Leflunomide

Leflunomide is an Anti-inflammatory and Immunosuppressive agent, belonging to the pharmacological class of disease-modifying antirheumatic drugs (DMARDs).

Leflunomide has been approved to relieve symptoms and also for the treatment and maintenance of BK Virus in Kidney Transplant Recipients, Cytomegalovirus Disease in Transplant Recipients Resistant to Standard Antivirals , Rheumatoid Arthritis.

Leflunomide is readily absorbed, with peak plasma concentrations typically observed between 6 to 12 hours post-administration. Its distribution within the body is reflected by a volume of distribution of 0.13 L/kg, while strong protein binding results in more than 99.3% of the drug being bound to plasma proteins. Metabolically, the compound undergoes hepatic conversion to its active form after oral intake. The route of elimination involves both further metabolism and subsequent renal excretion, as well as direct biliary excretion. In a study involving radiolabeled compound, approximately 43% of total radioactivity was excreted in urine and 48% in feces over 28 days.

The common side effects of Leflunomide include Diarrhea, Nausea, Hair loss, Elevated liver enzymes, Headache.

Leflunomide is available in the form of Tablets.

Leflunomide is approved in Germany, Japan, Malaysia, India, the U.K.,and China.

Leflunomide, belonging to the pharmacological class of disease-modifying antirheumatic drugs (DMARDs). , acts as an Immunosuppressants. .

Leflunomide is an isoxazole immunomodulatory compound that acts by inhibiting dihydroorotate dehydrogenase, an enzyme crucial in de novo pyrimidine synthesis. This inhibition results in antiproliferative effects. Numerous in vitro and in vivo experimental models have illustrated its capacity for anti-inflammatory action.

Leflunomide has been approved to relieve symptoms and also for the treatment and maintenance of BK Virus in Kidney Transplant Recipients, Cytomegalovirus Disease in Transplant Recipients Resistant to Standard Antivirals , Rheumatoid Arthritis.

Leflunomide can be used in the following treatment:

• BK Virus in Kidney Transplant Recipients
• Cytomegalovirus Disease in Transplant Recipients Resistant to Standard Antivirals
• Rheumatoid Arthritis

Leflunomide can help to relieve symptoms and also for the treatment and maintenance of BK Virus in Kidney Transplant Recipients, Cytomegalovirus Disease in Transplant Recipients Resistant to Standard Antivirals , Rheumatoid Arthritis.

Leflunomide is approved for use in the following clinical indications:

• BK Virus in Kidney Transplant Recipients
• Cytomegalovirus Disease in Transplant Recipients Resistant to Standard Antivirals
• Rheumatoid Arthritis

BK Virus in Kidney Transplant Recipients (off-label use; based on limited data):

For BK virus-related issues (viremia or nephropathy) in kidney transplant recipients:

• Loading dose: 100 mg/day for 5 days orally.
• Maintenance: Either 40 mg/day (Reference) or 60 mg/day for 2 days initially followed by 20 mg/day (Reference).
• Consider dose adjustments guided by serum concentrations of the active metabolite (Reference).
• Adjunctive Therapy for Cytomegalovirus Disease in Resistant Transplant Recipients (off-label use; based on limited data):

For cytomegalovirus disease in transplant recipients unresponsive to standard antiviral treatment:

• Oral: Initiate with 100 mg once daily for 3 to 5 days, then adjust to 20 to 40 mg/day.
• Consider dose modification based on active metabolite serum levels and potential adverse events (Reference).
• Rheumatoid Arthritis:

Note: Leflunomide can be considered as an alternative to methotrexate in disease-modifying antirheumatic drug-naive patients with moderate to high disease activity. It can also be used as adjunctive therapy for patients not achieving treatment goals despite maximum tolerated methotrexate therapy (Reference).

Potential Loading Dose (optional):

• Oral: Commence with 100 mg once daily for 3 days.
• Note: Omitting the loading dose may be suitable to minimize adverse effects, especially in patients at a heightened risk of hepatic or hematologic toxicity (e.g., those concurrently using methotrexate or other immunosuppressive agents). This approach could lead to a delayed onset of action (Reference).

Maintenance Dose:

• Oral: 20 mg once daily; if necessary due to tolerability, maintenance dose could be lowered to 10 mg once daily (maximum: 20 mg once daily).

Leflunomide is available in the following dosage forms and strengths:

• Tablets : 10mg, 20mg, 100mg

Tablets

• Dosage Adjustments in Kidney Patients:

The understanding of leflunomide's pharmacokinetics in cases of kidney impairment is not extensively defined. Following a solitary 100 mg dose, the teriflunomide half-life (active metabolite) displayed similarity in three patients on peritoneal dialysis, while it was diminished in hemodialysis patients when contrasted with healthy volunteers. However, the proportion of unbound teriflunomide in individuals undergoing dialysis (1.51%) surpassed that of healthy volunteers (0.62%), implying that prudence and careful monitoring are advisable for individuals with kidney dysfunction.

• Dosage Adjustments in Hepatic Impairment Patients:

US Labeling:

If ALT levels rise more than three times the upper limit of normal (ULN): Cease drug therapy and conduct an inquiry into the likely cause; if attributable to leflunomide, begin an expedited drug elimination regimen and observe liver function tests weekly until they return to normal.

Canadian Labeling:

For ALT elevations ranging from 2 to 3 times the ULN: Consider lowering the maintenance dose to 10 mg taken once daily; closely monitor ALT on a weekly basis.

For persistent ALT elevations surpassing 2 times the ULN or ALT levels exceeding three times the ULN: Discontinue treatment and initiate procedures for the elimination of the drug.

• Dosage Adjustments in Pediatric Patients:

Juvenile idiopathic arthritis (alternative treatment option): There is a scarcity of comprehensive data (Reference).

For Children and Adolescents:

• Less than 20 kg: Take 10 mg orally every other day.
• Between 20 and 40 kg: Take 10 mg orally once daily.

More than 40 kg: Take 20 mg orally once daily.

• Please be aware that although initial doses of 100 mg/dose were employed in early clinical trials, these doses might lead to adverse effects; more recent research excludes the use of loading doses.

While there are no specific dietary restrictions outlined for individuals taking leflunomide, it is advisable to maintain a balanced and healthy diet. However, since leflunomide can impact the liver, it's important to be mindful of alcohol consumption and to avoid excessive alcohol intake. Alcohol can potentially exacerbate the risk of liver-related side effects when combined with leflunomide.

Molecule Leflunomide may be contraindicated in the following conditions:

• Leflunomide should not be used by individuals with a known allergy to Leflunomide or any of its inactive components.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows :

Hepatotoxicity

Risk of Severe Liver Injury:

Severe liver damage, including fatal liver failure, has been documented in certain patients treated with Leflunomide. Individuals with pre-existing acute or chronic liver conditions, or those having serum alanine aminotransferase (ALT) levels exceeding twice the upper limit of normal (ULN) before commencing Leflunomide, should refrain from using the medication. Caution should be exercised when Leflunomide is administered alongside other drugs that could potentially harm the liver.

Monitoring and Management:

Regular monitoring of ALT levels is recommended, at a minimum of once a month for the initial six months after starting Leflunomide, followed by evaluations every 6-8 weeks thereafter. If ALT levels increase by more than three times the ULN, Leflunomide therapy should be temporarily halted while the cause of the elevation is investigated through close observation and further tests. If leflunomide-induced liver injury is probable, cholestyramine washout is advised along with weekly liver function test monitoring until normalization.

Combining Leflunomide and Methotrexate:

When Leflunomide and methotrexate are used concurrently, it's imperative to adhere to American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity. Regular monitoring of ALT, AST, and serum albumin levels is essential.

Immunosuppression Potential and Bone Marrow Suppression

Leflunomide in Immunosuppression:

Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or uncontrolled severe infections. In case of a serious infection, therapy with Leflunomide might need to be interrupted and cholestyramine or charcoal administered.

Increased Infection Susceptibility:

Immunosuppressive medications, including leflunomide, can heighten susceptibility to infections, particularly opportunistic ones like Pneumocystis jiroveci pneumonia, tuberculosis, and aspergillosis. Severe infections, even leading to fatality, have been reported, often complicated by concomitant immunosuppressant therapy and other underlying conditions.

Bone Marrow Suppression Monitoring:

Regular Monitoring:

Patients using Leflunomide should have their platelet count, white blood cell count, hemoglobin, or hematocrit monitored at baseline and monthly for six months following treatment initiation, then every 6-8 weeks. If used alongside methotrexate or other immunosuppressive agents, continuous monthly monitoring is recommended.

Risk Management and Stopping Treatment:

In the presence of bone marrow suppression, Leflunomide treatment should be discontinued. Cholestyramine or charcoal administration can be utilized to lower the plasma concentration of leflunomide's active metabolite.

Skin Reactions

Rare skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in individuals taking Leflunomide. In such cases, Leflunomide therapy should cease, and a drug elimination process should be considered.

It is advised to exercise caution when consuming alcohol while using leflunomide. Alcohol consumption may interact with leflunomide and exacerbate its potential side effects. Alcohol and leflunomide both have the potential to affect the liver. Combining the two could increase the risk of liver-related complications.

Nursing mothers should avoid the use of Leflunomide. The excretion of Leflunomide in human milk remains uncertain. Given that various drugs are excreted in human milk and there exists a possibility of significant adverse reactions in nursing infants due to Leflunomide, it becomes essential to make a careful decision regarding whether to continue nursing or to commence Leflunomide treatment. This decision should consider the drug's significance for the mother's health.

Pregnancy Category X

Leflunomide can induce harm to the developing fetus if administered to pregnant women. During the rat's organogenesis phase, oral administration of leflunomide at a dose of 15 mg/kg led to teratogenic effects, notably including anophthalmia or microophthalmia and internal hydrocephalus. The systemic exposure in rats at this dose was about one-tenth of the human exposure level based on AUC. In this exposure context, leflunomide also caused a reduction in maternal body weight and increased embryolethality, accompanied by decreased fetal body weight in surviving fetuses. In rabbits, oral exposure to 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose closely paralleled the maximum human exposure level based on AUC. Notably, leflunomide exhibited no teratogenic effects at doses of 1 mg/kg in rats and rabbits.

In cases where female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days prior to mating and continuing through lactation, the offspring demonstrated significant postnatal survival reduction (over 90%). The systemic exposure level at the 1.25 mg/kg dose was approximately 1/100th of the human exposure level based on AUC.

Leflunomide is contraindicated for use in women who are pregnant or may become pregnant. Should this medication be used during pregnancy or if a patient becomes pregnant while taking the drug, the patient should be informed about the potential risk to the fetus.

While there are no specific dietary restrictions outlined for individuals taking leflunomide, it is advisable to maintain a balanced and healthy diet. However, since leflunomide can impact the liver, it's important to be mindful of alcohol consumption and to avoid excessive alcohol intake. Alcohol can potentially exacerbate the risk of liver-related side effects when combined with leflunomide.

The adverse reactions related to Leflunomide can be categorized as follows:

Common

• Diarrhea
• Nausea
• Hair loss
• Elevated liver enzymes
• Headache

Less Common

• Abdominal pain
• High blood pressure
• Respiratory infections
• Increased risk of infections
• Weight loss

Rare

• Severe skin reactions (such as Stevens-Johnson syndrome or toxic epidermal necrolysis)
• Peripheral neuropathy (nerve damage)
• Hematologic abnormalities (such as pancytopenia, agranulocytosis, and thrombocytopenia)
• Immune system suppression, making patients more susceptible to infections
• Risk of malignancy, especially lymphoproliferative disorders

The clinically relevant drug interactions of Leflunomide is briefly summarized here:

Interaction with Oral Contraceptives and Cimetidine:

In vivo studies investigating drug interactions have indicated that there is no notable interaction between leflunomide and tri-phasic oral contraceptives or cimetidine.

Protein Binding and Warfarin:

In vitro investigations into protein binding have revealed that warfarin does not influence M1 protein binding. Meanwhile, M1 has demonstrated the ability to elevate the unbound fraction of diclofenac, ibuprofen, and tolbutamide by 13% to 50% within clinical concentration ranges. Furthermore, in vitro studies pertaining to drug metabolism have shown that M1 inhibits CYP 450 2C9, an enzyme responsible for metabolizing phenytoin, tolbutamide, warfarin, and several NSAIDs. M1's inhibitory effect on the formation of 4'-hydroxydiclofenac from diclofenac has also been observed. The clinical implications of these findings regarding phenytoin and tolbutamide remain uncertain. However, noteworthy concomitant use of NSAIDs in clinical studies did not reveal any differential effects.

