Pregnancy & Lactation : הריון/הנקה

4.6 Fertility, pregnancy and lactation
Pregnancy

The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when administered during pregnancy. Arava is contraindicated in pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during and up to 2 years after treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout period” below).

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite, by instituting the drug elimination procedure described below, at the first delay of menses may decrease the risk to the foetus from leflunomide.

In a small prospective study in women (n=64) who became inadvertently pregnant while taking leflunomide for no more than three weeks after conception and followed by a drug elimination procedure, no significant differences (p=0.13) were observed in the overall rate of major structural defects (5.4%) compared to either of the comparison groups (4.2% in the disease matched group [n=108] and 4.2% in healthy pregnant women [n=78]).

For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of A771726 (target concentration below 0.02 mg/L):

Waiting period

A771726 plasma levels can be expected to be above 0.02 mg/L for a prolonged period. The concentration may be expected to decrease below 0.02 mg/L about 2 years after stopping the treatment with leflunomide.

After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.
Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/L no teratogenic risk is to be expected.

For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).

Washout procedure
After stopping treatment with leflunomide:

• colestyramine 8 g is administered 3 times daily for a period of 11 days, 
• alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of 11 days.

However, also following either of the washout procedures, verification by 2 separate tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/L and fertilisation is required.

Women of childbearing potential should be told that a waiting period of 2 years after treatment discontinuation is required before they may become pregnant. If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure may be advisable.

Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with colestyramine or activated powdered charcoal. Use of alternative contraceptive methods is recommended.
Breast-feeding

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast-feeding women must, therefore, not receive leflunomide.

Fertility

Results of animal fertility studies have shown no effect on male and female fertility, but adverse effects on male reproductive organs were observed in repeated dose toxicity studies (see section 5.3).