leflunomide

Leflunomide is an immunosuppressant medication used in the treatment of active rheumatoid arthritis (RA). RA is an autoimmune disease in which the body’s own immune system mistakenly attacks the joints, causing inflammation and damage to the joints.

Leflunomide is a disease modifying antirheumatic drug (DMARD) that modulates the immune system to reduce inflammation and slow down disease progression. Leflunomide is a prodrug that is converted to its active metabolite A77 1726 (referred to as M1) in the body.

Inflammation in active rheumatoid arthritis is characterized by high T-lymphocyte (T-cell) activity. Activated T-cells have a much higher requirement of pyrimidine nucleotide than T-cells that are at rest. Pyrimidine nucleotide is a chemical compound that is essential for DNA and RNA synthesis for T-cells to grow and proliferate. Leflunomide affects the activated T-cells more because the T-cells at rest use the salvage pathway to meet their pyrimidine requirement.

Leflunomide prevents the expansion of activated autoimmune lymphocytes by inhibiting dihydroorotate dehydrogenase, an enzyme essential for fresh (de novo) synthesis of pyrimidine. By inhibiting pyrimidine synthesis, leflunomide arrests the cell cycle progression of the activated T-cells, controlling T-cell mediated inflammation.

The uses of leflunomide include:

FDA-approved:

• Rheumatoid arthritis

Off-label:

• BK virus in kidney transplant recipients
• Cytomegalovirus disease in transplant recipients resistant to standard antivirals, as an adjunct therapy

• Do not use in patients who are hypersensitive to leflunomide or any of its components.
• Do not use leflunomide in pregnant women, it may cause fetal harm.
  • Do not initiate leflunomide therapy in women of reproductive potential without first excluding pregnancy.
  • Advise women of child-bearing potential to use effective contraception during therapy. Do not use leflunomide in women who do not use reliable methods of contraception.
  • Advise women to avoid pregnancy until they complete accelerated drug elimination procedure with cholestyramine, and leflunomide levels are verified to be undetectable.
  • If pregnancy occurs during therapy, apprise the patient of the potential hazards to the fetus.
• Do not use leflunomide in patients receiving teriflunomide, an active metabolite of leflunomide.
• There have been reports of severe liver injury, including fatal liver failure.
  • Using leflunomide concurrently with other medications that can damage the liver increases the risk for liver injury.
  • Do not use leflunomide in patients with pre-existing liver disease and elevation of liver enzyme ALT two times more than the upper limit of normal (ULN).
  • Monitor ALT levels regularly and if it increases more than 3 times ULN, interrupt therapy and investigate the probable cause. If leflunomide-induced, initiate cholestyramine or activated charcoal to accelerate elimination of leflunomide and monitor ALT level until it returns to normal range. If it is not leflunomide-induced, consider resuming therapy.
• Leflunomide can cause immunosuppression and bone marrow depression.
  • Avoid use in patients with severe immunodeficiency, bone marrow dysplasia or severe uncontrolled infections.
  • In case of serious infection, interrupt therapy and initiate accelerated drug elimination procedure.
  • Monitor complete blood counts of patients and if there are signs of bone marrow depression, discontinue treatment and initiate cholestyramine.
• There are rare reports of severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis with leflunomide therapy. If a patient develops signs of skin reactions, discontinue leflunomide and initiate cholestyramine.
• There is a potential increased risk for malignancies, particularly lymphoproliferative disorders.
• Peripheral neuropathy has been reported, with persistent symptoms in some patients. Age older than 60 years, concomitant neurotoxic medications, and diabetes can increase the risk. If a patient develops symptoms, discontinue leflunomide and initiate drug elimination procedure.
• Interstitial lung disease has been reported with leflunomide treatment. If patient develops new onset or worsening of pulmonary symptoms, interrupt therapy, investigate cause, and if necessary, discontinue leflunomide and initiate drug elimination procedure.
• Screen patients for latent tuberculosis and if positive, treat tuberculosis with standard therapy before initiating leflunomide.
• Use with caution in patients with impaired kidney function.
• Do not administer live vaccines during leflunomide treatment and until the drug is undetectable in the serum.
• Check blood pressure before initiating leflunomide and monitor periodically thereafter.

