Lefno

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Lefno® (Lefno®)

Composition:

Active substance: leflunomide;

One tablet contains leflunomide 20 mg;

Excipients: Starlac*, povidone, sodium croscarmellose, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, talc, Kollicoat IR White II.

* Starlac: lactose monohydrate, corn starch.

Pharmaceutical form. Coated tablets.

Main physicochemical properties: oval, biconvex, white coated tablets.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Immunosuppressants. Dihydroorotate dehydrogenase (DHODH) inhibitors. Leflunomide. ATC code L04A K01.

Pharmacological properties.

Pharmacodynamics.

Leflunomide is a disease-modifying antirheumatic agent with antiproliferative properties.

Leflunomide is effective in animal models of arthritis and other autoimmune diseases, as well as in transplantation, primarily when administered during the sensitization phase. It has immunomodulatory/immunosuppressive properties, acts as an antiproliferative agent, and also exhibits anti-inflammatory effects. Leflunomide demonstrates the best protective effect in animal models of autoimmune diseases when administered at an early stage of disease development.

In vivo, leflunomide is rapidly and almost completely metabolized to A771726, which is active in vitro and is considered responsible for the therapeutic effect.

Mechanism of action.

A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity.

Pharmacokinetics.

Leflunomide is rapidly converted to the active metabolite A771726 via first-pass metabolism (ring opening) in the intestinal wall and liver. In a study using radiolabeled 14C-leflunomide in healthy volunteers, unchanged leflunomide was not detected in plasma, urine, or feces. In other studies, plasma levels of unchanged leflunomide were rarely detected. The only metabolite found in plasma was A771726. This metabolite is primarily responsible for the overall activity of leflunomide in the body.

Absorption

Between 82% and 95% of the leflunomide dose is absorbed. The time to reach maximum plasma concentration of A771726 varies widely: from 1 to 24 hours after single administration. Leflunomide can be taken with food, as the extent of absorption is similar whether the drug is taken after a meal or on an empty stomach. Due to the very long half-life of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used to achieve rapid attainment of steady-state levels. It has been established that without a loading dose, it may take almost two months of drug administration to reach steady-state plasma concentrations. Studies investigating different dosage regimens demonstrated that the pharmacokinetic parameters of A771726 are linear when the drug is administered within the dose range of 5 to 25 mg.

In these studies, clinical efficacy was closely related to the plasma concentration of A771726 and the daily dose of leflunomide. With a daily dose of 20 mg, the mean plasma concentration of A771726 at steady state is approximately 35 µg/mL. At steady state, the plasma concentration of A771726 is approximately 33–35 times higher compared to that after a single dose.

Distribution

In human plasma, A771726 is almost completely bound to protein (albumin). The unbound fraction of A771726 is approximately 0.62%. Binding of A771726 is linear within the therapeutic dose range. Binding of A771726 was found to be somewhat weaker and more variable in plasma from patients with rheumatoid arthritis or chronic renal insufficiency. Extensive protein binding of A771726 may lead to displacement of other highly protein-bound substances. However, in vitro interaction studies using warfarin at clinically relevant concentrations showed no interaction. Similar studies demonstrated that ibuprofen and diclofenac did not displace A771726, whereas in the presence of tolbutamide, the unbound fraction of A771726 increased 2–3 times. A771726 displaced ibuprofen, diclofenac, and tolbutamide, but the unbound fraction of these agents increased only by 10–50%. There is no evidence that these effects are clinically significant. Due to extensive protein binding, A771726 has a low apparent volume of distribution (approximately 11 liters). Preferential uptake into erythrocytes does not occur.

Metabolism

Leflunomide is metabolized to one major metabolite (A771726) and several minor metabolites, including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 is not controlled by a single specific enzyme and has been shown to occur in microsomal and cytosolic cellular fractions. Interaction studies using cimetidine (a non-specific cytochrome P450 inhibitor) and rifampicin (a non-specific cytochrome P450 inducer) indicate that cytochrome P450 enzymes play only a minor role in the in vivo metabolism of leflunomide.

