Leflunomide

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Leflunomide
Clinical data
Trade namesArava, Lefumide, Arabloc, others
AHFS/Drugs.comMonograph
MedlinePlusa600032
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80%[7]
Protein binding>99%[7]
MetabolismGI mucosa and liver[7]
MetabolitesTeriflunomide
Elimination half-life14–18 days[7]
ExcretionFaeces (48%), urine (43%)[7]
Identifiers
  • 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
JSmol)
  • O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C
  • InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18) checkY
  • Key:VHOGYURTWQBHIL-UHFFFAOYSA-N checkY
  (verify)

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (

pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.[9]

Bottle of Leflunomide (Arava) and tablet

Medical use

Sanofi Aventis and approved by the U.S. Food and Drug Administration in 1998. Clinical studies regarding the following diseases have been conducted:[11] There has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, PTEN, loss.[12][13] In PTEN negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells.[13]

Contraindications

Contraindications include:[7]

  • Pregnancy, women of childbearing potential (unless contraception used)
  • Liver disease, hepatitis B/C seropositive
  • Active serious infections
  • Hypersensitivity

Adverse effects

The dose-limiting side effects are liver damage, lung disease and immunosuppression.

leucopenia, pancytopenia, vasculitis, toxic epidermal necrolysis, Stevens–Johnson syndrome, cutaneous lupus erythematosus, severe infection, interstitial lung disease, cirrhosis and liver failure
.

Interactions

Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like

haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.[7]

The concomitant use of methotrexate, in particular, may lead to severe or even fatal liver-damage or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate.[30] However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.[30]

Pharmacology

Mechanism of action

Leflunomide is an

lymphocytes.[27]

The inhibition of human DHODH by

virion assembly.[27]

Pharmacokinetics

It has an oral

elimination half-life of 14–18 days and excretion routes of faeces (48%) and urine (43%).[7][27][2]

Leflunomide metabolism

Teriflunomide is the main active in vivo metabolite of leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the isoxazole ring. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[32]

E and Z enolic forms (and the corresponding keto-amide), with the Z-enol being the most stable and therefore most predominant form.[33][34]

"Regardless of the substance administered (leflunomide or teriflunomide), it is the same molecule (teriflunomide)—the one exerting the pharmacological, immunological or metabolic action in view of restoring, correcting or modifying physiological functions, and does not present, in clinical use, a new chemical entity to patients."[32] Because of this, the European Medicines Agency (EMA) initially had not considered teriflunomide to be a new active substance.[35]

References

  1. FDA
    . Retrieved 22 October 2023.
  2. ^ a b c "Arava Product Information" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 7 August 2012. Retrieved 11 March 2014.
  3. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. ^ a b "Arava 10mg Tablets - Summary of Product Characteristic". electronic Medicines Compendium. Sanofi. 21 February 2014. Retrieved 11 March 2014.
  5. ^ a b "Arava (leflunomide) tablet, film coated [sanofi-aventis U.S. LLC]". DailyMed. sanofi-aventis U.S. LLC. November 2012. Retrieved 11 March 2014.
  6. ^ "Arava EPAR". European Medicines Agency. 25 August 2023. Retrieved 26 August 2023.
  7. ^ a b c d e f g h i j k "Arava (leflunomide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 11 March 2014.
  8. PMID 15271770
    .
  9. PMID 17094333
    .
  10. ^
    ISBN 978-0-9805790-9-3.[page needed
    ]
  11. ^ "Leflunomide Search". ClinicalTrials.gov. U.S. National Library of Medicine.
  12. PMID 32661432
    .
  13. ^
    PMID 28255082
    .
  14. PMID 16998219
    .
  15. S2CID 1914281
    .
  16. S2CID 7202069
    .
  17. ^
    S2CID 28479334
    .
  18. S2CID 21101525
    .
  19. PMID 15608310
    .
  20. S2CID 21212960
    .
  21. S2CID 29918308
    .
  22. PMID 23032450
    .
  23. PMID 17641721
    .
  24. S2CID 41656726
    .
  25. ^ Clinical trial number NCT00004071 for "Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer" at ClinicalTrials.gov
  26. ^ Clinical trial number NCT00802243 for "Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)" at ClinicalTrials.gov
  27. ^
    PMID 20874647
    .
  28. ^ "Arava : EPAR - Product Information" (PDF). European Medicines Agency. Sanofi-Aventis Deutschland GmbH. 21 November 2013. Archived from the original (PDF) on 11 March 2014. Retrieved 11 March 2014.
  29. ^ "Data Sheet Arava" (PDF). Medsafe. sanofi-aventis new zealand limited. 29 June 2012. Retrieved 11 March 2014.
  30. ^
    S2CID 205543918
    .
  31. ^
    PMID 10600330
    .
  32. ^ a b Melchiorri D, van Zwieten-Boot B, Maciulaitis R, Vilceanu M, Bruins Slot K, Hudson I, et al. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000" (PDF). European Medicines Agency. p. 119. Archived from the original (PDF) on 17 July 2015. Retrieved 5 June 2015.
  33. S2CID 33745823
    .
  34. ^ "Clinical Pharmacology/Biopharmaceutics Review. Product: ARAVA (leflunomide tablets). Application Number: NDA 20905" (PDF). U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Retrieved 15 April 2016.
  35. ^ "Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)" (PDF). European Medicines Agency. Archived from the original (PDF) on 13 March 2016. Retrieved 15 April 2016.

Further reading
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