Arava belongs to a class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, anti-inflammatory and immunosuppressive properties. The active metabolite of equipoise dosage inhibited A771726 degidroorotat dehydrogenase enzyme and possess antiproliferative activity. A771726 under in vitro inhibits mitogen-induced proliferation and DNA synthesis of T lymphocytes. A771726 manifests antiproliferative activity, apparently at the level of pyrimidine biosynthesis, since the addition of uridine in the cell culture inhibitory effect eliminates metabolite A771726. With the use of radioisotope ligand shown that A771726 selectively binds to the enzyme dehydrogenase degidroorotat than due to its property to inhibit this enzyme and lymphocyte proliferation in the G1 phase. The proliferation of lymphocytes is one of the key stages of rheumatoid arthritis.
Simultaneously A771726 inhibits expression of receptors for interleukin-2 (CB-25) and core antigens Ki-67 and PCNA, associated with the cell cycle.
The therapeutic effect of equipoise dosage was shown in several animal models of autoimmune diseases including rheumatoid arthritis.
equipoise dosage reduces the symptoms and slow the progression of joint damage in the form of active rheumatoid arthritis.
The therapeutic effect usually evident after 4-6 weeks and can grow further for 4-6 months.
equipoise dosage is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces were seen only trace amounts of unchanged equipoise dosage.
The only determined metabolite A771726 is responsible for the basic properties of the drug in vivo.
If ingestion is absorbed from 82 to 95% of the drug. The maximum plasma concentration of A771726 are determined from 1 to 24 hours after a single dose of the dose. equipoise dosage can be taken together with food.
Because of the very long half-life A771726 (approximately 2 weeks) was used loading dose of 100 mg daily for 3 days. This has allowed to quickly reach an equilibrium state plasma concentrations of A771726. Without a loading dose to achieve equilibrium concentration would require a 2-month drug. In studies with multiple assignment A771726 drug pharmacokinetic parameters were dose-dependent within the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and a daily dose of equipoise dosage. At a dose of 20 mg per day, average plasma concentration of A771726 at equilibrium have the value of 35 ug / ml.
The plasma is rapid binding A771726 albumin. Unbound fraction of A771726 is about 0.62%. Binding of A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.
equipoise dosage is metabolised to one primary (A771726) and several secondary metabolites, including 4-triflyuorometilalanin.
The biotransformation of equipoise dosage to A771726 and subsequent metabolism of A771726 are controlled by several enzymes, and occur in microsomal and other cell fractions. Interaction studies with cimetidine (non-specific inhibitor of cytochrome P450) and rifampicin (non-specific inducer of cytochrome P450) showed that in vivo SYP-enzymes involved in the metabolism of equipoise dosage only to a small extent.
Excretion A771726 from the body and is characterized by a slow clearance of 31 ml / hr. equipoise dosage is excreted in the feces (probably due to biliary excretion) and in the urine. The half-life is about 2 weeks.
The pharmacokinetics of A771726 in patients on CAPD, is similar to that in healthy volunteers. A more rapid elimination of A771726 observed in patients on hemodialysis, which is not connected with the extraction of drug in the dialysate and displacing it from its association with the protein. Although A771726 clearance increased by approximately a factor of 2, terminal half-life is similar to that in healthy individuals, as at the same time increases the amount of the distribution.
The data on the pharmacokinetics of the drug in patients with hepatic impairment available.
Pharmacokinetic characteristics in patients younger than 18 years have not been studied.
Patients older age (65 or older) pharmacokinetic data correspond roughly to the middle age group.
As a basic means for the treatment of adult patients with active rheumatoid arthritis to reduce symptoms and the delay of progression of structural damage of the joints.
The active form of psoriatic arthritis.
The drug Arava should not be used in patients with hypersensitivity to equipoise dosage or to any other component of the drug.
