Last update: Aug. 15, 2019

Amethopterin

Low Risk for breastfeeding


Moderately safe. Probably compatible.
Mild risk possible. Follow up recommended.
Read the Comment.

Methotrexate (MTX) is an antineoplastic antimetabolite and folic acid analogue and antagonist with antineoplastic and immunosuppressive properties from interfering with the synthesis and cellular replication of DNA.
Indicated in the treatment of certain neoplasms, rheumatic problems: arthritis, severe psoriasis, Reiter’s syndrome (AEMPS 2018, EMA 2017) and, off-label, in inflammatory bowel disease, in multiple sclerosis and in some obstetric procedures: abortion, ectopic pregnancy, placenta accreta (Practice Committee of the American Society for Reproductive Medicine 2013, Kulier 2011).

Administration is generally oral (also subcutaneous or intramuscular) once a week, except in carcinomas where there are 5-day cycles every 12-14 days. In obstetrics, single or 3-day intramuscular doses of 50 mg/m2 of body surface area (mg/m2 BS) are administered for expulsion purposes.

Excretion in breastmilk is very limited (Brown 2017, Østensen 2006), perhaps due to a very low pKa that makes it very insoluble in liquids at physiological pH (Götestam 2016).

After isolated doses of 50 mg/m2 BS for obstetric purposes, even after doses of 92 mg (1,12 mg/kg) daily for 4 days, undetectable or negligible levels have been found in breastmilk (Baker 2018, Tanaka 2009). Zero or negligible transfer to milk has also been found when used in low weekly doses (25 mg) during the maintenance treatment of rheumatoid arthritis and other autoimmune diseases (Delaney 2017, Thorne 2014).
No problems have been recorded or observed in infants whose mothers were taking it (Thorne 2014).

The recommendations of experts and the practical attitude among clinicians about maintaining treatment during breastfeedingn are divided (Huang 2016, Götestam 2016, Martínez 2009, Weber 2008, Østensen 2007).
Several authors consider isolated or weekly use in low doses during breastfeeding to be safe (Anderson 2019, Delaney 2017, Noviani 2016, Thorne 2014, Koren 2013, Østensen 2009, Tanaka 2009, Weber 2008, Moretti 2000, Goldsmith 1989, Johns 1972).
Other authors and expert consensus discourage it (Flint 2016, Nguyen 2016, Götestam 2016, Kavanaugh 2015, van der Woude 2015, Mahadevan 2015, Grunewald 2015, Samaritano 2014, Mervic 2014, Mottet 2007, Temprano 2005, WHO 2002, AAP 2001, Janssen 2001).

In these cases, exposure can be reduced by almost half by interrupting breastfeeding 24 hours after taking the drug, expressing and discarding the milk in the meantime (Delaney 2017, Hale 2017 p628, Noviani 2016), which in practice means not breastfeeding the day MTX is taken and breastfeeding the rest of the week.
Some recommend clinical or hematologic monitoring or of MTX levels in the infant (Rademaker 2017, Almas 2016, Østensen 2009) and administering folic acid to the infant (Almas 2016).

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Although the levels found in breastmilk are very low (Johns 1972), during cancer treatment it is recommended to stop breastfeeding due to potentially serious side effects for the infant (Rademaker 2017, Moretti 2000). Chemotherapy does not affect milk production during or after treatment. Abrupt weaning can be psychologically traumatic for both the mother and the infant (Pistilli 2013). If the mother wishes, the production of milk can be maintained by regular expressing from the breast, being able to return to breastfeeding in the periods in which no significant traces of the drug remain in the milk (Anderson 2016) or at the end of the treatment (Pistilli 2013).

It is known from pharmacokinetics that after 3 elimination half-lives (T½) 87.5% of the drug is eliminated from the body; after 4 T½ it is 94%, after 5 T½, 96.9%, after 6 T½, 98.4% and after 7 T½ it is 99%. From 7 T½ the plasma concentrations of the drug in the body are negligible. In general, a period of at least five half-lives can be considered a safe waiting period before breastfeeding again (Anderson 2016).