Elimination

Elimination of A771726 is slow and characterized by an apparent clearance of 31 mL/h. In patients, the elimination half-life is approximately 2 weeks. After administration of a radiolabeled dose of leflunomide, radioactivity was observed equally in feces, likely due to biliary excretion, and in urine. A771726 continued to be detected in urine and feces up to 36 days after a single dose. The main metabolites excreted in urine were leflunomide glucuronides (predominantly in samples collected during the first day (0–24 hours) after dosing) and the oxanilic acid derivative of A771726. The main component excreted in feces was A771726.

It has been shown that in humans, oral administration of powdered activated charcoal suspension or cholestyramine leads to a rapid and significant increase in the elimination rate of A771726 and a reduction in its plasma concentration (see section "Overdose"). This is believed to be achieved via a mechanism of gastrointestinal dialysis and/or interruption of the enterohepatic metabolic cycle.

Pharmacokinetics in renal impairment

The pharmacokinetics of A771726 in subjects undergoing long-term peritoneal dialysis (PD) were similar to those in healthy volunteers. More rapid elimination of A771726 was observed in subjects undergoing hemodialysis, although this was not associated with drug extraction from the dialysate.

Pharmacokinetics in hepatic impairment

There are no data regarding treatment of patients with hepatic impairment. The active metabolite A771726 is highly protein-bound and eliminated via hepatic metabolism and biliary secretion. These processes may be impaired due to liver dysfunction.

Pharmacokinetics in pediatric patients

Patients with body weight ≤40 kg experience lower systemic exposure (defined as Css) to A771726 compared to adult patients with rheumatoid arthritis.

Pharmacokinetics in elderly individuals

Data on pharmacokinetics in elderly individuals (>65 years) are limited but consistent with pharmacokinetic data in younger adults.

Clinical characteristics.

Indications.

Treatment with a disease-modifying antirheumatic drug (DMARD) in the active phase of rheumatoid arthritis in adults.

Treatment of the active phase of psoriatic arthritis in adults.

Recent or concomitant treatment with hepatotoxic or hematotoxic DMARDs (e.g., methotrexate) may increase the risk of serious adverse reactions; therefore, initiation of leflunomide therapy should be carefully considered with regard to benefit/risk ratio.

In addition, switching from leflunomide to another DMARD without performing the elimination procedure (see section "Special instructions") may also increase the risk of serious adverse reactions, even after a prolonged period following the switch.

Contraindications.

• Hypersensitivity to leflunomide (especially in patients with a history of Stevens–Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme), to its primary active metabolite teriflunomide, or to any other components of the drug;
• Impaired liver function;
• Severe immunodeficiency states (including HIV infection);
• Marked bone marrow dysfunction or severe anemia, leukopenia, neutropenia, or thrombocytopenia due to other causes (other than rheumatoid or psoriatic arthritis);
• Severe infections;
• Moderate or severe renal impairment (due to limited clinical experience in this patient group);
• Severe hypoproteinemia (including nephrotic syndrome);
• Pregnancy;
• Breastfeeding;
• Use in women of childbearing potential who are not using reliable contraception during treatment and after treatment, if the plasma concentration of the active metabolite exceeds 0.02 mg/L.

Pregnancy must be excluded before initiating leflunomide therapy!

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

The risk of enhanced adverse reactions may increase with recent or concomitant use of hepatotoxic or hematotoxic drugs with leflunomide, or with leflunomide therapy initiated without allowing sufficient time for elimination of these drugs. Therefore, careful monitoring of liver enzymes and hematological parameters is recommended at the initial stage of leflunomide use following such a switch.

Methotrexate

When leflunomide (10–20 mg daily) was administered concomitantly with methotrexate (10–25 mg weekly), increases in liver enzyme levels by 2–3 times were observed. Elevated enzyme levels returned to normal either with continued treatment with both drugs or after discontinuation of leflunomide.

