Arava (Page 3 of 7)

5.9 Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of the active metabolite of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.

5.10 Blood Pressure Monitoring

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

6 ADVERSE REACTIONS

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

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 ARAVA 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 ARAVA 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 *
ARAVA PL MTX ARAVA PL SSZ ARAVA MTX
20 mg/day (n= 182) (n=118) 7.5–15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2 g/day (n=133) 20 mg/day (n=501) 7.5–15 mg/wk (n=498)
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.
ALT (SGPT)
>3-fold ULN (n %) 8(4.4) 3(2.5) 5(2.7) 2(1.5) 1(1.1) 2(1.5) 13(2.6) 83 (16.7)
Reversed to ≤2-fold ULN: 8 3 5 2 1 2 12 82
Timing of Elevation
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

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA 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 ARAVA-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 ARAVA treatment group).

Table 2: Percentage Of Patients With Adverse Events ≥5% In Any ARAVA 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 *
ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5–15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5–15 mg/wk (n=498) ARAVA (n=1339)
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine
*
Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate.
Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months).
Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials.
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%
Hypertension 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%

Adverse events during a second year of treatment with ARAVA 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 ARAVA 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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