2.1 Dosing Instructions

The recommended dose of AMEVIVE® is 15 mg intramuscularly once weekly for 12 weeks. The CD4+ T lymphocyte counts should be measured before initiating dosing.

AMEVIVE® therapy should not be initiated in patients who have CD4+ T lymphocyte counts below normal. The CD4+ T lymphocyte counts of patients receiving AMEVIVE® should be monitored every two weeks throughout the course of the 12-week dosing regimen. If CD4+ T lymphocyte counts are below 250 cells/µL, AMEVIVE® dosing should be withheld and weekly monitoring instituted. AMEVIVE® should be discontinued if the counts remain below 250 cells/µL for one month [see Warnings and Precautions (5.1)].

An additional 12-week course may be initiated if at least 12-weeks have passed since the previous treatment course and the CD4+ T lymphocyte counts are normal.

2.2 Preparation Instructions

• AMEVIVE® should be reconstituted using aseptic technique. Each vial is for single patient use only.
• AMEVIVE® 15 mg lyophilized powder should only be reconstituted with the supplied diluent (Sterile Water for Injection
• Do not add other medications to solutions containing AMEVIVE®. Do not filter reconstituted solution during preparation or administration.
• Using the supplied syringe and one of the supplied needles, withdraw 0.6 mL  of the diluent. Keeping the needle pointed at the sidewall of the vial, slowly inject the diluent into the vial of AMEVIVE®. Foaming will occur. Gently swirl the contents during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. Dissolution of AMEVIVE® generally takes less than two minutes.
• Inspect AMEVIVE® reconstituted solution visually for particulate matter and discoloration. AMEVIVE® reconstituted solution should be clear and colorless to slightly yellow. The solution should not be used if it is cloudy, if there is pronounced discoloration, or if particulate matter is present.
• The reconstituted product should be used immediately or within 4 hours if stored in the vial at 2-8°C (36-46°F). Discard AMEVIVE® not used within 4 hours of reconstitution.

2.3 Administration Instructions

• The reconstituted solution should be clear and colorless to slightly yellow. Do not administer the solution if cloudy or discolored or if undissolved material or particulate matter is present.
• Remove the needle used for reconstitution and attach the other supplied needle. Withdraw 0.5 mL of the AMEVIVE® solution into the syringe,  and inject the full 0.5 mL of solution intramuscularly. A volume of 0.5 mL of the reconstituted solution contains 15 mg of alefacept.  Rotate injection sites so that a different site is used for each new injection. New injections should be given at least one inch from a previous injection site and never into tender, bruised, erythematous, or indurated skin.
• Discard empty vials of AMEVIVE®.

5.1 Lymphopenia

AMEVIVE® induces dose-dependent reductions in circulating CD4+ and CD8+ T lymphocyte counts. CD4+ counts should be normal before initiating treatment with AMEVIVE® and should be closely monitored during AMEVIVE® treatment [see Dosage and Administration (2.1)]

5.2 Malignancies

AMEVIVE® may increase the risk of malignancies. Malignancies were reported in subjects who received AMEVIVE® in clinical studies [see Adverse Reactions (6.1, 6.3)].

In preclinical studies, animals developed B cell hyperplasia, and one animal developed a lymphoma [see Nonclinical Toxicology (13.1)]. AMEVIVE® should not be administered to patients with a history of systemic malignancy.

Exercise caution when considering the use of AMEVIVE® in patients at high risk for malignancy. Discontinue AMEVIVE® if a patient develops a malignancy.

5.3 Serious Infections

AMEVIVE® is an immunosuppressive agent and, therefore, has the potential to increase the risk of infection and reactivate latent, chronic infections. Serious infections (infections requiring hospitalization) were reported in subjects who received AMEVIVE® [see Adverse Reactions (6.1, 6.3)]. AMEVIVE® should not be administered to patients with a clinically important infection. Exercise caution 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 (6.1)].

5.4 Concomitant Therapies

Patients receiving other immunosuppressive agents or phototherapy should not receive concurrent therapy with AMEVIVE® because of the possibility of excessive immunosuppression.

5.5 Immunizations

The safety and efficacy of live or live-attenuated vaccines in 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.

5.6 Hypersensitivity Reactions

Urticaria and angioedema have been associated with the administration of AMEVIVE®. If an anaphylactic reaction or other serious allergic reaction occurs, discontinue AMEVIVE® immediately and initiate appropriate therapy.

5.7 Hepatic Injury

In post-marketing experience there have been reports of liver injury, including asymptomatic transaminase elevation, fatty infiltration of the liver, hepatitis, decompensation of cirrhosis with liver failure, and acute liver failure. Liver failure has been reported with concomitant alcohol use [see Adverse Reactions (6.3)].

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. While the exact relationship of these occurrences with the use of AMEVIVE® has not been established, patients with signs or symptoms of liver injury should be fully evaluated. AMEVIVE® should be discontinued in patients who develop clinical signs of liver injury.

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)].

7.1 Concomitant Therapies

The safety of AMEVIVE® in combination with immunosuppressive agents or phototherapy has not been evaluated [see Warnings and Precautions (5.4)].

7.2 CYP450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, a molecule that exerts its pharmacological effect by inhibiting the release of cytokines, such as AMEVIVE®, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of AMEVIVE® in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of AMEVIVE® in pregnant women. AMEVIVE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

The safety and efficacy of AMEVIVE® in pediatric patients have not been studied. AMEVIVE® is not indicated for pediatric patients.

8.5 Geriatric Use

Of the 1869 patients who received AMEVIVE® in clinical trials, a total of 129 patients were ≥ 65 years of age and 16 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.

12.1 Mechanism of Action

AMEVIVE® interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting the interaction between CD2 and its ligand, LFA-3. Activation of T lymphocytes involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in the pathophysiology of chronic plaque psoriasis.

AMEVIVE® also causes a reduction in subsets of CD2+ T lymphocytes and circulating total CD4+ and CD8+ T lymphocyte counts. In clinical studies of AMEVIVE®, minor changes in the numbers of circulating cells other than T lymphocytes have been observed.

12.2 Pharmacodynamics

At doses tested in clinical trials, AMEVIVE® therapy resulted in a dose-dependent decrease in circulating total lymphocytes. This reduction predominantly affected the memory effector subset of the CD4+ and CD8+ T lymphocyte compartments (CD4+CD45RO+ and CD8+CD45RO+), the predominant phenotype in psoriatic lesions. Circulating naïve T lymphocyte and natural killer cell counts appeared to be only minimally susceptible to AMEVIVE® treatment, while circulating B lymphocyte counts appeared not to be affected by AMEVIVE® [see Adverse Reactions (6.1)].

12.3 Pharmacokinetics

In patients with moderate to severe plaque psoriasis, following a 7.5 mg intravenous administration, the mean volume of distribution of alefacept was 94 mL/kg, the mean clearance was 0.25 mL/h/kg, and the mean elimination half-life was approximately 270 hours. Following an intramuscular injection, bioavailability was 63%.

The pharmacokinetics of alefacept in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alefacept have not been studied.

13.1 Carcinogenesis, Mutagenesis, Impairment of 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. 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 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 formal carcinogenicity or fertility studies were conducted.

Mutagenicity studies were conducted in vitro and in vivo; no evidence of mutagenicity was observed.