Leflunomide (Arava) is a pyrimidine synthesis inhibitor classified as a conventional disease-modifying antirheumatic drug (DMARD) used in patients with Rheumatoid arthritis.

Leflunomide (Arava) Uses:

• Rheumatoid arthritis:

  • Treatment of adults with active rheumatoid arthritis (RA).

• Off Label Use of Leflunomide in Adults:

  • BK virus (viremia or nephropathy; in kidney transplant recipients)
  • Cytomegalovirus disease (in transplant recipients resistant to standard antivirals)

Leflunomide (Arava) Dose in Adults:

Leflunomide (Arava) Dose in the treatment of BK virus (viremia or nephropathy), in kidney transplant recipients (off-label; based on limited data): Oral:

• Loading dose:
  • 100 mg/day for 5 days
  • Maintenance: 40 mg/day

Or

• Loading dose:
  • 60 mg/day for 2 days
  • Maintenance: 20 mg/day
• Consider adjusting dose based on active metabolite serum concentrations.

Leflunomide (Arava) Dose in the treatment of Cytomegalovirus disease, in transplant recipients resistant to standard antivirals, adjunctive therapy (off-label; based on limited data):

• Oral:
  • 100 mg OD for 3 to 5 days, followed by 20 to 40 mg/day
  • Consider adjusting dose based on active metabolite serum concentrations and/or adverse events.

Leflunomide (Arava) Dose in the treatment of Rheumatoid arthritis: Oral:

• Loading dose (optional; see Note):

  • 100 mg OD for 3 days
  • Maintenance dose: 20 mg OD, (may reduce dose to 10 mg OD if a higher dose is not tolerated)
  • Maximum dose: 20 mg OD.

Note:

• Loading dose may be omitted given the higher likelihood of side effects (eg, diarrhea), & especially may be omitted in patients who are at an increased risk of hepatic or hematologic toxicity (eg, recent concomitant methotrexate or other immunosuppressive agents)
• The onset of action may be delayed.
• Due to the long half-life of the active metabolite, serum concentrations may require a prolonged period to decline after dosage reduction.

Leflunomide (Arava) Dose in the treatment of Juvenile idiopathic arthritis (off-label use):

• Children ≥3 years and Adolescents: Oral:

  • <20 kg:
    • 100 mg as a stat dose followed by 10 mg every other day
  • 20 kg to 40 kg:
    • 100 mg OD for 2 days followed by 10 mg OD
  • >40 kg:
    • 100 mg OD for 3 days followed by 20 mg OD

Leflunomide (Arava) Pregnancy Risk Category: X

• [US Boxed Warning]
  • Leflunomide, which can cause fetal harm, is not recommended during pregnancy.
  • Animal reproduction studies showed adverse events at doses that were lower than what was expected for humans.
  • Stop taking leflunomide during pregnancy. Instead, use an accelerated elimination method.
  • Accelerated elimination may reduce potential risks for the fetus through a decrease in plasma concentration of teriflunomide, an active metabolite to leflunomide.
  • After treatment, it is important to avoid pregnancy until undetectable serum levels (0.02 mg/L are confirmed)
  • Information on the limited outcome of fetal leflunomide exposure in utero is available.
• [US Boxed Warning]
  • Females with reproductive potential should not have to become pregnant before treatment begins.
  • Recommend to females with reproductive potential to use effective contraception during treatment and during an accelerated elimination process after treatment is completed.
  • After pregnancy has been ruled out, the treatment should be stopped for females with reproductive potential.
  • They must also have been counseled about fetal risk and have had reliable contraceptive methods confirmed.
  • After treatment, it is important to avoid pregnancy until undetectable serum levels (0.02 mg/L are confirmed)
  • You can achieve this by using an enhanced drug removal procedure with cholestyramine
  • Two separate tests should be performed 14 days apart to verify serum concentrations below 0.02 mg/L
  • Consider additional cholestyramine therapy if serum levels are greater than 0.02 mg/L
  • After discontinuation of leflunomide, it is recommended that all females with reproductive potential use the accelerated elimination method.

