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Leflunomide
Overview
What is Leflunomide?
Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4’-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula CHFNO, a molecular weight of 270.2 and the following structural formula:
Each leflunomide tablet, for oral administration, contains 10 mg or 20 mg of leflunomide. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, and titanium dioxide.
What does Leflunomide look like?
What are the available doses of Leflunomide?
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What should I talk to my health care provider before I take Leflunomide?
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How should I use Leflunomide?
Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA):
Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with leflunomide (see
). The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied (see ).
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 leflunomide therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days.
Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past. (See ).
What interacts with Leflunomide?
Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide.
Leflunomide can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits.
When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.
Leflunomide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
What are the warnings of Leflunomide?
Immunosuppression Potential/Bone Marrow Suppression
Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal (see
). Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide, especially pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.
There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.
Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see
).
In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment.
Hepatotoxicity
RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH LEFLUNOMIDE. MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins). (See .)
At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly.
Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of leflunomide under close monitoring. If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, leflunomide should be discontinued and cholestyramine or charcoal should be administered (see
) with close monitoring, including retreatment with cholestyramine or charcoal as indicated.
In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate 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. shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added.
| US301 | MN301 | MN302 | ||||||
| LEF | PL | MTX | LEF | PL | SSZ | LEF | MTX | |
| ALT (SGPT) | ||||||||
| >3-fold ULN | 8 | 3 | 5 | 2 | 1 | 2 | 13 | 83 |
| (n %) | (4.4) | (2.5) | (2.7) | (1.5) | (1.1) | (1.5) | (2.6) | (16.7) |
| Reversed to | 8 | 3 | 5 | 2 | 1 | 2 | 12 | 82 |
| Timing of | ||||||||
| 0-3 Months | 6 | 1 | 1 | 2 | 1 | 2 | 7 | 27 |
| 4-6 Months | 1 | 1 | 3 | – | – | – | 1 | 34 |
| 7-9 Months | 1 | 1 | 1 | – | – | – | – | 16 |
| 10-12 Months | – | – | – | – | – | – | 5 | 6 |
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 leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses. (See ).
Skin Reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, leflunomide therapy should be stopped, and a drug elimination procedure is recommended (see ).
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 (see ). Women of childbearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with leflunomide, patients must be fully counseled on the potential for serious risk to the fetus.
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 fetus from leflunomide.
Upon discontinuing leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 mcg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk based on available animal data.
Drug Elimination Procedure
The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mcg/mL) after stopping treatment with leflunomide:
Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.
What are the precautions of Leflunomide?
General
The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from leflunomide, including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping leflunomide therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient.
Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours.
Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, M1, by 37% in 24 hours and by 48% in 48 hours.
These drug elimination procedures may be repeated if clinically necessary.
Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes (see ). Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the drug is necessary, initiation of wash-out procedures should be considered (see ).
Prior to initiating immunomodulatory therapies, including leflunomide, patients should be screened for latent tuberculosis infection with a tuberculin skin test. Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide.
Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of leflunomide in patients with renal impairment. Caution should be used when administering this drug in this population.
No clinical data are available on the efficacy and safety of vaccinations during leflunomide treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of leflunomide should be considered when contemplating administration of a live vaccine after stopping leflunomide.
Blood pressure should be checked before start of leflunomide treatment and periodically thereafter.
Information for Patients
Laboratory Tests
At minimum, patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter.
If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly. (See .)
ALT (SGPT) must be performed at baseline and monitored at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. (See .)
Due to a specific effect on the brush border of the renal proximal tubule, leflunomide has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients. These effects have not been seen together, nor have there been alterations in renal function.
Drug Interactions
Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration (see ).
Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of leflunomide with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A >3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met “ACR criteria” for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified (see ).
In studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.
In studies, M1 was shown to cause increases ranging from 13 to 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown.
Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~ 40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin.
Increased INR (International Normalized Ratio) when leflunomide and warfarin were co-administered has been rarely reported.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of leflunomide is not known.
Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the Mouse Micronucleus Assay nor in the Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the Mouse Micronucleus Assay nor in the Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC).
Pregnancy
(See section.)
Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972.
Nursing Mothers
Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with leflunomide, taking into account the importance of the drug to the mother.
Use in Males
Available information does not suggest that leflunomide would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 grams 3 times daily for 11 days.
Pediatric Use
The safety and effectiveness of leflunomide in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated. (See and ).
Geriatric Use
Of the total number of subjects in controlled clinical (Phase III) studies of leflunomide, 234 subjects were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65.
What are the side effects of Leflunomide?
Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See .)
Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
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.
| All RA Studies | Placebo-Controlled Trials | Active-Controlled Trials | |||||
| LEF | (N=1339) | MN 301 and US 301 | MN 302 | ||||
| LEF (N=315) | PBO (N=210) | SSZ (N=133) | MTX (N=182) | LEF (N=501) | MTX (N=498) | ||
| BODY AS A WHOLE | |||||||
| Allergic Reaction | 2% | 5% | 2% | 0% | 6% | 1% | 2% |
| Asthenia | 3% | 6% | 4% | 5% | 6% | 3% | 3% |
| Flu Syndrome | 2% | 4% | 2% | 0% | 7% | 0% | 0% |
| Infection, upper respiratory | 4% | 0% | 0% | 0% | 0% | 0% | 0% |
| Injury Accident | 5% | 7% | 5% | 3% | 11% | 6% | 7% |
| Pain | 2% | 4% | 2% | 2% | 5% | 1% | <1% |
| Abdominal Pain | 6% | 5% | 4% | 4% | 8% | 6% | 4% |
| Back Pain | 5% | 6% | 3% | 4% | 9% | 8% | 7% |
| CARDIOVASCULAR | |||||||
| Hypertension | 10% | 9% | 4% | 4% | 3% | 10% | 4% |
| New onset of hypertension | 1% | <1% | 0% | 2% | 2% | <1% | |
| Chest Pain | 2% | 4% | 2% | 2% | 4% | 1% | 2% |
| All RA Studies | Placebo-Controlled Trials | Active-Controlled Trials | |||||
| LEF | (N=1339) | MN 301 and US 301 | MN 302 | ||||
| LEF (N=315) | PBO (N=210) | SSZ (N=133) | MTX (N=182) | LEF (N=501) | MTX (N=498) | ||
| GASTROINTESTINAL | |||||||
| Anorexia | 3% | 3% | 2% | 5% | 2% | 3% | 3% |
| Diarrhea | 17% | 27% | 12% | 10% | 20% | 22% | 10% |
| Dyspepsia | 5% | 10% | 10% | 9% | 13% | 6% | 7% |
| Gastroenteritis | 3% | 1% | 1% | 0% | 6% | 3% | 3% |
| Abnormal Liver Enzymes | 5% | 10% | 2% | 4% | 10% | 6% | 17% |
| Nausea | 9% | 13% | 11% | 19% | 18% | 13% | 18% |
| GI/Abdominal Pain | 5% | 6% | 4% | 7% | 8% | 8% | 8% |
| Mouth Ulcer | 3% | 5% | 4% | 3% | 10% | 3% | 6% |
| Vomiting | 3% | 5% | 4% | 4% | 3% | 3% | 3% |
| METABOLIC AND NUTRITIONAL | |||||||
| Hypokalemia | 1% | 3% | 1% | 1% | 1% | 1% | <1% |
| Weight Loss | 4% | 2% | 1% | 2% | 0% | 2% | 2% |
| MUSCULO-SKELETAL SYSTEM | |||||||
| Arthralgia | 1% | 4% | 3% | 0% | 9% | <1% | 1% |
| Leg Cramps | 1% | 4% | 2% | 2% | 6% | 0% | 0% |
| Joint Disorder | 4% | 2% | 2% | 2% | 2% | 8% | 6% |
| All RA Studies | Placebo-Controlled Trials | Active-Controlled Trials | |||||
| LEF | (N=1339) | MN 301 and US 301 | MN 302 | ||||
| LEF (N=315) | PBO (N=210) | SSZ (N=133) | MTX (N=182) | LEF (N=501) | MTX (N=498) | ||
| MUSCULO-SKELETAL SYSTEM | |||||||
| Synovitis | 2% | <1% | 1% | 0% | 2% | 4% | 2% |
| Tenosynovitis | 3% | 2% | 0% | 1% | 2% | 5% | 1% |
| NERVOUS SYSTEM | |||||||
| Dizziness | 4% | 5% | 3% | 6% | 5% | 7% | 6% |
| Headache | 7% | 13% | 11% | 12% | 21% | 10% | 8% |
| Paresthesia | 2% | 3% | 1% | 1% | 2% | 4% | 3% |
| RESPIRATORY SYSTEM | |||||||
| Bronchitis | 7% | 5% | 2% | 4% | 7% | 8% | 7% |
| Increased Cough | 3% | 4% | 5% | 3% | 6% | 5% | 7% |
| Respiratory Infection | 15% | 21% | 21% | 20% | 32% | 27% | 25% |
| Pharyngitis | 3% | 2% | 1% | 2% | 1% | 3% | 3% |
| Pneumonia | 2% | 3% | 0% | 0% | 1% | 2% | 2% |
| Rhinitis | 2% | 5% | 2% | 4% | 3% | 2% | 2% |
| Sinusitis | 2% | 5% | 5% | 0% | 10% | 1% | 1% |
