Also known as AZA, AZTP, Imuran (tn)

A purine analogue with cytotoxic and immunosuppressive activity. Azathioprine is a prodrug that is converted by hepatic xanthine oxidase to its active metabolite 6-mercaptopurine (6-MP). 6-MP is further metabolized by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanosine-5′-phosphate (6-thio-GMP) and 6-thioinosine monophosphate (6-thio-IMP), both inhibit nucleotide conversions and de novo purine synthesis. This leads to inhibition of DNA, RNA, and protein synthesis. As a result, cell proliferation may be inhibited, particularly in lymphocytes and leukocytes.

Originator: NCI Thesaurus | Source: The website of the National Cancer Institute (http://www.cancer.gov)

Can I take Azathioprine while breastfeeding?

Most experts consider breastfeeding during azathioprine to be acceptable.[1][2][3][4][5][6][7] Studies in women with inflammatory bowel disease, systemic lupus erythematosus or transplantation taking doses of azathioprine up to 200 mg daily for immunosuppression have found either low or unmeasurable levels of the active metabolites in milk and infant serum. Some evidence indicates a lack of adverse effects on the health and development of infants exposed to azathioprine during breastfeeding up to 3.5 years of age, but long-term follow-up for effects such as carcinogenesis have not been performed. Mothers with decreased activity of the enzyme that detoxifies azathioprine metabolites may transmit higher levels of drug to their infants in breastmilk. Cases of mild, asymptomatic neutropenia have been reported, so it might be desirable to monitor exclusively breastfed infants with a complete blood count with differential, and liver function tests if azathioprine is used during lactation, although some authors feel that monitoring is unnecessary.[8] Avoiding breastfeeding for 4 to 6 hours after a dose should markedly decrease the dose received by the infant in breastmilk.

Drug levels

Azathioprine is rapidly metabolized to the active metabolite mercaptopurine which is further metabolized to active metabolites including 6-methylmercaptopurine, thioguanine, 6-thioguanine nucleosides (6-TGNs), 6-methylmercaptopurine, and 6-methylmercaptopurine nucleosides (6-MMPNs). The enzyme thiopurine methyltransferase (TPMT) is responsible for metabolism of 6-TGNs. Deficiencies in this enzyme can lead to excessive toxicity.

Maternal Levels. Mercaptopurine milk levels were measured in 2 patients receiving azathioprine following renal transplantation. In one mother who was 2 days postpartum, peak colostrum levels occurred 2 and 8 hours after a 75 mg oral dose and were 3.4 and 4.5 mcg/L, respectively. In the other mother who was 7 days postpartum, a peak mercaptopurine milk level of 18 mcg/L occurred 2 hours after a 25 mg oral dose.[9] The milk levels of these 2 mothers correspond to 0.05% and 0.6% of the maternal weight-adjusted dosages, respectively. Infant serum levels were not measured.