The drug is contraindicated in:
- in patients with impaired liver function;
- in patients with severe immunodeficiency (e.g., AIDS);
- in patients with significant disorders of bone marrow hematopoiesis, or with severe anemia, leukopenia or thrombocytopenia due to other reasons (other than rheumatoid arthritis);
- in patients with severe, uncontrolled infections;
- in patients with moderate or severe renal insufficiency (because of the small experience of clinical follow-up);
- in patients with severe hypoproteinemia (e.g., nephrotic syndrome);
- in pregnant women or women of childbearing age who are not using reliable contraception during treatment with equipoise dosage, and then as long as the plasma levels of the active metabolite remains above 0.02 mg / l (see. “Pregnancy and lactation”). Pregnancy must be excluded before starting treatment with equipoise dosage.
Contraindications receiving equipoise dosage during breastfeeding (see. “Pregnancy and breast-feeding”.)
Men receiving treatment with equipoise dosage should be warned about the possible foetotoxic effect of the drug (related to its possible impact on the father’s sperm) and the need to use reliable contraception.
Arava is not recommended for use in patients under 18 years since efficacy and safety data in this population are not available.
Pregnancy and breast-feeding
equipoise dosage should not be administered to pregnant women or women of childbearing age who are not using reliable contraception during treatment with equipoise dosage and for a while after this treatment (waiting period or abbreviated period of “laundering”; see below.). It must be ensured in the absence of pregnancy prior to treatment with equipoise dosage.
Patients should be informed that as soon as there comes a month or if the delay has another reason to assume pregnancy, they should immediately inform your doctor to do a pregnancy test; in the case of a positive pregnancy test physician should discuss with the patient the possible risk to this pregnancy. It is possible that the rapid decline in the level of the active metabolite in the blood with the help of the described below product launch procedures will help at the first delay of menses to reduce the risk to the fetus from equipoise dosage.
Women who take equipoise dosage and want to become pregnant, it is recommended to follow one of the following procedures to be sure that the fetus is not exposed to toxic concentrations of A771726 (control concentration below 0.02 mg / l).
The waiting period
can be expected that A771726 plasma concentration may be higher than 0.02 mg / l for a long period. It is believed that the concentration can be less than 0.02 mg / l in 2 years after stopping the treatment with equipoise dosage.
First time A771726 plasma concentration is measured after a two-year waiting period.
After that, you need to measure the concentration of A771726 in plasma, at least through 14 days. If the value of both measurements below 0.02 mg / l, is not expected any teratogenic risk.
The procedure of “laundering”
After stopping treatment with equipoise dosage:
- 8 g of cholestyramine administered three times a day for 11 days;
- Alternatively 50 g of charcoal, pulverized, administered 4 times a day for 11 days.
Regardless of the procedure “laundering” is necessary to inspect two separate tests at intervals of at least 14 days and to wait six weeks from the moment when the concentration of drug in plasma is first recorded below 0.02 mg / l, up to the moment of fertilization.
it is necessary to inform women of childbearing period that must elapse 2 years after stopping treatment with equipoise dosage, before they can try to get pregnant. If a 2-year waiting period under reliable contraception seems unreasonable, it may be advisable to conduct a “laundering” the procedure as a preventive measure.
And cholestyramine and activated charcoal may influence the absorption of oestrogens and progestogens, so reliable oral contraceptives do not provide an absolute guarantee in the period of “laundering “using cholestyramine or activated charcoal.
it is recommended to use alternative methods of contraception.
animal studies indicate that equipoise dosage or its metabolites pass into breast milk. Therefore, women who are breastfeeding should not take equipoise dosage.
Dosing and Administration
equipoise dosage treatment should start under the supervision of a physician who is experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.
With regard to recommendations for treatment for the control, see the section “Special instructions”.
equipoise dosage treatment begins with a single oral loading dose of 100 mg for 3 days. As maintenance dose for rheumatoid arthritis recommended intake of 10 mg to 20 mg of equipoise dosage once daily, psoriatic arthritis – 20 mg 1 time per day.
The therapeutic effect usually appears after 4 – 6 weeks, and can grow further to 4 – 6 months.
There are no recommendations regarding the dosage of the drug for patients suffering from renal insufficiency mild.
Do not require any dose adjustment for patients older than 65 years.
The drug should be administered by experts with the necessary experience in the treatment of rheumatoid arthritis.
