Arava

Pharmacological action
Base antirheumatic drug. Has antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory effect. The active metabolite of leflunomide A771726 inhibits the enzyme degidroorotat dehydrogenase and has an antiproliferative effect. A771726 inhibits in vitro cell proliferation caused by mitogens and DNA synthesis of T-lymphocytes. Antiproliferative activity A771726 seen, apparently at the level of pyrimidine biosynthesis, since the addition of cell culture eliminates the inhibitory effect of uridine metabolite A771726. With the use of radioisotope ligand shown that A771726 selectively binds to the enzyme degidroorotat dehydrogenase, which explains its properties this enzyme and inhibit proliferation of lymphocytes at the stage of G1. Simultaneously A771726 inhibits the expression of receptors for interleukin-2 and core antigen Ki-67 and PCNA, associated with the cell cycle.
Therapeutic effect of leflunomide has been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.
Pharmacokinetics
The absorption and distribution
After oral administration, absorbed 82-95% of the drug. Eating does not affect the absorption leflunamida. Leflunomide is rapidly metabolized with the formation of the active metabolite A771726. Cmax metabolite A771726 determined within 1-24 h after a single dose of the dose. In plasma A771726 rapidly binds to albumin. Untie A771726 fraction is 0.62%. Binding A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.
Due to the long T1 / 2 A771726 was used a loading dose of 100 mg for 3 days. Pharmacokinetic parameters A771726 have a linear dependence at doses from 5 mg to 25 mg. In these studies, the clinical effect is closely related to plasma concentration of A771726 and a daily dose of leflunomide. At a dose of 20 mg / day, mean plasma concentration of A771726 at steady-state was 35 micrograms / ml.
Metabolism
Leflunomide is rapidly metabolized in the intestinal wall and liver to one of the main (A771726) metabolite and several secondary metabolites, including 4-trifluorometilalanin. Biotransformation of leflunomide to A771726 and A771726 of the subsequent metabolism are controlled by several enzymes and occur in microsomal and other cell fractions.
Withdrawal
In plasma, urine and feces determined by the trace amounts of leflunomide. Removing A771726 slow and characterized by clearance of 31 mL / h. T1 / 2 – about 2 weeks.
Pharmacokinetics in special clinical cases
Patients on hemodialysis, elimination of the drug quickly and T1 / 2 is shorter.
Data on the pharmacokinetics in patients with liver failure are absent.
Pharmacokinetics in patients younger than 18 years has not been studied.
Elderly patients (65 years and older) pharmacokinetic data correspond approximately to the middle age group.
Indications
- As the reference drug for the treatment of active rheumatoid arthritis to reduce symptoms and delay the development of structural damage of joints.
Dosage regimen
Treatment is initiated with the appointment of a shock dose of 100 mg daily for 3 days. As a maintenance dose prescribed dose of 10 mg to 20 mg 1 time per day.
The therapeutic effect is evident after 4-6 weeks of admission and may grow within 4-6 months.
Tablets should be swallowed whole, drinking plenty of fluids.
Not require dose adjustment for patients older than 65 years.
There are currently no recommendations for dosing regime for patients with mild renal insufficiency.
Side effects
Classification of the alleged frequency of side effects: typical – 1-10%, atypical – 0.1-1%, rare – 0.01-0.1%, very rare – 0.01% or less.
Since the cardiovascular system: typical – increase blood pressure.
From the digestive system: typical – diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (thrush, mouth ulceration), abdominal pain, increased hepatic transaminases (particularly ALT, rarely – GGT, alkaline phosphatase, bilirubin); rarely – hepatitis, jaundice, cholestasis, very rarely – liver failure, acute liver necrosis.
On the part of the musculoskeletal system: typical – abscess, atypical – the gap ligaments.
Dermatological reactions: typical – hair loss, eczema, dry skin, atypical – Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme.
The part of the hemopoietic system: typical – leukopenia (white blood cells more 2000/mkl); atypical – anemia, thrombocytopenia (platelets less than 100 000/mkl); rarely – eosinophilia, leukopenia (leukocytes less 2000/mkl), pancytopenia, very rarely – agranulocytosis. The risk of hematologic disorders increases with the recent, concomitant and subsequent application of myelotoxic drugs.
Allergic reactions: typical – rash (including makulo-papular), pruritus; atypical – urticaria; very rare – anaphylactic reactions.
On the part of the exchange processes: hyperlipidemia, hypophosphatemia, reduced levels of uric acid. Laboratory data (not clinically confirmed) showed a modest increase lactate dehydrogenase, creatine phosphokinase.
Other: very rarely – the development of severe infection and sepsis may develop rhinitis, bronchitis and pneumonia. In the application of immunosuppressive drugs increases the risk of cancer and some lymphoproliferative processes.
We can not exclude the possibility of a reversible reduction of sperm concentration, total sperm count and motility.
Contraindications
- Human liver;
- Severe immunodeficiency (including AIDS);
- Pronounced disorders of bone marrow hematopoiesis or anemia, leukopenia, thrombocytopenia due to other causes (other than rheumatoid arthritis);
- Infection heavy flow;
- Moderate or severe renal insufficiency (because of the small experience of clinical observations);
- Severe hypoproteinemia (including with nephrotic syndrome);
- Pregnancy;
- Lactation (breastfeeding);
- Childhood and adolescence to 18 years;
- Hypersensitivity to the ingredients.
The drug is contraindicated in women of childbearing age who do not use adequate contraception.
Pregnancy and lactation
The drug should not be administered during pregnancy and women of childbearing age who are not using reliable contraception. You must verify the absence of pregnancy before starting treatment.
In experimental studies have found that the drug may have fetotoksicheskoe and teratogenic effect.
Patients should be informed that suspected pregnancy should seek medical advice immediately and do a pregnancy test. If the test is positive, the physician should inform the patient about the possible risk to the fetus.
Women who take leflunomide and want to become pregnant (or already in the ensuing pregnancy) procedure is recommended to launch the drug, which will rapidly reduce the concentration of leflunomide and its metabolite in blood plasma (after cessation of treatment prescribed leflunomide kolestiramin in a dose of 8 g 3 times / day within 11 days or 50 g of activated charcoal, crushed into powder, 4 times / day for 11 days).
Next, you need to determine the concentration of metabolite A771726 2 times with an interval of 14 days. From the moment when the concentration of the drug will be fixed below 20 mg / l until fertilization should take 1.5 months.
Note that without the procedure of removing the drug, reduced metabolite concentrations below 20 ug / l occurs in 2 years.
Kolestiramin and activated carbon can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee the necessary contraception during launch preparation. It is recommended to use alternative methods of contraception.
Studies in animals have shown that leflunomide or its metabolites are excreted in breast milk milk. Therefore, the need to designate a lactation should resolve the issue of termination of breastfeeding.
There is currently no information confirming the link between taking the drug Arava men and fetotoksicheskim action of the drug. Experimental studies in this direction were made. However, men receiving leflunomide therapy, should be warned of the possible effect of fetotoksicheskom and the need to use adequate contraception. To minimize risk when planning pregnancy should stop taking leflunomide and use kolestiramin to 8 mg 3 times daily for 11 days or 50 grams of powdered activated charcoal 4 times daily for 11 days.
Cautions
Note that the drug Arava may be imposed only after a medical examination (including before starting treatment and during treatment should monitor blood pressure).
Before treatment drug Arava should be mindful of possible increase in the number of side effects in patients previously treated with other basic tools for the treatment of rheumatoid arthritis, which have hepato-and gematotoksicheskim action.
The active metabolite of leflunomide A771726 characterized by long T1 / 2. Therefore, side effects can occur even after cessation of therapy. If you have any similar cases of toxicity or when moving to another base receiving the drug after treatment with leflunomide should be the procedure of removing the drug (after the cessation of leflunomide treatment prescribed kolestiramin in a dose of 8 g 3 times daily for 11 days or 50 g of activated carbon, crushed to powder, 4 times / day for 11 days).
Note that during the development of severe dermatologic adverse reactions, severe infections receiving the drug Arava should stop and immediately initiate the removal of the drug.
Need to monitor patients with tuberculin reactivity due to the risk of activating tuberculosis.
Given the long-term elimination of Arava is not recommended to vaccinate live vaccines against a background of leflunomide treatment.
Overdose
No data on overdose of leflunomide. Admission leflunomide 100 mg daily for 14 days was observed in 10 healthy volunteers. Two of them were removed after a week because of the increased level of transaminases in the blood plasma.
In case of overdose or toxicity is recommended to use kolestiramina or powdered activated carbon. Kolestiramin, take 3 healthy volunteers administered orally to 8 mg 3 times / day during the day, reduced levels of A771726 in plasma by approximately 40% after 24 h and 49-65% after 48 h.
Shown that introduction of activated charcoal orally or via oral gavage (50 mg every 6 hours during the day) reduced the concentration of the active metabolite A771726 in plasma by 37% after 24 h and 48% after 48 h.
Perhaps repetition procedures are preparation for clinical indications.
Drug Interactions
Increased adverse reactions may occur in the case of recent or concomitant use of hepatotoxic drugs or hematotoxicity or when receiving these drugs after starting leflunomide treatment procedure without removing the drug.
Not observed pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week).
Unknown clinically significant interactions with concomitant use of leflunomide and triphasic oral contraceptives, NSAIDs, cimetidine, rifampicin.
Studies in vitro showed that the metabolite of leflunomide A771726 inhibits the activity of cytochrome P450 2C9. Therefore, caution should be prescribed the drug Arava with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide).
Conditions and terms of storage
The product should be stored at temperatures not above 25 ° C. Shelf life – 3 years.
Conditions of supply of pharmacies
The drug is released with a prescription.

