PENICILLAMINE

Drugs in Pregnancy and Lactation.

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Name: PENICILLAMINE
Class: Chelating Agent
Risk Factor:    D

Fetal Risk Summary

Penicillamine is a chelating agent used in the treatment of Wilson's disease, cystinuria, and severe rheumatoid arthritis. Reproductive studies in rats at doses 6 times higher than the maximum recommended human dose revealed fetal anomalies consisting of skeletal defects, cleft palates, and fetal resorptions (1).

The use of penicillamine during pregnancy has been observed in more than 100 pregnancies (2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 and 18) . The mothers were treated for rheumatoid arthritis, cystinuria, or Wilson's disease. Most of the pregnancies resulted in healthy newborns that developed normally, but anomalies were observed in 8 infants: Cutis laxa, hypotonia, hyperflexion of hips and shoulders, pyloric stenosis, vein fragility, varicosities, impaired wound healing, death (3) Cutis laxa, growth retardation, inguinal hernia, simian crease, perforated bowel, death (7) Cutis laxa (4) Cutis laxa, mild micrognathia, low-set ears, inguinal hernia (12) Cutis laxa, inguinal hernia (13) Marked flexion deformities of extremities, dislocated hips, hydrocephalus, intraventricular hemorrhage, death (14) Cerebral palsy, blindness, bilateral talipes, sudden infant death at 3 months (14) Hydrocephalus (14) The relationship of the last three cases listed above to penicillamine is controversial because they did not include connective tissue anomalies. The drug may be partially responsible, but other factors, such as maternal infections and surgery, may have a stronger association with the defects (14). A small ventricular septal defect was observed in another newborn, but this was probably not related to penicillamine (9).

Penicillamine crosses the placenta to the fetus. A mother was treated for cystinuria throughout gestation with penicillamine hydrochloride 1050 mg/day (843 mg of penicillamine base) (2). The drug was found in the urine of her newborn infant. The baby's physical and mental development was normal at 3 months.

A 1993 report described the effects of untreated Wilson's disease on a fetus (19). A 23-year-old woman, diagnosed with Wilson's disease at 12 years of age, had been treated with penicillamine but she had stopped the therapy when she was 15 years old. Liver cirrhosis, thrombocytopenia, and low serum proteins developed during the 2nd trimester and, when the diagnosis of Wilson's disease was remade (the patient had withheld information about her past history), an elective cesarean section was performed at 36 weeks' gestation. The 2380-g male infant had hepatomegaly, elevated liver enzymes, slightly low serum ceruloplasmin, and high excretion of urinary copper (19). His development during the first year has been normal, as is his current serum ceruloplasmin concentration, but his liver enzymes have remained elevated, possibly as a result of copper accumulation in the fetal liver (19).

Several conflicting recommendations have appeared in the literature concerning the use of penicillamine during pregnancy. The authors of one review believe the drug should be avoided during pregnancy (20). Another suggested that therapy with penicillamine should be continued during pregnancy in women with Wilson's disease, but stopped in those with rheumatoid arthritis (21). Still others have recommended continuing therapy during the treatment of Wilson's disease, except during the 1st trimester (22).

Although the evidence is incomplete, maintaining the daily dose at 500 mg or less may reduce the incidence of penicillamine-induced toxicity in the newborn (6,11). The manufacturer recommends, however, that the dose be limited to 1 g/day and, if cesarean section is planned, to 250 mg/day for 6 weeks before delivery and postoperatively until wound healing is complete (1).

Breast Feeding Summary

No reports describing the use of penicillamine during lactation or if the drug is excreted in milk have been located. Authors of one review recommend avoiding penicillamine during lactation (19).

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References

  1. Product information. Cuprimine. Merck & Co, 1997.
  2. Crawhall JC, Scowen EF, Thompson CJ, Watts RWE. Dissolution of cystine stones during d-penicillamine treatment of a pregnant patient with cystinuria. Br Med J 1967;2:216–8.
  3. Mjolnerod OK, Rasmussen K, Dommerud SA, Gjeruldsen ST. Congenital connective-tissue defect probably due to d-penicillamine treatment in pregnancy. Lancet 1971;1:673–5.
  4. Laver M, Fairley KF. D-penicillamine treatment in pregnancy. Lancet 1971;1:1019–20.
  5. Scheinberg IH, Sternlieb I. Pregnancy in penicillamine-treated patients with Wilson's disease. N Engl J Med 1975;293:1300–3.
  6. Marecek Z, Graf M. Pregnancy in penicillamine-treated patients with Wilson's disease. N Engl J Med 1976;295:841–2.
  7. Solomon L, Abrams G, Dinner M, Berman L. Neonatal abnormalities associated with d-penicillamine treatment during pregnancy. N Engl J Med 1977;296:54–5.
  8. Walshe JM. Pregnancy in Wilson's disease. Q J Med 1977;46:73–83.
  9. Lyle WH. Penicillamine in pregnancy. Lancet 1978;1:606–7.
  10. Linares A, Zarranz JJ, Rodriguez-Alarcon J, Diaz-Perez JL. Reversible cutis laxa due to maternal d-penicillamine treatment. Lancet 1979;2:43.
  11. Endres W. D-penicillamine in pregnancy–to ban or not to ban? Klin Wochenschr 1981;59:535–7.
  12. Harpey JP, Jaudon MC, Clavel JP, Galli A, Darbois Y. Cutis laxa and low serum zinc after antenatal exposure to penicillamine. Lancet 1983;2:858.
  13. Beck RB, Rosenbaum KN, Byers PH, Holbrook KA, Perry LW. Ultrastructural findings in the fetal penicillamine syndrome (abstract). Presented at the 13th Annual Birth Defects Conference, March of Dimes and University of California, San Diego, June 1980.
  14. Gal P, Ravenel SD. Contractures and hydrocephalus with penicillamine and maternal hypotension. J Clin Dysmorphol 1984;2:9–12.
  15. Gregory MC, Mansell MA. Pregnancy and cystinuria. Lancet 1983;2:1158–60.
  16. Dupont P, Irion O, Béguin F. Pregnancy in a patient with treated Wilson's disease: a case report. Am J Obstet Gynecol 1990;163:1527–8.
  17. Hartard C, Kunze K. Pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate. Eur Neurol 1994;34:337–40.
  18. Berghella V, Steele D, Spector T, Cambi F, Johnson A. Successful pregnancy in a neurologically impaired woman with Wilson's disease. Am J Obstet Gynecol 1997;176:712–4.
  19. Oga M, Matsui N, Anai T, Yoshimatsu J, Inoue I, Miyakawa I. Copper disposition of the fetus and placenta in a patient with untreated Wilson's disease. Am J Obstet Gynecol 1993;169:196–8.
  20. Ostensen M, Husby G. Antirheumatic drug treatment during pregnancy and lactation. Scand J Rheumatol 1985;14:1–7.
  21. Miehle W. Current aspects of D-penicillamine and pregnancy. Z Rheumatol 1988;47(Suppl 1):20–3.
  22. Woods SE, Colón VF. Wilson's disease. Am Fam Physician 1989;40:171–8.

Index

Q&A about Penicillamine

sudeepta d
tell me the side effects of the drug "penicillamine-D" on long term usage?
Sam X9
Impotency, this drug is another brand of anti-biotic.