Elafra, 10 mg 30 pcs.

Elafra is a baseline antirheumatic drug that modifies the course of the disease, with antiproliferative activity. Active metabolite of leflunomide – A771726 – inhibits dihydrorotate dehydrogenase enzyme and has antiproliferative activity. In vitro A771726 inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes.

The antiproliferative activity of A771726 appears to be manifested at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the metabolite A771726. Using radioisotope ligands, it was shown that A771726 selectively binds to the enzyme dihydrorotate dehydrogenase, which explains its ability to inhibit this enzyme and lymphocyte proliferation at the G1 stage. At the same time A771726 inhibits the expression of receptors to interleukin-2 and the cell cycle related Ki-67 and PCNA antigens.

Therapeutic effects of leflunomide have been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Pharmacokinetics

Absorption and distribution

The absorption of the drug is 82-95% and is independent of food intake. The period to reach a stable concentration of the drug in plasma blood is approximately 2 months of daily administration, provided that a shock dose is not used at the beginning of treatment. Because of the long T_1/2 A771726, a loading dose of 100 mg for 3 days was used. This allowed the equilibrium plasma concentration of A771726 to be reached quickly.

The pharmacokinetic parameters of A771726 have a linear relationship when administered at doses ranging from 5 mg to 25 mg. In these studies, the clinical effect is closely related to the plasma concentration of A771726 and the daily dose of leflunomide. When administered at a dose of 20 mg/day, the average plasma concentrations of A771726 at equilibrium were 35 µg/ml. Plasma concentrations of the drug increased by a factor of 33-35 when administered multiple times compared to a single dose.

In plasma A771726 rapidly binds to albumin. The unbound fraction of A771726 is 0.62%. The binding of A771726 is more variable and is slightly reduced in patients with rheumatoid arthritis or chronic renal impairment.

Metabolism and excretion

Leflunomide is rapidly metabolized in the intestinal wall and liver to one major (A771726) metabolite and several minor metabolites, including 4-trifluoromethylalanine. The biotransformation of leflunomide to A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cellular fractions.

Trace amounts of leflunomide are detected in plasma, urine and feces. Excretion of A771726 is slow and characterized by a clearance of 31 ml/h. T_1/2 – about 2 weeks.

Indications

The active form of rheumatoid arthritis.

Active ingredient

Composition

1 film-coated tablet contains:

the active ingredient:

leflunomide 10 mg,

excipients:

lactose monohydrate,

low substituted hyprolose,

tartaric acid,

sodium lauryl sulfate,

magnesium stearate.

composition of the film coating:

polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum.

How to take, the dosage

The tablets are taken orally, swallowed whole with plenty of fluid. Food intake has no effect on the absorption of leflunomide.

The treatment with leflunomide should be started under the supervision of a doctor experienced in the treatment of rheumatoid arthritis. Treatment with leflunomide begins with a shock dose of 100 mg for 3 days.

The maintenance dose in rheumatoid arthritis is 10-20 mg once daily.

The therapeutic effect is usually seen after 4-6 weeks and may increase further up to 4-6 months.

There are no recommendations regarding dosing of the drug in patients with mild renal impairment.

Dose adjustment is not required in patients over 65 years of age.

Interaction

An increase in adverse reactions may occur in the case of recent or concomitant use of hepatotoxic or hematotoxic drugs or when these drugs are started after treatment with leflunomide without a “washout” procedure.

No pharmacokinetic interaction has been found between leflunomide (10-20 mg/day) and methotrexate (10-25 mg/week).

There have been no clinically significant interactions found with concomitant use of leflunomide and triphasic oral contraceptives, NSAIDs, cimetidine, rifampicin.

In vitro studies have shown that the metabolite of leflunomide A771726 inhibits the activity of CYP2C9. Caution should be exercised when prescribing leflunomide with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide).

Patients treated with leflunomide should not be given colestyramine or activated charcoal because this leads to a rapid and significant decrease in plasma concentrations of A771726 (the active metabolite of leflunomide). This is thought to be due to impaired recirculation of A771726 in the liver and small intestine and/or impaired gastrointestinal dialysis.

After concomitant administration of a single dose of leflunomide to patients receiving multiple doses of rifampicin (a nonspecific cytochrome P450 inducer), Cmax A771726 increased by approximately 40%, whereas AUC was not significantly changed. The mechanism of this effect is not clear.

