Chemical formula: C₂₃₀₆H₃₅₉₄N₆₁₀O₆₉₄S₂₆
Category B.
Women of childbearing potential make up a considerable segment of the patient population affected by psoriasis. Since the effect of alefacept on pregnancy and fetal development, including immune system development, is not known, health care providers are encouraged to enroll patients currently taking alefacept who become pregnant.
Reproductive toxicology studies have been performed in cynomolgus monkeys at doses up to 5 mg/kg/week (about 62 times the human dose based on body weight) and have revealed no evidence of impaired fertility or harm to the fetus due to alefacept. No abortifacient or teratogenic effects were observed in cynomolgus monkeys following intravenous bolus injections of alefacept administered weekly during the period of organogenesis to gestation. Alefacept underwent trans-placental passage and produced in utero exposure in the developing monkeys. In utero, serum levels of exposure in these monkeys were 23% of maternal serum levels. No evidence of fetal toxicity including adverse effects on immune system development was observed in any of these animals.
Animal reproduction studies, however, are not always predictive of human response and there are no adequate and well-controlled studies in pregnant women. Because the risk to the development of the fetal immune system and postnatal immune function in humans is unknown, alefacept should be used during pregnancy only if clearly needed. If pregnancy occurs while taking alefacept, continued use of the drug should be assessed.
It is not known whether alefacept is excreted in human milk. Because many drugs are excreted in human milk, and because there exists the potential for serious adverse reactions in nursing infants from alefacept, a decision should be made whether to discontinue nursing while taking the drug or to discontinue the use of the drug, taking into account the importance of the drug to the mother.
In a chronic toxicity study, cynomolgus monkeys were dosed weekly for 52 weeks with intravenous alefacept at 1 mg/kg/dose or 20 mg/kg/dose. One animal in the high dose group developed a B-cell lymphoma that was detected after 28 weeks of dosing. Additional animals in both dose groups developed B-cell hyperplasia of the spleen and lymph nodes. One-year post-treatment there was no evidence of alefacept-related lymphoma or B-cell hyperplasia in any of the remaining treated monkeys.
All animals in the study were positive for an endemic primate gammaherpes virus also known as lymphocryptovirus (LCV). Latent LCV infection is generally asymptomatic, but can lead to B-cell lymphomas when animals are immune suppressed.
In a separate study, baboons given 3 doses of alefacept at 1 mg/kg every 8 weeks were found to have centroblast proliferation in B-cell dependent areas in the germinal centers of the spleen following a 116-day washout period.
The role of alefacept in the development of the lymphoid malignancy and the hyperplasia observed in nonhuman primates and the relevance to humans is unknown. Immunodeficiency-associated lymphocyte disorders (plasmacytic hyperplasia, polymorphic proliferation, and B-cell lymphomas) occur in patients who have congenital or acquired immunodeficiencies including those resulting from immunosuppressive therapy.
No formal carcinogenicity or fertility studies were conducted.
Mutagenicity studies were conducted in vitro and in vivo; no evidence of mutagenicity was observed
The most serious adverse reactions were:
Commonly observed adverse events seen in the first course of placebo-controlled clinical trials with at least a 2% higher incidence in the alefacept-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 alefacept-treated patients compared to placebo-treated patients was chills (1% placebo vs. 6% alefacept), 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 patients and myocardial infarct in <1% of patients. These events were not observed in any of the 413 placebo-treated patients. The total number of patients hospitalized for cardiovascular events in the alefacept-treated group was 1.2% (11/876).
The most common events resulting in discontinuation of treatment with alefacept were CD4+ T lymphocyte levels below 250 cells/µL, headache (0.2%), and nausea (0.2%).
Because clinical trials are conducted under widely varying conditions, adverse event 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. The adverse reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.
The data described below reflect exposure to alefacept 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 alefacept. 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.
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 alefacept 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.
In the 24-week period constituting the first course of placebo-controlled studies, 13 malignancies were diagnosed in 11 alefacept-treated patients. The incidence of malignancies was 1.3% (11/876) for alefacept-treated patients compared to 0.5% (2/413) in the placebo group.
Among 1869 patients who received alefacept 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 alefacept-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).
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 alefacept-treated patients and 0.2% (1/413) in the placebo group. In patients receiving repeated courses of alefacept therapy, the rates of serious infections remained similar across courses of therapy. Serious infections among 1869 alefacept-treated patients included cellulitis, abscesses, wound infections, toxic shock, pneumonia, appendicitis, cholecystitis, gastroenteritis and herpes infections.
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%) alefacept-treated patients vs. 1 patient in the control group. Urticaria resulted in discontinuation of therapy in one of the alefacept-treated patients.
In post-marketing experience there have been reports of asymptomatic transaminase elevation, fatty infiltration of the liver, hepatitis, and severe liver failure.
In the 24-week period constituting the first course of placebo-controlled studies, 1.7% (15/876) of alefacept-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.
In the intramuscular study (Study 2), 16% of alefacept-treated patients and 8% of placebo-treated patients reported injection site reactions. In patients receiving repeated courses of alefacept IM 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 alefacept.
Approximately 3% (50/1357) of patients receiving alefacept developed low-titer antibodies to alefacept. No apparent correlation of antibody development and clinical response or adverse events was observed. The long-term immunogenicity of alefacept is unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to alefacept in an 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 alefacept with the incidence of antibodies to other products may be misleading.
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