Immunosuppressive and immune antineoplastic agents

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Azathioprine and cyclosporine have been given to lactating women, and levels in the mother and in the milk have been reported. Azathioprine, which metabolizes to 6-mercaptopurine (6-MP), was measured in the milk of two mothers and varied from 3.5 fig/1 to 18(tg/l, which were peak levels done at 2 hours post-dose (Grekas 1984). These levels would represent 0.1% of the maternal dose. Since peak plasma time is 1-2 hours and azathioprine is poorly orally bioavailablc (only 41-44%), the simple procedure of avoiding feeding for at least 2 hours post-dose would further decrease the amount available to the infant and maintain a level below 0.1% of the maternal dose. Among six breastfed children, one developed temporary

4.10.1 immunosuppressive and immune antineoplastic agents

symptoms of bone marrow dysfunction (Kharc 2003). Considering the low relative dose, a causal association is remote. However, infants with the rare deficiency of thiopurine-methyitransferasc (TPMT) could be sensitive to maternal long-term therapy while being breastfed. Even considering this case report, regular blood cell counts in breastfed children are not recommended.

Cyclosporins use in lactating women has been reported in several studies. Levels in maternal plasma studied in 15 mother-child pairs (Moretti 2003, Munoz-Flores-Thiagarajan 2001, Merlob 2000, Nyberg 1998. Thiru 1997) varied from 55 to 903 ng/ml. Corresponding milk levels were 14-1016 ng/ml. which works out at (at maximum) 2% of the weight-adjusted maternal dose. In another case, where the mother received 3 mg/kg per day, milk levels averaged 596|ig/l but infant trough blood levels remained under 3ng/l when mother's were 260 ng/1. In a series of five patients receiving cyclosporine. however, one clinically unremarkable infant had trough blood levels (131 jig/1) near therapeutic levels (Moretti 2003). The other four infants had levels below 25pg/l. Another 17 unremarkable breastfed infants were reported by Armenti (2003). The peak time for maternal blood level is 3.5 hours post-dose, so this would mean not breastfeeding for at least 4 hours to avoid peak milk levels. It is poorly absorbed orally (less than 30%).

Interferons are large molecules, and do not pass into the milk. They are not absorbed orally, and are given by injection. They are not contraindicated during lactation (Kumar 2000).

Tacrolimus is used for immunosuppression after liver transplant, and is reported on in 25 full-term pregnancies. The first milk samples after birth were measured at 0.6[ig/l, which suggests that the infant would receive less than 0.1 |ig/kg daily. This represents a relative dosage of about 0.1%. Because the babies were not breastfed, there are no observations of any possible effects available (fain 1997). A single case is reported where the mother received 0.1 mg/kg per day throughout pregnancy. Milk levels were measured sequentially. The maximum was measured at 1 hour post-dose, at 0.57|ig/l. This was estimated to be 0.06% of the maternal dose, or 0.02% absorbed by the infant based on the poor oral bioavailability (14-32%) (French 2003). A 29-year-old woman was exclusively breastfeeding her healthy 3-month-old infant while on tacrolimus 4mg daily plus other drugs relevant to her transplant. The milk-to-blood ratio was 0.23, and average tacrolimus concentrations in milk were 1.8 g/l. The baby ingested approximately 0.5% of the maternal weight-adjusted dose (Gardiner 2006). Armenti (2003) reported on the normal development of seven breastfed children.

There are no data on sirolimus, everolimus. and glatiramer during lactation. Glatiramer has a molecular mass of 4700-11 000, which makes transfer to the milk almost impossible.

740 4.10.2 Antineoplastics

In a mother receiving 25 mg etanercept twice weekly, the maximum measured in her milk was 75 ng/ml (Ostensen 2004), resulting in a weight-adjusted dose of <3%. As a protein, etanercept is scarcely absorbed in an active form via the intestine.

There are insufficient data on monoclonal antibodies, for example the tumor necrosis factor-a (TNF-a), infliximab, which has a halflife of 9.5 days, or the substances adalimumab, basiliximab (half-life 7 days), daclizumab, and muronomab-CD3.

This also applies for the immunosuppressive mycophenolate mofetil, with a half-life of 6 hours, and for the cytokines interleukin-10 and interleukin-11. for antibodies against CD4-positive lymphocytes, and for antibodies against interleukin-12, etc. whose immune modulator effect in practice is still being studied.

Boswellia serrata preparations (Indian incense tree), which arc among the phytopharmaceuticals. are said to inhibit 5-lipoxygenesis. Used for chronic inflammatory bowel diseases and rheumatoid illnesses. they too have not been studied sufficiently with respect to breastfeeding.

Recommendation. Azathioprine, mercaptopurine, cydosporine A, and interferons should not, considering these data, be obstacles to breastfeeding. Tacrolimus, etanercept, and glatiramer are probably also very acceptable. Caution is advised with others, pending specific information.

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