In a study in which leflunomide was administered to healthy female volunteers together with triphasic oral contraceptives containing 30 mcg ethinylestradiol, no reduction in the contraceptive effect of the pills was found, and the pharmacokinetics of A771726 were completely within the intended range.

There is currently no information regarding the co-administration of leflunomide with antimalarials used in rheumatology (e.g., chloroquine and hydroxychlorine), gold preparations (w/o or orally), D-penicillamine, azathioprine and other immunosuppressive agents (except for methotrexate). The risks associated with combination therapy are unknown, especially with long-term treatment. Since this type of therapy may lead to additional or even synergistic toxicity (e.g., hepato- or hematoxicity), combinations of Elafra with other basal drugs (e.g., methotrexate) are undesirable. Recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater degree of risk of hematologic effects. Immunosuppressants increase the risk of infections as well as malignant, especially lymphoproliferative diseases.

There are no clinical data regarding the efficacy and safety of vaccination in the setting of leflunomide treatment. However, vaccination with live vaccines is not recommended. Long T1/2 leflunomide should be considered when planning vaccination with live vaccines after withdrawal of Elafra.

Special Instructions

Elafra should only be prescribed to patients after a thorough medical examination.

Before initiating treatment with Elafra, be aware of possible increased side effects in patients who were previously treated with other basal agents for rheumatoid arthritis, which have hepatotoxic and hematotoxic effects.

The active metabolite of leflunomide, A771726, is characterized by a long T1/2, usually of 1-4 weeks, due to which even when leflunomide treatment is stopped, serious adverse effects (such as hepatotoxicity, hematotoxicity or allergic reactions) may occur or persist. In this case, a “washout” procedure should be performed (after stopping treatment with leflunomide, colestyramine at a dose of 8 g 3 times/day for 11 days or 50 g of activated charcoal crushed into a powder, 4 times/day for 11 days). The procedure can be repeated for clinical indications.

If severe immunological/allergic reactions such as Stevens-Johnson syndrome or Lyell syndrome are suspected, a complete “washout” procedure is mandatory.

If this type of toxicity occurs or if you switch to another baseline drug (e.g., methotrexate) after treatment with leflunomide, a “washout” procedure must be performed.

Because the active metabolite of leflunomide, A771726, binds to proteins and is eliminated by hepatic metabolism and bile secretion, it is thought that plasma levels of A771726 may be elevated in patients with hypoproteinemia.

Rare cases of severe liver damage, occasionally fatal, have been reported with leflunomide treatment. Most of these cases occurred within the first 6 months of treatment. Although a causal relationship of these adverse events to leflunomide has not been established, and in most cases there were several additional suspicious factors, accurate adherence to treatment monitoring recommendations is considered mandatory.

ALT levels should be checked before starting therapy with leflunomide and then every 2 weeks for the first 6 months of treatment, with follow-up once every 6-8 weeks.

There are the following recommendations for dosing adjustments or discontinuation of the drug depending on the severity and persistence of ALT elevation. If 2 to 3-fold elevation of ALT is confirmed, dose reduction from 20 mg/day to 10 mg/day may allow continued use of leflunomide, provided that this index is closely monitored. If a 2-3-fold ALT elevation persists or if there is a confirmed ALT elevation of more than 3 times the ULT, leflunomide should be discontinued and a “washout” procedure should be initiated.

Because of possible additional hepatotoxic effects, it is recommended to refrain from drinking alcohol during treatment with leflunomide.

A complete clinical blood count, including determination of the white blood cell count and platelet count, should be performed before starting treatment with leflunomide, and every 2 weeks during the first 6 months of treatment and every 6-8 weeks thereafter.

In patients with previous anemia, leukopenia and/or thrombocytopenia, as well as in patients with bone marrow dysfunction or with the risk of developing such disorders, the risk of hematological disorders increases. If this occurs, a “washout” procedure should be used to reduce plasma levels of A771726.

If serious hematologic reactions develop, including pancytopenia, Elafra and any other concomitant medication that inhibits bone marrow hematopoiesis should be stopped and a “wash” procedure should be initiated.

Because leflunomide persists in the body for a long time, switching to another baseline drug (e.g., methotrexate) without a proper “washout” procedure can increase the potential for additional risk even long after switching (e.g., kinetic interaction, organ toxicity). Similarly, recent treatment with hepatotoxic or hematotoxic drugs (e.g., methotrexate) can lead to increased adverse events, so starting treatment with leflunomide should carefully consider all the positive and negative aspects associated with taking this medication.

