L for one month. month. one for L / cells 250 below remain counts lymphocyte T CD4+ if discontinued µ

should be should VIVE AME instituted. monitoring weekly and withheld be should dosing AMEVIVE L, cells/ 250

µ ® ®

. If CD4+ T lymphocyte counts are below below are counts lymphocyte T CD4+ If . AMEVIVE with treatment of course subsequent a y or systemic therapy was not allowed. allowed. not was therapy systemic or y phototherap Concomitant steroids. topical potency low comitant ®

4+ T lymphocyte counts prior to an initial or initial an to prior counts lymphocyte T 4+ CD normal have should Patients dosing. guide to used and period

. Patients could receive con- receive could Patients . AMEVIVE or o placeb of 2) Study for IM 1, Study for (IV weeks 12 for tration

®

dosing AMEVIVE 12-week the during s week two every monitored be should counts lymphocyte T CD4+ The course consisted of once-weekly adminis- once-weekly of consisted course Each phototherapy. or therapy systemic received previously had ®

Laboratory Tests Laboratory ement of 10% who were candidates for or for candidates were who 10% of ement involv area surface body minimum a and psoriasis plaque year) 1 (>

ed studies in adults with chronic with adults in studies ed placebo-controll double-blind, randomized, two in evaluated was AMEVIVE

®

jaundice, easy bruising, dark urine or pale stools. pale or urine dark bruising, easy jaundice,

a, anorexia, fatigue, vomiting, abdominal pain, abdominal vomiting, fatigue, anorexia, a, nause persistent physician their to report to advised be should CLINICAL STUDIES STUDIES CLINICAL

. Patients . AMEVIVE receiving patients in eported r been has injury liver serious that advised be should Patients ®

). Pregnancy , PRECAUTIONS (see ). Counts Lymphocyte on Effect REACTIONS, ADVERSE (see

1-866-263-8483) to enroll into the Registry the into enroll to 1-866-263-8483) ( 1-866-AMEVIVE Call Registry. Pregnancy the in enroll to aged

o be affected by AMEVIVE by affected be o t not appeared counts lymphocyte B circulating while treatment, AMEVIVE to ble

® ®

) and be advised of the existence of and encour- and of existence the of advised be and ) AMEVIVE discontinuing of weeks 8 within (or AMEVIVE

l counts appeared to be only minimally suscepti- minimally only be to appeared counts l cel killer natural and lymphocyte T naïve Circulating lesions. ® ®

ns if they become pregnant while taking while pregnant become they if ns physicia their notify to advised be also should patients Female edominant phenotype in psoriatic in phenotype edominant pr the CD8+CD45RO+), and (CD4+CD45RO+ compartments lymphocyte T

bset of the CD4+ and CD8+ CD8+ and CD4+ the of bset su effector y r memo the affected predominantly reduction This . lymphocytes

2

. . AMEVIVE with treatment of course a g undergoin while malignancy or infection an of signs any develop

tal to circulating in decrease dose-dependent a in resulted therapy AMEVIVE trials, clinical in tested doses At ®

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vised to inform their physician promptly if they if promptly physician their inform to vised ad be should Patients malignancy. a or infection an developing Pharmacodynamics Pharmacodynamics

f o chances their increase could which counts, lymphocyte reduces AMEVIVE that informed be also should ®

ients Pat physician. a of supervision the under administered be must AMEVIVE that and therapy during tudied. s been not have alefacept of pharmacokinetics the on impairment ®

of white blood cell (lymphocyte) counts counts (lymphocyte) cell blood white of monitoring regular for need the of informed be should Patients t been studied. The effects of renal or hepatic or renal of effects The studied. been t no have patients pediatric in alefacept of pharmacokinetics The

Information for Patients Patients for Information

was 63%. 63%. was

injury. n intramuscular (IM) injection, bioavailability injection, (IM) intramuscular n a Following hours. 270 approximately was half-life elimination Cohort 2). 2). Cohort

ical signs of liver of signs ical clin significant develop who patients in discontinued be should AMEVIVE evaluated. fully be

clearance was 0.25 mL/h/kg, and the mean the and mL/h/kg, 0.25 was clearance mean the mL/kg, 94 was alefacept of distribution of volume mean

ebo (see ebo plac received who patients to compared 1) Cohort (see treatment AMEVIVE of course second ®