Leflunomide use during breastfeeding:

• It is unknown if breast milk contains leflunomide.
• The manufacturer recommends that breastfeeding be stopped during treatment with leflunomide because of the risk of serious adverse reactions.

Leflunomide (Arava) Dose in Kidney Disease:

• US labeling:

  • No dose adjustments provided in the manufacturer's labeling (has not been studied); use cautiously.

• Canadian labeling:

  • Mild impairment:
    • No dose adjustments provided in the manufacturer's labeling; use cautiously.
  • Moderate to severe impairment:
    •  Use is contraindicated.

Leflunomide (Arava) Dose in Liver disease:

• Hepatic function impairment at baseline:

  • US labeling:
    • Use is not recommended in patients with preexisting liver disease or those with baseline ALT >2 times ULN; monitor hepatic function should be closely monitored.
    • Contraindicated in severe hepatic impairment.
  • Canadian labeling:
    • Use is contraindicated.

• Hepatoxicity during treatment:

  • US labeling:

    • ALT elevations >3 times ULN:
      • Discontinue drug therapy & investigate for the probable cause
      • If leflunomide-induced, initiate accelerated drug elimination process & monitor hepatic function weekly until normalized.

  • Canadian labeling:

    • ALT elevations 2 to 3 times ULN:
      • May reduce maintenance dose to 10 mg OD
      • Weekly monitor ALT.
    • Persistent ALT elevations >2 times ULN or ALT elevations >3 times ULN:
      • Discontinue treatment & initiate drug elimination procedures.

Common Side Effects of Leflunomide (Arava):

• Central nervous system:

  • Headache

• Dermatologic:

  • Alopecia
  • Skin rash

• Gastrointestinal:

  • Diarrhea
  • Nausea

Less Common Side Effects of Leflunomide (Arava):

• Cardiovascular:

  • Hypertension

• Central nervous system:

  • Dizziness

• Dermatologic:

  • Pruritus

• Gastrointestinal:

  • Gastrointestinal pain
  • Abdominal pain
  • Oral mucosa ulcer
  • Vomiting

• Hepatic:

  • Abnormal hepatic function tests
  • Increased serum ALT

• Hypersensitivity:

  • Hypersensitivity reaction

• Neuromuscular & skeletal:

  • Back pain
  • Weakness
  • Tenosynovitis

• Respiratory:

  • Bronchitis
  • Rhinitis

Side effects of Leflunomide (Arava) (Frequency undefined):

• Cardiovascular:

  • Chest Pain
  • Increased Blood Pressure
  • Leg Thrombophlebitis
  • Palpitations
  • Varicose Veins

• Central Nervous System:

  • Drowsiness
  • Malaise

• Endocrine & Metabolic:

  • Increased Gamma-Glutamyl Transferase

• Gastrointestinal:

  • Anorexia
  • Enlargement Of Salivary Glands
  • Flatulence
  • Sore Throat
  • Xerostomia

• Genitourinary:

  • Vulvovaginal Candidiasis

• Hematologic & Oncologic:

  • Leukocytosis
  • Thrombocytopenia

• Hepatic:

  • Hyperbilirubinemia
  • Increased Serum Alkaline Phosphatase
  • Increased Serum AST

• Hypersensitivity:

  • Anaphylaxis

• Infection:

  • Abscess

• Ophthalmic:

  • Blurred Vision
  • Eye Disease
  • Papilledema
  • Retinal Hemorrhage
  • Retinopathy

• Respiratory:

  • Dyspnea
  • Flu-Like Symptoms

Contraindications to Leflunomide (Arava):

• Hypersensitivity to any component of the formulation, including anaphylaxis, is a known condition
• Hepatic impairment severe
• Combination treatment with teriflunomide
• Females who are pregnant.