Arava

Pharmacological action

Base antirheumatic drug. Has antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory effect. The active metabolite of leflunomide A771726 inhibits the enzyme degidroorotat dehydrogenase and has an antiproliferative effect. A771726 inhibits in vitro cell proliferation caused by mitogens and DNA synthesis of T-lymphocytes. Antiproliferative activity A771726 seen, apparently at the level of pyrimidine biosynthesis, since the addition of cell culture eliminates the inhibitory effect of uridine metabolite A771726. With the use of radioisotope ligand shown that A771726 selectively binds to the enzyme degidroorotat dehydrogenase, which explains its properties this enzyme and inhibit proliferation of lymphocytes at the stage of G1. Simultaneously A771726 inhibits the expression of receptors for interleukin-2 and core antigen Ki-67 and PCNA, associated with the cell cycle.

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

Pharmacokinetics

The absorption and distribution

After oral administration, absorbed 82-95% of the drug. Eating does not affect the absorption leflunamida. Leflunomide is rapidly metabolized with the formation of the active metabolite A771726. Cmax metabolite A771726 determined within 1-24 h after a single dose of the dose. In plasma A771726 rapidly binds to albumin. Untie A771726 fraction is 0.62%. Binding A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Due to the long T1 / 2 A771726 was used a loading dose of 100 mg for 3 days. Pharmacokinetic parameters A771726 have a linear dependence at doses from 5 mg to 25 mg. In these studies, the clinical effect is closely related to plasma concentration of A771726 and a daily dose of leflunomide. At a dose of 20 mg / day, mean plasma concentration of A771726 at steady-state was 35 micrograms / ml.

Metabolism

Leflunomide is rapidly metabolized in the intestinal wall and liver to one of the main (A771726) metabolite and several secondary metabolites, including 4-trifluorometilalanin. Biotransformation of leflunomide to A771726 and A771726 of the subsequent metabolism are controlled by several enzymes and occur in microsomal and other cell fractions.

