Why is pregnancy stated as a contraindication for colchicine treatment? Which stage during pregnanc

Fråga: Why is pregnancy stated as a contraindication for colchicine treatment? Which stage during pregnancy is the most vulnerable and for how long time will the effect of colchicine persist after withdrawal of the drug? Are there any known interactions between colchicine and oral contraceptives?

A 22-year-old woman is suffering from recurrent aphthous stomatitis since childhood. The symptoms relapse every other week and the patient has tried various local treatments, such as tetracycline, but without sufficient effect. Periodic treatment with colchicine (dose 0.5 mg two times per day, if necessary 1.0 mg 3-4 times per day) during the attacks is being considered. The patient does not plan to get pregnant during this year, but probably thereafter. She will now start taking contraceptives.

Sammanfattning: No congenital malformations have been reported in studies of human fetuses exposed to colchicine. However, colcicine inhibits the mitosis and could thereby theoretically affect the organogenesis during the first twelve weeks of pregnancy. Thereafter, the risk for fetal malformations due to maternal use of colchicine is probably lower. We recommend that colchicine should be avoided during the first trimester of pregnancy. The biological effects of colchicine are related to the intraleukocyte concentration. The half-life of colchicine in leukocytes is approximately 60 hours and the drug is expected to be eliminated from the body after approximately two weeks. There are no reports about interactions of clinical relevance between cholchicine and oral contraceptives.

Svar: Colchicine inhibits the mitosis and could thereby theoretically affect the organogenesis during the first twelve weeks of pregnancy (1-3). Thereafter, the risk for fetal malformations due to maternal use of cholchicine is probably lower (1). Colchicine has been shown to be teratogenic in laboratory animals (4), but no congenital malformations have been reported in studies of human fetuses exposed to colchicine (4-7). In one study, children of 116 women with Familial Mediterranean fever (225 completed pregnancies) were studied. The women in the study were divided into three groups; A) cholchicine-treatment during the whole pregnancy, B) no treatment during the first trimester, C) no treatment during the pregnancy. There was no unusual frequency of fetal abnormality among women taking colchicine during pregnancy (8). The same result has been concluded in smaller studies summarised in previous Drugline documents (5-7).

Colchicine and its metabolites undergo enterohepatic recirculation and are then excreted through the urine and faeces (2). Following oral route, the bioavailability is variable (24 to 88 percent of administered dose). Studies have shown that the biological effects of colchicine are not related to the plasma concentration but to the intraleukocyte concentration (3). The half-life in leukocytes is approximately 60 hours (2). The drug should be eliminated from the body after 4-5 half-lifes, ie approximately two weeks in this case.

Colchicine and estradiol in oral contraceptives are both metabolised by the enzyme cytochrome P4503A4 (2, 9), and could thereby theoretically interact at metabolism level. However, no reports on interactions of clinical relevance between cholchicine and oral contraceptives could be found in the literature. 1 Professor Bengt Källen, Torbladinstitutet, Lund: Personal communication

2 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone.
1999; C320-322
3 Ben-Chetrit E, Levy M. Colchicine 1998 update. Semin Arthritis Rheum 1998; 28: 48-59

4 Briggs GB, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins 1998; 255-258

5 Drugline no 16163 (year 1999)
6 Drugline no 11417 (year 1995)
7 Drugline no 06757 (year 1989) (enclosed)

8 Rabinovitch O, Zemer D, Kukia E, Sohar E, Mashiach S. Colchicine treatment in conception and pregnancy: Two hundred thirty-one pregnancies in patients with Familial Mediterranean Fever. Am J Reprod Immunol 1992; 28: 245-246 9 Martucci C P, Fishman J. P450 Enzymes of estrogen metabolism. Pharmaol Ther 1993; 57: 237-257