The most serious adverse reactions observed during treatment with RAPTIVA (efalizumab) are serious infections, including PML, malignancies, thrombocytopenia, hemolytic anemia, arthritis events, psoriasis worsening and variants, and neurologic events (see WARNINGS).
The most common adverse reactions associated with RAPTIVA (efalizumab) were a first dose reaction complex that included headache, chills, fever, nausea, and myalgia within two days following the first two injections. These reactions are dose-level related in incidence and severity and were largely mild to moderate in severity when a conditioning dose of 0.7 mg/kg was used as the first dose. In placebo-controlled trials, 29% of patients treated with RAPTIVA (efalizumab) 1 mg/kg developed one or more of these symptoms following the first dose compared with 15% of patients receiving placebo. After the third dose, 4% and 3% of patients receiving RAPTIVA (efalizumab) 1 mg/kg and placebo, respectively, experienced these symptoms. Less than 1% of patients discontinued RAPTIVA (efalizumab) treatment because of these adverse events.
Other adverse events resulting in discontinuation of RAPTIVA (efalizumab) treatment were psoriasis (0.6%), pain (0.4%), arthritis (0.4%), and arthralgia (0.3%).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect RAPTIVA (efalizumab) exposure for 2762 adult psoriasis patients (age range 18 to 75 years), including 2400 patients exposed for three months, 904 for six months, and 218 exposed for one year or more, in all controlled and uncontrolled studies. The median age of patients receiving RAPTIVA (efalizumab) was 44 years, with 189 patients above the age of 65; 67% were men, and 89% were Caucasian. These data include patients treated at doses higher than the recommended dose of 1 mg/kg weekly.
Controlled clinical trials provide the most informative basis for estimating the frequency of RAPTIVA (efalizumab) -related adverse drug reactions. Table 3 enumerates the adverse events occurring during controlled periods of the clinical trials where the frequency of the adverse events is at least 2% greater in the RAPTIVA (efalizumab) -treated group than the placebo group.
Table 3: Adverse Events in Placebo Controlled Study Periods Reported at a ≥ 2% Higher Rate in the 1 mg/kg/wk RAPTIVA (efalizumab) Treatment than Placebo Groups
(n = 715)
| RAPTIVA (efalizumab)
(n = 1213)
|Headache||159 (22%)||391 (32%)|
|Infectiona||188 (26%)||350 (29%)|
|Chills||32 (4%)||154 (13%)|
|Nausea||51 (7%)||128 (11%)|
|Pain||38 (5%)||122 (10%)|
|Myalgia||35 (5%)||102 (8%)|
|Flu Syndrome||29 (4%)||83 (7%)|
|Fever||24 (3%)||80 (7%)|
|Back pain||14 (2%)||50 (4%)|
|Acne||4 (1%)||45 (4%)|
|a Includes diagnosed infections and other non-specific infections. Most common non-specific infection was upper respiratory infection.|
Adverse events occurring at a rate between 1 and 2% greater in the RAPTIVA (efalizumab) group compared with placebo were arthralgia, asthenia, peripheral edema, and psoriasis.
The following serious adverse reactions were observed in RAPTIVA (efalizumab) -treated patients.
In the first 12 weeks of placebo-controlled studies, the proportion of patients with serious infection was 0.4% (7/1620) in the RAPTIVA (efalizumab) -treated group (5 of these were hospitalized, 0.3%) and 0.1% (1/715) in the placebo group (see WARNINGS: Serious Infections). In the complete safety data from both controlled and uncontrolled studies, the overall incidence of hospitalization for infections was 1.6 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.2 per 100 patient-years for placebo-treated patients. Including controlled, uncontrolled, and follow-up study treatment periods there were 27 serious infections in 2475 RAPTIVA (efalizumab) -treated patients. These infections included cellulitis, pneumonia, abscess, sepsis, sinusitis, bronchitis, gastroenteritis, aseptic meningitis, Legionnaire's disease, septic arthritis, and vertebral osteomyelitis. In controlled trials, the overall rate of infections in RAPTIVA (efalizumab) -treated patients was 3% higher than in placebo-treated patients (Table 3).
In postmarketing experience, serious bacterial, viral, fungal, and opportunistic infections have occurred, including JC virus infection resulting in PML. Some of these infections have been fatal. Worsening of infection despite antimicrobial treatment has been observed (see Boxed Warnings, CONTRAINDICATIONS, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).
Among the 2762 psoriasis patients who received RAPTIVA (efalizumab) at any dose (median duration 8 months), 31 patients were diagnosed with 37 malignancies (see WARNINGS: Malignancies). The overall incidence of malignancies of any kind was 1.8 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.6 per 100 patient-years for placebo-treated patients. Malignancies observed in the RAPTIVA (efalizumab) -treated patients included non-melanoma skin cancer, non-cutaneous solid tumors, Hodgkin's lymphoma and non-Hodgkin's lymphoma, and malignant melanoma. The incidence of non-cutaneous solid tumors (8 in 1790 patient-years) and malignant melanoma were within the range expected for the general population.
The majority of the malignancies were non-melanoma skin cancers; 26 cases (13 basal, 13 squamous) in 20 patients (0.7% of 2762 RAPTIVA (efalizumab) -treated patients). The incidence was comparable for RAPTIVA (efalizumab) -treated and placebo-treated patients. However, the size of the placebo group and duration of follow-up were limited and a difference in rates of non-melanoma skin cancers cannot be excluded.
