Leflunomide

270.21

270.21

1308068-626-2

G162GK9U4W

759864|677411

DTXSID9023201

C1128

Crystals from toluene

L04AA13|L - Antineoplastic and immunomodulating agents

2934999090

55.1

2.5

Solid

1.4±0.1 g/cm3

163-168°C

289.3°C at 760 mmHg

128.8±27.3 °C

1.541

8.44e-02 g/L

2-8°C

1.25X10-6 mm Hg at 25 deg C /Estimated/

Henry's Law constant = 1.23X10-10 atm-cu m/mol at 25 °C /Estimated/

Hydroxyl radical reaction rate constant = 7.33X10-12 cu cm/molc-sec at 25 °C /Estimated/

6.1

UN 2811 6.1/PG 3

3

22-36/37/38

26-36

NY2354200

Xn,Xi

P280-P301 + P310 + P330-P305 + P351 + P338-P337 + P313

H301-H315-H319-H335

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.

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.

|Danger|H301 (99.62%): Toxic if swallowed [Danger Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 262 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

LD50=100-250 mg/kg (acute oral toxicity)

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.

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/

LD50 Rabbit oral 132 mg/kg|LD50 Rat oral 235 mg/kg|LD50 Mouse oral 445 mg/kg

>99.3%

Leflunomide's production and use as an antirheumatic(1) may result in its release to the environment through various waste streams.

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).

The rate constant for the vapor-phase reaction of leflunomide with photochemically-produced hydroxyl radicals has been estimated as 7.33X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2.2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Leflunomide is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). Leflunomide is not expected to be susceptible to photolysis by sunlight since it does not contain any functional groups that would be expected to absorb light with wavelengths >290 nm(SRC).

An estimated BCF of 15 was calculated for leflunomide(SRC), using an estimated log Kow of 2.43(1) and a regression-derived equation(2). The BCF suggests the potential for bioconcentration in aquatic organisms is low(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.

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).

Occupational exposure to leflunomide may occur through inhalation and dermal contact with this compound at workplaces where leflunomide is produced or used. The general population may be exposed to leflunomide via ingestion of pharmaceutical products containing leflunomide. (SRC)

For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use.|FDA Label|Leflunomide is indicated for the treatment of adult patients with:active rheumatoid arthritis as a 'disease-modifying antirheumatic drug' (DMARD);active psoriatic arthritis.Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit / risk aspects.Moreover, switching from leflunomide to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching.|Leflunomide is indicated for the treatment of adult patients with:, , , active rheumatoid arthritis as a 'disease-modifying antirheumatic drug' (DMARD)., , , Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may result in an increased risk of serious adverse reactions, therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit / risk aspects., , Moreover, switching from leflunomide to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching.,|Leflunomide is indicated for the treatment of adult patients with:active rheumatoid arthritis as a ‘disease-modifying antirheumatic drug' (DMARD);active psoriatic arthritis.Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit / risk aspects.Moreover, switching from leflunomide to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching.|Leflunomide is indicated for the treatment of adult patients with active rheumatoid arthritis as a 'disease-modifying antirheumatic drug' (DMARD).Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit / risk aspects.Moreover, switching from leflunomide to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching.

Leflunomide is an immunomodulatory agent used in the therapy of rheumatoid arthritis and psoriatic arthritis. Leflunomide therapy is associated with frequent elevations in serum aminotransferase levels and with rare instances of clinically apparent acute liver injury which can be severe and even fatal.

Antirheumatic Agents

Antirheumatic|Leflunomide is indicated to alleviate the signs and symptoms of rheumatoid arthritis and to slow joint impairment. /Included in US product labeling/|Leflunomide, a new oral immunomodulatory agent, is effective for the treatment of rheumatoid arthritis. Its mechanism of action in suppressing inflammation is based in its inhibition of dihydroorotate dehydrogenase, an enzyme responsible for de novo synthesis of pyrimidine containing ribonucleotides. It is the first disease-modifying antirheumatic drug approved for treatment of rheumatoid arthritis with an indication for retardation of joint damage by radiography. Side effects are generally mild and include diarrhea, rashes, reversible alopecia, and elevation of hepatic transaminases. Despite the concern about hepatotoxicity, combination use with methotrexate in treating patients with rheumatoid arthritis has been shown to be safe. Other autoimmune diseases in which leflunomide has been used successfully include Felty syndrome, vasculitis, Sjogren syndrome, Wegener granulomatosis, and bullous pemphigoid.|Leflunomide has excellent antiviral activity against cytomegalovirus (CMV) in animal models and is considerably less expensive than intravenous ganciclovir. We used leflunomide in four consenting renal allograft recipients with symptomatic CMV disease, who were unable to afford ganciclovir and would otherwise remain untreated. This is the first report of efficacy of leflunomide in humans with CMV disease. They received loading dose of 100 mg of leflunomide once daily on days 1-3 and then 20 mg once daily for 3 months. All four patients were followed up three times weekly with physical examination, total leukocyte counts, blood urea and serum creatinine for a minimum period of 6 weeks. None of the patients showed drug related adverse events, alteration in cyclosporine levels, or decreased graft function, except one who developed leucopenia. Preliminary data presented suggests that leflunomide therapy for CMV disease is effective and could be used with careful monitoring in allograft recipients who cannot afford intravenous ganciclovir therapy. The duration of treatment and the role of leflunomide in secondary prophylaxis and in situations of ganciclovir resistance need to be studied further.

FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweights any possible benefit to the patient./|Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726) to decrease to undetectable concentrations (less than 0.02 ug/mL) following discontinuance of leflunomide, the possibility that adverse effects or drug interactions associated with the drug could continue to occur even thought the patient is no longer receiving leflunomide should be considered.|Opportunistic infections and serious infection, including sepsis and death, have been reported rarely in patients receiving leflunomide. Most serious infections reported in patients receiving leflunomide occurred in those receiving concomitant therapy with immunosuppressive agent and/or those with comorbid illness that, in addition to rheumatoid arthritis, could have predisposed them to infections.|Leflunomide, a new immunomodulatory agent, was prescribed to a 67-year-old female patient with rheumatoid arthritis. Fifteen days later she developed diarrhea and elevated liver enzymes. A liver biopsy showed a pattern of acute hepatitis. The patient was homozygous for the rare CYP2C9*3 allele, which determines the slowest metabolic rate for CYP2C9 enzymatic activity, that is probably involved in the metabolism of leflunomide. Liver damage subsided in few weeks. This case illustrates the risk of hepatotoxicity by leflunomide and suggests that it is possibly related to CYP2C9 polymorphism.|For more Drug Warnings (Complete) data for LEFLUNOMIDE (20 total), please visit the HSDB record page.

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.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)|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. (See all compounds classified as Immunosuppressive Agents.)

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/|M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.|For more Absorption, Distribution and Excretion (Complete) data for LEFLUNOMIDE (8 total), please visit the HSDB record page.

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.

2 weeks|2 weeks /M1 metabolite/

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.

Concurrent use with these medications /activated charcoal, or cholestyramine/ will significantly decrease the plasma concentration of M1 by inhibiting gastrointestinal absorption. /M1 metabolite/|Treatment of overdose: To enhance elimination: Administration of activated charcoal orally ... . Administration of cholestyramine ... post-ingestion. Supportive care: General supportive measures should be instituted. patients in whom intentional over dose is confirmed or suspected should be referred for psychiatric consultation.

/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.

Arava

Oral: Tablets 10 mg Arava (Aventis), 20 mg Arava (Aventis), 100 mg Arava (Aventis).

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)

HPLC determination of active metabolite in plasma.

Human drugs -> Arava -> EMA Drug Category|Immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Leflunomide Zentiva (previously Leflunomide Winthrop) -> EMA Drug Category|Human drugs -> Leflunomide ratiopharm -> EMA Drug Category|Human drugs -> Leflunomide medac -> EMA Drug Category|Selective immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Repso -> EMA Drug Category|Human drugs -> Leflunomide Teva -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients