Alefacept

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using alefacept. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, typhoid, yellow fever, varicella (chickenpox), H1N1 influenza, and nasal flu vaccine.

Tell your doctor about all other medicines you use, especially:

• a blood thinner such as warfarin (Coumadin, Jantoven);
• cyclosporine (Gengraf, Neoral, Sandimmune);
• digoxin (digitalis, Lanoxin, Lanoxicaps);
• fentanyl (Abstral, Actiq, Fentora, Duragesic, Lazanda, Onsolis);
• levothyroxine (Synthroid, Levothroid);
• lithium (Eskalith, Lithobid);
• pimozide (Orap);
• sirolimus (Rapamune) or tacrolimus (Prograf);
• theophylline (Elixophyllin, Theo-24, Theochron, Uniphyl);
• ergot medicine such as ergotamine (Ergomar, Cafergot) or dihydroergotamine (D.H.E. 45, Migranal Nasal Spray);
• seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), divalproex (Depakote), ethosuximide (Zarontin), phenytoin (Dilantin), or valproic acid (Depakene, Stavzor); or
• heart rhythm medication such as disopyramide (Norpace), procainamide (Procan, Pronestyl), or quinidine (Quin-G).

This list is not complete and other drugs may interact with alefacept. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Dosage Forms and Strengths

For injection; AMEVIVE® is supplied as 15 mg of lyophilized powder in a single-use vial for reconstitution with Sterile Water for Injection, USP.

AMEVIVE® (alefacept) is a sterile, white to off-white, preservative-free lyophilizate (15 mg/vial) for intramuscular administration provided in single-use glass vials with a bromobutyl rubber stopper and an aluminum overseal. Each vial contains 15 mg of alefacept.

AMEVIVE® is available as follows:

Store AMEVIVE® refrigerated between 2-8°C (36-46°F). Do not freeze. Store in carton until use to protect from light.

AMEVIVE® (alefacept) Manufactured by: Astellas Pharma US, Inc. Deerfield,IL 60015. Revised: 05/2012

The most serious adverse reactions described elsewhere in the labeling include the following:

• Lymphopenia [see WARNINGS AND PRECAUTIONS]
• Malignancies [see WARNINGS AND PRECAUTIONS]
• Serious Infections requiring hospitalization [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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], 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.

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].

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.

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).

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.

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%) AMEVrVE®-treated patients vs. 1 patient in the control group. Urticaria resulted in discontinuation of therapy in one of the AMEVIVE®-treated patients.

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.

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®.

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.

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.

In post-marketing experience there have been reports of malignancies including skin, solid organ, lymphomas and leukemias [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

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 and ADVERSE REACTIONS].

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 and ADVERSE REACTIONS].

Alefacept may be found in some form under the following brand names:

• Amevive

Alefacept is part of the drug class:

• Selective immunosuppressants

• Alefacept is given as an injection into your muscle.
• Alefacept is usually given one time each week for 12 weeks.
• Talk with your doctor to find out when you will receive injections. Keep all of your injection and follow-up appointments. It is important for you to stay under your doctor’s care during treatment.
• After you finish 12 weeks of treatment, you will stop treatment for at least 12 weeks.
• Your doctor may then decide that you should receive another 12 week treatment course of alefacept.

You should not use this medication if you are allergic to alefacept, or if you have HIV (human immunodeficiency virus).

To make sure you can safely take alefacept, tell your doctor if you have other medical conditions, especially:

• an active or chronic infection;
• a history of cancer;
• liver disease;
• if you are receiving phototherapy (light therapy); or
• if you use drugs that weaken the immune system (such as cancer medicine, steroids, and medicine to prevent organ transplant rejection).

Using alefacept may increase your risk of developing certain types of cancer. Talk with your doctor about your specific risk.

FDA pregnancy category B. Alefacept is not expected to harm an unborn baby. However, tell your doctor if you become pregnant during treatment or within 8 weeks after you stop using alefacept.

It is not known whether alefacept passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using alefacept.

Applies to alefacept: intramuscular powder for solution

Along with its needed effects, alefacept may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking alefacept:

• Chills
• cough
• fever
• hoarseness
• lower back or side pain
• painful or difficult urination

• Body aches or pain
• congestion
• dryness or soreness of the throat
• runny nose
• tender, swollen glands in the neck
• trouble with swallowing
• voice changes

• Arm, back, or jaw pain
• chest pain or discomfort
• chest tightness or heaviness
• fast or irregular heartbeat
• nausea
• pain or discomfort in the arms, jaw, back, or neck
• shortness of breath
• sweating
• vomiting

Some side effects of alefacept may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Pain, swelling, bleeding, skin rash, or lumps at the injection site

• Difficulty with moving
• dizziness
• itching skin
• joint pain
• muscle aching or cramping
• muscle pains or stiffness
• swollen joints

• Headache

Applies to alefacept: intramuscular powder for injection, intravenous powder for injection

Immunologic

Immunologic side effects including dose-dependent reductions in circulating CD4+ and CD8+ T lymphocyte counts have been reported.[Ref]

Cardiovascular

The total percentage of alefacept-treated patients hospitalized for cardiovascular events was 1.2%.[Ref]

Cardiovascular side effects including coronary artery disorder (

Women of childbearing potential make up a considerable segment of the patient population affected by psoriasis. Because the effect of alefacept on pregnancy and fetal development is not known, health care providers are encouraged by Biogen to enroll patients currently taking alefacept who become pregnant into the Biogen Pregnancy Registry by calling 1-866-AMEVIVE (1-866-263-8483).

Alefacept has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal any evidence of fetal toxicity including adverse effects on immune system development. There are no controlled data in human pregnancy. Alefacept should be given during pregnancy when need has been clearly established.