Canadian labeling: Additional contraindications not in the US labeling

• Hypersensitivity to Teriflunomide
• Moderate to severe renal impairment
• Immunodeficiency states
• Affected bone marrow function, significant anemia, neutropenia or significant anemia due to other causes than rheumatoidarthritis
• Severe infections
• Hepatic dysfunction
• Severe hypoproteinemia
• Females with reproductive potential who do not use reliable contraception during treatment with leflunomide for at least 2 years (or as long plasma levels of active metabolite exceed 0.02 mg/L).
• Breastfeeding
• Patients under 18 years old

Warnings and precautions

• Dermatologic reactions

  • Rare cases of dermatologic reactions, including Stevens-Johnson Syndrome, toxic epidermal Necrolysis and drug reaction with Eosinophilia, systemic symptoms and toxic epidermal Neolysis, have been reported.
  • If severe skin reactions are observed, discontinue use and begin rapid drug elimination.

• Hepatotoxicity: [US Boxed Warning]

  • Some patients who received leflunomide have suffered severe liver injury and even fatal liver failure.
  • Patients with severe hepatic impairment should not use this medication.
  • Concomitant use with potentially hepatotoxic drugs, such as leflunomide, may increase the risk of liver injury.
  • Patients with preexisting chronic or acute liver disease or ALT greater than 2 times the ULN before starting treatment are at higher risk. Leflunomide should not be used.
  • Monitoring ALT levels at least once a month after the start of leflunomide should be done, and then every 6-8 weeks thereafter.
  • Stop therapy immediately if ALT exceeds 3 times the ULN.
  • Stop leflunomide treatment if you suspect liver injury from leflunomide. Instead, begin an accelerated drug elimination process and continue to monitor your liver until it is normal.
  • Leflunomide-induced liver damage can be prevented by a second cause.
  • Follow the American College of Rheumatology guidelines to monitor methotrexate liver toxicities when taken concomitantly.

• Hematologic toxicities

  • Leflunomide therapy is not sufficient to treat thrombocytopenia, agranulocytosis, or pancytopenia.
  • Patients who are currently receiving methotrexate or another immunosuppressive agent or have recently stopped these treatments are most likely to experience hematologic toxicities.
  • Some patients had a history involving a serious hematologic disorder.
  • Patients should have their platelet, WBC and hemoglobin levels monitored at baseline and monthly for six months after therapy initiation and every 6 to eight weeks thereafter.
  • Chronic monitoring should be increased to once a month if methotrexate is used in conjunction with other immunosuppressive drugs.
  • If you suspect that your bone marrow is being suppressed, stop treatment immediately and start an accelerated drug elimination process.
  • Avoiding use of this drug in patients with bone marrow dysfunction should be discouraged.

• Hypertension:

  • It has been reported that blood pressure levels have increased.
  • Monitor blood pressure periodically throughout therapy and assess your blood pressure at baseline.

• Infections

  • Increased susceptibility to infection by opportunistic pathogens, especially Pneumocystis Jirovecii pneumonia, tuberculosis [including extrapulmonary tubeerculosis] & aspergillosis.
  • Reports of severe infections, sepsis, and fatalities have been made.
  • Patients with severe immune deficiencies or uncontrolled infections are not recommended.
  • Patients with a history or recurrent infections or conditions that predispose to infection, chronic, latent or localized infections should be cautious.
  • Patients with a new infection should be closely monitored. If the infection is severe, it may be necessary to stop treatment and initiate accelerated drug elimination.
  • Before starting leflunomide therapy, patients should be tested for tuberculosis, both active and latent.
  • Patients with latent tuberculosis have not shown safety.

• Interstitial lung disease:

  • There have been reports of interstitial lung diseases and worsening preexisting interstitial pulmonary disease, with some fatalities.
  • Patients with interstitial lung disease history are at greater risk.
  • Investigate the underlying causes of patients with new-onset or worsening pulmonary symptoms (eg., cough and dyspnea) along with associated fever.
  • If interstitial lung disease has forced the discontinuation of leflunomide, it is worth considering accelerated drug elimination.

• Malignancy

  • Some immunosuppressive drugs can increase the likelihood of malignancies, particularly lymphoproliferative disorders.
  • It is unclear what the impact of leflunomide upon the development and course of malignancies can be.

• Peripheral neuropathy:

  • There have been cases of peripheral neuropathy.
  • Although most patients feel better after discontinuing treatment, some patients may experience persistent symptoms.
  • Patients over 60 years old who are taking neurotoxic drugs or have diabetes, may be at greater risk of developing peripheral neuropathy.
  • If peripheral neuropathy is a concern, you might consider quitting leflunomide.

• Renal impairment

  • Be careful.

Leflunomide: Drug Interaction

Monitoring parameters:

Rheumatoid arthritis:

Manufacturer's labeling:

• Pregnancy test to rule out pregnancy prior to initiating therapy (in females of reproductive potential)
• A baseline evaluation for active TB and screen patients for latent TB
• Blood pressure at baseline and periodically thereafter.
• Signs and symptoms of severe infection or pulmonary symptoms (eg, cough, dyspnea)
• CBC (WBC, platelet count, hemoglobin, or hematocrit) at baseline and monthly during the initial 6 months of treatment; if stable, monitoring frequency may be decreased to every 6 to 8 weeks thereafter (continue monthly when used in combination with other immunosuppressive agents [eg, methotrexate])
• Liver function (transaminases) at least monthly for the first 6 months of treatment, then every 6 to 8 weeks thereafter (discontinue if ALT >3 times ULN, treat with accelerated elimination procedure, and monitor liver function at least weekly until normal).

Alternate recommendations:

• CBC, serum creatinine, serum transaminases:
  • Baseline and every 2 to 4 weeks during the initial 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment;
  • more frequent monitoring required if clinically indicated.

BK virus and cytomegalovirus disease (off-label uses):

• Monitor serum trough concentrations of the active metabolite (also see Reference Range).

How to administer Leflunomide (Arava)?

Administer without regard to meals.

Mechanism of action of Leflunomide (Arava):

• Leflunomide, an immunomodulatory agent, inhibits pyrimidine synthesis. This results in antiproliferative as well as anti-inflammatory effects.
• Leflunomide can be used as a prodrug. The active metabolite of the drug is responsible for its activity.
• Virion assembly may be affected by CMV infection.

Protein binding:

• Teriflunomide: >99% to albumin

Metabolism:

• It is metabolized in the liver to an active metabolite, teriflunomide. This account for almost all of its pharmacologic activity.
• Additional metabolism of inactive metabolites
• It is subject to enterohepatic and recirculation

Half-life elimination:

• Teriflunomide:
  • Mean: 18-19 days
  • The long half-life of this agent may be due to enterohepatic metabolism. Activated charcoal and cholestyramine significantly reduce plasma half life.

Time to peak:

• Teriflunomide: 6 to 12 hours

Excretion:

• Feces (37.5%)
• urine (22.6%)

International Brands of Leflunomide:

• Arava
• ACCEL-Leflunomide
• APO-Leflunomide
• Arava
• MYLAN-Leflunomide
• PMS-Leflunomide
• SANDOZ Leflunomide
• TEVA-Leflunomide
• Airuohua
• Almura
• Arabloc
• Arastad
• Arava
• Aravida
• Arheuma
• Arolef
• Arresto
• Artrilab
• Avnra
• Cartina
• Filarin
• Imaxetil
• Inflaxen
• Kinetos
• Leflu
• Lefluar
• Lefluartil
• Lefno
• Lefomed
• Lefora
• Lefra-20
• Lunava
• Motoral
• Movelef
• Nodia
• Piscaltoid
• R-A
• Repso
• Rheumide
• Rualba
• Synomid
• Vamid
• Youtong

Leflunomide Brand Names in Pakistan: