Pregnancy and Gleevec (imatinib)
Although many patients with gastrointestinal stromal tumor (GIST) are older adults, a minority are of childbearing age and are naturally concerned about having children.
Warnings and FDA Pregnancy Category D
|FDA Category D|
Studies in pregnant women, adequately well-controlled or observational, have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. [See link ]
The Federal Drug Administration in the USA (the FDA) classifies imatinib as a "Category D" drug with respect to pregnancy. The safety warnings and the prescribing information for imatinib (Gleevec) at www.gleevec.com advise that the drug should not be taken by:
- Women who are or could be pregnant. Fetal harm can occur when administered to a pregnant woman, therefore, women should not become pregnant, as well as be advised of the potential risk to the unborn child if Gleevec is used during pregnancy
- Women who are breast-feeding, because of the potential for serious adverse reactions in nursing infants
- Sexually active females should use adequate contraception while taking Gleevec
Quoting from the imatinib prescribing information:
"Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg). There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus."
Pregnant Women Taking Imatinib
There have been a few case reports in the medical literature about outcomes of pregnancies in patients taking Gleevec, but the only summary about a large number of cases is the following paper:
Pye SM, Cortes J, Ault P, Hatfield A, Kantarjian H, Pilot R, Rosti G, Apperley JF.
The effects of imatinib on pregnancy outcome.
Blood. 2008 Jun 15;111(12):5505-8. PMID: 18322153
This paper describes pregnancy outcomes for 125 pregnancies reported to Novartis, the manufacturer of imatinib (Gleevec). [An additional 55 cases also reported to Novartis were omitted because the outcomes were unknown.] Four of the 125 women took imatinib for gastrointestinal stromal tumor; the remaining 121 took it for chronic myelogenous leukemia. 71% took imatinib during the first trimester, while 26% continued on the drug throughout pregnancy. The outcomes were:
- 63 births of normal infants
- 35 elective terminations, including 3 due to identified fetal abnormalities
- 18 spontaneous abortions
- 8 live births of infants with abnormalities, 1 of whom died soon after birth
- 1 stillbirth of an infant with abnormalities (meningiocele)
Strikingly, there were 3 infants whose abnormalities were quite similar, suggesting a common cause (presumably imatinib). The birth defects in this group were: bone malformations (including bones of the skull and spine), kidney defects, and exomphalos (a congenital hernia in which some of the abdominal contents are found outside the abdomen in a thin clear sac to which the baby's umbilical cord is attached). The infant who died was affected by hydrocephalus, heart defects, and hypoplasia of the cerebellum (in the brainstem).
The authors stated that the pattern of bone defects was similar to defects found in studies on pregnant lab rats given imatinib. They hypothesized that inhibition of platelet derived growth factor signaling might be involved in the fetal abnormalities.
For a short audio interview with one of the authors, Dr. Jorge Cortes, link to a story on MedPage Today.
Men Taking Imatinib and Pregnancy in Their Partners
The following medical paper describes 8 men whose partners conceived children while the men were taking imatinib.
Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, Koller C, Giles F, Keating M, Talpaz M, Cortes J.
Pregnancy among patients with chronic myeloid leukemia treated with imatinib.
J Clin Oncol. 2006 Mar 1;24(7):1204-8. PMID: 16446320
Conceptions occurred after the men had been on imatinib for 4 weeks to 48 months (median duration of 18 months). One man's wife conceived twice while he took imatinib, so there were 9 pregnancies. Eight babies were born healthy, and there was one spontaneous abortion.
Shash et al (2011) summarized prior literature and added 2 additional cases of pregnancies among partners of men taking imatinib in a free-access letter. The table in this letter shows that of 40 reported pregnancies, there were 3 miscarriages, 2 induced abortions, and one birth defect (gut malrotation).
Gleevec and Tasigna Pregnancy Exposure Registry
Novartis has has plans to establish an online registry to learn about pregnancy outcomes and the health of women who have taken Gleevec or Tasigna within six months prior to conception or during pregnancy. This will be a website where your physician can report about your pregnancy, the health of your infant, and any effects of pregnancy on your own disease status. The registry is expected to open later in 2009.