The question concerns a 26-year-old previously healthy woman who has used Follistrel, i.e. the mini

Fråga: The question concerns a 26-year-old previously healthy woman who has used Follistrel, i.e. the minipill, which contains the gestagen levonorgestrel in a dose of 30 ug/tablet, for several years. She has recently used dextropropoxyphene 100 mg three times daily (Doloxene) because of pain secondary to disc herniation. After 10 days she became icteric, experienced itching and showed increasing evidence of liver damage of cholestatic type. Drug treatment, including use of Follistrel, was stopped. Over a period of six weeks the damage to the liver regressed. Two months after the drug treatment was stopped a liver biopsy showed the liver to be in a regeneration phase.

The clinician wonders (a) whether propoxyphene can induce this type of liver damage and (b) whether the combination of propoxyphene and a gestagen is known to increase the risk of liver damage?

Sammanfattning: It is well-known that dextropropoxyphene may infrequently cause cholestatic types of liver reactions. There is no known metabolic risk group for development of severe liver reactions. It is well-known that oral contraceptives can induce liver damage but it is much less common with contraceptives which contain only gestagens than with combination products containing a gestagen as well as an oestrogen compound. We have not found any documented case of severe liver reactions during simultaneous treatment with dextropropoxyphene and levonorgestrel. In this case it is possible that the symptoms may be caused by treatment with dextropropoxyphene but it cannot be excluded that the combination of dextropropoxyphene and levonorgestrel may increase the risk of liver reaction. The increased risk may be caused by the capacity of propoxyphene to inhibit drug metabolism of other drugs.

Svar: Dextropropoxyphene is eliminated from the body by metabolism (mainly through demethylation) and the elimination half life may vary between 8 and 24 hours among individuals (1). The rate of metabolism is induced by smoking, and dextropropoxyphene is a well-known potent inhibitor of metabolism of drugs such as carbamazepine and nortriptylin (1,2). We are not aware of any solid evidence that the rate of metabolism of dextropropoxyphene varies more than 5-fold among individuals (1,3). A total of 30 cases of adverse liver effects due to treatment with dextropropoxyphene were reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) from 1969 to 1992 (4). In 28 cases it was considered that there was a possible or probable relationship to treatment with dextropropoxyphene. Most of the cases concerned increased levels of transaminases or signs of intrahepatic cholestasis. In the literature the occurrence of cholestatic hepatitis after treatment with dextropropoxyphene is considered to be rare but well documented (5). The liver damage presents itself with jaundice and abdominal pain within one to five weeks after the beginning of treatment (6,7). Alkaline phosphatases are increased but transferases only moderately. In cases where biopsies have been carried out, an intrahepatic type of cholestasis has been seen (6). Clinical chemistry values are usually normalised within several weeks after discontinuation of drug treatment.

Levonorgestrel is excreted from the body mainly by liver drug metabolism (1). There are no known active metabolites of the drug. Steady-state plasma concentrations of levonorgestrel may vary 7-fold among individuals, implying important interindividual variability in drug metabolism (8). Available evidence suggests that oestrogens are more likely to induce cholestatic effects than gestagens such as levonorgestrel (7). A total of three cases of probable or possible adverse liver effects of levonorgestrel treatment have been reported to SADRAC during the period from 1977 to 1992 (4). The symptoms and signs consisted of icterus, increased alkaline phosphatases and one case of increased transaminases (4).

We have not found any reports to SADRAC or in the literature concerning severe liver reactions after combined use of levonorgestrel and dextropropoxyphene.

It is recommended that this case be reported to SADRAC. 1 Dollery, Therapeutic drugs. 1991;
2 Dr Markus Jerling, Department of Clinical Pharmacology, Huddinge University Hospital: Personal communication
3 Dr Juliette Säwe, Department of Clinical Pharmacology, Huddinge University Hospital: Personal communication
4 Swedish Adverse Drug Reactions Advisory Committe (SADRAC)

5 Bassendine MF, Woodhouse KW, Bennett M, James OF: Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease. Gut 1986; 27: 444-449 6 Drugline nr 09221 (year 1992) 7 Davies, Textbook of adverse drug reactions, 1991; 4th ed: page 268-271 8 Back DJ, Orme MLE: Interindividual variability in oral contraceptive disposition. TIPS 1984; 5: 480-484