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adverse reactions
6 ADVERSE REACTIONS The most serious adverse reactions described elsewhere in the labeling include the following: • Lymphopenia [see Warnings and Precautions ( 5.1 )] • Malignancies [see Warnings and Precautions ( 5.2 )] • Serious Infections requiring hospitalization [see Warnings and Precautions ( 5.3 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (incidence ≥ 2%) are: pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Commonly observed adverse events seen in the first course of placebo-controlled clinical trials with at least a 2% higher incidence in the AMEVIVE ® -treated patients compared to placebo-treated patients were: pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury. The only adverse event that occurred at a 5% or higher incidence among AMEVIVE ® -treated patients compared to placebo-treated patients was chills (1% placebo vs . 6% AMEVIVE ® ), which occurred predominantly with intravenous administration. The adverse reactions which most commonly resulted in clinical intervention were cardiovascular events including coronary artery disorder in <1% of subjects and myocardial infarct in <1% of subjects. These events were not observed in any of the 413 placebo-treated subjects. The total number of subjects hospitalized for cardiovascular events in the AMEVIVE ® -treated group was 1.2% (11/876). The most common events resulting in discontinuation of treatment with AMEVIVE ® were CD4+ T lymphocyte levels below 250 cells/µL [ see Warnings and Precautions ( 5.1 ) ], headache (0.2%), and nausea (0.2%). The data described below reflect exposure to AMEVIVE ® in a total of 1869 psoriasis patients, of whom 1315 (70%) received 1 to 2 courses of therapy and 554 (30%) received 3 or more courses. The median duration of follow-up was 8.4 months for the patients who received 1 to 2 courses and 27.7 months for the patients who received 3 or more courses of AMEVIVE ® . Of the 1869 total patients, 876 received their first course in placebo-controlled studies. The population studied ranged in age from 16 to 84 years, and included 69% men and 31% women. The patients were mostly Caucasian (88%), reflecting the general psoriatic population. Disease severity at baseline was moderate to severe psoriasis. Effect on Lymphocyte Counts In the intramuscular study (Study 2), 4% of patients temporarily discontinued treatment and no patients permanently discontinued treatment due to CD4+ T lymphocyte counts below the specified threshold of 250 cells/µL. In Study 2, 10%, 28%, and 42% of patients had total lymphocyte, CD4+, and CD8+ T lymphocyte counts below normal, respectively. Twelve weeks after a course of therapy (12 weekly doses), 2%, 8%, and 21% of patients had total lymphocyte, CD4+, and CD8+ T cell counts below normal. In the first course of the intravenous study (Study 1), 10% of patients temporarily discontinued treatment and 2% permanently discontinued treatment due to CD4+ T lymphocyte counts below the specified threshold of 250 cells/µL. During the first course of Study 1, 22% of patients had total lymphocyte counts below normal, 48% had CD4+ T lymphocyte counts below normal and 59% had CD8+ T lymphocyte counts below normal. The maximal effect on lymphocytes was observed within 6 to 8 weeks of initiation of treatment. Twelve weeks after a course of therapy (12 weekly doses), 4% of patients had total lymphocyte counts below normal, 19% had CD4+ T lymphocyte counts below normal, and 36% had CD8+ T lymphocyte counts below normal. For patients receiving a second course of AMEVIVE ® in Study 1, 17% of patients had total lymphocyte counts below normal, 44% had CD4+ T lymphocyte counts below normal, and 56% had CD8+ T lymphocyte counts below normal. Twelve weeks after completing dosing, 3% of patients had total lymphocyte counts below normal, 17% had CD4+ T lymphocyte counts below normal, and 35% had CD8+ T lymphocyte counts below normal [ see Warnings and Precautions ( 5.7 ) ]. In an open-label postmarketing study, subjects with psoriasis were treated with up to three courses of Amevive: each course consisted of Amevive 15 mg intramuscular weekly for twelve weeks, followed by twelve weeks of observation. Lymphocyte counts were assessed at regular intervals during the post-treatment observation period. For subjects whose counts went below 75% of the baseline at any time after the last dose in the study, the time from the last dose to the time that their lymphocyte count returned to ≥ 75% of baseline was analyzed. Of 