Drugs in Pregnancy and Lactation: Tenth Edition

PROCARBAZINE

Antineoplastic

PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

Although combined with other antineoplastics, structural anomalies have been observed when procarbazine was used in the 1st trimester. The drug is best avoided during organogenesis.

FETAL RISK SUMMARY

The use of procarbazine, in combination with other antineoplastic agents, during pregnancy has been described in nine patients, five during the 1st trimester (18). One of the 1st trimester exposures was electively terminated, but no details on the fetus were given (5). Congenital malformations were observed in the remaining four 1st trimester exposures (14):

Multiple hemangiomas (1)

Oligodactyly of both feet with webbing of third and fourth toes, four metatarsals on left, three on right, bowing of right tibia, cerebral hemorrhage, spontaneously aborted at 24 weeks’ gestation (2)

Malformed kidneys—markedly reduced size and malposition (3)

Small secundum atrial septal defect, intrauterine growth restriction (4)

A patient in her 12th week of pregnancy received procarbazine, 50 mg daily, in error for 30 days when she was given the drug instead of an iron/vitamin supplement (6). A normal 3575-g male infant was delivered at term.

Long-term studies of growth and mental development in offspring exposed to procarbazine during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (9). Data from one review indicated that 40% of the infants exposed to anticancer drugs were of low birth weight (10). This finding was not related to the timing of exposure.

Procarbazine is mutagenic and carcinogenic in animals (11). In combination with other antineoplastic drugs, procarbazine may produce gonadal dysfunction in males and females (1217). Ovarian and testicular function may return to normal, with successful pregnancies possible, depending on the patient’s age at the time of therapy and the total dose of chemotherapy received (1620).

It is not known if procarbazine crosses the human placenta. The molecular weight (about 222 for the free base) is low enough that exposure of the embryo–fetus should be expected.

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

BREASTFEEDING SUMMARY

No reports describing the use of procarbazine during lactation have been located. The molecular weight (about 222 for the free base) is low enough that excretion into breast milk should be expected. Because of the potential for tumorigenicity, women receiving this drug should not nurse (21).

References

1.Wells JH, Marshall JR, Carbone PP. Procarbazine therapy for Hodgkin’s disease in early pregnancy. JAMA 1968;205:935–7.

2.Garrett MJ. Teratogenic effects of combination chemotherapy. Ann Intern Med 1974;80:667.

3.Mennuti MT, Shepard TH, Mellman WJ. Fetal renal malformation following treatment of Hodgkin’s disease during pregnancy. Obstet Gynecol 1975;46:194–6.

4.Thomas PRM, Peckham MJ. The investigation and management of Hodgkin’s disease in the pregnant patient. Cancer 1976;38:1443–51.

5.Daly H, McCann SR, Hanratty TD, Temperley IJ. Successful pregnancy during combination chemotherapy for Hodgkin’s disease. Acta Haematol (Basel) 1980;64:154–6.

6.Daw EG. Procarbazine in pregnancy. Lancet 1970;2:984.

7.Johnson IR, Filshie GM. Hodgkin’s disease diagnosed in pregnancy: case report. Br J Obstet Gynaecol 1977;84:791–2.

8.Jones RT, Weinerman ER. MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) given during pregnancy. Obstet Gynecol 1979;54:477–8.

9.Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.

10.Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynecol Br Commonw 1968;75:307–12.

11.Lee IP, Dixon RL. Mutagenicity, carcinogenicity and teratogenicity of procarbazine. Mutat Res 1978;55:1–14.

12.Sherins RJ, DeVita VT Jr. Effect of drug treatment for lymphoma on male reproductive capacity: studies of men in remission after therapy. Ann Intern Med 1973;79:216–20.

13.Sherins RJ, Olweny CLM, Ziegler JL. Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N Engl J Med 1978;299:12–6.

14.Johnson SA, Goldman JM, Hawkins DF. Pregnancy after chemotherapy for Hodgkin’s disease. Lancet 1979;2:93.

15.Card RT, Holmes IH, Sugarman RG, Storb R, Thomas ED. Successful pregnancy after high dose chemotherapy and marrow transplantation for treatment of aplastic anemia. Exp Hematol 1980;8:57–60.

16.Schilsky RL, Sherins RJ, Hubbard SM, Wesley MN, Young RC, DeVita VT Jr. Long-term follow-up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am J Med 1981;71:552–6.

17.Shalet SM, Vaughan Williams CA, Whitehead E. Pregnancy after chemotherapy induced ovarian failure. Br Med J 1985;290:898.

18.Whitehead E, Shalet SM, Blackledge G, Todd I, Crowther D, Beardwell CG. The effect of combination chemotherapy on ovarian function in women treated for Hodgkin’s disease. Cancer 1983;52:988–93.

19.Andrieu JM, Ochoa-Molina ME. Menstrual cycle, pregnancies and offspring before and after MOPP therapy for Hodgkin’s disease. Cancer 1983;52:435–8.

20.Schapira DV, Chudley AE. Successful pregnancy following continuous treatment with combination chemotherapy before conception and throughout pregnancy. Cancer 1984;54:800–3.

21.Product information. Matulane. Sigma-Tau Pharmaceuticals, 2000.