Leflutab

Leflutab is a medication with immunosuppressive therapeutic activity. It is included in the group of basic antirheumatic substances.

The medicine prevents the processes of cell reproduction, regulates the immune function, and in addition, inhibits the immune response and has an anti-inflammatory effect. [1]

The leflunomide component is effective in treating arthritis and other autoimmune pathologies, and in addition to organ transplantation - 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 arthritis of a rheumatoid or psoriatic nature.

Release form

The release of the therapeutic substance is made in tablet form - 30 or 90 pieces (volume 10 mg) inside the container or 15, 30 or 90 pieces (volume 20 mg) inside the container.

Pharmacodynamics

Leflunomide has a more effective effect in autoimmune diseases when used early in the development of the lesion. In vivo, the component is almost completely and at a high rate is exchanged with the formation of A771726, which has an in vitro effect and provides therapeutic activity.

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

Pharmacokinetics

Leflunomide at high speed is transformed into the active decay product A771726 - during the processes of presystemic exchange (ring opening) inside the liver and intestinal wall.

Information on excretion obtained from tests using labeled 14C-leflunomide showed that less than 82-95% of the drug is absorbed. The term required to obtain the plasma Cmax of A771726 is variable; these indicators can be observed in the range of 1-24 hours from the moment of application of the 1st portion of the drug.

Leflunomide is allowed to be consumed with food, because the severity of absorption does not differ from the indicators when used on an empty stomach. Due to the long half-life of A771726 (about 14 days), in clinical tests to quickly obtain the plateau stage in A771726, a portion of saturation equal to 0.1 g was used over a period of 3 days. The plateau at plasma drug values without the use of a saturation dosage can be approximately 2 months.

In tests with multiple use of drugs in people with rheumatoid arthritis, the pharmacokinetics of A771726 was linear at any dose in the range of 5-25 mg. In these tests, the clinical effect was closely related to the plasma level of A771726 and the daily dose of leflunomide. After using a dosage of 20 mg per day, the average A771726 value inside the plasma at the plateau stage is 35 μg / ml. At the plateau stage, the accumulated intraplasma values are approximately 33-35 times higher than in the case of using a single portion.

Inside human blood plasma, A771726 undergoes extensive protein synthesis (with albumin). The unsynthesized fraction of the element A771726 is approximately 0.62%. The synthesis of A771726 is linear at any therapeutic dosage. A slightly reduced and more variable synthesis of A771726 was observed inside the plasma in individuals with rheumatoid arthritis or chronic renal failure.

Extensive protein synthesis of A771726 can provoke the displacement of other drugs with a high level of protein binding. In vitro testing of in vitro protein synthesis interactions using warfarin at clinically relevant parameters did not reveal any interaction. This showed that diclofenac with ibuprofen cannot replace A771726, while the free fraction of the A771726 component doubles / triples when using tolbutamide. Element A771726 replaced diclofenac with ibuprofen and tolbutamide, but the values of the free fractions of these drugs increased only by 10-50%. There is no evidence that such exposure is of clinical significance. Due to the pronounced protein synthesis of A771726, the indicators of its apparent distribution volume are rather low (about 11 liters). There was no significant absorption of the drug by erythrocytes.

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

Interaction testing using cimetidine (which nonspecifically slows down the action of hemoprotein P450), as well as rifampicin (which nonspecifically induces hemoprotein P450) revealed that in vivo CYP enzymes are not significantly involved in the metabolic processes of leflunomide.

Excretion of A771726 is carried out at a low speed with an apparent clearance of approximately 31 ml / h. The half-life is approximately 14 days.

When using a labeled dosage of leflunomide, the excretion of the radioactive label in equal parts occurred through urine and feces (probably with excretion through bile). Inside feces and urine, A771726 was determined after 36 days after 1-time use of drugs. Inside the urine, the main metabolic elements were glucuronides, leflunomide derivatives (mainly within the samples of the first 24 hours), as well as oxanilic acid (derivative A771726). Inside feces, mainly A771726 was noted.

When used inside a suspension of activated carbon or cholestyramine, the rate and rate of excretion of A771726 significantly increased, as well as its plasma values decreased. It is believed that this effect develops in connection with dialysis inside the gastrointestinal tract or with the interruption of utilization inside the liver and small intestine.

Dosing and administration

It is necessary to carry out therapy under the supervision of a physician.

Treatment begins with oral administration of a shock portion of 0.1 g. It is taken once a day for a period of 3 days. The maintenance dosage 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 the therapeutic effect is often noted after 1-1.5 months, and its increase continues up to 4-6 months.

• Application for children

Leflutab is not used in persons under the age of 18 - there is no information regarding the safety and therapeutic efficacy of drugs for juvenile-type rheumatoid arthritis.

Use Leflutab during pregnancy

It is prohibited to use the medication during breastfeeding or pregnancy. The likelihood 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 sensitivity to leflunomide or additional elements of the drug;
• severe types of immunodeficiency (for example, AIDS);
• hepatic dysfunction;
• significant disorders of hematopoietic processes within the bone marrow, severe leuko- or thrombocytopenia and anemia associated with other factors (excluding rheumatoid arthritis);
• severe infection that cannot be controlled;
• severe stage of hypoproteinemia (for example, during nephrotic syndrome);
• moderate or severe renal failure (due to limited clinical experience of use in such disorders);
• women of reproductive age who do not use contraceptives.