Coadministration with Methotrexate:

Coadministration of Leflunomide (100 mg/day x 2 days followed by 10-20 mg/day) with methotrexate (10-25 mg/week, with folate) in 30 patients exhibited no significant pharmacokinetic interaction between the two drugs. Nevertheless, combining these drugs increased the risk of hepatotoxicity.

Interaction with Rifampin:

After administering a single dose of Leflunomide alongside multiple doses of rifampin, peak levels of M1 were elevated by approximately 40% compared to Leflunomide administered alone. Given the potential for escalating Leflunomide levels with repeated dosing, caution is advised when patients receive both Leflunomide and rifampin.

The following are the side effects involving Leflunomide:

• Urine that is bloody or appears cloudy
• Cough
• Breathing that is challenging or accompanied by discomfort
• Painful or challenging urination, often accompanied by a burning sensation
• Dizziness
• Fever
• Frequent urgency to urinate
• Headache
• Decreased appetite
• Nausea or vomiting
• Sneezing
• Sore throat
• Feeling of tightness in the chest
• Yellowing of the skin or eyes

The use of Leflunomide should be prudent in the following group of special populations:

Pregnancy:

Pregnancy Category X

Leflunomide can induce harm to the developing fetus if administered to pregnant women. During the rat's organogenesis phase, oral administration of leflunomide at a dose of 15 mg/kg led to teratogenic effects, notably including anophthalmia or microophthalmia and internal hydrocephalus. The systemic exposure in rats at this dose was about one-tenth of the human exposure level based on AUC. In this exposure context, leflunomide also caused a reduction in maternal body weight and increased embryolethality, accompanied by decreased fetal body weight in surviving fetuses. In rabbits, oral exposure to 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose closely paralleled the maximum human exposure level based on AUC. Notably, leflunomide exhibited no teratogenic effects at doses of 1 mg/kg in rats and rabbits.

In cases where female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days prior to mating and continuing through lactation, the offspring demonstrated significant postnatal survival reduction (over 90%). The systemic exposure level at the 1.25 mg/kg dose was approximately 1/100th of the human exposure level based on AUC.

Leflunomide is contraindicated for use in women who are pregnant or may become pregnant. Should this medication be used during pregnancy or if a patient becomes pregnant while taking the drug, the patient should be informed about the potential risk to the fetus.

Lactation

Nursing mothers should avoid the use of Leflunomide. The excretion of Leflunomide in human milk remains uncertain. Given that various drugs are excreted in human milk and there exists a possibility of significant adverse reactions in nursing infants due to Leflunomide, it becomes essential to make a careful decision regarding whether to continue nursing or to commence Leflunomide treatment. This decision should consider the drug's significance for the mother's health.

Pediatric

The complete assessment of the safety and efficacy of Leflunomide in pediatric patients diagnosed with polyarticular course juvenile rheumatoid arthritis (JRA) has not been conducted.

Geriatric Use

Among the entire participant cohort in controlled clinical trials (Phase III) involving Leflunomide, a total of 234 individuals were aged 65 years and above. No significant variations in safety or efficacy were noted between these older subjects and their younger counterparts. Furthermore, available clinical observations have not indicated any divergences in responses between elderly and younger patients. However, it is important to acknowledge the possibility of heightened sensitivity in certain older individuals. In patients aged over 65, there is no necessity for dosage adjustments.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Leflunomide.

In acute toxicology studies conducted on mice and rats, the minimally toxic doses for oral leflunomide were found to be 200 - 500 mg/kg for mice and 100 mg/kg for rats. These doses represent a significantly higher value, approximately over 350 times, than the maximum recommended human dose.

Instances of chronic overdose have been noted in patients taking Leflunomide at daily doses up to five times the recommended level, as well as cases of acute overdose in both adults and children. The majority of case reports concerning overdose did not report any adverse events. In cases where adverse events were reported, they were consistent with the established safety profile of Leflunomide . The commonly observed adverse events included diarrhea, abdominal pain, leukopenia, anemia, and elevated liver function tests.