Four women receiving an immunomodulator to treat inflammatory bowel disease had metabolite levels measured in milk during the first 6 weeks postpartum. The abstract does not mention the specific drug and dose being taken, but the azathioprine metabolites 6-methylmercaptopurine (6-MMP) and 6-TGNs were measured. Although therapeutic levels were found in maternal serum, 6-MMP (<650 mcg/L) and 6-TGNs were undetectable (<123 mcg/L) in milk (time of collection not stated).[10] A case series described 2 mothers who took azathioprine 100 mg daily while breastfeeding. Each mother collected milk samples over a 24-hour period, 5 and 6 samples, respectively. Mercaptopurine was undetectable (<5 mcg/L) in all of the samples. The authors estimated that the maximum dose of mercaptopurine that a completely breastfed infant would receive would be 0.09% of the maternal weight-adjusted dosage or 0.07% of the dose given to infants following cardiac transplantation.[11] Ten women who were taking azathioprine 75 to 150 mg daily at the time of delivery for systemic lupus erythematosus (n = 7), renal transplant (n = 2) or Crohn’s disease (n = 1) donated milk samples on days 3 to 4, 7 to 10 and 28 postpartum. Milk was collected before the single daily dose and at each breastfeed for 12 to 18 hours for a total of 31 samples. Only one woman taking azathioprine 100 mg daily had mercaptopurine detected in her milk. On day 28 postpartum, milk mercaptopurine concentrations were 1.2 mcg/L at 3 hours and 7.6 mcg/L at 6 hours after the dose.[12] Eight lactating women who were 1.5 to 7 months postpartum were taking azathioprine in dosages ranging from 75 to 200 mg daily for inflammatory bowel disease. All of the women had wild type TPMT phenotypes. Peak mercaptopurine milk concentrations occurred within the first 4 hours after ingesting of the dose of azathioprine and ranged from 2 to 50 mcg/L. By 5 hours after the dose, the milk concentrations of mercaptopurine had dropped markedly in all patients. The authors estimated that the “worst case” infant intake of mercaptopurine would 0.0075 mg/kg daily which is less than 1% of the maternal weight-adjusted dosage.[13] Infant Levels. Four infants were breastfed (3 exclusively, 1 rarely received formula) during maternal use of azathioprine orally in dosages of 1.2 to 2.1 mg/kg daily. All of the mothers and infants had the wild type TPMT *1/*1 genotype and all of the mothers had normal enzyme activity. At 3 to 3.5 months of age, all of the infants had undetectable blood levels of 6-TGNs and 6-MMPN.[14] The authors later updated this report to include 2 previously unreported mother-infant pairs. These infant also had undetectable blood levels of 6-TGNs and 6-MMPN.

Seven infants were breastfed during maternal intake of azathioprine in single oral doses of 75 to 150 mg daily. None had detectable mercaptopurine or thioguanine in their blood obtained between days 1 and 28 postpartum.[12]

Three infants whose mothers were taking azathioprine for inflammatory bowel disease (n = 2) or systemic lupus erythematosus (n = 1) were breastfed during maternal use of azathioprine. Azathioprine doses were 100 mg (plus prednisolone), 150 mg (plus infliximab) and 175 mg daily. In 1 infant, thioguanine was low, but detectable in blood at 3 days of age and 6-MMPN was undetectable; at 3 weeks of age, neither metabolite was detectable. In another infant, neither metabolite was detectable at 3 weeks of age. Neither assay limits nor specific maternal doses were stated in the published abstract.[15]

A woman began taking azathioprine 100 mg (1.4 mg/kg) daily for Crohn’s disease while breastfeeding (extent not stated) her 3-month-old infant. After 8 days and 3 months of maternal therapy, 6-TGNs were measured, although breastfeeding had been tapered to zero by 3 months. On both occasions, 6-TGNs were not detectable in the blood of the infant. The assay limit was not stated.[16]

Effects in breastfed infants

Azathioprine is rapidly metabolized to the active metabolite mercaptopurine which is further metabolized to active metabolites including 6-methylmercaptopurine, thioguanine, 6-thioguanine nucleosides (6-TGNs), 6-methylmercaptopurine, and 6-methylmercaptopurine nucleosides (6-MMPNs). The enzyme thiopurine methyltransferase (TPMT) is responsible for metabolism of 6-TGNs. Deficiencies in this enzyme can lead to excessive toxicity.

Maternal Levels. Mercaptopurine milk levels were measured in 2 patients receiving azathioprine following renal transplantation. In one mother who was 2 days postpartum, peak colostrum levels occurred 2 and 8 hours after a 75 mg oral dose and were 3.4 and 4.5 mcg/L, respectively. In the other mother who was 7 days postpartum, a peak mercaptopurine milk level of 18 mcg/L occurred 2 hours after a 25 mg oral dose.[9] The milk levels of these 2 mothers correspond to 0.05% and 0.6% of the maternal weight-adjusted dosages, respectively. Infant serum levels were not measured.