®

ver injury should injury ver li of symptoms or signs with patients established, been not has AMEVIVE of use the with a 7.5 mg intravenous (IV) administration, the administration, (IV) intravenous mg 7.5 a following psoriasis, plaque severe to moderate with patients In core was greater in patients who received a received who patients in greater was core s PASI in reduction median The 1. Figure in shown is treatment ®

hile the exact relationship of these occurrences these of relationship exact the hile W normal. of limit upper the times 3 least at of elevations AST Pharmacokinetics Pharmacokinetics median PASI score) over the two courses of IV of courses two the over score) PASI median in (decrease response of level The normal. of limit lower the

nced ALT and/or ALT nced experie group placebo the of (5/413) 1.2% and patients -treated AMEVIVE of (15/876) 1.7% their CD4+ T lymphocyte count was above was count lymphocyte T CD4+ their and PGA by “clear” than less was psoriasis their if course ment ®

bo-controlled studies, bo-controlled place of course first the constituting period 24-week the In ). Injury Hepatic ing cells other than T lymphocytes have been observed. been have lymphocytes T than other cells ing urse were eligible to receive a second treat- second a receive to eligible were urse co treatment IV first the completed had who 1 Study in Patients

ADVERSE REACTIONS, ADVERSE (see use alcohol ant concomit with reported were failure liver of cases Two failure.

, minor changes in the numbers of circulat- of numbers the in changes minor , AMEVIVE of studies clinical In lymphocytes. T than other cells Retreatment

®

sation of cirrhosis with liver failure, and acute liver acute and failure, liver with cirrhosis of sation decompen hepatitis, liver, the of infiltration fatty elevation,

to affect the activation and numbers of numbers and activation the affect to IVE AMEV for exists potential the Therefore, lymphocytes. B marrow

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njury, including asymptomatic transaminase asymptomatic including njury, i liver of reports been have there experience post-marketing In e surface of natural killer cells and certain bone certain and cells killer natural of surface e th on levels low at expressed also is CD2 counts. lymphocyte T the first 2 weeks of the follow-up period. follow-up the of weeks 2 first the after visits more or one at score PASI baseline from reduction

Hepatic Injury Hepatic results in a reduction in circulating total CD4+ and CD8+ CD8+ and CD4+ total circulating in reduction a in results AMEVIVE with Treatment cells. killer natural

, respectively, achieved a 75% 75% a achieved respectively, , EVIVE AM with treated patients of (12/166) 7% and (42/367) 11% tional ®

®

c receptors on cytotoxic cells, such as such cells, cytotoxic on receptors c F immunoglobulin and lymphocytes target on CD2 between bridging st-dosing. In Studies 1 and 2, an addi- an 2, and 1 Studies In st-dosing. po weeks 2 beyond response maximal their achieved patients Some

continued immediately and appropriate therapy initiated. therapy appropriate and immediately continued

rily CD45RO+), presumably by presumably CD45RO+), rily (prima lymphocytes T CD2+ of subsets in reduction a causes also AMEVIVE

®

should be dis- be should AMEVIVE of administration urs, occ reaction allergic serious other or reaction anaphylactic an in PASI was maintained for a median of 7 months. 7 of median a for maintained was PASI in ®

. If . AMEVIVE of administration the with ted associa were angioedema) (urticaria, reactions Hypersensitivity

. . interferon as such cytokines, matory

retreatment, a 50% or greater reduction greater or 50% a retreatment, AMEVIVE before treatment active off followed were and IM mg 15 γ ®

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Allergic Reactions Allergic

lam- inf release and CD69) CD25, (e.g., markers activation express , marker CD45RO the of presence the by

7.5 mg IV or in Study 2 who received AMEVIVE received who 2 Study in or IV mg 7.5 AMEVIVE received who 1 Study in responders Among

1

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f the memory effector phenotype characterized phenotype effector memory the f o are lesions psoriatic in lymphocytes T of majority The asis.

in those patients undergoing AMEVIVE undergoing patients those in therapy. he pathophysiology of chronic plaque psori- plaque chronic of pathophysiology he t in role a plays lymphocytes T on CD2 and cells gen-presenting PASI through the 3-month observation period. observation 3-month the through PASI ®

d an experimental neo-antigen was preserved was neo-antigen experimental an d an antigen) (recall toxoid tetanus to immunity mount to ability involving the interaction between LFA-3 on anti- on LFA-3 between interaction the involving lymphocytes T of Activation interaction. LFA-3/CD2 inhibiting

or placebo maintained a 50% or greater reduction in reduction greater or 50% a maintained placebo or AMEVIVE either to responded had who patients Most

®

plaque psoriasis, the psoriasis, plaque chronic with patients 46 of study a In studied. been not have AMEVIVE with treated

o the lymphocyte antigen, CD2, and CD2, antigen, lymphocyte the o t binding specifically by activation lymphocyte with interferes AMEVIVE ®

®

attenuated vaccines, administered to patients being patients to administered vaccines, attenuated live- or live specifically vaccines, of efficacy and safety The

-treated patients and placebo-treated patients. placebo-treated and patients -treated AMEVIVE both for

®

CLINICAL PHARMACOLOGY PHARMACOLOGY CLINICAL ration of response was approximately 2 months 2 approximately was response of ration du median the route), (IM 2 Study In patients. placebo-treated

with AMEVIVE with because of the possibility of excessive immunosuppression. excessive of possibility the of because

