Rhulef™

[Leflunomide]

Description / Properties

Rhulef™ (leflunomide) is a pyrimidines synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl) - 5-methylisoxazole- 4 -carboxamide, Rhulef™ is available for oral administration as tablets containing 10, 20mg & 100mg of active drug.

Indications

Rhulef™ is indicated in adults for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage as evidenced by X-ray erosions and joint space narrowing.

Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with Rhulef™ (see DRUG INTERACTION). The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine. azathioprine, or methotraxate has not been adequately studied.

Contraindication

Drug Interactions

Under construction

Side Effects

Adverse reactions associated with the use of leflunomide in RA include diarrhoea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies, the following adverse events (>3%) were reported, regardless of causality (1339 patients).

BODY AS A WHOLE
Allergic Reaction 2%, Asthenia 3%, 'Flu Syndrome 2%, Infection 4%, Injury Accident 5%, Pain 2%, Abdominal Pain 6%, Back Pain 5%.

CARDIOVASCULAR
Hypertension 10%, chest pain 2%.

GASTROINTESTINAL
Anorexia 3%, Diarrhea 17%, Dyspepsia 5%, Gastroenteritis 3%, Abnormal Liver Enzymes 5%, Nausea 9%, GI/Abdominal Pain 5%, Mouth Ulcer, 3% Vomiting 3%.

METABOLIC AND NUTRITIONAL
Hypokalemia 1%, Weight Loss 4%

MUSCULO-SKELETAL SYSTEM
Arthralgia 1%, Leg Cramps 1%, Joint Disorder 4%, Synovitis 2%, Tenosynovitis 3%.

NERVOUS SYSTEM
Dizziness 4%, Headache 7%, Paresthesia 2%.

RESPIRATORY SYSTEM
Bronchitis 7% Increased Cough 3%, Respiratory Infection 15%, Pharyngitis 3%, Pneumonia 2%, Rhinitis 2%, Sinusitis 2%.

SKIN AND APPENDAGES
Alopecia 10%, Eczema 2%, Pruritis 4%, Rash 10%, Dry Skin 2%.

UROGENITAL SYSTEM
Urinary Tract Infection 5%

In addition, the following adverse events have been reported in 1 % to <3% of the RA patients in the leflunomide treatment group in controlled clinical trials.

Body as a Whole: Abscess, Cyst, Fever, Hernia, Malaise, Pain, Neck pain, Pelvic pain;

Cardiovascular: Angina Pectoris, Migraine, Palpitation, Tachycardia, Varicose vein, Vasculitis, Vasodilatation,

Gastrointestinal: Cholelithiasis, Colitis, constipation, Esophagitis, Flatulence, Gastritis, Gingivitis, Melena. Oral Moniliasis, Pharyngitis, Salivary gland enlarged, Stomatitis (or aphthous stomatitis), Tooth disorder.

Endocrine: Diabetes mellitus, Hyperthyroidism;

Hemic and Lymphatic System: anemia (Including iron deficiency anemia) ecchymosis;

Metabolic and Nutritional: Creatinine phosphokinase increased, Hyperglycemia, Hyperlipidemia, Peripheral edema;

Musculo-Skeletal System: Arthrosis, Bone necrosis, Bone pain, Bursitis, Muscle Cramps, Myalgia, Tendon rupture

Nervous System: Anxiety, Depression, Dry mouth, Insomnia, Neuralgia. Neuritis, Sleep disorder, Increase Sweating. Vertigo,

Respiratory System: Asthma, Dyspnea, Epistaxis. Lung disorder;

Skin and Appendages: Acne, Contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster. maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;

Special Senses: blurred vision, cataract, conjuctivitis, eye disorder, taste perversion;

Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis. Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare): urticaria; eosinophilia; transient thrombocytopenia (rare): and leukopenia <2000 WBC/mm (rare). In postmarketing experience, rare cases of pancytopenia. Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported.

Warning and Precautions

Pregnancy must be excluded before the start of treatment with Rhulef™. Rhulef™ is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during Rhulef™ treatment or prior to the completion of the drug elimination procedure after Rhulef™ treatment.

lmmunosuppression Potential
Rhulef™ is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infections. There have been rare reports of pancytopenia in patients receiving leflunomide. In most of these cases, patients received concomitant treatment with methotrexate or other immunosuppressive agents, or they had recently discontinued these therapies; in some cases patients had a prior history of a significant haematologic abnormality. If Rhulef™ is used in such patients, it should be administered with caution and with frequent clinical and haematologic monitoring. The use of leflunomide in combination therapy with methotrexate has not been adequately studied in a controlled setting. If evidence of bone marrow suppression occurs in a patient taking RHULEF, treatment with Rhulef™ should be stopped and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite.

In any situation in which the decision is made to switch from Rhulef™ to another anti-rheumatic agent with a known potential for haematologic suppression, it would be prudent to monitor for haematologic toxicity, because there will be overlap of systemic exposure to both compounds. Rhulef™ washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to Rhulef™ treatment.

Skin Reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide. If a patient taking Rhulef™ develops any of these conditions, Rhulef™ therapy should be stopped and a drug' elimination procedure is recommended.

Hepatotoxicity In clinical trials, leflunomide treatment was associated with elevations of liver enzymes primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment.

At minimum, ALT (SGPT) should be performed at baseline and monitored initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation.

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows. For confirmed ALT elevations >2-fold ULN, dose reduction to 10 mg/day may allow continued administration of RHULEF. If elevations >2 but 3-fold ULN persist despite dose reduction, liver biopsy is recommended if continued treatment is desired. It elevations >3-fold ULN persist despite dose reduction. Rhulef™ should be discontinued and cholestyramine should be administered with dose monitoring including re-treatment with cholestyramine as indicated. Rare elevations of alkaline phosphatase and bilirubin have been observed.

Pre-existing Hepatic Disease
Given the possible risk of increased hepatotoxicity and the role of the liver in drug activation elimination and recycling, the use of Rhulef™ is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses.

Malignancy
The risk of malignancy particularly lymphoproliferative disorders is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with leflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide.

Use in Women of Childbearing Potential
There are no adequate and well-controlled studies evaluating leflunomide in pregnant women. However based on animal studies leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman. Women of childbearing potential must not be started on Rhulef™ until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with RHULEF, patients must be fully counselled on the potential risk or serious risk to the foetus.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the foetus from RHULEF.

Upon discontinuing RHULEF, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving Rhulef™ treatment who wish to become pregnant must discontinue Rhulef™ and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 痢/mL by two tests at least 14 days apart. If plasma levels are higher than 0.02 痢/mL, additional cholestyramine treatment should be considered.

Dosage

Loading Dose
Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that Rhulef™ therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days.

Maintenance Therapy
Daily dosing of 20 mg is recommended for treatment of patients with RA. Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Liver enzymes should be monitored and dose adjustments -may be necessary (see WARNING: (Hepatotoxicity). Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline.

Presentations Available

Rhulef™ tablet 10mg: Each film coated tablet contains Leflunomide U.S.P .... 10mg

Rhulef™ tablet 20mg: Each film coated tablet contains Leflunomide U.S.P .... 20mg

Rhulef™ tablet 100mg: Each film coated tablet contains Leflunomide U.S.P .... 100mg

MORE PRODUCTS >