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Medications

Medications2020-09-29T11:09:29+00:00

√ The Go List

Pregnancy Compatible

  • Hydroxychloroquine

  • Chloroquine

  • Azathioprine

  • Cyclosporine

  • Tacrolimus

  • Colchicine

  • Prednisone

Δ The Caution List

INSUFFICIENT INFORMATION

  • Rituximab

  • Belimumab

× The Stop List*

MAY CAUSE BIRTH DEFECTS

  • Leflunomide

  • Methotrexate

  • Mycophenolate (CellCept) & Mycophenolic acid (Myfortic)

  • Cyclophosphamide

  • Thalidomide & Lenalidomide (Revlimid)

*If currently pregnant, immediately stop STOP list medications and read: What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients. 

If planning pregnancy, talk with your doctor BEFORE you stop.

GO List

Hydroxychloroquine

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Hydroxychloroquine: Hydroxychloroquine, sometimes called “Lupus Life Insurance” has been shown to decrease the risk of a lupus flare during and after pregnancy2,3.  It has not been associated with birth defects or any negative effects on the offspring1.  Some studies suggest that hydroxychloroquine may decrease the risk of pregnancy loss in women with lupus and other studies suggest it might decrease the risk of preterm delivery3,4. All women with lupus  who can tolerate hydroxychloroquine are encouraged to take it during and following pregnancy.  

Recommendations:

  • American College of Rheumatology: Recommend that all women with SLE take hydroxychloroquine during pregnancy if possible.
  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission or treatment of disease flare5.
  • British Society of Rheumatology: Should be continued during pregnancy. Remains the antimalarial of choice in women planning a pregnancy with rheumatic disease7.

Chloroquine

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Chloroquine is prescribed to some women as a replacement for hydroxychloroquine. It has similar safety and benefits to hydroxychloroquine for controlling lupus during pregnancy.

Recommendations

  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission or treatment of disease flare5.
  • British Society of Rheumatology: Compatible with pregnancy7.

Azathioprine

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Azathioprine is widely considered the safest immunosuppressant during pregnancy for women with lupus. Azathioprine has been prescribed for several decades to pregnant women with kidney transplants without an increase in birth defects or pregnancy loss. Pregnant women taking azathioprine are more likely than others to deliver preterm, but it isn’t possible to tell if this is due to the azathioprine or due to the underlying disease (kidney transplant, inflammatory bowel disease, lupus, or other illnesses). Some azathioprine transfers across the placenta, which may put some infants at some level of immunosuppression in the first weeks of life. Women taking azathioprine during pregnancy who have no significant disease activity might be able to hold the drug for the 1 week prior to delivery to decrease this risk of immunosuppression. Holding azathioprine is not recommended for women with active lupus prior to delivery.

6-mercaptopurine (6-MP) is an acceptable alternative to azathioprine during pregnancy with similar potential risks and benefits.

Recommendations

  • American College of Rheumatology: Strongly recommend as compatible with pregnancy.
  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission or treatment of disease flare5.
  • British Society of Rheumatology: Compatible throughout pregnancy at less than or equal to 2mg/kg/day7.

Cyclosporine

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Cyclosporine has been prescribed throughout pregnancy to women with transplanted organs for many years and has not been associated with birth defects or pregnancy loss. As with azathioprine, women taking cyclosporine have some increased risk for preterm birth or low birth weight infants, but it isn’t clear if this is related to the drug or the mother’s underlying disease.

Hypertension (high blood pressure) is a side effect of cyclosporine in up to 10% of patients. As preeclampsia and hypertension are common in lupus pregnancies, blood pressure should be monitored closely.

At delivery, a baby will have a cyclosporine level roughly half that of the mother, so consider holding the drug in the final 1-2 weeks of pregnancy if lupus is well controlled.

Recommendations

  • American College of Rheumatology: Recommend compatible with pregnancy with monitoring for elevated blood pressure.
  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission or treatment of disease flare5. Acceptable benefit/risk ratio6.
  • British Society of Rheumatology: Compatible throughout pregnancy at lowest effective dose7.

Tacrolimus

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Tacrolimus has been used during pregnancy in women with solid-organ transplants for many years and is not associated with birth defects or pregnancy loss. Pregnancies in women taking tacrolimus are more likely to deliver early and women may be more likely to have hypertension during pregnancy. Several small case series8,9 in pregnant women with lupus suggest that tacrolimus can be an effective therapy for lupus nephritis. At delivery a baby will have a tacrolimus level roughly half that of the mother, so consider holding the drug in the final 1-2 weeks of pregnancy if lupus is well controlled.