The tablets must be swallowed whole, drinking plenty of fluids. Food intake has no effect on the absorption of equipoise dosage.
The classification of the intended frequency of side effects:
common = 1 – 10% of patients; atypical = 0.1 – 1% of patients; Rare = 0.01 – 0.1% of patients; very rare = 0.01% of patients or less.
- The cardiovascular system
- Common: mild increase in blood pressure.
Rare: marked increase in blood pressure
Very rare: vasculitis (due to the presence of underlying disease causal relationship to equipoise dosage intake could not be established).
- The gastrointestinal tract, liver,
- Common: diarrhea, nausea, vomiting, anorexia, oral mucosal disorders (eg, aphthous stomatitis, ulceration of the mouth), abdominal pain, increased activity of “liver” transaminases (especially ALT), less often – GGT and alkaline phosphatase, hyperbilirubinemia.
Rare: . hepatitis, jaundice / cholestasis
Very rare: severe liver injury such as liver failure, acute hepatic necrosis that may be fatal; pancreatitis.
- Respiratory system and mediastinal disorders
- Very rare: interstitial pulmonary process (including interstitial pneumonitis), which can be fatal.
- Metabolism and nutrition
- Common: weight loss, fatigue
- Nervous system
- Common: headache, dizziness, fatigue, paresthesia.
Atypical: taste disturbance, anxiety.
Very rare: peripheral neuropathy
- Locomotor apparatus
- Typical:. Tenosynovitis
Atypical: tendon rupture
- Leather and derivatives
- Common: increased hair loss, eczema, dry skin.
Very rare: erythema multiforme.
- Common: mild allergic reactions, rash (including maculopapular rash), pruritus.
Very rare: severe anaphylactic / anaphylactoid reactions, Stevens – Johnson syndrome, Lyell’s syndrome.
- Rare:. The development of serious infections, including opportunistic and sepsis, which can be fatal
may increase the number of possible infections (in particular, rhinitis, bronchitis and pneumonia).
- hematopoietic system and lymphatic system
- Typical:. Leukopenia (leukocytes> 2000 cells / mm)
Atypical: anemia, slight thrombocytopenia (platelets <100,000 / microliter).
Rare: eosinophilia, leukopenia (leukocytes <2000 / L), pancytopenia (presumably due to the antiproliferative effect)
Very rare : agranulocytosis.
Recent, concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of hematological effects.
The risk of cancer, especially lymphoproliferative diseases increases with the use of certain immunosuppressive agents.
There may be a slight hyperlipidemia. Uric acid levels usually decrease.
Laboratory data, the clinical significance of which is not established, are not clinically proven, include a small increase in the levels of lactate dehydrogenase and creatine kinase in the blood plasma. Atypical manifestation of hypophosphatemia is easy.
We can not exclude the possibility of a reversible decrease in sperm concentration, total sperm count and motility.
Symptoms. There have been reports of chronic overdose in patients treated with equipoise dosage at a dose up to 5 times the recommended daily dose, and reports of acute overdose in adults and children.
In most cases of overdose have been reported on the development of adverse events. Emerging adverse events were comparable to the safety profile of equipoise dosage. The most commonly observed adverse events were diarrhea, abdominal pain, leukopenia, anemia, and increase performance tests of functional liver condition. Treatment. In case of overdose or toxicity is recommended to take cholestyramine or activated charcoal, to accelerate the cleansing of the body. Kolestiramin received three healthy volunteers orally 8 g three times a day for 24 hours decreased the level of A771726 in plasma by about 40% at 24 hours and 49 – 65% after 48 hours. it was shown that the introduction of activated carbon (powder converted into a slurry) orally or gavage (50 g every 6 hours during the day) to reduce the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and 48% after 48 hours. These procedures are “laundering” can be repeated as clinically indicated. Studies with hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the main metabolite of equipoise dosage, is not able to be displayed by dialysis.
Interaction with other drugs, laboratory and diagnostic tests
Increased side effects may occur in case of recent or concomitant use of hepatotoxic (including alcohol) or gematotoksichnosti and immunosuppressive drugs or when taking these drugs is started after equipoise dosage treatment without a “laundering” procedure (see. “Special Instructions”).
