Leflutab

Leflutab is a drug with immunosuppressive therapeutic activity. It belongs to the group of basic antirheumatic substances.

The drug prevents cell proliferation processes, regulates immune function, and in addition, suppresses immune reactions and has an anti-inflammatory effect. [ 1 ]

The component leflunomide is effective in arthritis and other autoimmune pathologies, and also in organ transplants – mostly when used during the sensitization stage. [ 2 ]

Indications Leflutab

It is used as a basic element (to reduce the intensity of the manifestations of the disease and delay the processes of damage to the structure of the joints) in the treatment of the active phase of rheumatoid or psoriatic arthritis.

Release form

The therapeutic substance is released in tablet form - 30 or 90 pieces (volume 10 mg) inside a container or 15, 30 or 90 pieces (volume 20 mg) inside a container.

Pharmacodynamics

Leflunomide has a more effective effect in autoimmune diseases when used at an early stage of the lesion. In vivo, the component is almost completely and rapidly metabolized to form A771726, which has an in vitro effect and exerts therapeutic activity.

Element A771726, which is the active metabolic component of leflunomide, inhibits the action of the enzyme dehydroorotate dehydrogenase and has antiproliferative properties. [ 3 ]

Pharmacokinetics

Leflunomide is rapidly transformed into the active breakdown product A771726 during presystemic metabolism (ring opening) processes within the liver and intestinal wall.

Excretion data obtained from tests using 14C-labeled leflunomide showed that less than 82-95% of the drug is absorbed. The time needed to obtain plasma Cmax of A771726 is variable; these values can be observed in the range of 1-24 hours from the time of administration of the first portion of the drug.

Leflunomide can be taken with food, because the absorption rate is no different from that when taken on an empty stomach. Due to the long half-life of A771726 (approximately 14 days), in clinical tests, a saturation dose of 0.1 g was used for 3 days to quickly obtain a plateau phase for A771726. It was found that the duration of the plateau phase at plasma drug values without using a saturation dose can be approximately 2 months.

In repeated-dose studies in people with rheumatoid arthritis, the pharmacokinetics of A771726 were linear across the 5-25 mg dose range. In these studies, the clinical impact was closely related to plasma A771726 levels and the daily dose of leflunomide. Following a 20 mg daily dose, the mean plasma A771726 plateau was 35 μg/mL. At plateau, the accumulated plasma levels were approximately 33-35 times higher than those following a single dose.

In human blood plasma, A771726 undergoes extensive protein synthesis (with albumin). The unsynthesized fraction of the A771726 element is approximately 0.62%. Synthesis of A771726 is linear at all therapeutic doses. Somewhat reduced and more variable synthesis of A771726 was observed in plasma of individuals with rheumatoid arthritis or chronic renal failure.

Extensive protein synthesis of A771726 may cause displacement of other drugs with a high level of protein binding. In vitro protein synthesis interaction tests using warfarin at clinically relevant parameters did not reveal any interaction. This showed that diclofenac with ibuprofen cannot substitute for A771726, although the free fraction of the A771726 component increases twofold/threefold when using tolbutamide. Element A771726 substituted diclofenac with ibuprofen and tolbutamide, but the values of the free fractions of these drugs increased by only 10-50%. There is no information that such an effect is of clinical significance. Due to the pronounced protein synthesis of A771726, the values of its apparent distribution volume are quite low (approximately 11 L). No significant absorption of the drug by red blood cells was noted.

Leflunomide undergoes metabolism with the formation of primary (A771726) and many secondary, including TFMA, metabolic elements. The transformation of the drug into A771726 and the subsequent processes of A771726 metabolism do not occur with the help of a single enzyme, but are realized within the cytosolic and microsomal fractions of cells.

Interaction studies with cimetidine (which non-specifically inhibits the action of hemoprotein P450) and rifampin (which non-specifically induces hemoprotein P450) showed that CYP enzymes are not significantly involved in the metabolism of leflunomide in vivo.

A771726 is excreted at a low rate with apparent clearance rates of approximately 31 ml/hour. The half-life is approximately 14 days.