Recommendations

  • American College of Rheumatology: Recommend compatible with pregnancy with monitoring for elevated blood pressure.
  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission or treatment of disease flare5. Acceptable benefit/risk ratio6.
  • British Society of Rheumatology: Compatible throughout pregnancy at lowest effective dose7.

Colchicine

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Colchicine can be continued during pregnancy as it does not appear to increase the risk for birth defects or pregnancy loss10. A review of over 500 pregnancies in women with Familial Mediterranean Fevers demonstrated excellent pregnancy outcomes. Colchicine is sometimes used to manage pericarditis in women with lupus and can be continued during pregnancy if needed.

Recommendations

  • American College of Rheumatology: Strongly recommend as compatible with pregnancy.
  • EULAR: Proven compatible with pregnancy. Should be continued in pregnancy for maintenance of remission and treatment of disease flare5.
  • British Society of Rheumatology: Not addressed.

Prednisone

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Prednisone is considered safe in pregnancy when used to control active disease and manage flares. While prednisone is the medication that most rheumatologists are the most comfortable prescribing during pregnancy, it is not without potential risks. Because of this, we recommend managing lupus activity with pregnancy-compatible medications (particularly hydroxychloroquine and azathioprine) to limit prednisone use when possible during pregnancy. If a woman is having a significant lupus flare, however, the benefits of treating the inflammation with prednisone outweighs the risk of the drug.

There is conflicting data suggesting an association with cleft lip and palate with first trimester use – there are large studies showing no association and others showing an increased risk11. The important potential maternal side effects of prednisone are weight gain, diabetes, and hypertension, all of which are known to negatively impact pregnancies and offspring. Studies of prednisone in asthma, rheumatoid arthritis, antiphospholipid syndrome suggest that prednisone increases the risk for preterm delivery12.

Recommendations

  • American College of Rheumatology: Recommend as compatible with pregnancy and recommend taping to less than 20mg/day by adding pregnancy-compatible immunosuppressants.
  • EULAR: Safe for maintenance treatment during pregnancy. Used to control disease activity/manage flares. High-dose glucocorticoids (including pulses of intravenous methylprednisolone) used in treatment of severe SLE flares6.
  • British Society of Rheumatology: Compatible with each trimester of pregnancy7.

CAUTION List

Rituximab

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Rituximab is an IgG antibody, so likely has minimal transfer across the placenta until week 16 of pregnancy; there is data on about 250 pregnancies exposed to the drug13. If rituximab is needed to control disease, we suggest that it be given prior to conception or in the first half of pregnancy. Dosing after pregnancy week 16 will expose the developing fetus to rituximab. An estimated half of infants exposed to rituximab after week 16 will be born without B cells. These infants appear to restore B cell levels over the first year of life, but the impact on immune system function and long-term immune-competency isn’t known.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients 

Recommendations

  • American College of Rheumatology: Recommend discontinuing at conception; can be used for life-or organ-threatening disease.
  • EULAR: Limited documentation on safe use in pregnancy and should be replaced before conception by other medication. Should only be used during pregnancy when no other pregnancy-compatible drug can effectively control maternal disease5.
  • British Society of Rheumatology: Should be stopped 6 months before conception. Limited evidence has not shown rituximab to be teratogenic and only second/third trimester exposure is associated with neonatal B cell depletion. Therefore, unintentional rituximab exposure early in the first trimester is unlikely to be harmful7.

Belimumab

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Belimumab is an IgG antibody, so likely has minimal transfer across the placenta until week 16 of pregnancy; there is data on about 150 pregnancies exposed to the drug in the first trimester. At this time there is insufficient data to suggest the safety of continuing the drug during pregnancy. We recommend stopping belimumab prior to conception. For women who conceive while taking belimumab, we suggest stopping the drug and replacing it with a pregnancy-compatible medication like azathioprine and monitoring lupus activity.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

Recommendations

  • American College of Rheumatology: Recommend discontinuing at conception and not dosing during pregnancy.
  • EULAR: Limited documentation on safe use in pregnancy and should be replaced before conception by other medication. Should be used during pregnancy only when no other pregnancy-compatible drug can effectively control maternal disease5.
  • British Society of Rheumatology: Insufficient documentation to recommend in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful7.

STOP List

Leflunomide

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If it is stopped early in pregnancy, human experience suggests that leflunomide does not increase the risk for birth defects despite animal studies with different results. Four published studies have shown no increased risk for pregnancy loss or birth defects in pregnancies conceived while the woman was taking leflunomide14, 15, 16, 17. In all cases, leflunomide was stopped upon discovery of the pregnancy and most women completed the prescribed cholestyramine washout (8g by mouth 3 times per day for 11 days).

Based on this information, we still strongly recommend that leflunomide is stopped and a cholestyramine washout is completed PRIOR to pregnancy. Check a teriflunomide level to ensure the drug is fully removed. Leflunomide should not be taken during pregnancy.

If a pregnancy is conceived on leflunomide, the drug should be stopped and cholestyramine washout completed. The mother can be reassured, however, that her pregnancy is not at increased risk for pregnancy loss or birth defects.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

Recommendations

  • American College of Rheumatology: Recommend stopping prior to conception and wash-out with cholestyramine if there are detectable levels of drug in maternal blood.
  • EULAR: Insufficient data concerning use in pregnancy, should be avoided until further evidence is available5.
  • British Society of Rheumatology: Based on limited evidence, leflunomide may not be a teratogen but is still not recommended for pregnancy7.

Methotrexate

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Methotrexate is a teratogen that is associated with an increase in pregnancy loss (~40%) and birth defects (~7%). Pregnancy loss may occur early or late in pregnancy. Most of the birth defects, but not all, will be identified on a level II ultrasound, generally completed around week 17-20 of pregnancy.

Women taking methotrexate who wish to conceive should stop it at least 1 month and typically 3 months prior to conception. To avoid a lupus flare, switch to a GO List medication; continue folic acid replacement once methotrexate has been stopped.

If there is methotrexate exposure at the time of conception, stop the drug immediately, increase folic acid to 5mg daily to help limit the risk of developing neural tube defects, and discuss the potential risks of the drug to the offspring and her disease. Women in this circumstance should be referred to Maternal-Fetal Medicine for evaluation, monitoring, and discussion of options.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

Recommendations

  • American College of Rheumatology: Recommend stopping 1-3 months prior to conception; if exposure in pregnancy, recommend giving folic acid 5mg/day through pregnancy.
  • EULAR: Teratogenic and should be withdrawn before pregnancy5.
  • British Society of Rheumatology: Should be avoided in pregnancy and stopped 3 months in advance of conception. In Women treatment treated with low-dose methotrexate within 3 months prior to conception or in the case of accidental pregnancy should continue folate supplementation (5 mg/day) throughout pregnancy7.

Mycophenolate (CellCept) & Mycophenolic acid (Myfortic)

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Mycophenolate mofetil and mycophenolic acid are major teratogens, causing pregnancy loss in ~40% of pregnancies and major birth defects in ~25% of live born infants. These anomalies generally involve the face and ears and can leave offspring deaf. Mycophenolate should be stopped prior to conception to reduce the risk of pregnancy loss and birth defects. As many women take mycophenolate to control lupus, prior to pregnancy these women should switch to a GO list option, most commonly azathioprine. Once the woman has switched and her lupus has remained stable for 3-6 months, then she can proceed to conception.

If there is mycophenolate exposure at the time of conception, stop the drug immediately, discuss the potential risks of the drug to the offspring and her disease to her physical body. Women in this circumstance should be referred to Maternal-Fetal Medicine for evaluation, monitoring, and discussion of options.

The FDA has mandated a Risk Evaluation and Mitigation Strategy (REMS) Program to avoid conception while a woman takes mycophenolate. The major goal of the REMS program is to mitigate the risk of fetal toxicity associated with mycophenolate use during pregnancy by educating healthcare providers and females of reproductive age. (https://www.mycophenolaterems.com)

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

Recommendations

  • American College of Rheumatology: Recommend stopping at least 6 weeks prior to conception and assessing disease stability off drug. Do not give during pregnancy.
  • EULAR: Teratogenic and should be withdrawn before pregnancy5.
  • British Society of Rheumatology: Contraindicated during pregnancy. Treatment with mycophenolate should be stopped at least 6 weeks before planned pregnancy7.

Cyclophosphamide

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Cyclophosphamide is a major teratogen, causing pregnancy loss in ~50% of pregnancies and major birth defects in ~25% of live born infants with first trimester exposure. Check a pregnancy test prior to each cyclophosphamide infusion to help avoid accidental exposure in pregnancy. As women receiving cyclophosphamide generally have severe lupus activity, pregnancy should be delayed until therapy is complete and lupus is controlled. Once cyclophosphamide therapy is complete, the woman can be switched to a GO List medication and observed for 3-6 months for any signs of worsening disease activity. If her disease remains stable on pregnancy-compatible medications, then she can proceed to conception.