In patients with rheumatoid arthritis do not was found no pharmacokinetic interaction between equipoise dosage (10 – 20 mg per day) and methotrexate. (10 – 25 mg per week)
Patients receiving equipoise dosage, it is recommended not to give colestyramine or active carbon, because it leads to rapid and substantial reduction A771726 concentration ( active metabolite of equipoise dosage) in the blood plasma. It is believed that this is due A771726 recirculation breach in the liver and small intestine and / or violation of its gastrointestinal dialysis.
If the patient is already taking non-steroidal antiinflammatory drugs (NSAIDs) and / or corticosteroids, they can continue to take after starting treatment with equipoise dosage.
Enzymes involved in the metabolism of equipoise dosage and its metabolites are not exactly known. In vivo studies of its interaction with cimetidine (non-specific inhibitor of cytochrome P450) showed no significant interaction. After concomitant administration of a single dose of equipoise dosage subjects who received multiple doses of rifampicin (non-specific inducer of cytochrome P450), A771726 peak levels increased by approximately 40%, whereas the area under the concentration-time curve is not significantly changed. The mechanism of this effect is not clear.
Studies in vitro have shown that A771726 inhibits cytochrome R4502S9 (CYP2C9). In clinical trials, there was not any problems with the co-administration of equipoise dosage and NSAIDs metabolized CYP2C9.Special care should be given equipoise dosage with other medications, non-NSAIDs metabolized by means of CYP2C9, such as phenytoin, warfarin and tolbutamide. Reported an increase in prothrombin time, while the appointment of equipoise dosage and warfarin.
In a study in which equipoise dosage was given to healthy volunteers female together with three-phase oral contraceptive containing 30 mcg ethinyl estradiol, no decrease of contraceptive effect of the tablets were found, and pharmacokinetics of A771726 completely fits within the specified range.
at the moment there is no information on the joint use of equipoise dosage with antimalarials used in rheumatology (eg chloroquine and gidroksihlorina), preparations of Au (V / m or orally), the D-penicillamine, azathioprine and other. immunosuppressive drugs ( except methotrexate). Unknown risks associated with carrying out a comprehensive therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) are undesirable. A recent concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of haematological effects. Immunosuppressive drugs increase the risk of infections and malignancies, especially lymphoproliferative disorders.
There are no clinical data on the efficacy and safety of vaccinations under equipoise dosage treatment. However, it is not recommended to be vaccinated with live vaccines. It is necessary to take into account the long half-life of the drug Arava when planning vaccination with live vaccine after the abolition of the drug Arava.
Arava can be administered to patients only after careful medical examination.
Before you start treatment with Arava should be aware of a possible increase in the number of side effects in patients previously treated with other basic facilities for the treatment of rheumatoid arthritis, which have a hepato-and haematological effects.
The active metabolite of equipoise dosage, A771726, It characterized by a long half-life, usually from 1 st to 4 weeks.
Because of the long half-life of the active metabolite of equipoise dosage, A771726, even when stopping treatment with equipoise dosage may arise or persist serious adverse effects (eg, hepatotoxicity, gematoksichnost or allergic reactions, see . below). In this case, carry out the procedure “laundering” .Protseduru can be repeated as clinically indicated. For suspected severe immunological / allergic reactions such as the syndrome of Stevens -. Johnson and toxic epidermal necrolysis holding full procedure “laundering” necessarily
So when similar cases, toxicity, or the transition to receiving another reference drug (eg, methotrexate) after treatment with equipoise dosage is necessary to carry out the procedure ” money “(see. below).
Since the active metabolite of equipoise dosage, A771726, bound to proteins and excreted by hepatic metabolism and secretion of bile, it is assumed that the level of A771726 in plasma may be increased in patients with hypoproteinemia. The drug Arava is contraindicated in patients with severe hypoproteinaemia or impairment of liver function. (see. section “Contraindications”.).
It was reported about rare cases of severe liver injury, in some cases fatal, in the treatment with equipoise dosage.
