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Pronunciation |
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(le
FLU no
mide) |
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U.S. Brand
Names |
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Arava™ |
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Generic
Available |
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No |
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Pharmacological Index |
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Antimetabolite |
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Use |
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Treatment of active rheumatoid arthritis to reduce signs and symptoms and to
retard structural damage as evidenced by x-ray erosions and joint space
narrowing |
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Pregnancy Risk
Factor |
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X |
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Pregnancy/Breast-Feeding
Implications |
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Has been associated with teratogenic and embryolethal effects in animal
models at low doses. Leflunomide is contraindicated in pregnant women or women
of childbearing potential who are not using reliable contraception. Pregnancy
must be excluded prior to initiating treatment. Following treatment, pregnancy
should be avoided until the drug elimination procedure is completed.
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Contraindications |
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Pregnancy/breast-feeding; known hypersensitivity to leflunomide or any
component |
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Warnings/Precautions |
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Hepatic disease (including seropositive hepatitis B or C patients) may
increase risk of hepatotoxicity; immunosuppression may increase the risk of
lymphoproliferative disorders or other malignancies; women of childbearing
potential should not receive leflunomide until pregnancy has been excluded,
patients have been counseled concerning fetal risk and reliable contraceptive
measures have been confirmed. Caution in renal impairment. Not recommended for
patients with severe immune deficiency, bone marrow dysplasia or uncontrolled
infection. Has been associated with rare pancytopenia; use with caution in
patients with a prior history of significant hematologic abnormalities.
Discontinue if evidence of bone marrow suppression occurs, and begin procedure
for accelerated removal (cholestyramine and activated charcoal, see
Toxicology/Overdose). The use of live vaccines is not recommended. Leflunomide
will increase uric acid excretion. |
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Adverse
Reactions |
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>10%:
Gastrointestinal: Diarrhea (17%)
Respiratory: Respiratory tract infection (15%)
1% to 10%:
Cardiovascular: Hypertension (10%), chest pain (2%), palpitation,
tachycardia, vasculitis, vasodilation, varicose vein, edema (peripheral)
Central nervous system: Headache (7%), dizziness (4%), pain (2%), fever,
malaise, migraine, anxiety, depression, insomnia, sleep disorder
Dermatologic: Alopecia (10%), rash (10%), pruritus (4%), dry skin (2%),
eczema (2%), acne, dermatitis, hair discoloration, hematoma, herpes infection,
nail disorder, subcutaneous nodule, skin disorder/discoloration, skin ulcer,
bruising
Endocrine & metabolic: Hypokalemia (1%), diabetes mellitus,
hyperglycemia, hyperlipidemia, hyperthyroidism, menstrual disorder
Gastrointestinal: Nausea (9%), abdominal pain (5%), dyspepsia (5%), weight
loss (4%), anorexia (3%), gastroenteritis (3%), stomatitis (3%), vomiting (3%),
cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis,
gingivitis, melena, candidiasis (oral), enlarged salivary gland, tooth disorder,
xerostomia, taste disturbance
Genitourinary: Urinary tract infection (5%), albuminuria, cystitis, dysuria,
hematuria, vaginal candidiasis, prostate disorder, urinary frequency
Hematologic: Anemia
Hepatic: Abnormal LFTs (5%)
Neuromuscular & skeletal: Back pain (5%), joint disorder (4%), weakness
(3%), tenosynovitis (3%), synovitis (2%), arthralgia (1%), paresthesia (2%),
muscle cramps (1%), neck pain, pelvic pain, increased CPK, arthrosis, bursitis,
myalgia, bone necrosis, bone pain, tendon rupture, neuralgia, neuritis
Ocular: Blurred vision, cataract, conjunctivitis, eye disorder
Respiratory: Bronchitis (7%), cough (3%), pharyngitis (3%), pneumonia (2%),
rhinitis (2%), sinusitis (2%), asthma, dyspnea, epistaxis, lung disorder
Miscellaneous: Infection (4%), accidental injury (5%), allergic reactions
(2%), diaphoresis
<1%: Anaphylaxis, urticaria, eosinophilia, thrombocytopenia, leukopenia,
pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis
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Overdosage/Toxicology |
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There is no human experience with overdosage. Leflunomide is not dialyzable.
Cholestyramine and/or activated charcoal enhance elimination of leflunomide's
active metabolite (MI). In cases of significant overdose or toxicity,
cholestyramine 8 g every 8 hours for 1-3 days may be administered to enhance
elimination. Plasma levels are reduced by approximately 40% in 24 hours and 49%
to 65% after 48 hours of cholestyramine dosing. |
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Drug
Interactions |
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Cytochrome P-450 2C9 enzyme inhibitor
Decreased effect: Administration of cholestyramine and activated charcoal
enhance the elimination of leflunomide's active metabolite |
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Stability |
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Protect from light; store at 25°C
(77°F) |
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Mechanism of
Action |
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Inhibits pyrimidine synthesis, resulting in antiproliferative and
anti-inflammatory effects |
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Pharmacodynamics/Kinetics |
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Distribution: Vd: 0.13 L/kg
Metabolism: Hepatic, to A77 1726 (MI) which accounts for nearly all
pharmacologic activity; further metabolism to multiple inactive metabolites
Bioavailability: 80%
Half-life: Mean 14-15 days; enterohepatic recycling appears to contribute to
the long half-life of this agent, since activated charcoal and cholestyramine
substantially reduce plasma half-life
Time to peak: 6-12 hours
Elimination: Urine 43%; Feces 48% |
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Usual Dosage |
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Adults: Oral: Initial: 100 mg/day for 3 days, followed by 20 mg/day; dosage
may be decreased to 10 mg/day in patients who have difficulty tolerating the 20
mg dose. Due to the long half-life of the active metabolite, plasma levels may
require a prolonged period to decline after dosage reduction.