Four women receiving an immunomodulator to treat inflammatory bowel disease had metabolite levels measured in milk during the first 6 weeks postpartum. The abstract does not mention the specific drug and dose being taken, but the azathioprine metabolites 6-methylmercaptopurine (6-MMP) and 6-TGNs were measured. Although therapeutic levels were found in maternal serum, 6-MMP (<650 mcg/L) and 6-TGNs were undetectable (<123 mcg/L) in milk (time of collection not stated).[10] A case series described 2 mothers who took azathioprine 100 mg daily while breastfeeding. Each mother collected milk samples over a 24-hour period, 5 and 6 samples, respectively. Mercaptopurine was undetectable (<5 mcg/L) in all of the samples. The authors estimated that the maximum dose of mercaptopurine that a completely breastfed infant would receive would be 0.09% of the maternal weight-adjusted dosage or 0.07% of the dose given to infants following cardiac transplantation.[11] Ten women who were taking azathioprine 75 to 150 mg daily at the time of delivery for systemic lupus erythematosus (n = 7), renal transplant (n = 2) or Crohn’s disease (n = 1) donated milk samples on days 3 to 4, 7 to 10 and 28 postpartum. Milk was collected before the single daily dose and at each breastfeed for 12 to 18 hours for a total of 31 samples. Only one woman taking azathioprine 100 mg daily had mercaptopurine detected in her milk. On day 28 postpartum, milk mercaptopurine concentrations were 1.2 mcg/L at 3 hours and 7.6 mcg/L at 6 hours after the dose.[12] Eight lactating women who were 1.5 to 7 months postpartum were taking azathioprine in dosages ranging from 75 to 200 mg daily for inflammatory bowel disease. All of the women had wild type TPMT phenotypes. Peak mercaptopurine milk concentrations occurred within the first 4 hours after ingesting of the dose of azathioprine and ranged from 2 to 50 mcg/L. By 5 hours after the dose, the milk concentrations of mercaptopurine had dropped markedly in all patients. The authors estimated that the “worst case” infant intake of mercaptopurine would 0.0075 mg/kg daily which is less than 1% of the maternal weight-adjusted dosage.[13] Infant Levels. Four infants were breastfed (3 exclusively, 1 rarely received formula) during maternal use of azathioprine orally in dosages of 1.2 to 2.1 mg/kg daily. All of the mothers and infants had the wild type TPMT *1/*1 genotype and all of the mothers had normal enzyme activity. At 3 to 3.5 months of age, all of the infants had undetectable blood levels of 6-TGNs and 6-MMPN.[14] The authors later updated this report to include 2 previously unreported mother-infant pairs. These infant also had undetectable blood levels of 6-TGNs and 6-MMPN.

Seven infants were breastfed during maternal intake of azathioprine in single oral doses of 75 to 150 mg daily. None had detectable mercaptopurine or thioguanine in their blood obtained between days 1 and 28 postpartum.[12]

Three infants whose mothers were taking azathioprine for inflammatory bowel disease (n = 2) or systemic lupus erythematosus (n = 1) were breastfed during maternal use of azathioprine. Azathioprine doses were 100 mg (plus prednisolone), 150 mg (plus infliximab) and 175 mg daily. In 1 infant, thioguanine was low, but detectable in blood at 3 days of age and 6-MMPN was undetectable; at 3 weeks of age, neither metabolite was detectable. In another infant, neither metabolite was detectable at 3 weeks of age. Neither assay limits nor specific maternal doses were stated in the published abstract.[15]

A woman began taking azathioprine 100 mg (1.4 mg/kg) daily for Crohn’s disease while breastfeeding (extent not stated) her 3-month-old infant. After 8 days and 3 months of maternal therapy, 6-TGNs were measured, although breastfeeding had been tapered to zero by 3 months. On both occasions, 6-TGNs were not detectable in the blood of the infant. The assay limit was not stated.[16]

Possible effects on lactation

Relevant published information was not found as of the revision date.

Alternate drugs to consider

Budesonide, Cyclosporine , Hydroxychloroquine, Infliximab, Mesalamine, Prednisone, Tacrolimus

References

1. Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation. Nat Rev Gastroenterol Hepatol. 2014;11:116-27. PMID: 23897285

2. Constantinescu S, Pai A, Coscia LA et al. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28:1163-73. PMID: 25271063

3. Mahadevan U, Matro R. Care of the pregnant patient with inflammatory bowel disease. Obstet Gynecol. 2015;126:401-12. PMID: 26241432

4. Nguyen GC, Seow CH, Maxwell C et al. The Toronto Consensus Statements for the Management of IBD in Pregnancy. Gastroenterology. 2016;150:734-57. PMID: 26688268