Taking as reference the longest published T½ (17 hours), these 5 T½ would correspond to 3.5 days and 7 T½ would be almost 5 days, which is what expert authors recommend waiting after the last dose to restart breastfeeding. (Hale 2017 p628). Meanwhile, express and discard milk from the breast regularly.

When it is possible to do so, detections in the breastmilk of each patient to determine the total elimination of the drug would be the best indicator of resuming breastfeeding between two cycles of chemotherapy.

Some chemotherapeutic agents with antibiotic effects can alter the composition of the microbiota (bacterial cluster or bacterial flora) of the milk and the concentration of some of its components (Urbaniak 2014). This possibly occurs temporarily with subsequent recovery, although no harmful effects are expected nor have been reported in breastfed infants.

Women undergoing chemotherapy during pregnancy have lower rates of breastfeeding due to experiencing difficulties with breastfeeding (Stopenski 2017), needing more support to achieve it.

Given the strong evidence that exists regarding the benefits of breastfeeding for the development of babies and the health of mothers, it is advisable to evaluate the risk-benefit of any maternal treatment, including chemotherapy, individually advising each mother who wishes to continue with breastfeeding (Koren 2013).

Alternatives

We do not have alternatives for Amethopterin.

Suggestions made at e-lactancia are done by APILAM´s pediatricians and pharmacists, and are based on updated scientific publications.
It is not intended to replace the relationship you have with your doctor but to compound it.

Jose Maria Paricio, Founder & President of APILAM/e-Lactancia

Your contribution is essential for this service to continue to exist. We need the generosity of people like you who believe in the benefits of breastfeeding.

Thank you for helping to protect and promote breastfeeding.

José María Paricio, founder of e-lactancia.

Other names

Amethopterin is also known as Methotrexate. Here it is a list of alternative known names::


Amethopterin in other languages or writings:

Groups

Amethopterin belongs to these groups or families:

Tradenames

Main tradenames from several countries containing Amethopterin in its composition:

Pharmacokinetics

Variable Value Unit
Oral Bioavail. 60 (20 - 95) %
Molecular weight 454 daltons
Protein Binding 50 %
VD 0,4 - 0,8 l/Kg
pKa 3,41 -
Tmax 1 - 2 hours
T1/2 3 - 17 hours
M/P ratio 0,08 - 0,1 -
Theoretical Dose 0,0004 mg/Kg/d
Relative Dose 0,08 - 0,3 %
Relat.Ped.Dose 0,04 - 0,1 %