In patients with rheumatoid arthritis, no pharmacokinetic interaction was observed between leflunomide (10–20 mg daily) and methotrexate (10–25 mg weekly).

Vaccination

There are no clinical data on the efficacy and safety of vaccination during leflunomide therapy; however, live vaccines are not recommended. The long elimination half-life of leflunomide should be taken into account when planning administration of a live vaccine after discontinuation of the drug.

Warfarin and other coumarin anticoagulants

Increased prothrombin time has been reported with concomitant use of leflunomide and warfarin. A pharmacodynamic interaction between warfarin and metabolite A771726 has been identified. Therefore, careful monitoring of INR (international normalized ratio) is necessary when warfarin or another coumarin anticoagulant is used in patients receiving leflunomide.

NSAIDs/corticosteroids

Patients already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids may continue their use concomitantly with leflunomide.

Cholestyramine, activated charcoal

Treatment with cholestyramine or powdered activated charcoal is not recommended in patients taking leflunomide, as it leads to a rapid and significant reduction in plasma concentrations of A771726 (the active metabolite of leflunomide). This effect is believed to be due to interruption of enterohepatic recirculation of metabolite A771726 and/or interference with its gastrointestinal dialysis.

CYP450 inhibitors and inducers

In vitro inhibition studies using human liver microsomes indicate that cytochrome P450 (CYP) 1A2, 2C19, and 3A4 are involved in leflunomide metabolism. A drug interaction study between leflunomide and cimetidine (a nonspecific weak inhibitor of cytochrome P450) showed no significant effect on the exposure of metabolite A771726.

After administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), approximately a 40% increase in peak levels of A771726 was observed, while the AUC (area under the concentration-time curve) was not significantly altered. The mechanism of this effect is unknown.

Effect of leflunomide on other drugs

Oral contraceptives

In healthy female volunteers receiving leflunomide concomitantly with triphasic oral contraceptives containing 30 µg ethinylestradiol, no reduction in contraceptive efficacy was observed, and the pharmacokinetics of metabolite A771726 remained within predicted ranges. Pharmacokinetic interactions with oral contraceptives were observed for A771726.

Findings from studies on pharmacokinetic and pharmacodynamic interactions with A771726 (the primary metabolite of leflunomide) should be considered for leflunomide, as similar interactions cannot be excluded in patients receiving leflunomide at recommended doses.

Effect on repaglinide (CYP2C8 substrate)

After repeated dosing of metabolite A771726, increases in mean Cmax and AUC of repaglinide (by 1.7- and 2.4-fold, respectively) were observed, indicating that A771726 is an in vivo inhibitor of CYP2C8. Therefore, patients receiving drugs metabolized by CYP2C8 (e.g., repaglinide, paclitaxel, pioglitazone, or rosiglitazone) during leflunomide therapy should be closely monitored, as higher drug concentrations may occur.

Effect on caffeine (CYP1A2 substrate)

After repeated dosing of metabolite A771726, mean Cmax and AUC of caffeine (a CYP1A2 substrate) decreased by 18% and 55%, respectively, supporting the hypothesis that metabolite A771726 may be a weak in vivo inducer of CYP1A2. Medicinal products metabolized by CYP1A2 (e.g., duloxetine, alosetron, theophylline, and tizanidine) should be used cautiously during leflunomide therapy, as reduced efficacy may occur.

Effect on organic anion transporter 3 (OAT3) substrates

After repeated dosing of metabolite A771726, mean Cmax and AUC of cefaclor increased by 1.43- and 1.54-fold, respectively, confirming that A771726 is an in vivo inhibitor of OAT3. Therefore, caution is recommended when coadministering OAT3 substrates such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, or zidovudine.

