Treatment choronological Antirheumatic drugs (HMIRS) of the active phase of rheumatoid arthritis in adults. Treatment of the active phase of psoriatic arthritis in adults. Recent or simultaneous treatment with hepatotoxic or hematotoxic CKD (e.g. methotrexate) may increase the risk of serious adverse reactions; therefore, the initiation of treatment with Leflunomide should be carefully considered with the benefit / risk in mind.
active substance: leflunomide;
1 tablet contains leflunomide 20 mg;
Excipients: starlac *, povidone, croscarmellose sodium, sodium lauryl sulfate, colloidal anhydrous silica, talc, IR white colicoate II.
* Starlac: lactose monohydrate, corn starch.
Lefno Dosage form
Main physical and chemical properties: oval biconvex white tablets, coated.
Lefno Pharmacotherapeutic group
Immunosuppressants. ATX code L04A A13.
Lefno Pharmacological properties
Leflunomide is a disease-modifying antirheumatic agent with antiproliferative properties.
Mechanism of action
A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase (DGODG) and exhibits antiproliferative activity.
Leflunomide is rapidly converted to the active metabolite A771726 by presystemic metabolism (ring opening) in the intestinal and hepatic walls. Plasma levels of unchanged leflunomide were rare. The only metabolite found in blood plasma was A771726. This metabolite mainly causes all the activity of leflunomide in the body.
Absorbed from 82 to 95% of the dose of leflunomide. The time to reach the maximum concentration of A771726 in blood plasma is very different: from 1 to 24 hours after a single application. Leflunomide can be taken with food, as the amount of absorption when taking the drug after a meal and on an empty stomach is similar. 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 a stable level of A771726 quickly. It was found that without the use of a loading dose to achieve a stable concentration in blood plasma may require almost two months of taking the drug. Studies examining different dosages of the drug have shown that the pharmacokinetic parameters of A771726 are linear when using the drug in the dose range from 5 to 25 mg.
In these studies, the clinical effect was closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose of 20 mg / day, the average plasma concentration of A771726 in the saturation stage is approximately 35 μg / ml. In the saturation stage, the concentration of A771726 in blood plasma is approximately 33-35 times higher than that with a single application of the drug.
In human plasma, A771726 is almost completely bound to protein (albumin). The unbound fraction of A771726 is about 0.62%. Binding of A771726 is linear within therapeutic doses. Binding of A771726 was found to be slightly weaker and more variable in the blood plasma of patients with rheumatoid arthritis or chronic renal failure. Extensive protein binding of A771726 may result in the displacement of other substances that are highly protein bound. However, the results of an in vitro protein binding interaction study with warfarin at clinically appropriate doses did not show an interaction. Similar studies showed that ibuprofen and diclofenac did not displace A771726, whereas in the presence of tolbutamide the unbound fraction of A771726 increased 2-3-fold. A771726 supplanted ibuprofen, diclofenac, and tolbutamide, but the unbound fraction of these drugs increased by only 10–50%. There is no evidence that these effects are of clinical significance. With significant protein binding, A771726 has a low apparent volume of distribution (approximately 11 liters). Predominant absorption by erythrocytes does not occur.
Leflunomide is metabolized to one major (A771726) and many minor metabolites, including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and the subsequent metabolism of A771726 are not controlled by a single specific enzyme, and have been shown to occur in microsomal and cytosolic cell fractions. Interaction studies with cimetidine (a non-specific cytochrome P450 inhibitor) and rifampicin (a non-specific cytochrome P450 inducer) indicate that in vivo CYP enzymes are only slightly involved in leflunomide metabolism.