Colchicine

 Risk Factor: DM
 Class: MISCELLANEOUS

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Colchicine is used in the treatment of gout and familial Mediterranean fever. Seven animal studies, reviewed by Shepard in 1989, indicated that colchicine, or its derivative, demecolcine (desacetylmethylcolchicine), were teratogenic in mice and rabbits at low doses and embryocidal in mice, rats, and rabbits at higher doses (1). Mutagenic effects were also observed in rabbit blastocysts. No adverse fetal effects were observed in limited studies with pregnant monkeys (1).

No congenital malformations have been reported in a small number of human fetuses exposed to colchicine (2,3,4,5,6 and 7). A 1960 review of the effects of cancer chemotherapy on the fetus cited three cases in which demecolcine had been used for the treatment of leukemia (2). In one of these cases, the mother was treated with 6-mercaptopurine, aminopterin, and high-dose (10 mg four times) demecolcine. The colchicine derivative was administered, along with 6-mercaptopurine, during the 6th month of gestation shortly before an infant, without malformations, was delivered prematurely. The infant expired at 19 hours. The other two mothers were treated throughout gestation with doses ranging between 1.5 and 7.5 mg/day. Both newborns were normal at birth, and one was developing normally at 2 years of age. The second child died at 2 years of age of postnecrotic cirrhosis, probably secondary to undiagnosed hepatitis (2). A double renal artery and a large calculus in the left kidney were found at autopsy.

A woman conceived while being treated with colchicine for familial Mediterranean fever (FMF) and continued the drug during the first 5 weeks of pregnancy (3,4). A healthy infant was eventually delivered. Four other reports briefly described the results of 10 pregnancies conceived while mothers were being treated with colchicine for FMF (5,6,7 and 8). Seven of the women continued therapy throughout gestation and six gave birth to normal infants, but the status of the seventh infant was not mentioned (5,7). Of the seven who stopped colchicine after pregnancy detection, three gave birth to healthy newborns, three were still pregnant, and one, with nephrotic syndrome due to amyloidosis, aborted in the 2nd month (5).

The known mutagenic effects of colchicine and the possible relationship of this drug to sperm abnormalities and the production of congenital malformations were the subjects of a number of publications (9,10,11,12,13,14,15 and 16). A 1965 report described three pregnancies occurring in a woman between the ages of 24 and 27 years, two of which ended abnormally (9). Her first pregnancy resulted in the spontaneous abortion of a macerated fetus at 4.5 months, her second in the delivery of a normal girl, and her third in the delivery of a male with atypical Down's syndrome, who died 24 hours after birth. The infant had palmar transverse folds on the hands, inner epicanthic folds, unspecified cardiac malformations, trigger thumbs, syndactly in the second and third toes, hypognathous, cleft palate, low-set ears, and an incompletely developed scapha helix (9). The father was 27 to 30 years of age during these pregnancies and was being treated for gout on an intermittent basis with 12 mg/day of colchicine. Cultures of leukocytes obtained from him demonstrated mutagenic changes when exposed to colchicine, but blood and sperm samples, collected 3 months after the end of colchicine therapy, were normal. The investigators theorized that the colchicine therapy may have caused diploid spermatozoa that resulted in the production of triploid children (9).

A brief report, from the same laboratory as the Reference above, described the analysis of lymphocyte cultures from three male patients being treated with colchicine (10). Compared to controls, a significant increase in the number of cells with abnormal numbers of chromosomes was found in the colchicine-exposed men. The investigators proposed that this finding indicated that these men were at higher risk of producing trisomic offspring than were nonexposed men (10). Of 54 children with Down's syndrome (trisomy 21) in their clinic, two had been fathered by men being treated with colchicine. The validity of this proposed association between colchicine and Down's syndrome was the subject of several References (11,12,13 and 14). One of the arguments against the association included the high possibility of Down's syndrome and colchicine therapy occurring at the same time in an older population (12). Moreover, several References have described healthy children fathered by men who were being treated with colchicine (3,4 and 5,15,16).

Colchicine may induce azoospermia. Hamsters and mice treated chronically with subcutaneous injections of demecolcine developed extensive damage to the germinal epithelium, resulting in azoospermia within 3545 days (17). One study observed azoospermia in a 36-year-old patient induced by 1.2 mg/day of colchicine, but not with 0.6 mg/day (18). A second study, however, using 1.82.4 mg/day in seven healthy men 2025 years old, measured no effect on sperm production or on serum levels of testosterone, luteinizing hormone, or follicle-stimulating hormone (19). The authors of this second report, however, could not exclude the fact that some men may be unusually sensitive to the drug, resulting in testicular toxicity (19).

In summary, the indications for colchicine therapy in pregnancy are few; thus, the number of exposures to this drug during gestation are also few. Although no cases of congenital malformations or other toxicity resulting from maternal consumption of colchicine have been located, the drug should be used cautiously during pregnancy because of the limited data available in humans and the teratogenicity observed in animals. The use of colchicine by the father prior to conception does not seem to present a significant reproductive risk, but azoospermia may be a rare complication.

Breast Feeding Summary

Colchicine is excreted into breast milk (6,7 and 8). A 31-year-old woman, receiving long-term therapy with colchicine, 0.6 mg twice daily, for familial Mediterranean fever (FMF), was treated throughout a normal pregnancy, labor, and delivery (6). Milk, urine, and serum samples were obtained from her between 16 and 21 days after delivery. Colchicine was detected in three of five milk samples collected on days 1620 with levels ranging from 1.22.5 ng/mL (test sensitivity 0.5 ng/mL). However, the authors could not determine whether their analysis method was recovering all of the drug in the milk because of the high lipid content of the samples (6). Two serum samples collected on days 19 and 21 measured 0.7 and 1.0 ng/mL of the drug, indicating that the milk:plasma ratio exceeded 1.0. Daily urine colchicine concentrations (days 1620) ranged from 70390 ng/mL. No apparent effects were observed in the nursing infant over the first 6 months of life.