Effect on breast cancer resistance protein (BCRP) substrates and/or organic anion transporting polypeptides B1 and B3 (OATP1B1/B3) substrates

After repeated dosing of metabolite A771726, mean Cmax and AUC of rosuvastatin increased by 2.65- and 2.51-fold, respectively. However, no notable effect of increased rosuvastatin plasma exposure on HMG-CoA reductase activity was observed. When coadministered with leflunomide, the rosuvastatin dose should not exceed 10 mg once daily. Caution is also recommended when coadministering other BCRP substrates (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and OATP family substrates, particularly HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin). Patients should be closely monitored for signs and symptoms indicating increased exposure to these drugs, and dose reduction should be considered in such patients.

Effect on oral contraceptives (containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel)

After repeated dosing of metabolite A771726, mean Cmax and AUC_0–24 of ethinylestradiol increased by 1.58- and 1.54-fold, respectively, and Cmax and AUC_0–24 of levonorgestrel increased by 1.33- and 1.41-fold, respectively. Although an adverse effect of this interaction on the efficacy of oral contraceptives is not expected, the type of oral contraceptive used should be taken into account.

Effect on warfarin (CYP2C9 substrate)

Repeated dosing of metabolite A771726 did not affect the pharmacokinetics of S-warfarin, indicating that metabolite A771726 is neither an inhibitor nor an inducer of the CYP2C9 isoenzyme. However, when metabolite A771726 was coadministered with warfarin, a 25% reduction in maximum INR values was observed compared to warfarin alone. Therefore, INR should be carefully monitored when coadministered with warfarin.

Special precautions for use.

Concomitant use of hepatotoxic or hematotoxic DMARDs (e.g., methotrexate) is not recommended.

The active metabolite of leflunomide, A771726, has a prolonged elimination half-life, typically ranging from 1 to 4 weeks. Serious adverse effects (e.g., hepatotoxicity, hematotoxicity, or allergic reactions; see below) may occur even after leflunomide treatment has been discontinued. Therefore, in case of such toxic effects or for any other reason, A771726 should be rapidly eliminated from the body by performing an elimination procedure. This procedure may be repeated depending on clinical requirements. Elimination procedures and other recommended actions in case of desired or unplanned pregnancy are described in the section "Use during pregnancy or breastfeeding."

Hepatic reactions

Rare cases of severe liver injury, including fatal outcomes, have been reported during leflunomide treatment. Most of these cases occurred within the first 6 months of treatment. Concomitant use of other hepatotoxic medicinal products was often observed. Monitoring and strict adherence to recommendations regarding concomitant use are essential.

ALT (SGPT) levels should be assessed before initiating leflunomide therapy and monitored with the same frequency as complete blood count testing (every 2 weeks) during the first 6 months of treatment, and every 8 weeks thereafter.

If ALT (SGPT) levels increase to 2–3 times the upper limit of normal, consider reducing the leflunomide dose from 20 mg to 10 mg. ALT (SGPT) levels should then be monitored weekly. If ALT (SGPT) levels remain above twice the upper limit of normal or increase to three times the upper limit of normal, leflunomide should be discontinued and an elimination procedure initiated. After discontinuation of leflunomide, monitoring of liver enzymes should continue until values return to normal.

Due to the potential for additional hepatotoxic effects, alcohol consumption should be avoided during leflunomide treatment.

Since the active metabolite of leflunomide, A771726, is highly protein-bound and eliminated via hepatic metabolism and biliary secretion, increased plasma levels of A771726 are expected in patients with hypoproteinemia. Leflunomide is contraindicated in patients with severe hypoproteinemia or impaired liver function (see section "Contraindications").

Hematological reactions

In addition to monitoring ALT levels before initiating leflunomide treatment, a complete blood count, including white blood cell differential and platelet count, should be performed every 2 weeks during the first 6 months of treatment and every 8 weeks thereafter.

Patients with anemia, leukopenia, and/or thrombocytopenia, as well as those with bone marrow dysfunction or at risk of bone marrow suppression, are at increased risk of hematological disorders. In case such effects occur, elimination of the drug (see below) should be considered to reduce plasma levels of A771726.