Leflunomide should be stopped if ulcerative stomatitis develops.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving leflunomide. In the case of skin and/or mucous membrane reactions, Elafra and any other related drug should be discontinued and a “washout” procedure should be initiated immediately. It is necessary to achieve complete elimination of the drug from the body. In such cases re administration of the drug is contraindicated.

Leflunomide-like drugs with immunosuppressive properties are known to increase the susceptibility of the patient’s body to various types of infections, including opportunistic infections (occurring only in conditions of reduced immunity). Infectious diseases are usually severe and require early and intensive treatment. If severe infectious disease occurs, it may be necessary to interrupt treatment with leflunomide and begin a “washout” procedure.

Patients who test positive for tuberculin should be closely monitored because of the risk of reactivation of tuberculosis.

Rare cases of interstitial lung disease have been reported with leflunomide therapy. Symptoms such as cough and dyspnea may be reasons for discontinuing leflunomide.

Before starting treatment with leflunomide and periodically thereafter, BP should be monitored.

There are no data on the risk of fetotoxicity (associated with the drug’s toxic effect on paternal spermatozoa) when leflunomide is used in men. To minimize the possible risk, men should stop using leflunomide and use a “washout” procedure when planning to have a baby. While using the drug, men should take measures to prevent their partner from becoming pregnant.

Impact on driving and operating machinery

Cautiousness should be exercised when driving vehicles and performing work requiring increased concentration and speed of psychomotor reactions.

Contraindications

Side effects

The most common side effects (1-10%): Leukopenia; allergic reactions; loss of appetite, weight loss (usually minor); fatigue (weakness), headache, dizziness, paresthesia; moderate increase in BP; diarrhea, nausea, vomiting, erosive and ulcerative lesions of the oral mucosa, abdominal pain, increased liver function tests; increased hair loss, eczema, dry skin, rash, itching; tendovaginitis, increased activity of some enzymes in blood (creatine phosphokinase).

Atypical side effects (0.1-1%): decreased number of red blood cells, thrombocytopenia; decreased blood potassium levels; anxiety; impaired taste sensation; urticaria; increased blood lipid concentration (cholesterol and triglycerides), decreased blood phosphate levels.

Rare side effects (0.01-0.1%): eosinophilia, leukopenia, pancytopenia; sharp increase of BP; liver function disorders as hepatitis, cholestasis, jaundice; sepsis (possibly fatal).

Very rare side effects (0.001% or less): agranulocytosis, severe allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, vasculitis, peripheral neuropathy, pancreatitis.

Overdose

Symptoms: diarrhea, abdominal pain, leukopenia, anemia and increased liver function tests.

Treatment: In case of overdose or toxicity, it is recommended to take colestyramine or activated charcoal to speed up cleansing of the body. Colestiramine taken orally by three healthy volunteers at 8 g 3 times/day for 24 h decreased plasma levels of A771726 by approximately 40% after 24 hours and by 49-65% after 48 hours. Administering activated charcoal (powder turned into suspension) orally or through a gastric tube (50 g every 6 hr for 24 hr) was shown to decrease plasma concentrations of the active metabolite A771726 by 37% – after 24 hr and by 48% – after 48 hr.

Pregnancy use

The drug is contraindicated in pregnancy and in women of childbearing age who are not using reliable contraception.

Women need to protect themselves against pregnancy for 2 years after stopping the use of the drug.

It is important to make sure there is no pregnancy before starting treatment. Women who take leflunomide and want to get pregnant (or who are already pregnant) are recommended to undergo a procedure of “washing” of the drug, which will quickly reduce the level of the active metabolite in the blood plasma (after stopping treatment with leflunomide colestyramine in a dose of 8 g 3 times per day for 11 days or 50 g of activated charcoal ground into a powder 4 times per day for 11 days).

Next, the concentration of the metabolite A771726 must be determined 2 times at 14-day intervals. It should take 1.5 months from the time the concentration of the drug is first recorded below 20 µg/L to the time of fertilization. Note that without the drug “washout” procedure, it takes 2 years for the metabolite concentration to drop below 20 µg/L. Colestiramine and activated charcoal can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee the necessary contraception during the drug withdrawal period. Alternative methods of contraception are recommended.

Leflunomide and its metabolites pass into breast milk. Therefore, the use of leflunomide during breastfeeding is contraindicated.