Leflunomide

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Structural formula
Structural formula of leflunomide
General
Non-proprietary name Leflunomide
other names
  • N - (4'-Trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide ( IUPAC )
  • HWA 486
Molecular formula C 12 H 9 F 3 N 2 O 2
External identifiers / databases
CAS number 75706-12-6
EC number 616-254-6
ECHA InfoCard 100.123.883
PubChem 3899
ChemSpider 3762
DrugBank DB01097
Wikidata Q248550
Drug information
ATC code

L04 AA13

Drug class

Immunosuppressant , basic therapeutic agent

properties
Molar mass 270.21 g · mol -1
Physical state

firmly

Melting point

167 ° C

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic

danger

H and P phrases H: 301-315-319-335
P: 261-301 + 310-305 + 351 + 338
Toxicological data

235 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Leflunomide is a drug from the group of immunosuppressants that is used as a basic therapeutic agent in the treatment of rheumatic diseases .

Clinical information

Application areas (indications)

Leflunomide is a long-acting anti-inflammatory drug that is used as a basic therapeutic ( DMARD ) in the treatment of rheumatoid arthritis and psoriatic arthritis . An improvement in symptoms is expected after about two to three weeks.

Drug interactions

Simultaneous treatment with other basic therapeutic agents ( methotrexate , chloroquine, etc.) should be carried out under strict criteria and, like other basic therapies and combinations, should be started and controlled by appropriately experienced and trained specialists if possible. The (well-effective) combination of leflunomide with methotrexate may reduce the risk. a. severe liver damage (e.g. granulomatous hepatitis ) or more dangerous infections; The risk of such a combination therapy as a long-term treatment is also not sufficiently known. Nevertheless, the combination therapy with leflunomide and methotrexate in internal rheumatology has meanwhile a fairly broad practical meaning.

Use during pregnancy and breastfeeding

Use during pregnancy and breastfeeding is strictly contraindicated . Leflunomide can cause severe birth defects in unborn life. Pregnancy must therefore be ruled out before starting therapy. Reliable contraception during treatment with leflunomide is also a prerequisite for therapy with this drug.

Adverse effects (side effects)

Common side effects of leflunomide are diarrhea , nausea, dyspeptic symptoms, itching, and increased blood pressure. In around 10% of patients, skin changes of varying severity occur. Leflunomide can also lead to hair loss. Patients are also at increased risk of respiratory infections. An increase in transaminases can be observed in around one in ten . Manageable side effects of the drug usually diminish with prolonged use.

Serious, sometimes life-threatening side effects can rarely occur. Leflunomide can cause neutropenia or thrombocytopenia . As a result, a regular laboratory check of the blood cells is considered mandatory when using the drug. In rare cases, skin changes with leflunomide can turn into life-threatening Stevens-Johnson syndrome . Similarly, a can angioedema in the sense of an allergic reaction occur. The rate of fatal liver failure is 14 / 100,000 patient years of treatment. In the case of serious side effects, leflunomide can be removed from the body more quickly by giving cholestyramine or activated charcoal , which takes around 11 days until the drug can no longer be detected in the body. If the intake is interrupted, it takes an average of 22 weeks until the active ingredient is no longer detectable in the blood. The side effect profile of leflunomide is comparable to that of other drugs in basic rheumatological therapy such as sulfasalazine and methotrexate . There are case reports of fatal acute interstitial pneumonia, which can only become clinically noticeable after discontinuation of the drug. Due to the increased incidence of lung damage, some authors recommend that leflunomide not be used in patients with pre-existing lung diseases and that an X-ray examination of the lungs should be carried out before starting therapy.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Leflunomide inhibits dihydroorotate dehydrogenase, an important enzyme in pyrimidine metabolism that is of particular importance in the division of T lymphocytes . In addition, leukocyte migration is inhibited.

Absorption and distribution in the body (pharmacokinetics)

About 82–95% of leflunomide is absorbed in the intestine after oral intake . Leflunomide is converted into its active metabolite A771726 (teriflunomide) in the intestinal wall and the liver by what is known as first-pass metabolism . This is metabolized into other active substances by various enzymes and has a half-life of 1 to 4 weeks in the body. Leflunomide and its active metabolites are excreted in the stool and urine.

The metabolite teriflunomide was approved for use in multiple sclerosis in 2013 , following phase III clinical development .

toxicology

The symptoms of an overdose correspond in the broadest sense to the side effect profile (abdominal pain, nausea, etc.). In case of leflunomide overdose or poisoning, cholestyramine or activated charcoal is recommended to speed up elimination.

Other Information

History

Leflunomide was developed at Hoechst . Its anti-rheumatic properties were first described in 1985. The first leflunomide-containing drug, Arava , was approved in the United States on September 10, 1998 . On September 2, 1999, approval for the European Union followed .

