptic drugs. In most cases these changes are reversible and the laboratory signs subside when the drugs are withdrawn. Moderate increases in aminotransferase concentrations have to be tolerated during therapy because of the strong treatment indications. When marked aminotransferase increase is obtained, the dose should be reduced or the drug withdrawn. In the present case the patient was also treated with chlorpromazine which has a well-known hepatotoxic potential.

Svar: Increased transaminase concentrations have been observed as a side effect of clozapine. In a Danish investigation one patient with clozapine monotherapy had a rise in ALAT levels (1). At a steady state (275 mg daily) and during decreasing dosage the S-ALAT level was 1.24 and became normal after withdrawal of the drug. Another patient had normal ALAT levels during clozapine treatment, but they were later increased when the clozapine dose was decreased (from 0.77 to 1.29 ukat/l).

Another study by the same authors of examined side effects in 17 psychotic patients on long-term treatment with clozapine and, in some of the cases, in combination with other neuroleptics (2). Three of these patients had moderately elevated ALAT levels ranging from 0.75 to 1.84 ukat/l. The clozapine dosage was between 100 and 800 mg daily. Two of the patients had had increased levels of transaminases before beginning clozapine treatment. In the third patient the values were normal after one month of continued clozapine treatment.

The Swedish Adverse Drug Reaction Advisory Committee (SADRAC) has received 7 reports concerning adverse effects on the liver connected with clozapine treatment. They were all judged as possible adverse effects of clozapine; 4 of them concerned increased transaminases and 2 increased transaminase and ALP/GT. In five of the cases there was normalization of the high values after withdrawal of clozapine.

According to expert consultation, an increase in ASAT/ALAT levels during clozapine treatment is not unusual (3). Withdrawal of clozapine is recommended when the transferase concentrations are above 3-4 ukat/l.

We suggest that this case should be reported to SADRAC as a possible side effect of clozapine.