LEFLUNOMIDE (Page 3 of 7)

5.9 Vaccinations

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 the active metabolite of leflunomide should be considered when contemplating administration of a live vaccine after stopping leflunomide.

5.10 Blood Pressure Monitoring

In placebo-controlled studies with the active metabolite of leflunomide, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with leflunomide and monitored periodically thereafter [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

  • Hepatotoxicity [see Warnings and Precautions (5.2)]
  • Immunosuppression [see Warnings and Precautions (5.4)]
  • Bone marrow suppression [see Warnings and Precautions (5.4)]
  • Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5)]
  • Peripheral neuropathy [see Warnings and Precautions (5.7)]
  • Interstitial lung disease [see Warnings and Precautions (5.8)]

6.1 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 leflunomide 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 EnzymesTreatment with leflunomide 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**

Trial 1 Trial 2 Trial 3*
Leflunomide20 mg/day(n= 182) PL(n=118) MTX 7.5 – 15 mg/wk (n=182) Leflunomide 20mg/day (n=133) PL(n=92) SSZ 2.0 g/day (n=133) Leflunomide 20 mg/day (n=501) MTX 7.5 – 15 mg/wk (n=498)
ALT (SGPT)>3-fold ULN (n%)Reversed to ≤ 2-fold ULN: 8(4.4) 8 3(2.5) 3 5(2.7) 5 2(1.5) 2 1(1.1) 1 2(1.5) 2 13(2.6) 12 83 (16.7)82
Timing of Elevation 6 1 1 2 1 2 7 27
0-3 Months
4-6 Months 1 1 3 1 34
7-9 Months 1 1 1 16
10-12 Months 5 6

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, leflunomide 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 leflunomide-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 leflunomide treatment group).

Table 2. Percentage Of Patients With Adverse Events ≥5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA

Placebo-Controlled Trials Active-Controlled Trials All RA Studies
Trial 1 and 2 Trial 3 1
Leflunomide 20 mg/day(N=315) PL(N=210) SSZ 2.0g/day (N=133) MTX 7.5 – 15 mg/wk(N=182) Leflunomide 20 mg/day (N=501) MTX 7.5 – 15 mg/wk (N=498) Leflunomide (N=1339)2
Diarrhea 27% 12% 10% 20% 22% 10% 17%
Headache 13% 11% 12% 21% 10% 8% 7%
Nausea 13% 11% 19% 18% 13% 18% 9%
Rash 12% 7% 11% 9% 11% 10% 10%
Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5%
Alopecia 9% 1% 6% 6% 17% 10% 10%
Hypertension3 9% 4% 4% 3% 10% 4% 10%
Asthenia 6% 4% 5% 6% 3% 3% 3%
Back Pain 6% 3% 4% 9% 8% 7% 5%
GI/Abdominal Pain 6% 4% 7% 8% 8% 8% 5%
Abdominal Pain 5% 4% 4% 8% 6% 4% 6%
Allergic Reaction 5% 2% 0% 6% 1% 2% 2%
Bronchitis 5% 2% 4% 7% 8% 7% 7%
Dizziness 5% 3% 6% 5% 7% 6% 4%
Mouth Ulcer 5% 4% 3% 10% 3% 6% 3%
Pruritus 5% 2% 3% 2% 6% 2% 4%
Rhinitis 5% 2% 4% 3% 2% 2% 2%
Vomiting 5% 4% 4% 3% 3% 3% 3%
Tenosynovitis 2% 0% 1% 2% 5% 1% 3%

MTX = methotrexate, PL = placebo, SSZ = sulfasalazine
1 Only 10% of patients in Trial3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate.
2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).
3 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials

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.

Less Common Adverse Reactions
In addition, in controlled clinical trials, the following adverse events in the leflunomide 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;

Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;

Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;

General Disorders: malaise;

Immune System: anaphylactic reaction;

Infection: abscess, flu syndrome, vaginal moniliasis;

Nervous System: dizziness, headache, somnolence;

Respiratory System: dyspnea;

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