In case of severe hematological effects, including pancytopenia, leflunomide and any myelosuppressive agents should be discontinued and an elimination procedure initiated.

Combination with other therapies

The use of leflunomide in combination with antimalarial agents used in rheumatic diseases (e.g., chloroquine and hydroxychloroquine), intramuscular or oral gold compounds, D-penicillamine, azathioprine, and other immunosuppressive agents, including TNF-alpha inhibitors (except methotrexate; see section "Interaction with other medicinal products and other forms of interaction") has not been studied to date. The risk associated with combination therapy, especially with long-term treatment, is unknown. Since such therapy may lead to additive or even mutually enhancing toxic effects (e.g., hepatotoxicity or hematotoxicity), combination with other DMARDs (e.g., methotrexate) is not recommended.

Concomitant use of teriflunomide with leflunomide is not recommended, as teriflunomide is a metabolite of leflunomide.

Switching to other therapies

Since leflunomide remains in the body for a prolonged period, switching to another DMARD (e.g., methotrexate) without performing an elimination procedure (see below) may increase the risk of additive adverse effects even after a long period following the switch (kinetic interaction, organ toxicity).

Similarly, recent treatment with hepatotoxic or hematotoxic medicinal products (e.g., methotrexate) may lead to an increased risk of adverse reactions. Therefore, initiation of leflunomide therapy should be preceded by a careful benefit-risk assessment, and close monitoring of the patient is recommended during the initial period following the switch.

Skin reactions

If ulcerative stomatitis occurs, leflunomide should be discontinued.

Very rare cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome have been reported in patients treated with leflunomide. In case of skin and/or mucosal reactions that may be associated with the development of the aforementioned severe skin reactions, leflunomide and any other potentially causative medicinal products should be discontinued immediately and an elimination procedure initiated. Complete elimination of the drug is crucial in such cases. Re-administration of leflunomide to such patients is contraindicated (see section "Contraindications").

Cases of pustular psoriasis and psoriasis exacerbation have been reported following leflunomide use. Discontinuation of treatment may be considered as necessary, depending on the patient's disease and medical history.

Skin ulcers may occur in patients during leflunomide treatment. If leflunomide-related skin ulceration is suspected or if skin ulcers do not resolve despite appropriate therapy, discontinuation of leflunomide and initiation of a complete elimination procedure should be considered. The decision to resume leflunomide treatment after skin ulceration should be based on clinical assessment of adequate wound healing.

Infectious diseases

Medicinal products with immunosuppressive properties similar to leflunomide are known to increase patients' susceptibility to infectious diseases, including opportunistic infections. Infections may be more severe and thus may require early and intensive treatment. In cases of severe uncontrolled infections, discontinuation of leflunomide treatment and initiation of the elimination procedure described below may be necessary. Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving leflunomide in combination with other immunosuppressive agents.

Before initiating leflunomide treatment, all patients should be evaluated for active or inactive ("latent") tuberculosis according to standard guidelines. This may include medical history, possible prior exposure to tuberculosis carriers, and/or, if necessary, appropriate examinations (chest X-ray, tuberculin skin test, and/or interferon-gamma release assay). Prescribers should be aware of the risk of false-negative tuberculin skin test results, particularly in severely ill patients or those with immunodeficiency disorders.

Patients with a history of tuberculosis receiving leflunomide should be closely monitored due to the risk of infection reactivation.

Respiratory reactions

Cases of interstitial lung disease and isolated cases of pulmonary hypertension have been reported during leflunomide treatment (see section "Adverse reactions"). The risk of these conditions may be higher in patients with a history of such diseases. Interstitial lung disease may be fatal and may develop acutely during therapy. Respiratory symptoms such as cough and dyspnea may warrant discontinuation of therapy and, depending on the clinical situation, further diagnostic evaluation.