In early 2001, the European Medicines Agency (EMA) warned of the occurrence of liver complications during treatment with leflunomide. The drug was particularly from 2002 onwards the focus of public interest, as the US consumer advocacy group Public Citizen , the local Ministry of Health in a petition for withdrawal of marketing authorizations for Arava asked. The reason for the petition was the more frequent occurrence of fatal liver complications, high blood pressure and Stevens-Johnson syndrome compared to other rheumatic drugs . The petition also relied on the EMA's warning. Although the US Medicines Agency's Drug Safety Division endorsed the petition in a statement in late 2002, the agency's management rejected the petition in March 2004.

Teriflunomide

The active metabolite teriflunomide is effective in the treatment of the relapsing form of multiple sclerosis . The drug has been approved since 2013 under the trade name Aubagio ® (manufacturer: Genzyme / Sanofi ). From the point of view of the Drugs Commission of the German Medical Association (AkdÄ) , there is no overall additional benefit for teriflunomide in the absence of superior efficacy and no difference in harm potential . However, the Federal Joint Committee (G-BA) decides on the additional benefit .

In a large international placebo-controlled randomized study over two years, the annual relapse rate for the two teriflunomide doses (7 and 14 mg daily) was 0.37 compared to 0.54 for placebo. The difference was statistically significant with a relative risk reduction of 31%. Progressive disability was also noticeably less frequent (27.3% with placebo, 21.7% with 7 mg / d and 20.2% with 14 mg / d teriflunomide), but serious infections were slightly more common.

Trade names

Leflunomide is marketed as the original preparation in both the European Union and Switzerland under the name Arava and is marketed by Sanofi-Aventis . Generics with the drug leflunomide have also been approved in the European Union since 2010 .

Web links

literature

Individual evidence

  1. ↑ a b c d Leflunomide data sheet at Sigma-Aldrich , accessed on June 25, 2017 ( PDF ).
  2. ^ A b P.L. van Riel, JS Smolen, P. Emery, JR Kalden, M. Dougados: Leflunomide: a manageable safety profile. In: J Rheumatol Suppl. , 71, Jun 2004, pp. 21-24. PMID 15170904 .
  3. ↑ M. Takeishi, Y. Akiyama, H. Akiba, D. Adachi, M. Hirano: Leflunomide induced acute interstitial pneumonia. In: J Rheumatol. 32 (6), Jun 2005, pp. 1160-1163. PMID 15940779 .
  4. ↑ a b Aubagio - teriflunomide , Summary of the European public assessment report (EPAR) for Aubagio, accessed on February 5, 2014.
  5. ↑ Bernd Kieseier: Review of teriflunomide and its potential in the treatment of multiple sclerosis. In: Neuropsychiatric Disease and Treatment. P. 333, doi: 10.2147 / NDT.S4474 . PMID 19557143 .
  6. ^ RR Bartlett, R. Schleyerbach: Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity - I. Disease modifying action on adjuvant arthritis of the rat. In: Int J Immunopharmacol . , 7, 1985, pp. 7-18. PMID 3873420 .
  7. ↑ Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations . US Food and Drug Administration; Retrieved October 10, 2010.
  8. ↑ Public statement on Leflunomide (Arava) - Severe and serious hepatic reactions . (PDF; 46 kB) European Medicines Agency, March 12, 2001; Retrieved October 10, 2010.
  9. ^ Petition to ban arthritis drug leflunomide (Arava) (HRG Publication # 1614) . (PDF; 113 kB) Public Citizen; Retrieved October 10, 2010.
  10. ^ Postmarketing Safety Review (PID # D020157). Drug: leflunomide (Arava ® , NDA 20-905). Reaction: Severe Hepatotoxicity and Liver Failure. (PDF; 381 kB) US FDA Office of Drug Safety; Retrieved October 10, 2010.
  11. ^ Letter of March 24, 2004 . (PDF; 1.0 MB) US FDA Center for Drug Evaluation and Research; Retrieved October 10, 2010.
  12. ^ Opinion of the Drugs Commission of the German Medical Association ( Memento of the original from February 23, 2014 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. , for the benefit assessment according to Section 35a SGB V from Aubagio, accessed on February 11, 2014. @1@ 2Template: Webachiv / IABot / www.akdae.de
  13. ↑ Drugs Directive / Annex XII: Teriflunomide , decision of the G-BA, (early) benefit assessment according to § 35a SGB V (XII).
  14. ^ P. O'Connor et al. a .: Randomized trial of oral teriflunomide for relapsing multiple sclerosis. In: New England Journal of Medicine , 365, 2011, pp. 1293-1303.