Withdrawal

In plasma, urine and feces determined by the trace amounts of leflunomide. Removing A771726 slow and characterized by clearance of 31 mL / h. T1 / 2 – about 2 weeks.

Pharmacokinetics in special clinical cases

Patients on hemodialysis, elimination of the drug quickly and T1 / 2 is shorter.

Data on the pharmacokinetics in patients with liver failure are absent.

Pharmacokinetics in patients younger than 18 years has not been studied.

Elderly patients (65 years and older) pharmacokinetic data correspond approximately to the middle age group.

Indications

- As the reference drug for the treatment of active rheumatoid arthritis to reduce symptoms and delay the development of structural damage of joints.

Dosage regimen

Treatment is initiated with the appointment of a shock dose of 100 mg daily for 3 days. As a maintenance dose prescribed dose of 10 mg to 20 mg 1 time per day.

The therapeutic effect is evident after 4-6 weeks of admission and may grow within 4-6 months.

Tablets should be swallowed whole, drinking plenty of fluids.

Not require dose adjustment for patients older than 65 years.

There are currently no recommendations for dosing regime for patients with mild renal insufficiency.

Side effects

Classification of the alleged frequency of side effects: typical – 1-10%, atypical – 0.1-1%, rare – 0.01-0.1%, very rare – 0.01% or less.

Since the cardiovascular system: typical – increase blood pressure.

From the digestive system: typical – diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (thrush, mouth ulceration), abdominal pain, increased hepatic transaminases (particularly ALT, rarely – GGT, alkaline phosphatase, bilirubin); rarely – hepatitis, jaundice, cholestasis, very rarely – liver failure, acute liver necrosis.

On the part of the musculoskeletal system: typical – abscess, atypical – the gap ligaments.

Dermatological reactions: typical – hair loss, eczema, dry skin, atypical – Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme.

The part of the hemopoietic system: typical – leukopenia (white blood cells more 2000/mkl); atypical – anemia, thrombocytopenia (platelets less than 100 000/mkl); rarely – eosinophilia, leukopenia (leukocytes less 2000/mkl), pancytopenia, very rarely – agranulocytosis. The risk of hematologic disorders increases with the recent, concomitant and subsequent application of myelotoxic drugs.

Allergic reactions: typical – rash (including makulo-papular), pruritus; atypical – urticaria; very rare – anaphylactic reactions.

On the part of the exchange processes: hyperlipidemia, hypophosphatemia, reduced levels of uric acid. Laboratory data (not clinically confirmed) showed a modest increase lactate dehydrogenase, creatine phosphokinase.

Other: very rarely – the development of severe infection and sepsis may develop rhinitis, bronchitis and pneumonia. In the application of immunosuppressive drugs increases the risk of cancer and some lymphoproliferative processes.

We can not exclude the possibility of a reversible reduction of sperm concentration, total sperm count and motility.

Contraindications

- Human liver;

- Severe immunodeficiency (including AIDS);

- Pronounced disorders of bone marrow hematopoiesis or anemia, leukopenia, thrombocytopenia due to other causes (other than rheumatoid arthritis);

- Infection heavy flow;

- Moderate or severe renal insufficiency (because of the small experience of clinical observations);

- Severe hypoproteinemia (including with nephrotic syndrome);

- Pregnancy;

- Lactation (breastfeeding);

- Childhood and adolescence to 18 years;

- Hypersensitivity to the ingredients.

The drug is contraindicated in women of childbearing age who do not use adequate contraception.

Pregnancy and lactation

The drug should not be administered during pregnancy and women of childbearing age who are not using reliable contraception. You must verify the absence of pregnancy before starting treatment.

In experimental studies have found that the drug may have fetotoksicheskoe and teratogenic effect.

Patients should be informed that suspected pregnancy should seek medical advice immediately and do a pregnancy test. If the test is positive, the physician should inform the patient about the possible risk to the fetus.