Peripheral neuropathies

Cases of peripheral neuropathies have been reported in patients taking leflunomide. Most cases improved after discontinuation of the drug. However, outcomes of peripheral neuropathies may vary. In some patients, neuropathy symptoms resolve completely, while in others, symptoms may persist. The risk of peripheral neuropathies increases in patients over 60 years of age, those taking other neurotoxic agents concomitantly, and in patients with diabetes mellitus. If signs of peripheral neuropathy develop during leflunomide treatment, discontinuation of therapy and performance of an elimination procedure should be considered (see section "Special precautions for use").

Impaired postoperative wound healing

Cases of impaired postoperative wound healing have been reported in patients receiving leflunomide (see section "Adverse reactions"). Based on individual assessment, interruption of leflunomide treatment in the postoperative period and performance of an elimination procedure may be considered. In case of treatment interruption, the decision to resume leflunomide therapy should be based on clinical assessment of adequate wound healing.

Colitis

Colitis, including microscopic colitis, has been reported during leflunomide therapy. The onset of chronic diarrhea of unknown origin in patients receiving leflunomide requires appropriate diagnostic evaluation.

Arterial pressure

Arterial pressure should be measured before initiating leflunomide treatment and periodically thereafter.

Reproduction (recommendations for men)

Male patients should be aware of the potential for fetal toxicity. Reliable contraception should be used during treatment.

Currently, there is no evidence demonstrating embryotoxic/fetotoxic risk from sperm of men taking leflunomide. Animal studies specifically evaluating this risk have not been conducted. To minimize any potential risk, men planning to father a child should consider discontinuing leflunomide and undergoing an elimination procedure. In any case, plasma concentrations of A771726 should be measured twice (immediately after discontinuation and at least 14 days apart). If plasma concentrations of A771726 are below 0.02 mg/L in both measurements, and also 3 months after discontinuation of leflunomide, the risk of fetal toxicity is considered very low.

Elimination procedure for leflunomide

Administer cholestyramine 8 g orally three times daily or 50 g of powdered activated charcoal orally four times daily. The duration of the complete elimination procedure is typically 11 days. Duration may vary depending on clinical or laboratory parameters.

Effect on ionized calcium plasma measurements

During treatment with leflunomide and/or teriflunomide (active metabolite of leflunomide), false results in ionized calcium plasma measurements (falsely low values) may occur depending on the analyzer used (e.g., blood gas analyzer). Thus, low ionized calcium levels in patients receiving leflunomide or teriflunomide may not reflect true values. In case of questionable results, plasma calcium concentration should be measured (corrected for total albumin).

Excipients

Lactose

This medicinal product contains lactose. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicine.

Maize starch

This medicinal product contains maize starch and therefore should not be used in patients with celiac disease (gluten-sensitive enteropathy).

Sodium

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding

Pregnancy

There is suspicion that the active metabolite of leflunomide, A771726, may cause severe fetal malformations when leflunomide is used during pregnancy. Lefno® is contraindicated during pregnancy.

Women of childbearing potential must use effective contraception during treatment and for 2 years after treatment completion (see "Waiting period" below) or for 11 days after treatment completion (see "Elimination procedure for leflunomide" below).

Patients should be informed that in case of missed menstruation or other signs suggesting pregnancy, they must immediately inform their physician to confirm pregnancy. If pregnancy is confirmed, the physician must discuss with the patient the risks of leflunomide therapy for the fetus. The risk to the fetus from leflunomide intake can be reduced by rapidly lowering the blood level of the active metabolite through initiation of an elimination procedure upon missed menstruation.

In a small study involving women who became pregnant unexpectedly while taking leflunomide for no more than three weeks after conception and underwent an elimination procedure, no significant differences in the overall rate of major fetal malformations were observed compared to any of the comparison groups (corresponding disease group and healthy pregnant women).

Women taking leflunomide who wish to become pregnant are recommended to undergo one of the leflunomide elimination procedures to minimize the potential toxic effect of A771726 on the fetus (target A771726 level should be below 0.02 mg/L).

