Get emergency medical help if you have signs of an allergic reaction to Leflumine: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have:
fever, swollen glands, body aches, flu symptoms;
pale skin, easy bruising or bleeding;
numbness, tingling, or burning pain in your hands or feet;
upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes);
new or worsening cough with fever, trouble breathing; or
severe skin reactionGadavistfever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.
Common Leflumine side effects may include:
nausea, upset stomach;
abnormal liver function tests;
cold symptoms such as stuffy nose, sneezing, sore throat;
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Side effects of Leflumine in details
A side effect of any drug can be defined as the unwanted or undesired effect produced by the drug. The side effect can be major or in few medications minor that can be ignored. Side effects not only vary from drug to drug, but it also depends on the dose of the drug, the individual sensitivity of the person, brand or company which manufactures it. If side effects overweigh the actual effect of the medicine, it may be difficult to convince the patient to take the drug. Few patients get specific side effects to specific drugs; in that case, a doctor replaces the drug with another. If you feel any side effect and it troubles you, do not forget to share with your healthcare practitioner.
The following serious adverse reactions are described elsewhere in the labeling:
Bone marrow suppression
Stevens-Johnson syndrome and toxic epidermal necrolysis
Interstitial lung disease
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with Leflumine administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.
Elevation of Liver Enzymes
Treatment with Leflumine 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. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
Table 1: Liver Enzyme Elevations > 3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3**
Leflumine 20 mg/day
MTX 7.5 - 15 mg/wk
SSZ 2.0 g/day
Leflumine 20 mg/day
MTX 7.5 - 15 mg/wk
ALT (SGPT) > 3-fold ULN (n %)
Reversed to ≤ 2-fold ULN:
Timing of Elevation
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal
*Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate.
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, Leflumine was administered 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.
Most Common Adverse Reactions
The most common adverse reactions in Leflumine-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year ( ≥ 5% in any Leflumine treatment group).
Table 2: Percentage Of Patients With Adverse Events ≥ 5% In Any Leflumine Treated Group in all RA Studies in Patients with RA
All RA Studies
Trial 1 and 2
Trial 3 Hypertension as a preexisting condition was overrepresented in all Leflumine treatment groups in phase III trials
Adverse events during a second year of treatment with Leflumine in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
Less Common Adverse Reactions
In addition, in controlled clinical trials, the following adverse events in the Leflumine treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug.
Blood and Lymphatic System: leukocytosis, thrombocytopenia;
Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein;
The following additional adverse reactions have been identified during postapproval use of Leflumine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;
Infection: opportunistic infections, severe infections including sepsis;
Gastrointestinal: acute hepatic necrosis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure
Immune System: angioedema;
Nervous system: peripheral neuropathy;
Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.
What is the most important information I should know about Leflumine?
Leflumine may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Leflumine with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
Drinking alcohol while you are taking Leflumine may increase the risk of liver problems. Talk with your doctor before drinking alcohol while taking Leflumine.
Leflumine may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.
Leflumine may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.
Do not receive a live vaccine (eg, measles, mumps) while you are taking Leflumine. Talk with your doctor before you receive any vaccine.
The safety of Leflumine in patients with inactive TB has not been confirmed. You may need to have a TB skin test before you start Leflumine to determine if you have TB infection. Discuss any questions or concerns with your doctor.
Serious and sometimes fatal liver problems have been reported with Leflumine. Contact your doctor right away if you develop symptoms such as dark urine, pale stools, yellowing of the skin or eyes, stomach pain, severe or persistent nausea or loss of appetite, or unusual tiredness.
A serious and sometimes fatal lung problem (interstitial lung disease) has been reported with Leflumine. Contact your doctor right away if you develop new or worsening breathing problems, such as cough or shortness of breath (with or without fever).
Serious and sometimes fatal skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been rarely reported with Leflumine. Contact your doctor right away if you develop a rash; red, swollen, blistered, or peeling skin; or blisters on the inside of the eyes, nose, or mouth.
Lab tests, including liver function, blood pressure, and complete blood cell counts, may be performed to monitor your progress or check for side effects. Be sure to keep all doctor and lab appointments.
Use Leflumine with caution in the ELDERLY; they may be more likely to develop burning, numbness, or tingling.