Side effects Leflutab

The main side effects:

• disorders in the gastrointestinal tract: nausea, diseases affecting the oral mucosa (ulcers on the lips, aphthous stomatitis), loose stools, pain in the peritoneal area and loss of appetite, and in addition, hepatitis, cholestasis with jaundice, pancreatitis and severe stages of hepatic disorders (insufficiency or active phase of necrosis);
• problems with hematopoietic processes: leuko- or thrombocytopenia, agranulocytosis, anemia and eosinophilia;
• dysfunction of the CVS: a strong or moderate increase in blood pressure and vasculitis;
• changes in metabolic processes: hypokalemia, asthenia and weight loss;
• respiratory problems: interstitial processes (among them pneumonia);
• neurological disorders: dizziness, taste disorder, paresthesia, asthenia, polyneuropathy, anxiety and headaches;
• epidermal lesions: severe alopecia, epidermal dryness, eczema, allergies and erythema polyformis;
• disorders associated with the work of ODA: inflammation or rupture of tendons;
• infections: severe infections (also of the 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 canceled, as well as the use of sorbents with cholestyramine.

Interactions with other drugs

The severity of side symptoms can be potentiated with the recent or joint use of hematotoxic or hepatotoxic substances, and in addition, in the case of administration of medications after the use of leflunomide, when the time required for its full elimination is not taken into account. Because of this, at the initial stage after the transition, it is necessary to carefully monitor the indicators of liver enzymes and hematological values.

Vaccination processes.

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

Warfarin and other coagulants of an indirect type of influence.

There is information regarding an increase in PTV values in the case of using the drug in combination with warfarin. The interaction of pharmacokinetic parameters with warfarin was observed in clinical testing using A771726. Because of this, in the case of using a combination with warfarin or another coumarin anticoagulant, you need to carefully monitor the MHB indicators.

GCS or NSAIDs.

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

The impact of other medications on leflunomide.

Suspension of activated carbon or cholestyramine.

Persons who use leflunomide should not use the above substances, because they cause a significant and very rapid decrease in the plasma level of A771726. It is assumed that this effect develops due to the interruption of the processes of utilization of the element inside the liver and small intestine or dialysis A771726 inside the gastrointestinal tract.

Drugs that induce or slow down the activity of hemoprotein P450.

Separate in vitro tests, in which intrahepatic microsomes were used, showed that hemoprotein P450 (CYP) 1A2, and in addition 2C19 with 3A4, are participants in the metabolic processes of leflunomide.

When using one portion of the drug in individuals using multiple doses of rifampicin (which nonspecifically induces the action of hemoprotein P450), the Cmax A771726 values increased by approximately 40%, while the AUC indicator remained almost unchanged. It has not yet been possible to determine the mechanism of such a reaction.

The effect of leflunomide in relation to other medicines.

Exposure relative to repaglinide (is a substrate of the CYP2C8 element).

The average Cmax values, as well as the AUC of the substance, increased by 1.7, as well as 2.4 times when using repeated dosages of A771726. This suggests that the element A771726 slows down the CYP2C8 enzyme when acting in vivo. It is required to monitor the condition of persons using drugs whose metabolic processes are carried out with the participation of CYP2C8 (among them, in addition to repaglinide, also pioglitazone with paclitaxel or rosiglitazone), because they are capable of having a more intense effect.

Impact on caffeine (which is a substrate for the CYP1A2 element).

When using repeated portions of A771726, the average level of Cmax, as well as the AUC of the substance, decreased by 18%, as well as 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 element CYP1A2 (among them alosetron with duloxetine, tizanidine and theophylline) must be used very carefully - since their effectiveness may be weakened.

Effects on substrates of the OATP element 3.

There was an increase in the average values of cefaclor - Cmax (1.43 times) and AUC (1.54) with the introduction of repeated dosages of A771726. This suggests that the element A771726 slows down the activity of OATP 3 in vivo. Because of this, Leflutab must be used with extreme caution in combination with substrates of the OATP 3 substance (in addition to cefaclor, among them are ciprofloxacin, methotrexate with benzylpenicillin, zidovudine with indomethacin, cimetidine and ketoprofen, and besides this furosemide).

Exposure to the substrates of BCRP breast carcinoma resistance protein or P1B1 / B3 OATP components.

There was an increase in the average Cmax values, as well as the AUC of the substance rosuvastatin (by 2.65, as well as 2.51 times) with repeated administration of portions of A771726. But such an increase did not cause a significant effect on the activity of HMG-CoA reductase. In the case of administration with medication, the daily dosage of rosuvastatin should be a maximum of 10 mg.

When using other BCRP substances (this includes sulfasalazine, doxorubicin with methotrexate, daunorubicin and topotecan), as well as substrates of the OATP element, in particular those inhibiting the action of HMG-CoA reductase (this includes pravastatin with rifampicin, simvastatin and repagstatin with atorva ), be careful too. It is required to constantly monitor the condition of patients in order to timely identify signs of excessive exposure to the above drugs and reduce their portion, if necessary.

Effects on oral contraception (ethinylestradiol 0.03 mg and levonogestrel 0.15 mg).

There is an increase in the average Cmax values, as well as the AUC in ethinylestradiol (1.58 and 1.54 times) and levonorgestrel (1.33, and 1.41 times) with the repeated use of the A771726 element. While no negative impacts have been identified with regard to the effectiveness of contraceptives, the type of OC used should be taken into account.

Effects regarding warfarin.

There was a 25% decrease in the peak INR values in the case of using A771726 in combination with warfarin (when compared with the administration of warfarin alone). Because of this, with these combinations, the MHB level must be closely monitored.

Storage conditions

Leflutab must be kept out of the reach of small children, inside a tightly sealed container to prevent moisture penetration.

Shelf life

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

Analogs

An analogue of the drug is the medicine Arava.