When using a labeled dose of leflunomide, excretion of the radioactive label occurred in equal parts via urine and feces (probably with excretion via bile). In feces and urine, A771726 was determined after 36 days after a single use of the drug. In urine, the main metabolic elements were glucuronides, leflunomide derivatives (mainly in samples of the first 24 hours), and oxanilic acid (derivative A771726). In feces, A771726 was mainly noted.

When activated carbon or cholestyramine suspension was used orally, the excretion rate and rate of A771726 were significantly increased, and its plasma values were decreased. It is believed that such an effect develops due to dialysis within the gastrointestinal tract or interruption of utilization within the liver and small intestine.

Dosing and administration

Therapy must be carried out under the supervision of a physician.

Treatment begins with oral administration of a shock dose of 0.1 g. It is taken once a day for 3 days. The maintenance dose in the case of rheumatoid arthritis is 10-20 mg (once a day), and in the case of psoriatic arthritis - 20 mg (once a day).

The development of therapeutic effect is often noted after 1-1.5 months, and its increase continues for up to 4-6 months.

• Application for children

Leflutab is not used in individuals under 18 years of age - there is no information regarding the safety and therapeutic efficacy of the drug in juvenile rheumatoid arthritis.

Use Leflutab during pregnancy

The use of the medication during breastfeeding or pregnancy is prohibited. The possibility of pregnancy should be excluded before starting therapy.

Men using the drug should be warned about the fetotoxic effect of the drug and the need to use contraception.

Contraindications

Among the contraindications:

• severe hypersensitivity to leflunomide or additional components of the drug;
• severe types of immunodeficiency (for example, AIDS);
• liver dysfunction;
• significant disorders of hematopoietic processes within the bone marrow, severe leukopenia or thrombocytopenia and anemia associated with other factors (excluding rheumatoid arthritis);
• severe infestation that cannot be controlled;
• severe stage of hypoproteinemia (for example, during nephrotic syndrome);
• moderate to severe renal impairment (due to limited clinical experience with use in such disorders);
• women of reproductive age who do not use contraceptives.

Side effects Leflutab

Main side effects:

• gastrointestinal disorders: nausea, diseases affecting the oral mucosa (ulcers on the lips, aphthous stomatitis), loose stools, pain in the peritoneum and loss of appetite, as well as hepatitis, cholestasis with jaundice, pancreatitis and severe stages of liver disorders (insufficiency or active phase of necrosis);
• problems with hematopoietic processes: leukopenia or thrombocytopenia, agranulocytosis, anemia and eosinophilia;
• CVS dysfunction: severe or moderate increase in blood pressure and vasculitis;
• changes in metabolic processes: hypokalemia, asthenia and weight loss;
• problems with respiratory activity: interstitial processes (including pneumonia);
• neurological disorders: dizziness, taste disorders, paresthesia, asthenia, polyneuropathy, anxiety and headaches;
• epidermal lesions: severe alopecia, epidermal dryness, eczema, allergy and erythema multiforme;
• disorders associated with the functioning of the musculoskeletal system: inflammation or rupture of tendons;
• infections: severe forms of infections (also opportunistic type) and sepsis.

Overdose

In case of poisoning, pain in the abdominal area, leukopenia, diarrhea, anemia and an increase in intrahepatic tests develop.

The medication is discontinued, and sorbents with cholestyramine are used.

Interactions with other drugs

The severity of side effects may be potentiated by recent or concomitant use of hematotoxic or hepatotoxic substances, and also in case of administration of medications after leflunomide administration, when the time required for its complete elimination is not taken into account. For this reason, liver enzymes and hematological values should be closely monitored in the initial stage after the transition.

Vaccination processes.

Vaccination with live vaccines should not be performed. If such a procedure is planned after discontinuation of the drug, the long half-life of leflunomide should be taken into account.

Warfarin and other indirect coagulants.

There is information regarding an increase in the PT values when the drug is used in combination with warfarin. The interaction of pharmacokinetic parameters with warfarin was noted in clinical testing using A771726. Because of this, when using a combination with warfarin or another coumarin anticoagulant, it is necessary to closely monitor the MHB values.

GCS or NSAIDs.