Leflumine may remain in the body for 2 years or longer after you stop taking it. Your doctor may prescribe medicine to help remove Leflumine from your body more quickly after you finish treatment (drug elimination procedure). Talk with your doctor for more information.
The risk of harm or death to a fetus fathered by a man using Leflumine is not known. Men who take Leflumine should talk with their doctor about the need to use a condom when having sex with a woman who may become pregnant. If you wish to father a child, talk with your doctor. You may need to stop Leflumine and complete the drug elimination procedure to remove it from your blood before you father a child.
If you are able to become pregnant, you must not start Leflumine unless it has been confirmed that you are not pregnant. You will need to use an effective form of birth control while you take Leflumine and for as long as Leflumine remains in your body. If you plan to become pregnant, talk with your doctor about stopping Leflumine and completing the drug elimination procedure before you become pregnant. Talk with your doctor for more information or if you have questions about effective birth control.
PREGNANCY and BREAST-FEEDING: Do not use Leflumine if you are pregnant. It may cause birth defects or fetal death. You must have a negative pregnancy test before you start treatment with Leflumine. Do not become pregnant while you are taking it. Contact your doctor at once if your period does not occur when expected or if you suspect that you are pregnant. It is not known if Leflumine is found in breast milk. Do not breast-feed while taking Leflumine.
Contraindication can be described as a special circumstance or a disease or a condition wherein you are not supposed to use the drug or undergo particular treatment as it can harm the patient; at times, it can be dangerous and life threatening as well. When a procedure should not be combined with other procedure or when a medicine cannot be taken with another medicine, it is called Relative contraindication. Contraindications should be taken seriously as they are based on the relative clinical experience of health care providers or from proven research findings.
Patients with hypersensitivity to Leflumine or to any of the excipients of Leflumine.
Severe deficiency of the immune system (eg, AIDS); significant impairment of the bone marrow function or a marked decrease in the number of red or white blood cells (anemia or leukopenia/neutropenia) or of platelets (thrombocytopenia), due to causes other than rheumatoid or psoriatic arthritis; serious infections; liver function impairment; severe excessive reduction in blood protein concentration (hypoproteinemia due eg, to a renal disease (nephrotic syndrome); moderate to severe renal insufficiency, since available clinical experience is insufficient.
Use in pregnancy & lactation: Pregnancy must be excluded before the start of treatment with Leflumine in pregnant women or in women of childbearing potential who do not use reliable contraception. This applies during treatment and after treatment discontinuation, as long as the plasma levels of the active metabolite are >0.02 mg/L. Pregnancy must be excluded before the start of treatment with Leflumine.
Sufficient elimination of the metabolite from the body prior to pregnancy is essential to avoid the risk of malformation in the infant. Therefore, women wishing to become pregnant who are taking Leflumine (or have taken it within the previous 2 years) must first speak with their physician, who may advise, as a follow-up measure to the discontinuation of Leflumine, either implementing the elimination procedure (for 11 days) or waiting until 2 full years have elapsed.
If there is any delay in onset of the period or any other reason to suspect pregnancy, the physician must be notified immediately and pregnancy testing carried out. If positive, the risk to the pregnancy must be discussed. Carrying out the elimination procedure at the 1st delay of the period may decrease the risk to the fetus from Leflumine.
Based on available information, the risk of malformations in newborn infants of men taking Leflumine cannot be excluded. Men should be aware of such a risk and should not take Leflumine without using reliable contraceptive measures. To minimize any possible risk, men wishing to father a child should contact their physician, who may advise that intake of Leflumine be discontinued and the previously mentioned elimination procedure be carried out for 11 days.
In both sexes, sufficient elimination of active metabolite should subsequently be confirmed by 2 separate blood laboratory tests, the first to be carried out after conclusion of the elimination procedure (or alternatively in the case of women, 2 years after discontinuation), and the second at least 14 days later. If both test values of active metabolite are <0.02 mg/L in blood plasma, the risk of malformation is very low.
Leflumine or its metabolites may pass into breast milk. Breastfeeding women must, therefore, not receive Leflumine.
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European Chemicals Agency - ECHA. "5-Methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide: The information provided here is aggregated from the "Notified classification and labelling" from ECHA's C&L Inventory. ". https://echa.europa.eu/information-o... (accessed September 17, 2018).
The results of a survey conducted on ndrugs.com for Leflumine 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 Leflumine. 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.
Consumer reported side effects
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