References

  1. Baker T, Datta P, Rewers-Felkins K, Hale TW. High-Dose Methotrexate Treatment in a Breastfeeding Mother with Placenta Accreta: A Case Report. Breastfeed Med. 2018 Abstract
  2. Rademaker M, Agnew K, Andrews M, Armour K, Baker C, Foley P, Frew J, Gebauer K, Gupta M, Kennedy D, Marshman G, Sullivan J. Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration. Australas J Dermatol. 2018 Abstract
  3. AEMPS-Wyeth. Metotrexato. Ficha técnica. 2018 Full text (in our servers)
  4. Anderson PO. Drug Treatment of Rheumatoid Arthritis During Breastfeeding. Breastfeed Med. 2018 Nov;13(9):575-577. Abstract
  5. Delaney S, Colantonio D, Ito S. Methotrexate in breast milk. 30 Annual Education Meeting of the Organization of Teratology Information Specialist (OTIS) and MotherToBaby Affiliates. Birth Defects Res. 2017;109 (SI):711. Poster-Abstract 7. 2017
  6. EMA-Therakind Ltd. Methotrexate. Drug Summary 2017 Full text (in our servers)
  7. Bermas BL. Lactation and Management of Postpartum Disease. Rheum Dis Clin North Am. 2017 May;43(2):249-262. Abstract
  8. Brown SM, Aljefri KA, Waas R, Hampton PJ. Systemic medications used in treatment of common dermatological conditions: Safety profile with respect to pregnancy, breast feeding and content in seminal fluid. J Dermatolog Treat. 2017 Abstract
  9. McConnell RA, Mahadevan U. Pregnancy and the Patient with Inflammatory Bowel Disease: Fertility, Treatment, Delivery, and Complications. Gastroenterol Clin North Am. 2016 Abstract
  10. Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, Arthanari S, Cunningham J, Flanders L, Moore L, Crossley A, Purushotham N, Desai A, Piper M, Nisar M, Khamashta M, Williams D, Gordon C, Giles I; BSR and BHPR Standards, Guidelines and Audit Working Group. 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 Sep;55(9):1693-7. Abstract Full text (link to original source) Full text (in our servers)
  11. Noviani M, Wasserman S, Clowse ME. Breastfeeding in mothers with systemic lupus erythematosus. Lupus. 2016 Aug;25(9):973-9. Abstract
  12. Almas S, Vance J, Baker T, Hale T. Management of Multiple Sclerosis in the Breastfeeding Mother. Mult Scler Int. 2016 Abstract Full text (link to original source) Full text (in our servers)
  13. Huang VW, Chang HJ, Kroeker KI, Goodman KJ, Hegadoren KM, Dieleman LA, Fedorak RN. Management of Inflammatory Bowel Disease during Pregnancy and Breastfeeding Varies Widely: A Need for Further Education. Can J Gastroenterol Hepatol. 2016;2016:6193275. Epub 2016 Sep 20. Abstract Full text (link to original source) Full text (in our servers)
  14. Anderson PO. Cancer Chemotherapy. Breastfeed Med. 2016 May;11:164-5. Abstract Full text (link to original source) Full text (in our servers)
  15. Nguyen GC, Seow CH, Maxwell C, Huang V, Leung Y, Jones J, Leontiadis GI, Tse F, Mahadevan U, van der Woude CJ; IBD in Pregnancy Consensus Group. The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. Gastroenterology. 2016 Abstract Full text (link to original source) Full text (in our servers)
  16. Götestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, da Silva J, Nelson-Piercy C, Cetin I, Costedoat-Chalumeau N, Dolhain R, Förger F, Khamashta M, Ruiz-Irastorza G, Zink A, Vencovsky J, Cutolo M, Caeyers N, Zumbühl C, Østensen M. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016 May;75(5):795-810. Abstract Full text (link to original source) Full text (in our servers)
  17. Mahadevan U, Matro R. Care of the Pregnant Patient With Inflammatory Bowel Disease. Obstet Gynecol. 2015 Aug;126(2):401-12. Abstract
  18. Kavanaugh A, Cush JJ, Ahmed MS, Bermas BL, Chakravarty E, Chambers C, Clowse M, Curtis JR, Dao K, Hankins GD, Koren G, Kim SC, Lapteva L, Mahadevan U, Moore T, Nolan M, Ren Z, Sammaritano LR, Seymour S, Weisman MH. Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res (Hoboken). 2015 Abstract Full text (link to original source) Full text (in our servers)
  19. Grunewald S, Jank A. New systemic agents in dermatology with respect to fertility, pregnancy, and lactation. J Dtsch Dermatol Ges. 2015 Abstract Full text (link to original source) Full text (in our servers)
  20. van der Woude CJ, Ardizzone S, Bengtson MB, Fiorino G, Fraser G, Katsanos K, Kolacek S, Juillerat P, Mulders AG, Pedersen N, Selinger C, Sebastian S, Sturm A, Zelinkova Z, Magro F; European Crohn’s and Colitis Organization. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015 Abstract Full text (link to original source) Full text (in our servers)