Most of these cases were observed within the first six months of treatment. Although not established a causal relationship between these adverse events with equipoise dosage, and in most cases there are several other suspicious factors, the exact implementation of the recommendations on the treatment for control is considered necessary.
The level of ALT should be checked before starting treatment with equipoise dosage, and then every 2 weeks for the first 6 months treatment, followed by a test once every 6-8nedel.
The following recommendations for the correction of a regimen of dosage or discontinuation of the drug, depending on the severity and persistence increased ALT.
When confirmed by 2-3 fold excess of the upper limit of normal ALT dose reduction from 20 mg to 10 mg per day can afford to continue receiving equipoise dosage with careful monitoring of this indicator.
If a 2-3 fold excess of the upper limit of normal ALT persists, or if there is a confirmed rise in ALT levels above the upper limit of normal in more than 3 times, taking equipoise dosage should be discontinued and should begin the process of “laundering”.
due to the possible additional hepatotoxic effects, it is recommended to abstain from alcohol during treatment with equipoise dosage.
Full blood count, including the determination of leukocyte and platelet counts should be performed prior to initiating treatment with equipoise dosage and every 2 weeks during the first 6 months of treatment and then every 6-8 weeks.
In patients with previously took place anemia , leukopenia and / or thrombocytopenia and patients with impaired bone marrow function or at risk of developing such disorders increases the risk of hematological disorders. If you have this kind of phenomena should be used “laundering” the procedure for reducing the level of A771726 in plasma.
In the case of severe haematological reactions, including pancytopenia, you must stop taking Arava medication and any other concomitant medication that suppresses bone marrow blood, and begin the process of “laundering” .
The combined use with other treatments
Currently, There are no data regarding the joint use of equipoise dosage with antimalarials used in rheumatology (eg chloroquine and hydroxychloroquine), administered by intramuscular injection or oral preparations of gold, D-penicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate). Not known risk associated with the appointment of combination therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematotoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) is not advisable.
Switching to other treatments
As equipoise dosage long stored in the body, the transition to receiving another reference drug (eg, methotrexate) without sootvetstvuyuschegoprovedeniya “laundering” the procedure may increase the possibility of additional risk, even long after the transition (for example, the kinetic interaction organotoksichnost).
Similarly, recent treatment of hepatotoxic or gematoksichnymi drugs (eg methotrexate) may result in an increase in the number of side effects, so starting equipoise dosage treatment, it is necessary to carefully consider all the positive and negative aspects associated with the intake of this drug.
In case of ulcerative stomatitis should stop taking equipoise dosage.
It was reported about rare cases of Syndrome Stevens – Johnson and toxic epidermal necrolysis in patients treated with equipoise dosage. In case of skin reactions and / or reactions on the part of the mucous membranes need to stop taking the drug Arava and any other associated preparation and immediately begin the process of “laundering”. It is necessary to achieve complete excretion of the drug. In such cases, the re-appointment of the drug is contraindicated.
is known that drugs like equipoise dosage and having immunosuppressive properties, making patients more susceptible to various infections, including opportunistic infections (infections caused by fungi and microorganisms capable of causing infection only in reducing immune). Arisen infections occur, usually hard and require early and intensive treatment. In the event of severe infection may need to interrupt equipoise dosage treatment and begin the process of “laundering”.
It is necessary to carefully monitor patients with a positive reaction to the tuberculin due to the risk of reactivation of tuberculosis.
The reactions of the respiratory tract
In the treatment with equipoise dosage were marked by rare cases of interstitial pulmonary process. Symptoms such as cough and dyspnoea may cause discontinuation of equipoise dosage.
before treatment with equipoise dosage and periodically after the start should be controlled blood pressure.
should be careful in the appointment of drugs metabolized by the action of CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs (non-steroidal anti-inflammatory drugs).
Advice for men
There are no data on the risk of fetotoxicity (related to the toxic effects of the drug on the father’s sperm) when using equipoise dosage men. The experimental data in this area have been conducted. To minimize the potential risk men when planning a baby must stop taking the use of equipoise dosage and colestyramine 8 g 3 times a day for 11 days or 50 g of pulverized activated carbon 4 times a day for 11 days.