Waiting period

Plasma concentrations of A771726 are expected to remain above 0.02 mg/L for a prolonged period. It is considered that concentrations decrease below 0.02 mg/L approximately 2 years after discontinuation of leflunomide treatment. Plasma concentration of A771726 is first measured after completion of the 2-year waiting period. A second measurement is performed at least 14 days later. If both measurements show A771726 concentrations below 0.02 mg/L, teratogenic risk is not expected.

Elimination procedure for leflunomide

After discontinuation of leflunomide treatment:

• Cholestyramine 8 g orally three times daily for 11 days;
• Alternatively, 50 g of powdered activated charcoal orally four times daily for 11 days.

Regardless of the chosen elimination method, plasma concentration of A771726 should be measured twice, with at least a 14-day interval, before conception. Conception should be delayed for 45 days from the date when the first plasma concentration of A771726 below 0.02 mg/L is recorded.

Women of childbearing potential should be informed that they must wait 2 years after discontinuation of the drug before attempting pregnancy. If a waiting period of approximately 2 years with reliable contraception is considered unacceptable, prophylactic performance of the leflunomide elimination procedure should be recommended.

Both cholestyramine and activated charcoal may affect the absorption of estrogens and progestogens; therefore, reliable oral contraceptives do not provide 100% efficacy during the leflunomide elimination procedure. Alternative contraceptive methods are recommended.

Breastfeeding period

Animal studies indicate that leflunomide and its metabolites are excreted in breast milk. Therefore, leflunomide is contraindicated in women who are breastfeeding.

Fertility

Animal studies did not demonstrate any effect of leflunomide on fertility in males or females. However, adverse effects on the male reproductive system were observed in repeat-dose toxicity studies.

Ability to influence the ability to drive and use machines

If dizziness occurs as an adverse effect, the patient's ability to concentrate and react appropriately may be impaired. In such cases, patients should refrain from driving or operating complex machinery.

Dosage and Administration

Treatment with leflunomide must be initiated and monitored by a physician experienced in the treatment of rheumatoid and psoriatic arthritis.

Concurrently and with the same frequency throughout leflunomide treatment, serum alanine aminotransferase (ALT) or glutamate pyruvate transaminase (GPT) levels should be monitored, along with a complete blood count, including differential white blood cell count and platelet count:

• before starting leflunomide;
• once every 2 weeks during the first 6 months of treatment;
• once every 8 weeks thereafter (see section "Special Instructions").

Tablets should be swallowed whole with water, without chewing. The extent of leflunomide absorption is not affected by food intake.

Rheumatoid arthritis:

• loading dose: 100 mg once daily for the first 3 days;
• maintenance dose: 10* to 20 mg once daily, depending on the severity (activity) of the disease.

* If a 10 mg dose is required, tablets containing the corresponding amount of active substance should be taken.

If the loading dose is omitted, the risk of adverse reactions is reduced (see section "Pharmacological Properties").

Psoriatic arthritis:

• loading dose: 100 mg once daily for the first 3 days;
• maintenance dose: 20 mg once daily.

Therapeutic effect begins to appear within 4–6 weeks after initiation of treatment and may continue to improve over 4–6 months of treatment.

Patients with moderate renal impairment: dose adjustment is not required.

Patients aged over 65 years: dose adjustment is not required.

Children.

The drug is not recommended for use in children under 18 years of age (efficacy and safety in juvenile rheumatoid arthritis have not been established).

Overdose.

Symptoms

Chronic overdose has been reported in patients taking leflunomide at daily doses up to five times higher than the recommended daily dose. Acute overdose has also been reported in adults and children. In most reported cases, no adverse reactions were observed. Adverse reactions observed were consistent with the safety profile of leflunomide: abdominal pain, nausea, diarrhea, elevated liver enzymes, anemia, leukopenia, pruritus, and rash.

