Leflunomide

Registered South African indications:

• Rheumatoid arthritis

Contraindications

• Hypersensitivity to leflunomide, the principal active metabolite teriflunomide (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to any of the excipients in the tablets
• Leflunomide is contraindicated in patients with impairment of liver function
• Patients with severe immunodeficiency states, e.g. AIDS
• Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis
• Patients with serious infections
• Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group
• Patients with severe hypoproteinaemia, e.g. in nephritic syndrome
• Pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are above 0.02mg/l. Pregnancy must be excluded before the start of treatment with leflunomide
• Women must not breastfeed while receiving leflunomide
• Male patients should be aware of the possible male-mediated fetal toxicity. Reliable contraception during treatment with leflunomide should also be guaranteed
• Leflunomide is not recommended for use in patients under 18 years as its safety and efficacy have not been studied in this age group

Cautions

• Mild renal impairment
• Alcohol consumption
• Interstitial lung disease
• Diabetes mellitus
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Peripheral neuropathy
• Hypertension
• Opportunistic infections
• Allergic to peanut or soy
• Live attenuated vaccines

Forms avail. in SA and covered in this monograph: tab, fct

Active rheumatoid arthritis

• Oral (tab, fct): Loading dose: 100mg, dly for 3 days; Maintenance: 10-20mg, dly

The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months

Not established for use in children below 18 years

Pregnancy

• Contraindicated 
• The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when administered during pregnancy. Leflunomide is contraindicated in pregnancy
• 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 doctor immediately for pregnancy testing, and if positive, the doctor 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
• Washout procedure
• After stopping treatment with leflunomide:
• - cholestyramine 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 cholestyramine 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 cholestyramine or activated powdered charcoal. Use of alternative contraceptive methods is recommended

Breastfeeding

• Contraindicated
• Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breastfeeding 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 

Renal Impairment

• Mild: Caution; no dose adjustment recommended
• Moderate to severe: Contraindicated

Hepatic Impairment

• Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Anxiety
• Paraesthesia
• Headache
• Dizziness
• Peripheral neuropathy

Cardiovascular Disorders

• Increased blood pressure

Respiratory Disorders

• Rhinitis
• Bronchitis
• Pneumonia
• Interstitial lung disease 
• Pulmonary hypertension

Gastrointestinal Disorders

• Colitis
• Diarrhoea
• Nausea and vomiting
• Aphthous stomatitis
• Mouth ulceration
• Abdominal pain
• Taste disturbances

Hepatobiliary Disorders

• Pancreatitis
• Elevation of liver enzymes
• Hepatitis
• Jaundice
• Cholestasis
• Hepatic failure 
• Acute hepatic necrosis 

Endocrine and Metabolic Disorders

• Increased creatine phosphokinase
• Hypokalaemia
• Hyperlipidemia
• Hypophosphataemia
• Increased low density lipoprotein
• Hypouricemia

Musculoskeletal Disorders

• Tenosynovitis

Skin and Subcutaneous Tissue Disorders

• Increased hair loss
• Eczema
• Rash 
• Pruritus
• Dry skin
• Urticaria
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema multiforme
• Cutaneous lupus erythematosus
• Pustular psoriasis 
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Mild allergic reactions
• Anaphylaxis
• Cutaneous necrotizing vasculitis
• Sepsis
• Opportunistic infections
• Lymphoproliferative disorders
• Leucopenia
• Anaemia
• Thrombocytopenia
• Pancytopenia
• Eosinophilia
• Agranulocytosis

Others

• Benign and malignant neoplasms

• Methotrexate
• Live attenuated vaccines
• Warfarin
• Cholestyramine
• Activated charcoal 
• Cytochrome P450 inducers
• CYP1A2 substrates
• OAT3 substrates
• BCRP substrates
• Oral contraceptives

• Blood pressure
• Pregnancy test
• Tuberculosis screening
• Full blood count
• Differential count
• Hepatic function

A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase and exhibits antiproliferative activity.

Tablet 10mg

• Arava (Sanofi) originator
• Ravalef (Activo)
• Rheumalef (Adcock Ingram)

Tablet 20mg

• Arava (Sanofi) originator
• Lunar (Cipla)
• Ravalef (Activo)
• Rheumalef (Adcock Ingram)