  21. Thorne JC, Nadarajah T, Moretti M, Ito S. Methotrexate use in a breastfeeding patient with rheumatoid arthritis. J Rheumatol. 2014 Abstract Full text (link to original source) Full text (in our servers)
  22. Huang VW, Habal FM. From conception to delivery: managing the pregnant inflammatory bowel disease patient. World J Gastroenterol. 2014 Abstract Full text (link to original source) Full text (in our servers)
  23. Mervic L. Management of moderate to severe plaque psoriasis in pregnancy and lactation in the era of biologics. Acta Dermatovenerol Alp Pannonica Adriat. 2014 Abstract Full text (link to original source) Full text (in our servers)
  24. Sammaritano LR, Bermas BL. Rheumatoid arthritis medications and lactation. Curr Opin Rheumatol. 2014 Abstract
  25. Pistilli B, Bellettini G, Giovannetti E, Codacci-Pisanelli G, Azim HA Jr, Benedetti G, Sarno MA, Peccatori FA. Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: how should we counsel cancer patients about breastfeeding? Cancer Treat Rev. 2013 May;39(3):207-11. Abstract
  26. Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013 Abstract
  27. Koren G, Carey N, Gagnon R, Maxwell C, Nulman I, Senikas V; Society of Obstetricians and Gynaecologists of Canada. Cancer chemotherapy and pregnancy. J Obstet Gynaecol Can. 2013 Mar;35(3):263-278. Abstract Full text (link to original source) Full text (in our servers)
  28. Kulier R, Kapp N, Gülmezoglu AM, Hofmeyr GJ, Cheng L, Campana A. Medical methods for first trimester abortion. Cochrane Database Syst Rev. 2011 Abstract
  29. Tanaka T, Walsh W, Verjee Z, Ratnapalan S, Sharma K, Ito S. Methotrexate use in a lactating woman with an ectopic pregnancy. 22 International Conference of the Organization of Teratology Information Specialist (OTIS). Birth Defects Res;85:494 Abstract 4. 2009
  30. Ostensen M. Management of early aggressive rheumatoid arthritis during pregnancy and lactation. Expert Opin Pharmacother. 2009 Abstract
  31. Weber JC, Kuhnert C. Traitements de fond des affections inflammatoires systémiques au cours de l’allaitement. [Breastfeeding and drug management in connective tissue and rheumatic diseases]. Rev Med Interne. 2008 Abstract
  32. Mottet C, Juillerat P, Pittet V, Gonvers JJ, Froehlich F, Vader JP, Michetti P, Felley C. Pregnancy and breastfeeding in patients with Crohn's disease. Digestion. 2007 Abstract
  33. Østensen M, Motta M. Therapy insight: the use of antirheumatic drugs during nursing. Nat Clin Pract Rheumatol. 2007 Abstract
  34. Østensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, Doria A, Rai R, Meroni P, Cetin I, Derksen R, Branch W, Motta M, Gordon C, Ruiz-Irastorza G, Spinillo A, Friedman D, Cimaz R, Czeizel A, Piette JC, Cervera R, Levy RA, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006 Abstract Full text (link to original source) Full text (in our servers)
  35. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum. 2005 Abstract
  36. WHO / UNICEF. BREASTFEEDING AND MATERNAL MEDICATION Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs. Department of Child and Adolescent Health and Development (WHO/UNICEF) 2002 Full text (link to original source) Full text (in our servers)
  37. AAP - American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001 Sep;108(3):776-89. Abstract Full text (link to original source) Full text (in our servers)
  38. Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med. 2000 Abstract Full text (link to original source) Full text (in our servers)
  39. Moretti ME, Lee A, Ito S. Which drugs are contraindicated during breastfeeding? Practice guidelines. Can Fam Physician. 2000 Sep;46:1753-7. Review. Abstract Full text (link to original source) Full text (in our servers)
  40. Connell WR. Safety of drug therapy for inflammatory bowel disease in pregnant and nursing women. Inflamm Bowel Dis. 1996 Abstract
  41. Goldsmith DP. Neonatal rheumatic disorders. View of the pediatrician. Rheum Dis Clin North Am. 1989 Abstract
  42. Johns DG, Rutherford LD, Leighton PC, Vogel CL. Secretion of methotrexate into human milk. Am J Obstet Gynecol. 1972 Abstract

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