Common side effects of leflunomide include:

• Diarrhea
• Nausea
• Vomiting
• Indigestion (dyspepsia)
• Abdominal pain
• Gastrointestinal pain
• Mouth ulcer
• Gum inflammation (gingivitis)
• Oral inflammation (stomatitis)
• Salivary gland enlargement
• Dry mouth (xerostomia)
• Oral Candida yeast infection (moniliasis/candidiasis)
• Gastroenteritis
• Inflammation of the esophagus (esophagitis)
• Gastritis
• Colon inflammation (colitis)
• Gas (flatulence)
• Constipation
• Tarry black stools (melena)
• Loss of appetite (anorexia)
• Elevated levels of liver enzymes ALT and AST
• Gallstones (cholelithiasis)
• Hair loss (alopecia)
• Rash
• Itching (pruritus)
• Eczema
• Dry skin
• High blood pressure (hypertension)
• Chest pain
• Chest pain related to coronary artery disease (angina pectoris)
• Palpitations
• Rapid heart rate (tachycardia)
• Varicose veins
• Dilation of blood vessels (vasodilation)
• Blood vessel inflammation (vasculitis)
• Upper respiratory tract infection
• Increased cough
• Bronchial inflammation (bronchitis)
• Sinus inflammation (sinusitis)
• Throat inflammation (pharyngitis)
• Nasal inflammation (rhinitis)
• Nasal bleeding (epistaxis)
• Pneumonia
• Asthma
• Shortness of breath (dyspnea)
• Lung disorder
• Urinary tract infection
• Bladder inflammation (cystitis)
• Albumin in urine (albuminuria)
• Painful urination (dysuria)
• Blood in urine (hematuria)
• Urinary frequency
• Prostate disorder
• Menstrual disorder
• Vaginal candidiasis
• Migraine
• Headache
• Dizziness
• Skin tingling and numbness (paresthesia)
• Joint disorder
• Inflammation of membrane around tendons (tenosynovitis)
• Inflammation of the connective tissue that lines joints (synovitis)
• Inflammation of the fluid-filled sacs that cushion joints (bursitis)
• Joint pain (arthralgia)
• Joint degeneration (arthrosis)
• Bone tissue death (necrosis)
• Bone pain
• Tendon rupture
• Muscle cramps
• Muscle pain (myalgia)
• Leg cramps
• Back pain
• Neck pain
• Pelvic pain
• Weakness (asthenia)
• Flu syndrome
• Fever
• Injury accident
• Pain
• Feeling unwell (malaise)
• Hernia
• Abscess
• Cyst
• Allergic reaction
• Weight loss
• Low blood potassium levels (hypokalemia)
• High blood glucose levels (hyperglycemia)
• High blood fats (hyperlipidemia)
• Increase in creatine phosphokinase
• Swelling of extremities (peripheral edema)
• Diabetes mellitus
• Overactive thyroid (hyperthyroidism)
• Low red blood cell count (anemia)
• Skin reactions including:
  • Acne
  • Contact dermatitis
  • Fungal dermatitis
  • Flat and raised skin lesions (maculopapular rash)
  • Bleeding under the skin (hematoma)
  • Discoloration of skin from bleeding underneath (ecchymosis)
  • Skin and subcutaneous nodules
  • Skin ulcers
  • Skin disorders
  • Nail disorders
  • Herpes simplex
  • Herpes zoster
  • Hair discoloration
• Anxiety
• Depression
• Sleep disorder
• Sleeplessness (insomnia)
• Vertigo
• Nerve inflammation (neuritis)
• Nerve pain (neuralgia)
• Increased sweating
• Eye disorder
• Blurred vision
• Cataract
• Inflammation of conjunctiva, the membrane over the eye whites and inner eyelid surfaces (conjunctivitis)
• Taste perversion

Less common and rare side effects of leflunomide include:

• Opportunistic and severe infections including sepsis
• Hypersensitivity reactions including:
  • Hives (urticaria)
  • Swelling under the skin and mucous membranes (angioedema)
  • Severe allergic reaction (anaphylaxis)
  • High level of eosinophils in blood (eosinophilia)
• Serious skin reactions including:
  • Erythema multiforme
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Cutaneous necrotizing vasculitis
• Blood disorders including:
  • Severely low count of granulocyte immune cells (agranulocytosis)
  • Low count of neutrophil immune cells (neutropenia)
  • Low count of leukocyte immune cells (leukopenia)
  • Low count of platelets (thrombocytopenia)
  • Low count of all types of blood cells (pancytopenia)
• Inflammation of the pancreas (pancreatitis)
• Liver inflammation (hepatitis)
• Impaired bile flow (cholestasis)
• Jaundice
• Severe liver damage including hepatic failure and necrosis
• Lung scarring diseases (interstitial lung disease) such as:
  • Pulmonary fibrosis
  • Interstitial pneumonitis
• Peripheral nerve disease (neuropathy)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 10 mg
• 20 mg
• 100 mg

