Drugs in Pregnancy and Lactation: Tenth Edition

GEMCITABINE

Antineoplastic (Antimetabolite)

PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

Two case reports have described the use of gemcitabine in the 2nd trimester. One of the reports speculated that two unusual complications (chronic lung disease and excessive lung excretions) might have been related to the therapy. The animal data suggest risk. Gemcitabine is indicated for the treatment of cancers with a high mortality, often in combination with other antineoplastics. Nevertheless, the maternal benefit appears to outweigh the unknown fetal risk, but avoiding organogenesis is a reasonable option.

FETAL RISK SUMMARY

Gemcitabine is a nucleoside analog antineoplastic. It is classified as an antimetabolite in the subclass of pyrimidine analogs. Other antineoplastic agents in the subclass are capecitabine, cytarabine, floxuridine, and fluorouracil. Gemcitabine is indicated in combination with carboplatin for ovarian cancer, with paclitaxel for breast cancer, and with cisplatin for non-small-cell lung cancer. It also is indicated for locally advanced or metastatic adenocarcinoma of the pancreas. Gemcitabine is metabolized intracellularly to the active diphosphate and triphosphate nucleosides. Gemcitabine triphosphate can be extracted from peripheral blood mononuclear cells and has a half-life of the terminal phase from these cells of 1.7–19.4 hours. An inactive metabolite is found in the plasma. The half-lives of gemcitabine in women 29 and 45 years of age were 49 and 57 minutes, respectively. Plasma protein binding is negligible (1).

Reproduction studies have been conducted in mice and rabbits. In mice, gemcitabine was embryotoxic, causing cleft palate and incomplete ossification at doses about 1/200th of the recommended human dose based on BSA (RHD). This dose was also maternally toxic. Fetotoxicity or embryolethality was observed at about 1/1300th of the RHD (1). A 1993 study in mice that was conducted by the manufacturer expanded on the maternal and developmental toxicities noted above (2). In rabbits, embryotoxicity (decreased fetal viability, reduced live litter sizes, and developmental delays) and fetotoxicity (fused pulmonary artery and absence of the gall bladder) at doses about 1/600th of the RHD (1).

Carcinogenesis studies have not been conducted with gemcitabine. The drug was associated with mutagenic and clastogenic effects in some assays. Effects on the fertility of male mice were noted at a dose 1/700th of the RHD, consisting of hypospermatogenesis, decreased fertility, and decreased implantations. The fertility of female mice was not affected at doses up to about 1/200th of the RHD (1).

It is not known if gemcitabine crosses the human placenta. The molecular weight (about 264 for the free base) and negligible plasma protein binding suggest that the drug will cross the placenta. However, the very short plasma elimination half-life of the drug should reduce the amount reaching the embryo–fetus.

A 2008 report described the use of gemcitabine, docetaxel, and cisplatin in a woman who had lung cancer with brain metastases and an unrecognized pregnancy (3). Very early in gestation, she underwent craniotomy with tumor removal, followed by whole brain irradiation. Starting at 9 weeks’ gestation, she was treated with four cycles of docetaxel and cisplatin (days 1 and 8) every 3 weeks. At 19 weeks’, therapy was changed to gemcitabine and cisplatin (days 1 and 8) at 3-week intervals for two cycles. About 2 months after the last dose, her pregnancy was diagnosed. A cesarean section was performed at 33 weeks to deliver a normal, 1490-g female infant (normal karyotype 46, XX) with Apgar scores of 8, 9, and 10 at 1, 5, and 10 minutes, respectively, and normal blood counts. An extensive examination of the infant failed to find any abnormalities. She was developing normally at 10 months of age (3).

In a second case, a 38-year-old woman was treated for lung cancer at 25 weeks’ gestation with gemcitabine (1000 mg/m2 on day 1 and 8) and carboplatin AUC 5 (day 1) (4). She gave birth by an elective cesarean section at 28 4/7 weeks to a baby girl with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. The infant had multiple complications secondary to prematurity. The authors speculated that two unusual features, chronic lung disease and excessive secretions from her lungs, might have been related to either the chemotherapy or an effect of the malignancy itself. At 8 months of age, the infant had been weaned off of oxygen therapy and her neurodevelopment was age-appropriate (4).

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

It is not known if gemcitabine is excreted into human breast milk. The molecular weight (about 264 for the free base) and negligible plasma protein binding suggest that the drug will be excreted into milk, but the very short elimination half-life (49–57 minutes) should mitigate the amount entering milk. However, the cytotoxicity of the drug and its use in combination with other antineoplastics strongly suggests that women being treated with gemcitabine should not breastfeed.

References

1.Product information. Gemzar. Eli Lilly, 2007.

2.Eudaly JA, Tizzano JP, Higdon GL, Todd GC. Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD-1 mice. Teratology 1993;48:365–81.

3.Kim JH, Kim HS, Sung CW, Kim KJ, Kim CH, Lee KY. Docetaxel, gemcitabine, and cisplatin administered for non-small cell lung cancer during the first and second trimester of an unrecognized pregnancy. Lung Cancer 2008;59:270–3.

4.Gurumurthy M, Koh P, Singh R, Bhide A, Satodia P, Hocking M, Anbarasu A, Wood LEP. Metastatic non-small-cell lung cancer and the use of gemcitabine during pregnancy. J Perinatol 2009;29:63–5.