AMEVIVE® INDUCES DOSE-DEPENDENT REDUCTIONS IN CIRCULATING CD4+ AND CD8+ T LYMPHOCYTE COUNTS.
A COURSE OF AMEVIVE® THERAPY SHOULD NOT BE INITIATED IN PATIENTS WITH A CD4+ T LYMPHOCYTE COUNT BELOW NORMAL. THE CD4+ T LYMPHOCYTE COUNTS OF PATIENTS RECEIVING AMEVIVE® SHOULD BE MONITORED WEEKLY THROUGHOUT THE COURSE OF THE 12-WEEK DOSING REGIMEN. DOSING SHOULD BE WITHHELD IF CD4+ T LYMPHOCYTE COUNTS ARE BELOW 250 CELLS/µL. THE DRUG SHOULD BE DISCONTINUED IF THE COUNTS REMAIN BELOW 250 CELLS/µL FOR ONE MONTH (SEE DOSAGE AND ADMINISTRATION).
AMEVIVE® may increase the risk of malignancies. Some patients who received AMEVIVE® in clinical studies developed malignancies (see ADVERSE REACTIONS, Malignancies). In preclinical studies, animals developed B cell hyperplasia, and one animal developed a lymphoma (see PRECAUTIONS, Carcinogenesis, Mutagenesis, and Fertility). AMEVIVE® should not be administered to patients with a history of systemic malignancy. Caution should be exercised when considering the use of AMEVIVE® in patients at high risk for malignancy. If a patient develops a malignancy, AMEVIVE® should be discontinued.
AMEVIVE® is an immunosuppressive agent and, therefore, has the potential to increase the risk of infection and reactivate latent, chronic infections. AMEVIVE® should not be administered to patients with a clinically important infection. Caution should be exercised when considering the use of AMEVIVE® in patients with chronic infections or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection during or after a course of AMEVIVE® . New infections should be closely monitored. If a patient develops a serious infection, AMEVIVE® should be discontinued (see ADVERSE REACTIONS, Infections).
EFFECTS ON THE IMMUNE SYSTEM
Patients receiving other immunosuppressive agents or phototherapy should not receive concurrent therapy with AMEVIVE® because of the possibility of excessive immunosuppression. The duration of the period following treatment with AMEVIVE® before one should consider starting other immunosuppressive therapy has not been evaluated.
The safety and efficacy of vaccines, specifically live or live-attenuated vaccines, administered to patients being treated with AMEVIVE® have not been studied. In a study of 46 patients with chronic plaque psoriasis, the ability to mount immunity to tetanus toxoid (recall antigen) and an experimental neo-antigen was preserved in those patients undergoing AMEVIVE® therapy.
Hypersensitivity reactions (urticaria, angioedema) were associated with the administration of AMEVIVE® . If an anaphylactic reaction or other serious allergic reaction occurs, administration of AMEVIVE® should be discontinued immediately and appropriate therapy initiated.
INFORMATION FOR PATIENTS
Patients should be informed of the need for regular monitoring of white blood cell (lymphocyte) counts during therapy and that AMEVIVE® must be administered under the supervision of a physician. Patients should also be informed that AMEVIVE® reduces lymphocyte counts, which could increase their chances of developing an infection or a malignancy. Patients should be advised to inform their physician promptly if they develop any signs of an infection or malignancy while undergoing a course of treatment with AMEVIVE® .
Female patients should also be advised to notify their physicians if they become pregnant while taking AMEVIVE® (or within 8 weeks of discontinuing AMEVIVE® ) and be advised of the existence of and encouraged to enroll in the Pregnancy Registry. Call 1-866-AMEVIVE (1-866-263-8483) to enroll into the Registry (see PRECAUTIONS, Pregnancy).
CD4+ T lymphocyte counts should be monitored weekly during the 12-week dosing period and used to guide dosing. Patients should have normal CD4+ T lymphocyte counts prior to an initial or a subsequent course of treatment with AMEVIVE® . Dosing should be withheld if CD4+ T lymphocyte counts are below 250 cells/µL. AMEVIVE® should be discontinued if CD4+ T lymphocyte counts remain below 250 cells/µL for one month.
No formal interaction studies have been performed. The duration of the period following treatment with AMEVIVE® before one should consider starting other immunosuppressive therapy has not been evaluated.
CARCINOGENESIS, MUTAGENESIS, AND FERTILITY
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.
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 AMEVIVE® in the development of the lymphoid malignancy and the hyperplasia observed in non-human 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 carcinogenicity or fertility studies were conducted.
Mutagenicity studies were conducted in vitro and in vivo; no evidence of mutagenicity was observed.
PREGNANCY (CATEGORY B)
Women of childbearing potential make up a considerable segment of the patient population affected by psoriasis. Since the effect of AMEVIVE® on pregnancy and fetal development, including immune system development, is not known, health care providers are encouraged to enroll patients currently taking AMEVIVE® who become pregnant into the Biogen Pregnancy Registry by calling 1-866-AMEVIVE (1-866-263-8483).
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 AMEVIVE® . No abortifacient or teratogenic effects were observed in cynomolgus monkeys following intravenous bolus injections of AMEVIVE® administered weekly during the period of organogenesis to gestation. AMEVIVE® 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, AMEVIVE® should be used during pregnancy only if clearly needed. If pregnancy occurs while taking AMEVIVE® , continued use of the drug should be assessed.
It is not known whether AMEVIVE® 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 AMEVIVE® , 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.
Of the 1357 patients who received AMEVIVE® in clinical trials, a total of 100 patients were >/= 65 years of age and 13 patients were >/= 75 years of age. No differences in safety or efficacy were observed between older and younger patients, but there were not sufficient data to exclude important differences. Because the incidence of infections and certain malignancies is higher in the elderly population, in general, caution should be used in treating the elderly.
The safety and efficacy of AMEVIVE® in pediatric patients have not been studied. AMEVIVE® is not indicated for pediatric patients.