ADVERSE REACTIONS
The most frequently reported serious adverse reactions with Rebif® were psychiatric disorders including depression and suicidal ideation or attempt (see WARNINGS). The incidence of depression of any severity in the Rebif® -treated groups and placebo-treated group was approximately 25%. The most commonly reported adverse reactions were injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities. The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of Rebif® , adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were injection site disorders, influenza-like symptoms, depression and elevation of liver enzymes (see WARNINGS).
In Study 1, 6 patients randomized to Rebif® 44 mcg tiw (3%), and 2 patients who received Rebif® 22 mcg tiw (1%) developed injection site necrosis during two years of therapy. Rebif® was continued in 7 patients and interrupted briefly in one patient. There was one report of injection site necrosis in Study 2 during 48 weeks of Rebif treatment. All events resolved with conservative management; none required skin debridement or grafting.
The rates of adverse reactions and association with Rebif® in patients with relapsing-remitting multiple sclerosis are drawn from the placebo-controlled study (n = 560) and the active comparator-controlled study (n = 339).
The population encompassed an age range from 18 to 55 years. Nearly three-fourths of the patients were female, and more than 90% were Caucasian, largely reflecting the general demographics of the population of patients with multiple sclerosis.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Rebif® cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
Table 3 enumerates adverse events and laboratory abnormalities that occurred at an incidence that was at least 2% more in either Rebif® -treated group than was observed in the placebo group.
Table 3. Adverse Reactions and Laboratory Abnormalities in Study 1
| Body System Preferred Term |
Placebo tiw (n=187) |
Rebif® 22 mcg tiw (n=189) |
Rebif® 44 mcg tiw (n=184) |
|
BODY AS A WHOLE
|
|
Influenza-like symptoms
Headache
Fatigue
Fever
Rigors
Chest Pain
Malaise
|
51%
63%
36%
16%
5%
5%
1%
|
56%
65%
33%
25%
6%
6%
4%
|
59%
70%
41%
28%
13%
8%
5%
|
|
INJECTION SITE DISORDERS
|
|
Injection Site Reaction
Injection Site Necrosis
|
39%
0%
|
89%
1%
|
92%
3%
|
|
CENTRAL & PERIPH NERVOUS SYSTEM DISORDERS
|
|
Hypertonia
Coordination Abnormal
Convulsions
|
5%
2%
2%
|
7%
5%
5%
|
6%
4%
4%
|
|
ENDOCRINE DISORDERS
|
|
Thyroid Disorder
|
3%
|
4%
|
6%
|
|
GASTROINTESTINAL SYSTEM DISORDERS
|
|
Abdominal Pain
Dry Mouth
|
17%
1%
|
22%
1%
|
20%
5%
|
|
LIVER AND BILIARY SYSTEM DISORDERS
|
|
SGPT Increased
SGOT Increased
Hepatic Function Abnormal
Bilirubinaemia
|
4%
4%
2%
1%
|
20%
10%
4%
3%
|
27%
17%
9%
2%
|
|
MUSCULO-SKELETAL SYSTEM DISORDERS
|
|
Myalgia
Back Pain
Skeletal Pain
|
20%
20%
10%
|
25%
23%
15%
|
25%
25%
10%
|
|
HEMATOLOGIC DISORDERS
|
|
Leukopenia
Lymphadenopathy
Thrombocytopenia
Anemia
|
14%
8%
2%
3%
|
28%
11%
2%
3%
|
36%
12%
8%
5%
|
|
PSYCHIATRIC DISORDERS
|
|
Somnolence
|
1%
|
4%
|
5%
|
|
SKIN DISORDERS
|
|
Rash Erythematous
Rash Maculo-Papular
|
3%
2%
|
7%
5%
|
5%
4%
|
|
URINARY SYSTEM DISORDERS
|
|
Micturition Frequency
Urinary Incontinence
|
4%
2%
|
2%
4%
|
7%
2%
|
|
VISION DISORDERS
|
|
Vision Abnormal
Xerophthalmia
|
7%
0%
|
7%
3%
|
13%
1%
|
|
The adverse reactions were generally similar in Studies 1 and 2, taking into account the disparity in study durations.
IMMUNOGENICITY
As with all therapeutic proteins, there is a potential for immunogenicity. In study 1, the presence of neutralizing antibodies (NAb) to Rebif® was determined by collecting and analyzing serum pre-study and at 6 month time intervals during the 2 years of the clinical trial. Serum NAb were detected in 59/189 (31%) and 45/184 (24%) of Rebif® -treated patients at the 22 mcg and 44 mcg tiw doses, respectively, at one or more times during the study. The clinical significance of the presence of NAb to Rebif® is unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to Rebif® using an antiviral cytopathic effect assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of NAb positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Rebif® with the incidence of antibodies to other products may be misleading.
Anaphylaxis and other allergic reactions have been observed with the use of Rebif® (see WARNINGS: Anaphylaxis).
DRUG ABUSE AND DEPENDENCE
There is no evidence that abuse or dependence occurs with Rebif® therapy. However, the risk of dependence has not been systematically evaluated.
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