Treatment of overdose

In case of overdose or toxic effects, administration of cholestyramine or activated charcoal is recommended to accelerate elimination. Cholestyramine, administered orally at a dose of 8 g three times daily for 24 hours in three healthy volunteers, reduced plasma levels of A771726 by approximately 40% at 24 hours and by 49–65% at 48 hours.

Activated charcoal (powder as a suspension), administered orally or via nasogastric tube (50 g every 6 hours for 24 hours), has been shown to reduce plasma concentrations of the active metabolite A771726 by 37% at 24 hours and by 48% at 48 hours.

The elimination procedure for leflunomide may be repeated if clinically indicated.

Studies on hemodialysis and chronic ambulatory peritoneal dialysis indicate that the active metabolite of leflunomide, A771726, is not dialyzable.

Adverse Reactions

Criteria for assessing the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Infections and infestations:

rare – severe infections, including sepsis (including fatal cases).

Like other immunosuppressive agents, leflunomide may increase patients' susceptibility to various types of infections, including opportunistic infections (see section "Special precautions for use"). Thus, the risk of developing infections, particularly rhinitis, bronchitis, and pneumonia, is increased.

Benign, malignant and unspecified neoplasms (cysts and polyps):

With the use of some immunosuppressive medicinal products, the risk of developing malignant neoplasms, particularly lymphoproliferative disorders, may be increased.

Blood and lymphatic system disorders:

common – leukopenia (white blood cells > 2 g/L);

uncommon – anemia, mild thrombocytopenia (platelets < 100 g/L);

rare – pancytopenia (likely due to antiproliferative effect), leukopenia (white blood cells < 2 g/L), eosinophilia;

very rare – agranulocytosis.

Prior, concomitant, or subsequent use of potentially myelotoxic medicinal products may be associated with an increased risk of hematological effects.

Immune system disorders:

common – mild allergic reactions;

very rare – severe anaphylactic/anaphylactoid reactions, vasculitis (including cutaneous necrotizing vasculitis).

Metabolism and nutrition disorders:

common – increased creatine phosphokinase levels;

uncommon – hypokalemia, hyperlipidemia, hypophosphatemia;

rare – increased lactate dehydrogenase levels;

not known – decreased uric acid levels (hypouricemia).

Psychiatric disorders:

uncommon – anxiety.

Nervous system disorders:

common – paresthesia, headache, dizziness, peripheral neuropathies.

Cardiovascular system disorders:

common – moderate increase in blood pressure;

rare – marked increase in blood pressure.

Respiratory system disorders:

rare – interstitial lung disease (including interstitial pneumonitis), including fatal cases;

not known – pulmonary hypertension.

Gastrointestinal disorders:

common – colitis (including microscopic colitis such as lymphocytic colitis and collagenous colitis), diarrhea, nausea, vomiting, oral mucosal disorders (aphthous stomatitis, ulcers), abdominal pain;

uncommon – taste disturbances;

very rare – pancreatitis.

Hepatobiliary disorders:

common – increased liver enzyme levels (alanine aminotransferase [ALT], gamma-glutamyl transferase, and alkaline phosphatase), hyperbilirubinemia;

rare – hepatitis, jaundice, cholestasis;

very rare – severe liver injury (liver failure or acute hepatic necrosis, including fatal cases).

Skin and subcutaneous tissue disorders:

common – increased hair loss, eczema, skin rash (including maculopapular rash), pruritus, dry skin;

uncommon – urticaria;

very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme;

not known – cutaneous lupus erythematosus, pustular psoriasis or exacerbation of psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), skin ulcer.

Musculoskeletal and connective tissue disorders:

common – tenosynovitis;

uncommon – tendon rupture.

Renal and urinary disorders:

not known – renal failure.

Reproductive system and breast disorders:

not known – mild decrease in sperm concentration (reversible), decreased total sperm count and motility.

General disorders:

common – anorexia, weight loss (usually mild), asthenia.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.