A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Arava Side Effects, and Drug Interactions - Leflunomide
Arava Side Effects, and Drug Interactions - Leflunomide
SIDE EFFECTS
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 Table 8.)
|
Table 8. Percentage Of Patients With Adverse Events
³3% In Any Leflunomide Treated Group
|
| |
All RA Studies
|
Placebo-Controlled Trials
|
Active-Controlled Trials
|
| |
MN 301/3 and US 301
|
MN 302*
|
|
LEF
|
LEF
|
PBO
|
SSZ
|
MTX
|
LEF
|
MTX
|
|
(N=1339)1
|
(N=315)
|
(N=210)
|
(N=133)
|
(N=182)
|
(N=501)
|
(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
|
|
Hypertension2
|
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%
|
|
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 Loss3
|
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%
|
|
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%
|
|
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%
|
|
* Only 10% of patients in MN302 received folate. All
patients in US301 received folate; none in MN301 received folate.
|
|
1 Includes all controlled and uncontrolled trials with
leflunomide (duration up to 12 months).
|
|
2 Hypertension as a preexisting condition was overrepresented
in all leflunomide treatment groups in phase III trials.
|
|
3 In a meta-analysis of all phase II and III studies,
during the first 6 months in patients receiving leflunomide, 10% lost
10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs
(4 cases/100 patient years). Of patients receiving leflunomide, 4% lost
10% of their baseline weight during the first 6 months of treatment.
|
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.
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/mm3 (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;
Nervous system: peripheral neuropathy
Skin and Appendages: erythema multiforme, Stevens-Johnson
syndrome, toxic epidermal necrolysis.
DRUG ABUSE AND DEPENDENCE
ARAVA has no known potential for abuse or dependence.
DRUG INTERACTIONS
Cholestyramine and Charcoal
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 PRECAUTIONS
– General – Need for Drug Elimination). Hepatotoxic Drugs 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 ARAVA 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 CLINICAL
PHARMACOLOGY).
NSAIDs
In in vitro studies, M1 was shown to cause increases
ranging from 13 - 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.
Tolbutamide
In in vitro studies, M1 was shown to cause increases
ranging from 13 - 50% in the free fraction of tolbutamide at concentrations
in the clinical range. The clinical significance of this finding is unknown.
Rifampin
Following concomitant administration of a single dose of ARAVA
to subjects receiving multiple doses of rifampin, M1 peak levels were increased
(~40%) over those seen when ARAVA was given alone. Because of the potential
for ARAVA levels to continue to increase with multiple dosing, caution should
be used if patients are to be receiving both ARAVA and rifampin.
Warfarin
Increased INR (International Normalized Ratio) when ARAVA and
warfarin were co-administered has been rarely reported.
Pediatric Use
The safety and efficacy of ARAVA in the pediatric population
have not been studied. Use of ARAVA in patients less than 18 years of age is
not recommended.
Geriatric Use
No dosage adjustment is needed in patients over 65.
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