In situations involving a substantial overdose or notable toxicity, it is advisable to consider the administration of cholestyramine or charcoal to hasten the process of elimination .

Research involving hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) has demonstrated that M1, which is the primary metabolite of leflunomide, cannot be effectively removed through dialysis.

Pharmacodynamics:

Leflunomide is an inhibitor of pyrimidine synthesis prescribed for adults to treat active rheumatoid arthritis (RA). Rheumatoid arthritis is an autoimmune condition characterized by heightened T-cell activity. T cells possess two distinct routes for generating pyrimidines: the salvage pathways and the de novo synthesis. When inactive, T lymphocytes fulfill their metabolic needs through the salvage pathway. In contrast, activated lymphocytes necessitate a substantial 7- to 8-fold increase in their pyrimidine reserves, while the expansion of the purine pool is limited to 2- to 3-fold. To address the augmented requirement for pyrimidines, activated T cells engage the de novo pathway for pyrimidine synthesis. Consequently, activated T cells, which rely on the de novo pyrimidine synthesis route, are more vulnerable to the inhibitory effects of leflunomide on dihydroorotate dehydrogenase compared to other cell types that utilize the salvage pathway for pyrimidine synthesis.

Pharmacokinetics:

Absorption

Upon oral administration, the active metabolite M1 reached its peak concentrations within the range of 6 to 12 hours post-dosing. Because of M1's significantly prolonged half-life of approximately two weeks, a loading dose of 100 mg for three days was utilized in clinical investigations to expedite the achievement of steady-state levels of M1. In the absence of a loading dose, it is estimated that nearly two months of dosing would be required to attain steady-state plasma concentrations. The resultant plasma concentrations after both loading doses and ongoing clinical dosing demonstrate a proportional relationship with M1 plasma levels.

In comparison to an oral solution, Leflunomide tablets exhibit 80% bioavailability. The co-administration of leflunomide tablets with a high-fat meal did not significantly affect M1 plasma levels.

Distribution

M1 possesses a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding maintains linearity at therapeutic concentrations. The free fraction of M1 is slightly elevated in rheumatoid arthritis patients and approximately doubled in those with chronic renal failure; the reasons for these increments remain unidentified.

Metabolism

Leflunomide is metabolized into one primary metabolite (M1) and numerous minor metabolites. Among these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, existing at low levels in some patients' plasma. The parent compound is rarely detectable. Presently, the precise site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest the involvement of both the gastrointestinal wall and the liver in drug metabolism. While no specific enzyme has been identified as the primary metabolic route for leflunomide, hepatic cytosolic and microsomal cellular fractions have been recognized as sites of drug metabolism.

Elimination

The active metabolite M1 undergoes further metabolism and subsequent renal and biliary excretion. In a 28-day elimination study (n=3) using radiolabeled compound, approximately 43% of total radioactivity was excreted through urine and 48% through feces. Analysis revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1, while the primary fecal metabolite was M1. Between these two elimination pathways, renal elimination is more prominent during the initial 96 hours, after which fecal elimination becomes predominant. In an intravenous M1 administration study, the clearance was estimated at 31 mL/hr.

Utilizing activated charcoal (n=1) or cholestyramine (n=3) to enhance drug elimination resulted in a reduction of M1's in vivo plasma half-life from over one week to approximately one day. Similar reductions in plasma half-life were observed in pharmacokinetic trials involving volunteers (n=96) given cholestyramine. This suggests that biliary recycling significantly contributes to the prolonged elimination half-life of M1. Studies involving hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicated that M1 is not dialyzable.

1. https://go.drugbank.com/drugs/DB01097
2. https://reference.medscape.com/drug/Leflunomide-leflunomide-343203
3. https://www.medsafe.govt.nz/profs/PUarticles/Leflunomide.htm
4. https://www.drugs.com/mtm/leflunomide.html
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020905s022lbl.pdf
6. https://www.sandoz.ca/sites/www.sandoz.ca/files/Leflunomide_Product_Monograph.pdf