Dosing adjustment in renal impairment: No specific dosage adjustment
is recommended. There is no clinical experience in the use of leflunomide in
patients with renal impairment. The free fraction of MI is doubled in dialysis
patients. Patients should be monitored closely for adverse effects requiring
dosage adjustment.
Dosing adjustment in hepatic impairment: No specific dosage
adjustment is recommended. Since the liver is involved in metabolic activation
and subsequent metabolism/elimination of leflunomide, patients with hepatic
impairment should be monitored closely for adverse effects requiring dosage
adjustment.
Guidelines for dosage adjustment or discontinuation based on the severity and
persistence of ALT elevation secondary to leflunomide have been developed. For
ALT elevations >2 times the upper limit of normal, dosage reduction to 10
mg/day may allow continued administration. Cholestyramine 8 g 3 times/day for
1-3 days may be administered to decrease plasma levels. If elevations >2
times but less than or equal to 3 times the upper limit of normal persist, liver
biopsy is recommended. If elevations >3 times the upper limit of normal
persist despite cholestyramine administration and dosage reduction, leflunomide
should be discontinued and drug elimination should be enhanced with additional
cholestyramine as indicated.
Elderly: Although hepatic function may decline with age, no specific dosage
adjustment is recommended. Patients should be monitored closely for adverse
effects which may require dosage adjustment. |
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Dietary
Considerations |
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No interactions with food have been noted |
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Monitoring
Parameters |
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Serum transaminase determinations at baseline and monthly during the initial
phase of treatment; if stable, monitoring frequency may be decreased to
intervals determined by the individual clinical situation |
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Mental Health: Effects
on Mental Status |
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May cause dizziness, malaise, anxiety, depression, or
insomnia |
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Mental Health:
Effects on Psychiatric
Treatment |
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May rarely cause leukopenia, caution with clozapine and
carbamazepine |
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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |
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Dental Health:
Effects on Dental Treatment |
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1% to 10% of patients may experience stomatitis (3%), gingivitis, candidiasis
(oral), enlarged salivary gland, tooth disorder, dry mouth, and taste
disturbance |
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Patient
Information |
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Take as directed; do not increase dose without consulting prescriber.
Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict
fluid intake). Store medication away from light. You may experience diarrhea
(buttermilk, boiled milk, or yogurt may help); nausea, vomiting, loss of
appetite, and flatulence (small frequent meals, frequent mouth care, chewing
gum, or sucking lozenges may help); dizziness (use caution when driving or
engaging in tasks requiring alertness until response to drug is known). If
diabetic, monitor blood sugars closely; this medication may alter glucose
levels. Report chest pain, palpitations, rapid heartbeat, or swelling of
extremities; persistent gastrointestinal problems; skin rash, redness,
irritation, acne, ulcers, or easy bruising; frequency, painful or difficult
urination, or genital itching or irritation; depression, acute headache,
anxiety, or difficulty sleeping; weakness, muscle tremors, cramping or weakness,
back pain, or altered gait; cough, cold symptoms, wheezing, or difficulty
breathing; easy bruising/bleeding; blood in vomitus, stool, urine; or other
unusual effects related to this medication. Pregnancy/breast-feeding
precautions: Inform prescriber if you are pregnant. Do not get pregnant or
have sex unless using appropriate barrier contraception while on this
medication. This drug may cause severe fetal defects. Do not
breast-feed. |
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Dosage Forms |
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Tablet: 10 mg, 20 mg, 100 mg |
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References |
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Fox RI, "Mechanism of Action of Leflunomide in Rheumatoid Arthritis," J
Rheumatol, 1998, 53:20-6.
"New Drugs for Rheumatoid Arthritis," Med Lett Drugs Ther, 1998,
40(1040):110-2.
Popovic M, Stefanovic D, Pejnovic N, et al,
"Comparative Study of the Clinical Efficacy of Four DMARDs (Leflunomide, Methotrexate, Cyclosporine, and Levamisole) in Patients With Rheumatoid Arthritis,"
Trans Proc, 1998, 30(8):4135-6.
Rozman B, "Clinical Experience With Leflunomide in Rheumatoid Arthritis,"
J Rheumatol, 1998, 53:27-32.
Smolen JS, Kalden JR, Scott DL, et al,
"Efficacy and Safety of Leflunomide Compared With Placebo and Sulfasalazine in Active Rheumatoid Arthritis: A Double-Blind, Ramdomised, Multicentre Trial,"
Lancet, 1999, 353(9149):259-66.
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