Leflunomide
Risk Factor: XM
Class: Immunologic agents
/ Antirheumatic agents
Contents of this page:
Fetal Risk Summary
Leflunomide, a pyrimidine synthesis inhibitor, is indicated for the treatment of active rheumatoid arthritis to reduce signs and symptoms and retard structural damage. The drug is metabolized to an active metabolite that has an elimination half-life of about 2 weeks (1).
Leflunomide is contraindicated in pregnancy because it has exhibited dose-related teratogenicity and embryo/fetal toxicity in animals at doses that resulted in systemic exposures at or below those obtained in humans. Therefore, in women of childbearing age, leflunomide should not be started until pregnancy has been excluded and the use of reliable contraception has been confirmed (1).
In reproduction studies with pregnant rats during organogenesis, an oral dose that produced systemic exposure approximately 10% of the human exposure level based on area under the plasma concentration curve (HE) was teratogenic (anophthalmia or microphthalmia and internal hydrocephalus) (1). This dose also resulted in an increase in embryo death and a decrease in maternal and surviving fetuses' body weight. In rabbits, an oral dose equivalent to the maximum HE during organogenesis resulted in fused, dysplastic sternebrae (1). No teratogenic effects were noted at lower doses in either species. In rats treated with doses 1% of the HE for 14 days before mating and continued until the end of lactation, more than 90% of the offspring failed to survive the postnatal period (1).
Leflunomide was not carcinogenic in rats, but mice exhibited dose-related increases in lymphoma (males) and bronchoalveolar adenomas and carcinomas combined (females). The incidence of the lung tumors, however, was within the spontaneous range for the mouse strain (2). The drug was not mutagenic or clastogenic in various assays although a minor metabolite (4-trifluoromethylaniline; TFMA) was in some tests (1). Because of the very low amounts of this metabolite, the results were not thought to be clinically significant (2).
It is not known if leflunomide crosses the human placenta. The molecular weight (about 270) is low enough that passage to the fetus should be expected. It is also not known if the active metabolite can cross the placenta or if the fetus can metabolize the parent compound to the active metabolite.
Because it may take up to 2 years to reach non-detectable plasma levels (<0.02 g/mL) of the active metabolite, the manufacturer has developed a drug elimination procedure in the event that a woman taking leflunomide becomes pregnant: (a) administer cholestyramine 8 g 3 times daily for 11 days (not necessarily consecutive unless there is a need to lower the plasma level rapidly); (b) verify plasma levels less than 0.02 g/mL by two tests at least 14 days apart. If plasma levels are higher than 0.02 g/mL, additional cholestyramine treatment should be considered (1).
Information relating to the risks of leflunomide use in human pregnancy has been published (2,3). A 2000 review on the treatment of rheumatic diseases briefly mentioned the agent, stating that it was contraindicated in pregnancy (3). It also reviewed the drug elimination procedure in the manufacturer's product literature. A 2001 Reference thoroughly reviewed the reproductive risks of leflunomide and provided detailed information on counseling of men and women who might have been exposed to the agent and were either contemplating fathering a child, were pregnant, or were planning a pregnancy (2). The drug blood level considered safe was 0.03 g/mL, which was 123 and 136 times lower than the no-effect blood levels in rats and rabbits, respectively. The safe concentration was about 0.1% of the average steady-state plasma level of the active metabolite. The author mentioned that approximately 30 women had become pregnant on leflunomide, 29 of whom were exposed to therapeutic levels of the drug during early organogenesis in spite of initiating the drug elimination protocol as soon as pregnancy was diagnosed. Only 3 pregnancies were continuing (no outcome data available), however, as 27 women had elected to undergo termination (2).
In summary, leflunomide is an animal teratogen but, except for the data above, no human pregnancy experience has been published and the risk for congenital malformations cannot be determined. The drug and its active metabolite are eliminated from the body very slowly and may take up to 2 years to reach nondetectable plasma metabolite levels. The drug is contraindicated in pregnancy. In women of childbearing age, pregnancy should be excluded and the woman should be on a reliable contraceptive before starting therapy. In the event of inadvertent conceptions, a drug elimination procedure has been developed and is included in the product information. However, the procedure for preventing embryo exposure to therapeutic levels in unplanned pregnancies, based on the above report, appears to be clinically ineffective. In inadvertent pregnancies, the procedure, to be at least partially effective, should be initiated no later then the time of the first missed menstrual period (2). Pregnancy loss and anomalies occurring early in organogenesis would still be a risk, but drug-induced microcephaly and mental retardation would be prevented (2). A pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to leflunomide. Health care providers are encouraged to register such patients at 1-877-311-8972 (1,2).
Breast Feeding Summary
No reports describing the use of leflunomide during human lactation have been located. The molecular weight (about 270) is low enough that excretion into breast milk should be expected. The effects of this exposure on a nursing infant are unknown. Because of the potential for serious adverse effects and without information on the amount of drug in milk, nursing mothers receiving this drug should probably not breast feed (2).
References
- Product information. Arava. Aventis Pharmaceuticals, 2001.
- Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001; 63:10612.
-
Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med 2000;160:6109.
Questions and Answers
Is there anyone out there on Leflunomide for Inflammatory Arthritis?, I was just wondering if it is working for you and just how long it took to make a difference?
Is it enough and what dose are you on?
I've been on it for 2 weeks with prednisolone support for 6 weeks. I am hopeing I can tolerate it and that it works for me.
I am interested to hear any experiences. :).
I used it but it wasn't that effective. I went to another item to help me.
Can leflunomide cause bleeding to the back passage?, Take leflunomide for rheumatoid arthritis and have been told today to stop taking drug because liver check is high, however, passed blood in stool yesterday
The following was taken from a drug information fact sheet:
"Taking leflunomide can also affect the blood count (one of the effects is that fewer blood cells are made) and it can make you more likely to develop infections. If you develop a sore throat or other infection, a fever, unexplained bruising, bleeding or rash, or if you become breathless, or develop any other unexpected new symptoms after starting leflunomide, you should report to your doctor or rheumatology nurse specialist as soon as possible.
Leflunomide may affect the liver. This may cause problems ranging from abnormalities in the blood tests without causing ill health to severe liver damage which may be fatal. If you develop symptoms such as unusual tiredness, abdominal pain, or jaundice (eyes or skin turning yellow), inform your doctor or rheumatology nurse specialist immediately."
As you can see, the abnormal liver enzymes were enough to get you off this drug. The bleeding in the stools is also probably a result of the medication. Just to be safe, you should probably discuss this with your doctor as soon as possible. Good luck.
What is the mechanism of action for Leflunomide? Are there any side effects?,
Leflunomide is a prodrug, it inhibits pyrimidine synthesis, reduces leucocyte adhesion and cell infiltration, it also stimulates tissue growth factor beta formation and reduces the amount of osteoclasts (increases bone density as there are no more cells to break bone down!).
S/e include allopecia, diarrhea, vomiting and is embryotoxic
Hope this helps!