| All RA Studies | Placebo-Controlled Trials | Active-Controlled Trials | |||||
| LEF | (N=1339) | MN 301 and US 301 | MN 302 | ||||
| LEF (N=315) | PBO (N=210) | SSZ (N=133) | MTX (N=182) | LEF (N=501) | MTX (N=498) | ||
| SKIN AND APPENDAGES | |||||||
| Alopecia | 10% | 9% | 1% | 6% | 6% | 17% | 10% |
| Eczema | 2% | 1% | 1% | 1% | 1% | 3% | 2% |
| Pruritus | 4% | 5% | 2% | 3% | 2% | 6% | 2% |
| Rash | 10% | 12% | 7% | 11% | 9% | 11% | 10% |
| Dry Skin | 2% | 3% | 2% | 2% | 0% | 3% | 1% |
| UROGENITAL SYSTEM | |||||||
| Urinary Tract Infection | 5% | 5% | 7% | 4% | 2% | 5% | 6% |
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
creatine 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, sweating increased, 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, conjunctivitis, 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).
Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
In post-marketing experience, the following have been reported rarely:
Body as a Whole
opportunistic infections, severe infections including sepsis that may be fatal;
Gastrointestinal
pancreatitis;
Hematologic
agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;
Hypersensitivity
angioedema;
Hepatic
hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal;
Respiratory
interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;
Nervous System
peripheral neuropathy;
Skin and Appendages
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis.
Adverse Reactions (Pediatric Patients)
The safety of leflunomide was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2- and 3-fold the upper limit of normal, five between 3- and 8-fold the upper limit of normal.
What should I look out for while using Leflunomide?
Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide.
Leflunomide can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits.
When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.
Leflunomide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
What might happen if I take too much Leflunomide?
In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200 to 500 mg/kg and 100 mg/kg, respectively (approximately >350 times the maximum recommended human dose, respectively).
There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults or children. There were no adverse events reported in the majority of case reports of overdose. Adverse events were consistent with the safety profile for leflunomide (see ). The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.
In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination (see
).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable (see ).
How should I store and handle Leflunomide?
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Leflunomide tablets, 10 mg are white, round, film-coated tablets, debossed GG on one side and 993 on the reverse side and are supplied as follows:Leflunomide tablets, 20 mg are white, round, film-coated tablets, debossed GG on one side and 994 on the reverse side and are supplied as follows:Leflunomide tablets, 10 mg are white, round, film-coated tablets, debossed GG on one side and 993 on the reverse side and are supplied as follows:Leflunomide tablets, 20 mg are white, round, film-coated tablets, debossed GG on one side and 994 on the reverse side and are supplied as follows:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several and experimental models have demonstrated an anti-inflammatory effect.
Non-Clinical Toxicology
Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide.Leflunomide can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits.
When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.
Leflunomide is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See .)
Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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