Adult:

Rheumatoid Arthritis

• 100 mg orally once daily for 3 days initially, THEN 10-20 mg orally once daily

Dosage Modifications

Renal impairment

• No dosage adjustment provided by the manufacturer; use with caution

Hepatic Impairment

• Preexisting liver disease: Not recommended
• Baseline ALT more than 2 times ULN: Not recommended
• Severe hepatic impairment: Contraindicated
• Hepatotoxicity following administration: Discontinue therapy and determine cause; if leflunomide induced, discontinue treatment and initiate accelerated drug elimination process

Dosing Considerations

Discontinuing leflunomide

• Drug elimination process recommended to achieve nondetectable plasma levels (i.e., below 0.02 mg/L) after discontinuation
• Step 1: Administer cholestyramine 8 g orally thrice daily for 11 days; the 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly
• Step 2: Verify whether plasma levels are below 0.02 mg/L by 2 separate tests at least 14 days apart; if plasma levels are above 0.02 mg/L, consider additional cholestyramine treatment
• Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels below 0.02 mg/L due to individual variation in drug clearance

Pediatric:

• Safety and efficacy not established

Overdose

• Leflunomide overdose may cause abdominal pain and diarrhea, reduced red blood cell and leukocyte counts (anemia and leukopenia), and elevated liver function tests.
• Overdose is treated with cholestyramine and activated charcoal to accelerate the elimination of the drug.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Leflunomide has no known severe interactions with other drugs.
• Leflunomide has serious interactions with at least 74 different drugs.
• Leflunomide has moderate interactions with at least 60 different drugs.
• Mild interactions of leflunomide include:
  • activated charcoal
  • alosetron
  • luvasta
  • celecoxib
  • diclofenac
  • flurbiprofen
  • ovastatin
  • ibuprofen
  • ibuprofen IV
  • meloxicam
  • piroxicam
  • ramelteon
  • rifampin
  • shark cartilage
  • sulfamethoxazole
  • tolbutamide
  • voriconazole

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or healthcare provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Do not use leflunomide in pregnant women, it may cause fetal harm. There are no adequate and well-controlled studies in pregnant women, however animal studies show leflunomide may increase the risk of fetal malformation and fetal death.
• Do not initiate leflunomide therapy in women of reproductive potential without first excluding pregnancy. Women of pregnancy potential should use effective contraception during therapy.
• Women wishing to become pregnant must discontinue leflunomide therapy, undergo accelerated drug elimination procedure with cholestyramine, and avoid pregnancy until leflunomide levels are verified to be undetectable. Without the accelerated drug elimination procedure, it may take up to 2 years for leflunomide to be eliminated.
• Available information does not indicate leflunomide therapy for men is associated with fetal risks, however, to minimize risks, men wishing to father a child should consider first discontinuing leflunomide and undergoing drug elimination procedure.
• It is not known if leflunomide is present in breast milk, however, many drugs are excreted in breast milk. Leflunomide should not be used in nursing mothers because of the potential for serious adverse reactions in the breastfed infant. Decision to continue nursing or initiate leflunomide therapy should be taken based on the importance of the treatment to the mother.
• A pregnancy exposure registry monitors pregnancy outcomes in women exposed to therapy during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972.

• Take leflunomide exactly as prescribed.
• You will need periodic tests while on leflunomide therapy. Do not miss your appointments.
• Notify your physician immediately if you experience:
  • Any skin reactions
  • Liver injury symptoms such as abdominal pain, jaundice, or unusual tiredness
  • Onset or worsening of lung disease symptoms such as cough or shortness of breath
  • Symptoms of immunosuppression and bone marrow depression such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness.
  • Symptoms of peripheral neuropathy such as numbness, pain, or tingling in extremities
• Do not take live vaccines while on leflunomide therapy.
• Store safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.