In cases where the patient is already using GCS or NSAIDs, their use can be prolonged after the start of Leflutab.

Interactions with other medicinal products on leflunomide.

Activated carbon suspension or cholestyramine.

Individuals using leflunomide should not take the above substances because they cause a significant and very rapid decrease in plasma levels of A771726. This effect is thought to occur due to interruption of the processes of utilization of the element in the liver and small intestine or dialysis of A771726 within the gastrointestinal tract.

Agents that induce or inhibit the activity of hemoprotein P450.

Separate in vitro tests using intrahepatic microsomes have shown that hemoprotein P450 (CYP) 1A2, as well as 2C19 and 3A4, are involved in the metabolic processes of leflunomide.

When a single dose of the drug was administered to individuals receiving multiple doses of rifampicin (which non-specifically induces the action of hemoprotein P450), the Cmax values of A771726 increased by approximately 40%, while the AUC value remained almost unchanged. The mechanism of this reaction has not yet been determined.

Effects of leflunomide on other drugs.

Effects relative to repaglinide (a CYP2C8 substrate).

The mean Cmax and AUC values of the substance increased by 1.7 and 2.4 times with repeated doses of A771726. This suggests that the element A771726 inhibits the CYP2C8 enzyme when acting in vivo. It is necessary to monitor the condition of individuals using drugs whose metabolic processes are realized with the participation of CYP2C8 (among them, in addition to repaglinide, also pioglitazone with paclitaxel or rosiglitazone), because they can have a more intense effect.

The effect that is exerted on caffeine (is a substrate of the CYP1A2 element).

When using repeated doses of A771726, the mean Cmax and AUC of the substance decreased by 18% and 55%. From this it can be concluded that A771726 is able to weakly induce the action of CYP1A2 under in vivo conditions. Therefore, substances whose metabolism is associated with the CYP1A2 element (among them alosetron with duloxetine, tizanidine and theophylline) should be used with great caution - since their effectiveness may be weakened.

Effects on OATP element 3 substrates.

An increase in the mean values of cefaclor - Cmax (by 1.43 times) and AUC (by 1.54) was observed with the introduction of repeated doses of A771726. This suggests that the element A771726 inhibits the activity of OATP 3 in vivo. Because of this, it is necessary to use Leflutab with extreme caution in combination with substrates of the substance OATP 3 (in addition to cefaclor, these include ciprofloxacin, methotrexate with benzylpenicillin, zidovudine with indomethacin, cimetidine and ketoprofen, as well as furosemide).

Effects developing in relation to substrates of the breast carcinoma resistance protein BCRP or OATP components P1B1/B3.

An increase in the mean Cmax values, as well as AUC of rosuvastatin (by 2.65 and 2.51 times) was observed with repeated administration of portions of A771726. However, such an increase did not cause a significant effect on the activity of HMG-CoA reductase. In case of administration together with the drug, the daily dose of rosuvastatin should be a maximum of 10 mg.

Caution is also required when using other BCRP agents (including sulfasalazine, doxorubicin with methotrexate, daunorubicin, and topotecan) and OATP substrates, especially those that inhibit HMG-CoA reductase (including pravastatin with rifampicin, simvastatin and repaglinide with atorvastatin, and nateglinide). Patients should be monitored closely to detect signs of excessive exposure to the above-mentioned drugs and reduce their dose if necessary.

Effects on oral contraception (ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg).

An increase in the mean Cmax values, as well as AUC, is observed for ethinyl estradiol (by 1.58 and 1.54 times) and levonorgestrel (by 1.33 and 1.41 times) with repeated use of element A771726. Although no negative impact on contraceptive efficacy was detected, the type of OC used should be taken into account.

Effect relative to warfarin.

A 25% decrease in peak INR values was observed when A771726 was used in combination with warfarin (compared to warfarin alone). Therefore, careful monitoring of INR levels is required with these combinations.

Storage conditions

Leflutab should be stored out of the reach of small children in a tightly closed container to prevent moisture from entering.

Shelf life

Leflutab can be used within a 30-month period from the date of manufacture of the therapeutic product.

Analogues

The analogue of the drug is the drug Arava.