5. van der Woude CJ, Ardizzone S, Bengtson MB et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015;9:107-24. PMID: 25602023

6. Flint J, Panchal S, Hurrell A et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016. PMID: 26750124

7. Gotestam Skorpen C, Hoeltzenbein M, Tincani A et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795-810. PMID: 26888948

8. Christensen LA, Dahlerup JF, Nielsen MJ et alK. Azathioprine treatment during lactation: authors’ reply. Aliment Pharmacol Ther. 2009 ;30:91. PMID: 19566905

9. Coulam CB, Moyer TP, Jiang NS et al. Breast-feeding after renal transplantation. Transplant Proc. 1982;13:605-9. PMID: 6817481

10. Kane SV, Present DH. Metabolites to immunomodulators are not detected in breast milk. Am J Gastroenterol. 2004;99 (10 Suppl S):S246-7. Abstract 761.

11. Moretti ME, Verjee Z, Ito S, Koren G. Breast-feeding during maternal use of azathioprine. Ann Pharmacother. 2006;40:2269-72. PMID: 17132809

12. Sau A, Clarke S, Bass J et al. Azathioprine and breastfeeding-is it safe? BJOG. 2007;114:498-501. PMID: 17261122

13. Christensen LA, Dahlerup JF, Nielsen MJ et al. Azathioprine treatment during lactation. Aliment Pharmacol Ther. 2008;28:1209-13. PMID: 18761704

14. Gardiner SJ, Gearry RB, Roberts RL et al. Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs. Br J Clin Pharmacol. 2006;62:453-6. PMID: 16995866

15. Bernard N, Garayt C, Chol F et al. Prospective clinical and biological follow-up of three breastfed babies from azathioprine-treated mothers. Fundam Clin Pharmacol. 2007;21 (Suppl 1) :62-3. Abstract.

16. Zelinkova Z, De Boer IP, Van Dijke MJ et al. Azathioprine treatment during lactation. Aliment Pharmacol Ther. 2009;30:90-1; author reply 91. PMID: 19566905

17. Grekas DM, Vasiliou SS, Lazarides AN. Immunosuppresive therapy and breast-feeding after renal transplantation. Nephron. 1984;37:68. Letter. PMID: 6371564

18. Madill JE, Levy G, Greig P. Pregnancy and breast-feeding while receiving cyclosporine A. In: Williams BAH S-GD, eds. Trends in organ transplantation. New York: Springer Publishing Company, 1996:109-21.

19. Nyberg G, Haljamae U, Frisenette-Fich C et al. Breast-feeding during treatment with cyclosporine. Transplantation. 1998;65:253-5. PMID: 9458024

20. Munoz-Flores-Thiagarajan KD, Easterling T, Davis C et al. Breast-feeding by a cyclosporine-treated mother. Obstet Gynecol. 2001;97(5 pt 2):816-8. PMID: 11336764

21. Gardiner SJ, Gearry RB, Roberts RL et al. Comment: breast-feeding during maternal use of azathioprine. Ann Pharmacother. 2007. PMID: 17389671

22. Khare MM, Lott J, Currie A, Howarth E. Is it safe to continue azathioprine in breast feeding mothers? J Obstet Gynaecol. 2003;23 (Suppl 1):S48. Abstract 53.

23. Werner M, Bjornsson E, Prytz H et al. Autoimmune hepatitis among fertile women: strategies during pregnancy and breastfeeding? Scand J Gastroenterol. 2007;42:986-91. PMID: 17613929

24. Angelberger S, Reinisch W, Messerschmidt A et al. Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding. J Crohns Colitis. 2011;5:95-100. PMID: 21453877

25. de Meij TG , Jharap B, Kneepkens CM et al. Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38:38-43. PMID: 23675854

26. Bernard N, Gouraud A, Paret N et al. Azathioprine and breastfeeding: long-term follow-up. Fundam Clin Pharmacol. 2013;27 (Suppl 1):12. Abstract 05-03.

27. Mahadevan U, Martin CF, Sandler RS et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology . 2012;142 (5 Suppl 1):S149. Abstract 865.

Last Revision Date

20160426

Disclaimer:Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

Source: LactMed – National Library of Medicine (NLM)

3D Model of the Azathioprine molecule

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