In the combined safety database of 2762 RAPTIVA (efalizumab) -treated patients, there were eight occurrences (0.3%) of thrombocytopenia of < 52,000 cells per µL reported (see WARNINGS: Immune-Mediated Thrombocytopenia). Three of the eight patients were hospitalized for thrombocytopenia, including one patient with heavy uterine bleeding; all cases were consistent with an immune-mediated thrombocytopenia. Antiplatelet antibody was evaluated in one patient and was found to be positive. Each case resulted in discontinuation of RAPTIVA (efalizumab) . Based on available platelet count measurements, the onset of platelet decline was between 8 and 12 weeks after the first dose of RAPTIVA (efalizumab) in 5 of the patients. Onset was more delayed in 3 patients, occurring as late as one year in 1 patient. In these cases, the platelet count nadirs occurred between 12 and 72 weeks after the first dose of RAPTIVA (efalizumab) .
Immune-Mediated Hemolytic Anemia
Two reports of hemolytic anemia were observed in clinical trials. Additional cases were reported in the postmarketing setting. The anemia was diagnosed 4-6 months after the start of RAPTIVA (efalizumab) and in two serious cases the hemoglobin level decreased to 6 and 7 g/dl. RAPTIVA (efalizumab) treatment was discontinued, erythrocyte transfusions and other therapies were administered (see WARNINGS: Immune-Mediated Hemolytic Anemia).
Adverse Events of Psoriasis
In the combined safety database from all studies, serious psoriasis adverse events occurred in 19 RAPTIVA (efalizumab) -treated patients (0.7%) including hospitalization in 17 patients (see WARNINGS: Psoriasis Worsening/Variants). Most of these events (14/19) occurred after discontinuation of study drug and occurred in both patients responding and not responding to RAPTIVA (efalizumab) treatment. Serious adverse events of psoriasis included pustular, erythrodermic, and guttate subtypes. During the first 12 weeks of treatment within placebo-controlled studies, the rate of psoriasis adverse events (serious and non-serious) was 3.2% (52/1620) in the RAPTIVA (efalizumab) -treated patients and 1.4% (10/715) in the placebo-treated patients.
Infrequent new onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing (see PRECAUTIONS: Arthritis Events).
Symptoms associated with a hypersensitivity reaction (e.g., dyspnea, asthma, urticaria, angioedema, maculopapular rash) were evaluated by treatment group. In the first 12 weeks of the controlled clinical studies, the proportion of patients reporting at least one hypersensitivity reaction was 8% (95/1213) in the 1 mg/kg/wk group and 7% (49/715) of patients in the placebo group. Urticaria was observed in 1% of patients (16/1213) receiving RAPTIVA (efalizumab) and 0.4% of patients (3/715) receiving placebo during the initial 12-week treatment period. Other observed adverse events in patients receiving RAPTIVA (efalizumab) that may be indicative of hypersensitivity included: laryngospasm, angioedema, erythema multiforme, asthma, and allergic drug eruption. One patient was hospitalized with a serum sickness-like reaction.
In the entire RAPTIVA (efalizumab) clinical development program of 2762 RAPTIVA (efalizumab) -treated patients, inflammatory, potentially immune-mediated adverse events resulting in hospitalization included inflammatory arthritis (12 cases, 0.4% of patients) and interstitial pneumonitis (2 cases). One case each of the following serious adverse reactions was observed: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, sialadenitis, and sensorineural hearing loss. Myositis, eosinophilic pneumonitis, resolving after discontinuation of RAPTIVA (efalizumab) have been reported postmarketing.
The following adverse reactions have been identified during postapproval use of RAPTIVA (efalizumab) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections: serious bacterial, fungal, viral and other opportunistic infections, including JC virus resulting in PML (see Boxed Warnings, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).
Skin: toxic epidermal necrolysis and photosensitivity reactions
Neurologic: Guillain-Barré Syndrome, chronic inflammatory demyelinating
polyneuropathy, transverse myelitis, and facial palsy (see WARNINGS: Neurologic Events).
In RAPTIVA (efalizumab) -treated patients, a mean elevation in alkaline phosphatase (5 Units/L) was observed; 4% of RAPTIVA (efalizumab) -treated patients experienced a shift to above normal values compared with 0.6% of placebo-treated patients. The clinical significance of this change is unknown. Higher numbers of RAPTIVA (efalizumab) -treated patients experienced elevations above normal in two or more liver function tests than placebo (3.1% vs. 1.5%).
Other laboratory adverse reactions that were observed included thrombocytopenia (see WARNINGS, and ADVERSE REACTIONS: Immune-Mediated Thrombocytopenia), lymphocytosis (40%) (including three cases of transient atypical lymphocytosis), and leukocytosis (26%).
In patients evaluated for antibodies to RAPTIVA (efalizumab) after RAPTIVA (efalizumab) treatment ended, predominantly low-titer antibodies to RAPTIVA (efalizumab) or other protein components of the RAPTIVA (efalizumab) drug product were detected in 6.3% (67/1063) of patients. The long-term immunogenicity of RAPTIVA (efalizumab) is unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to RAPTIVA (efalizumab) in the ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody 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 RAPTIVA (efalizumab) with the incidence of antibodies to other products may be misleading.