Women who take leflunomide and want to become pregnant (or already in the ensuing pregnancy) procedure is recommended to launch the drug, which will rapidly reduce the concentration of leflunomide and its metabolite in blood plasma (after cessation of treatment prescribed leflunomide kolestiramin in a dose of 8 g 3 times / day within 11 days or 50 g of activated charcoal, crushed into powder, 4 times / day for 11 days).

Next, you need to determine the concentration of metabolite A771726 2 times with an interval of 14 days. From the moment when the concentration of the drug will be fixed below 20 mg / l until fertilization should take 1.5 months.

Note that without the procedure of removing the drug, reduced metabolite concentrations below 20 ug / l occurs in 2 years.

Kolestiramin and activated carbon can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee the necessary contraception during launch preparation. It is recommended to use alternative methods of contraception.

Studies in animals have shown that leflunomide or its metabolites are excreted in breast milk milk. Therefore, the need to designate a lactation should resolve the issue of termination of breastfeeding.

There is currently no information confirming the link between taking the drug Arava men and fetotoksicheskim action of the drug. Experimental studies in this direction were made. However, men receiving leflunomide therapy, should be warned of the possible effect of fetotoksicheskom and the need to use adequate contraception. To minimize risk when planning pregnancy should stop taking leflunomide and use kolestiramin to 8 mg 3 times daily for 11 days or 50 grams of powdered activated charcoal 4 times daily for 11 days.

Cautions

Note that the drug Arava may be imposed only after a medical examination (including before starting treatment and during treatment should monitor blood pressure).

Before treatment drug Arava should be mindful of possible increase in the number of side effects in patients previously treated with other basic tools for the treatment of rheumatoid arthritis, which have hepato-and gematotoksicheskim action.

The active metabolite of leflunomide A771726 characterized by long T1 / 2. Therefore, side effects can occur even after cessation of therapy. If you have any similar cases of toxicity or when moving to another base receiving the drug after treatment with leflunomide should be the procedure of removing the drug (after the cessation of leflunomide treatment prescribed kolestiramin in a dose of 8 g 3 times daily for 11 days or 50 g of activated carbon, crushed to powder, 4 times / day for 11 days).

Note that during the development of severe dermatologic adverse reactions, severe infections receiving the drug Arava should stop and immediately initiate the removal of the drug.

Need to monitor patients with tuberculin reactivity due to the risk of activating tuberculosis.

Given the long-term elimination of Arava is not recommended to vaccinate live vaccines against a background of leflunomide treatment.

Overdose

No data on overdose of leflunomide. Admission leflunomide 100 mg daily for 14 days was observed in 10 healthy volunteers. Two of them were removed after a week because of the increased level of transaminases in the blood plasma.

In case of overdose or toxicity is recommended to use kolestiramina or powdered activated carbon. Kolestiramin, take 3 healthy volunteers administered orally to 8 mg 3 times / day during the day, reduced levels of A771726 in plasma by approximately 40% after 24 h and 49-65% after 48 h.

Shown that introduction of activated charcoal orally or via oral gavage (50 mg every 6 hours during the day) reduced the concentration of the active metabolite A771726 in plasma by 37% after 24 h and 48% after 48 h.

Perhaps repetition procedures are preparation for clinical indications.

Drug Interactions

Increased adverse reactions may occur in the case of recent or concomitant use of hepatotoxic drugs or hematotoxicity or when receiving these drugs after starting leflunomide treatment procedure without removing the drug.

Not observed pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week).

Unknown clinically significant interactions with concomitant use of leflunomide and triphasic oral contraceptives, NSAIDs, cimetidine, rifampicin.

Studies in vitro showed that the metabolite of leflunomide A771726 inhibits the activity of cytochrome P450 2C9. Therefore, caution should be prescribed the drug Arava with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide).


Conditions and terms of storage

The product should be stored at temperatures not above 25 ° C. Shelf life – 3 years.

Conditions of supply of pharmacies

The drug is released with a prescription.

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January 21, 2010 | Tags: | No Comments »

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