In four lactating women on long-term colchicine therapy (at least 7 years) for FMF, 11.5 mg/day, serum and milk samples were drawn before a dose and at 1, 3, and 6 hours after a dose (7). Maximum breast milk drug concentrations ranged between 1.9 and 8.6 ng/mL, whereas maximum serum concentrations ranged from 3.6 to 6.46 ng/mL. The peak concentrations in milk and serum both occurred at 1 hour and the colchicine concentration time curves for milk and serum were parallel. No apparent effects in the nursing infants were observed over a 10-month period. The authors concluded that nursing was safe for women taking colchicine, but that waiting 12 hours after a dose to breast-feed would minimize exposure of the nursing infant (7).

Much higher colchicine milk concentrations were measured in a second study. A 21-year-old woman had taken colchicine, 1 mg/day, throughout gestation and continued while breast feeding her normal infant (8). On postpartum days 5 and 15, colchicine concentrations in the mother's 24-hour urine sample were 276,000 and 123,000 ng/24 hours, respectively, while none was detected (test sensitivity 5 ng/mL) in the infant's 12-hour urine collection. Milk samples were collected four times each on day 5 (2, 4, 15, and 21 hours after a dose) and day 15 (0, 4, 7, and 11 hours after a dose). Colchicine concentrations in the 2- and 4-hour samples on day 5 were 31 and 24 ng/mL, respectively, and below the level of detection at 15 and 21 hours. On day 15, levels at 0 and 11 hours were below detection, while those at 4 and 7 hours were 27 and 10 ng/mL, respectively. Assuming 100% of the dose in milk was absorbed, the estimated dose per kg the infant was receiving, during the 8 hour-period after a dose, was 10% of the mother's dose per kg (8). Although no adverse effects were observed in the infant, the authors recommended that a mother could minimize drug exposure from her milk by taking her dose at bedtime and waiting 8 hours to breast-feed (8).

Because of the absence of infant toxicity observed during nursing in one of the above cases (6), the American Academy of Pediatrics considers colchicine to be compatible with breast feeding (20).

References

1. Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:1646.
2. Sokal JE, Lessmann EM. Effects of cancer chemotherapeutic agents on the human fetus. JAMA 1960;172:176572.
3. Cohen MM, Levy M, Eliakim M. A cytogenetic evaluation of long-term colchicine therapy in the treatment of familial Mediterranean fever (FMF). Am J Med Sci 1977;274:14752.
4. Levy M, Yaffe C. Testicular function in patients with familial Mediterranean fever on long-term colchicine treatment. Fertil Steril 1978;29:6678.
5. Zemer D, Pras M, Sohar E, Gafni J. Colchicine in familial Mediterranean fever. N Engl J Med 1976; 294:1701.
6. Milunsky JM, Milunsky A. Breast-feeding during colchicine therapy for familial Mediterranean fever. J Pediatr 1991;119:164.
7. Ben-Chetrit E, Scherrmann JM, Levy M. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis Rheum 1996;39:12137.
8. Guillonneau M, Aigrain EJ, Galliot M, Binet M-H, Darbois Y. Colchicine is excreted at high concentrations in human breast milk. Eur J Obstet Gynecol Reprod Biol 1995;61:1778.
9. Cestari AN, Botelho Vieira Filho JP, Yonenaga Y, Magnelli N, Imada J. A case of human reproductive abnormalities possibly induced by colchicine treatment. Rev Bras Biol 1965;25:2536.
10. Ferreira NR, Buoniconti A. Trisomy after colchicine therapy. Lancet 1968;2:1304.
11. Walker FA. Trisomy after colchicine therapy. Lancet 1969;1:2578.
12. Timson J. Trisomy after colchicine therapy. Lancet 1969;1:370.
13. Hoefnagel D. Trisomy after colchicine therapy. Lancet 1969;1:1160.
14. Ferreira NR, Frota-Pessoa O. Trisomy after colchicine therapy. Lancet 1969;1:11601.
15. Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Prevention of recurrent gouty arthritis over a mean period of five years in 208 gouty subjects. Ann Intern Med 1961;55:17992.
16. Goldfinger SE. Colchicine for familial Mediterranean fever: possible adverse effects. N Engl J Med 1974;290:56.
17. Poffenbarger PL, Brinkley BR. Colchicine for familial Mediterranean fever: possible adverse effects. N Engl J Med 1974;290:56.
18. Merlin HE. Azoospermia caused by colchicinea case report. Fertil Steril 1972;23:1801.
19. Bremer WJ, Paulsen CA. Colchicine and testicular function in man. N Engl J Med 1976; 294:13845.
20. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.
    
    

Questions and Answers

What if a pregnant woman who is on her 1st trimester of pregnancy accidentally take 1 tablet of colchicine?

it happens, when a pharmacy assistant in a certain drugstore accidentally gave a wrong medicine for a pregnant woman, instead a medicine for cough the one that was given was Colchicine and without reading on the label of the medicine she bought she accidentally took it and after that she feel a sudden pain on her stomach. Do you think it is because of the colchicine she took?

Call your doctor or the doctor on call ASAP!!! Also, call the pharmacy and make sure they know of the mix up!

is there a side effect on the baby if a pregnant woman take 1 tablet only of a colchicine 500mcg?

if your doctor prescribed you the meds and knows you are pregnant.. i dont see why you cant take it! but if you had it b4 your pregnancy..i wouldnt take it! i would ask a doctor to be safe..b/c not all prescribed meds are safe for pregnancy! but a doctor can prescribe you something that you need!! and will be safe for baby!