115 evaluable subjects for total lymphocyte counts, the median time of recovery was 2.1 months with a range of 0.6 to 11.1 months. Of the 123 evaluable subjects for CD4+ T cell counts, the median time to recovery was 2.3 months with the range of 0.6 to 12.4 months. Of the 105 evaluable subjects for CD8+ T cell counts, the median time to recovery was 1.6 months with a range of 0.6 to 8.7 months. Malignancies In the 24-week period constituting the first course of placebo-controlled studies, 13 malignancies were diagnosed in 11 AMEVIVE ® -treated patients. The incidence of malignancies was 1.3% (11/876) for AMEVIVE ® -treated patients compared to 0.5% (2/413) in the placebo group. Among 1869 patients who received AMEVIVE ® at any dose in clinical trials, 43 patients were diagnosed with 63 treatment-emergent malignancies. The majority of the malignancies were non-melanoma skin cancers: 46 cases (20 basal cell, 26 squamous cell carcinomas) in 27 patients. Other malignancies observed in AMEVIVE ® -treated patients included melanoma (n=3), solid organ malignancies (n=12 in 11 patients), and lymphomas (n=5); the latter consisted of two Hodgkin’s and two non-Hodgkin’s lymphomas, and one cutaneous T cell lymphoma (mycosis fungoides). Infections In the 24-week period constituting the first course of placebo-controlled studies, serious infections (infections requiring hospitalization) were seen at a rate of 0.9% (8/876) in AMEVIVE ® -treated patients and 0.2% (1/413) in the placebo group. In patients receiving repeated courses of AMEVIVE ® therapy, the rates of serious infections remained similar across courses of therapy. Serious infections among 1869 AMEVIVE ® -treated patients included cellulitis, abscesses, wound infections, toxic shock, pneumonia, appendicitis, cholecystitis, gastroenteritis and herpes infections. Hypersensitivity Reactions In clinical studies, 4 of 1869 (0.2%) patients were reported to experience angioedema: two of these patients were hospitalized. In the 24-week period constituting the first course of placebo-controlled studies, urticaria was reported in 6 (<1%) AMEVIVE ® -treated patients vs . 1 patient in the control group. Urticaria resulted in discontinuation of therapy in one of the AMEVIVE ® -treated patients. Hepatic Injury In the 24-week period constituting the first course of placebo-controlled studies, 1.7% (15/876) of AMEVIVE ® -treated patients and 1.2% (5/413) of the placebo group experienced ALT and/or AST elevations of at least 3 times the upper limit of normal. Injection Site Reactions In the intramuscular study (Study 2), 16% of AMEVIVE ® -treated patients and 8% of placebo-treated patients reported injection site reactions. In patients receiving repeated courses of AMEVIVE ® intramuscular therapy, the incidence of injection site reactions remained similar across courses of therapy. Reactions at the site of injection were generally mild, typically occurred on single occasions, and included either pain (7%), inflammation (4%), bleeding (4%), edema (2%), non-specific reaction (2%), mass (1%), or skin hypersensitivity (<1%). In the clinical trials, a single case of injection site reaction led to the discontinuation of AMEVIVE ® . 6.2 Immunogenicity Approximately 3% (40/1357) of patients receiving AMEVIVE ® developed low-titer antibodies to alefacept as determined by an ELISA. When anti-alefacept antibodies were assessed using a dual specificity Biacore assay, 72% (72/100) of patients receiving AMEVIVE ® were positive for anti-alefacept antibodies. The long-term immunogenicity of AMEVIVE ® is unknown. Results 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 alefacept with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of AMEVIVE. Because these reactions are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Malignancies In post-marketing experience there have been reports of malignancies including skin, solid organ, lymphomas and leukemias [ see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 ) ]. Serious Infections In post-marketing experience there have been reports of infections including sepsis, opportunistic infections (viral, fungal, bacterial), cellulitis, urinary tract infection (UTI), Clostridium difficile colitis and pharyngitis [ see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 ) ]. Hepatic Injury In post-marketing experience there have been reports of asymptomatic transaminase elevation, fatty infiltration of the liver, hepatitis, and severe liver failure [ see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 ) ].