Leflunomide

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Immunosuppressants

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

log Kow = 2.43 /Estimated/

2.8

3.9

In water, 153 mg/L at 25 °C /Estimated/

8.44e-02 g/L

Breast Feeding; Lactation; Milk, Human; Antirheumatic Agents; Immunosuppressive Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

165-166 °C

166.5 °C

165 - 166 °C

Danger

H301 (99.3%): Toxic if swallowed [Danger Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 134 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leflunomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Concurrent use with rifampin may increase the plasma concentration of leflunomide; caution is recommended.

Concurrent use with these medications /hepatotoxic medications or methotrexate/ may increase the risk of side effects and medication-induced hepatic toxicity; in a small study evaluating the concurrent use of leflunomide (100 mg/day followed by 10 to 20 mg/day) and methotrexate (10 to 25 mg/week with folate), an increased risk of hepatotoxicity was reported; dosage adjustment may be needed.

In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.

M1 was shown to cause increases ranging from 13-50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of many NSAIDs. M1 has been shown to inhibit the formation of 4'-hydroxydiclofenac from diclofenac in vitro.

Concurrent use with these medications /activated charcoal, or cholestyramine/ will significantly decrease the plasma concentration of M1 by inhibiting gastrointestinal absorption. /M1 metabolite/

Up to 15% of subjects treated with leflunomide develop transient serum aminotransferase elevations that are usually asymptomatic and mild, in the range of 1 to 3 times the upper limit of normal (ULN). Elevations above 3 times the ULN occur in 1% to 4% of patients.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,300(SRC), determined from a structure estimation method(2), indicates that leflunomide is expected to have slight mobility in soil(SRC). Volatilization of leflunomide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.23X10-10 atm-cu m/mole(3), using a fragment constant estimation method(3). Leflunomide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.25X10-6 mm Hg(4), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2004).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2,300(SRC), determined from a structure estimation method(2), indicates that leflunomide is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.23X10-10 atm-cu m/mole(4), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 15(SRC), from an estimated log Kow of 2.43(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Biodegradation data were not available(SRC, 2004).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), leflunomide, which has a an estimated vapor pressure of 1.25X10-6 mm Hg at 25 °C(2), is expected to exist in both the vapor and the particulate phases in the ambient atmosphere. Vapor-phase leflunomide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.2 days, calculated from its rate-constant of 7.33X10-12 cu cm/molecule sec(SRC), that was derived using a structure estimation method(3). Particulate-phase leflunomide may be removed from the air by wet and dry deposition(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for leflunomide can be estimated to be 2,300(SRC). According to a classification scheme(2), this estimated Koc value suggests that leflunomide is expected to have slight mobility in soil.

/SIGNS AND SYMPTOMS/ During postmarketing surveillance, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiform have been reported rarely in patients receiving leflunomide.

/SIGNS AND SYMPTOMS/ Allergic reaction has occurred in 2% of patients receiving leflunomide in clinical studies. Drug rechallenge resulted in an anaphylactic reaction in at least one patient who had experienced rash while receiving leflunomide in a phase II study. Angioedema has been reported rarely.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Leflunomide

vMost-DILI-concern

8

Box warning

DOI:10.1016/j.drudis.2016.02.015

The Henry's Law constant for leflunomide is estimated as 1.23X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that leflunomide is expected to be essentially nonvolatile from water surfaces(2). Leflunomide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.25X10-6 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg . However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied. Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg ...

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). ... Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. ... At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.

/GENOTOXICITY/ Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leflunomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

L04AA13

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.

Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.

Leflunomide exhibits anit-inflammatory activity by inhibiting cyclooxygenase-2 (COX-2).

It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interference with cell cycle progression. ... In vitro data indicate that leflunomide interferes with cell cycle progression by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase; there also is in vitro evidence that the drug inhibits protein tyrosine kinase activity in dividing cells and possesses other effect that may contribute to its immunomodulating activity.

... In this study, we examined the effect of A771726 /active metabolite of leflunomide/ on osteoclast formation and bone-resorbing activity in vitro, using cultures of bone marrow-derived osteoclast progenitors and purified functionally mature osteoclasts, and then we elucidated the molecular mechanism of action of the effect of A771726 on osteoclasts. A771726 inhibited osteoclast formation from macrophage colony-stimulating factor (M-CSF)-dependent osteoclast progenitors in the presence of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL), without any other types of cells present, in a dose-related manner, similar to the inhibition in cultures of unfractionated bone marrow cells. In addition, A771726 suppressed bone resorption by isolated mature osteoclasts. These results indicate that A771726 directly and intrinsically inhibited the differentiation and function of osteoclast lineage cells without any mediation by other cells. The inhibition by A771726 was not restored by the simultaneous addition of uridine, and may be independent of the blockade of NF-kappaB activation and the tyrosine phosphorylation of proteins. Thus, leflunomide, through its active metabolite, has the potential to prevent bone loss by directly inhibiting osteoclastogenesis and osteoclast function. This inhibition suggests a novel mechanism for leflunomide in the retardation of the joint destruction observed in rheumatoid arthritis patients.

2 weeks

2 weeks /M1 metabolite/

Primarily hepatic. Leflunomide is converted to its active form following oral intake.

Leflunomide is metabolized to M1 and other minor active metabolites. An active metabolite, 4-trifluoromethylaniline, is present in plasma at low concentrations. Although the specific site of leflunomide metabolism is unknown, it has been suggested that the gastrointestinal wall and liver play a role in the metabolism.

The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active alpha-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. ... Although A771726 formation in human liver microsomes or recombinant p4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the p450Fe(II) form of the enzyme. A mechanism for the p450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from p450Fe(II) to the C=N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.

Leflunomide has known human metabolites that include (E)-3-Hydroxy-2-methanimidoyl-N-[4-(trifluoromethyl)phenyl]but-2-enamide.

G162GK9U4W

LEFLUNOMIDE

Established Pharmacologic Class [EPC] - Antirheumatic Agent

Leflunomide is an Antirheumatic Agent.

LEFLUNOMIDE

Antirheumatic Agent [EPC]

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.

Well absorbed, peak plasma concentrations appear 6-12 hours after dosing

The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.

0.13 L/kg

Following oral administration of leflunomide, the drug is rapidly converted to A77 1726 in the GI mucosa and liver.

Time to peak concentration: Approximately 6 to 12 hours. /M1 metabolite/

M1 metabolite is 80% bioavailable. Administration of leflunomide with a high-fat meal has no effect on the plasma concentration of M1. /M1 metabolite/

Medication: antirheumatic

Use (kg; approx.) in Germany (2009): >250

Preparation: F.J. Kaemmerer, R. Schleyerbach, DE 2854439; eidem, US 4284786 (1980, 1981 both to Hoechst)

Information available in 2004 indicated that Leflunomide was used in the manufacture of pharmaceutical preparations in the following countries: Algeria, Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Croatia, Czech Republic, Denmark, Dominican Republic, Ecuador, El Salvador, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Norway, New Zealand, Panama, Portugal, Romania, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, United Kingdom, USA, Yugoslavia (1,2)