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Actions of Avara-Arava in details
The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
Pharmacology: Mechanism of Action: Avara-Arava is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Pharmacokinetics: Following oral administration, Avara-Arava is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of Avara-Arava are occasionally seen at very low levels.
Absorption: Following oral administration, peak levels of the active metabolite, M1, occurred between 6-12 hrs after dosing. Due to the very long half-life of M1 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly 2 months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.
Relative to an oral solution, Avara-Arava tablets are 80% bioavailable. Co-administration of Avara-Arava tablets with a high-fat meal did not have a significant impact on M1 plasma levels.
Distribution: M1 has a low volume of distribution (Vss= 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein-binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.
Metabolism: Avara-Arava is metabolized to 1 primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occuring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time, the specific site of Avara-Arava metabolism is unknown. In vivo and in vitro studies suggest a role for both the gastrointestinal wall and the liver in the drug metabolism. No specific enzyme has been identified as the primary route of metabolism of Avara-Arava; however, hepatic cytosolic acid and microsomal cellular fractions have been identified as sites of drug metabolism.
Elimination: The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28-day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces.
Special Populations: Age and Gender: Neither age nor gender has been shown to cause a consistent change in the in vivo pharmacokinetics of M1.
Smoking: A population-based pharmacokinetic analysis of the phase III data indicated that smokers had a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Chronic Renal Impairment: In single-dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of Avara-Arava use in subjects with renal insufficiency, caution should be used when Avara-Arava is administered to these patients.
Hepatic Impairment: Studies of the effects of hepatic impairment on M1 pharmacokinetics have not been done. Given the need to metabolized Avara-Arava into the active species, the role of the liver in drug elimination/recycling and the possible risk of increased hepatic toxicity, the use of Avara-Arava in patients with hepatic insufficiency is not recommended.
How should I take Avara-Arava?
Take Avara-Arava exactly as prescribed by your doctor. Before you start treatment with Avara-Arava, your doctor may perform tests to make sure you do not have tuberculosis or other infections.
Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.
Your blood pressure will need to be checked often.
Avara-Arava can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your treatment may be stopped for a short time based on the results of these tests.
After you stop taking Avara-Arava, you may need to be treated with other medicines to help your body eliminate Avara-Arava quickly. If you do not undergo this drug elimination procedure, Avara-Arava could stay in your body for up to 2 years. Follow your doctor's instructions.
You will also need to go through this drug elimination procedure if you plan to become pregnant after you stop taking Avara-Arava.
Arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.
Store at room temperature away from moisture, heat, and light.
Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Before you start taking Avara-Arava, you may need a skin test to make sure you do not have tuberculosis.
Your doctor may occasionally change your dose to make sure you get the best results.
Avara-Arava can lower blood cells that help your body fight infections. This can make it easier for you to get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.
After you stop taking Avara-Arava, you may need to be treated with other medications to help your body eliminate Avara-Arava quickly. Without receiving this drug elimination procedure, Avara-Arava could stay in your body for up to 2 years. Follow your doctor's instructions.
Rheumatoid arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.
Store at room temperature away from moisture, heat, and light.
Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
Mechanism Of Action
Avara-Arava is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Following oral administration, Avara-Arava is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Avara-Arava's in vivo activity. Plasma concentrations of the parent drug, Avara-Arava, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of Avara-Arava have primarily examined the plasma concentrations of the active metabolite, teriflunomide.
Following oral administration, peak teriflunomide concentrations occurred between 6 - 12 hours after dosing. Due to the very long half-life of teriflunomide (18-19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.
Effect of Food
Co-administration of Avara-Arava tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
Teriflunomide is extensively bound to plasma protein ( > 99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
Teriflunomide, the active metabolite of Avara-Arava, has a median half-life of 18-19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, due to individual variation in drug clearance. After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in Avara-Arava metabolism. In vivo, Avara-Arava is metabolized to one primary (teriflunomide) and many minor metabolites. In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely detectable in plasma.
Teriflunomide, the active metabolite of Avara-Arava, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.
Gender. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.
Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.
Drug Interaction Studies
Drug interaction studies have been conducted with both Avara-Arava (Avara-Arava) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
The Potential Effect of Other Drugs on Avara-Arava
The Potential Effect of Avara-Arava on Other Drugs
The efficacy of Avara-Arava in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. In these trials, efficacy was evaluated by:
Reduction of Signs And Symptoms
Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An “ACR20 Responder” is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An “ACR20 Responder at Endpoint” is a patient who completed the study and was an ACR20 Responder at the completion of the study.
Inhibition of Structural Damage
Inhibition of structural damage compared to control was assessed using the Sharp Score, a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.
Improvement In Physical Function
Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).
In all Avara-Arava trials, participants of at least 18 years of age and in ARA functional class of I, II or III received an initial loading dosage of 100 mg Avara-Arava per day for three days, followed by 20 mg per day thereafter.
Exclusion criteria included patients with a history of hypersensitivity to the study medication; women who were pregnant or breast feeding and men or women of child bearing age and potential who had not received contraceptives for at least 4 weeks before entering the study and to be maintained throughout the study and for at least 6 months after discontinuing treatment; Patients with a history of inflammatory disease, impaired renal function or liver impairment, cardiac failure, congenital or acquired immunodeficiency, impaired coagulation, or a history of recent major traumatic injury; patients taking intra-articular or systemic concomitant medications which could affect the safety and/or efficacy of the study medication.
Trial 1, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to Avara-Arava 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. The primary analysis was at 52 weeks with blinded treatment to 104 weeks.
Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 Avara-Arava, 101 methotrexate, 36 placebo). Avara-Arava dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 Avara-Arava, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.
Trial 2 randomized 358 patients with active RA to Avara-Arava 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of Trial 2 without the placebo arm, resulting in a 12-month comparison of Avara-Arava and sulfasalazine.
Of the 168 patients who completed 12 months of treatment, 146 patients (87%) entered a 1-year extension study of double blind active treatment; (60 Avara-Arava, 60 sulfasalazine, 26 placebo/ sulfasalazine). Patients continued on the same daily dosage of Avara-Arava or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 Avara-Arava, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.
Trial 3 randomized 999 patients with active RA to Avara-Arava 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.
Of the 736 patients who completed 52 weeks of treatment in study Trial 3, 612 (83%) entered the double-blind, 1-year extension study (292 Avara-Arava, 320 methotrexate). Patients continued on the same daily dosage of Avara-Arava or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 Avara-Arava, 277 methotrexate) who completed 2 years of double-blind treatment.
Clinical Trial Results
The ACR20 Responder at Endpoint rates are shown in Figure 1. Avara-Arava was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study Trial 1 (at the primary 12 months endpoint) and Trial 2 (at 6 month endpoint). ACR20 Responder at Endpoint rates with Avara-Arava treatment were consistent across the 6 and 12 month studies (41 - 49%). No consistent differences were demonstrated between Avara-Arava and methotrexate or between Avara-Arava and sulfasalazine. Avara-Arava treatment effect was evident by 1 month, stabilized by 3 - 6 months, and continued throughout the course of treatment as shown in Figure 1.
Figure 1: Percentage of ACR20 Responders at Endpoint in Patients with Active RA in Trials 1, 2, and 3
Figure 2: ACR20 Responders over Time in Patients with Active RA in Trial 1*
ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 3). Mean change for the individual components of the ACR Responder Index are shown in Table 4.
Table 3: Summary of ACR Response Rates in Patients with Active RA in Trials 1,2, and 3*
Physical Function Response
The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. Avara-Arava was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.
The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In Trial 1, at 12 months, Avara-Arava provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.
Figure 4: Change in Functional Ability Measure in Patients with Active RA in Trials 1, 2, and 3*
Maintenance of effect
The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.
ReviewsThe results of a survey conducted on ndrugs.com for Avara-Arava are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Avara-Arava. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.
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Information checked by Dr. Sachin Kumar, MD Pharmacology