If a pregnancy has cyclophosphamide exposure, stop the drug immediately, discuss the potential risks of the drug to the offspring and her disease to her physical body. Women in this circumstance should be referred to Maternal-Fetal Medicine for evaluation, monitoring, and discussion of options.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

Recommendations

  • American College of Rheumatology: Recommend stopping at least 3 months prior to conception. Can be considered for life-or organ-threatening disease in the 2nd and 3rd trimesters.
  • EULAR: Use during the 1st trimester of pregnancy has been associated with increased risk for the fetus. Reserved only for the management of severe, life-threatening or refractory SLE manifestations during the second or third trimester5.
  • British Society of Rheumatology: Teratogenic and gonadotoxic, should only be considered in pregnancy in life/organ threatening maternal disease7.

Thalidomide & Lenalidomide (Revlimid)

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Thalidomide is the original drug that brought attention to the potential teratogenicity of medications. In the 1950-60’s, when it was approved for over-the-counter, prescription-free purchase in Europe to treat morning sickness early in pregnancy, it caused major limb defects in an estimated 20% of exposed offspring. Thalidomide and its cousin lenalidomide should be stopped at least a month prior to conception and replaced with a GO list medication, most often azathioprine. Each of these drugs has a rigorous approval process that requires monthly pregnancy testing to obtain a prescription.

If a pregnancy has thalidomide or lenalidomide exposure, stop the drug immediately, discuss the potential risks of the drug exposure to the offspring and her disease. Women in this circumstance should be referred to Maternal-Fetal Medicine for evaluation, monitoring, and discussion of options. To report pregnancy exposure contact www.FDA.gov/medwatch.

TO REPORT SUSPECTED ADVERSE REACTIONS OR EMBRYO-FETAL EXPOSURE: CONTACT CELGENE CORPORATION AT 1-888-423-5436 OR FDA AT 1-800-FDA-1088 OR WWW.FDA.GOV/MEDWATCH.

What to do if pregnant on a STOP or CAUTION medication – For Providers | For Patients

  • American College of Rheumatology: Recommend stopping 1-3 months prior to conception. Do not dose during pregnancy.

Resources

  1.  Diav-Citrin O, Blyakhman S, Shechtman S, et al. Pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study. Reproductive Toxicology. 2013;39:58–62.
  2.  Clowse ME, Magder L, Witter F, et al. Hydroxychloroquine in lupus pregnancy. Arthritis & Rheumatology. 2006;54:3640–7.
  3.  Eudy AM, Siega-Riz AM, Engel SM, et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases. 2018;77:855-60.
  4.  Leroux M, Desveaux C, Parcevaux M, et al. Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus. 2015;24:1384–91.
  5.  Skorpen CG, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Annals of the Rheumatic Diseases. 2016;75:795-810.
  6.  Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Annals of the Rheumatic Diseases. 2017;76:476-85.
  7.  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. 2016;55:1693-7.
  8.  Ichinose K, Sato S, Kitajima Y, et al. The efficacy of adjunct tacrolimus treatment in pregnancy outcomes in patients with systemic lupus erythematosus. Lupus. 2018;27:1312-20.
  9.  Webster P, Wardle A, Bramham K, et al. Tacrolimus is an effective treatment for lupus nephritis in pregnancy. Lupus. 2014;23:1192-6.
  10.  Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology. 2017;57:382-7.
  11.  Palmsten K, Rolland M, Hebert MF, et al. Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: Daily and cumulative dose. Pharmacoepidemiology and Drug Safety. 2018;27:430-8.
  12.  Østensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Research & Therapy. 2006;8:209.
  13.  Chakravarty EF, Murray ER, Kelman A, et al. Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011;117:1499-506.
  14.  Bérard A, Zhao JP, Shui I, et al. Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes. Annals of the Rheumatic Diseases. 2018 1;77:500-9.
  15. Cassina M, Johnson DL, Robinson LK, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis & Rheumatism. 2012;64:2085-94.
  16. Weber-Schoendorfer C, Beck E, Tissen-Diabaté T, et al. Leflunomide–a human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database. Reproductive Toxicology. 2017;71:101-7.
  17. Chambers CD, Johnson DL, Robinson LK, et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis & Rheumatism. 2010;62:1494-503.

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