-treated patients and 1 month for for month 1 and patients -treated VE AMEVI for months 3.5 was PASI) in reduction greater or 75% a of ®

®

py should not receive concurrent therapy concurrent receive not should py photothera or agents immunosuppressive other receiving Patients ration of response (defined as maintenance maintenance as (defined response of ration du median the route), (IV 1 Study in therapy of course one With

Effects on the Immune System Immune the on Effects .5 mL. mL. .5 0 per monohydrate acid citric mg 0.06 and dihydrate, citrate um

2.5 mg sucrose, 5.0 mg glycine, 3.6 mg sodi- mg 3.6 glycine, mg 5.0 sucrose, mg 2.5 1 contain also formulations Both solution. reconstituted of mL 60 days after the start of therapy. of start the after days 60

PRECAUTIONS PRECAUTIONS for intravenous injection contains 7.5 mg alefacept per 0.5 per alefacept mg 7.5 contains injection intravenous for AMEVIVE solution. reconstituted of mL 0.5 per

treatment (at least a 50% reduction of baseline PASI) began PASI) baseline of reduction 50% a least (at treatment AMEVIVE to response of onset studies, both In ®

®

for intramuscular injection contains 15 mg alefacept mg 15 contains injection intramuscular for AMEVIVE formulations. two in available is AMEVIVE

® ®

0.2% (1/413) in the placebo group. placebo the in (1/413) 0.2% was not statistically significant. significant. statistically not was

76) in AMEVIVE in 76) (8/8 0.9% of rate a at observed were hospitalization) requiring -treated patients and and patients -treated

is clear, with a pH of approximately 6.9. approximately of pH a with clear, is AMEVIVE of as higher than placebo, but the difference the but placebo, than higher as w dose IM mg 10 the to responders of proportion the 2, Study In ®

®

trolled studies, serious infections (infections infections serious studies, trolled placebo-con of course first the constituting period 24-week the ed Sterile Water for Injection, USP, the solution the USP, Injection, for Water Sterile ed suppli the of mL 0.6 with reconstitution After administration.

In ). Infections , REACTIONS ADVERSE (see discontinued be should AMEVIVE infection, serious a develops

AMEVIVE , lyophilized powder for parenteral for powder lyophilized , preservative-free white-to-off-white, sterile, a as supplied is ®

®

of infection during or after a course of AMEVIVE of course a after or during infection of . New infections should be closely monitored. If a patient a If monitored. closely be should infections New . ®

ts should be monitored for signs and symptoms and signs for monitored be should ts Patien infection. recurrent of history a or infections chronic tons. tons.

in patients with patients in AMEVIVE of use the ing consider when exercised be should Caution infection. important cular weight of alefacept is 91.4 kilodal- 91.4 is alefacept of weight cular mole The system. expression cell mammalian (CHO) Ovary Hamster ®

and reactivate latent, chronic infections. AMEVIVE infections. chronic latent, reactivate and should not be administered to patients with a clinically a with patients to administered be not should binant DNA technology in a Chinese a in technology DNA binant recom by produced is Alefacept IgG1. human of portion domains) ®

to increase the risk of infection of risk the increase to potential the has therefore, and, agent immunosuppressive an is AMEVIVE 3 C and 2 C (hinge, Fc the to linked 3) (LFA- antigen-3 function leukocyte human the of portion binding H H ®

consists of the extracellular CD2- extracellular the of consists that protein fusion dimeric immunosuppressive an is (alefacept) AMEVIVE

®

Serious Infections Infections Serious

DESCRIPTION DESCRIPTION

should be discontinued. be should AMEVIVE malignancy, a develops ®

should be exercised when considering the use of AMEVIVE of use the considering when exercised be should in patients at high risk for malignancy. If a patient a If malignancy. for risk high at patients in ®

ic malignancy. Caution malignancy. ic system of history a with patients to administered be not should AMEVIVE ). Fertility

(alefacept) AMEVIVE

® ®

 

PRECAUTIONS, Carcinogenesis, Mutagenesis, and Mutagenesis, Carcinogenesis, PRECAUTIONS, (see lymphoma a developed animal one and plasia,

In preclinical studies, animals developed B cell hyper- cell B developed animals studies, preclinical In ). Malignancies REACTIONS, ADVERSE (see group

-treated patients compared to 0.5% (2/413) in the placebo the in (2/413) 0.5% to compared patients -treated AMEVIVE for (11/876) 1.3% was malignancies ®

-treated patients. The incidence of incidence The patients. -treated VIVE AME 11 in diagnosed were malignancies 13 studies, bo-controlled ®

nstituting the first course of place- of course first the nstituting co period 24-week the In malignancies. of risk the increase may AMEVIVE ®

I63007-5 Malignancies

COUNTS REMAIN BELOW 250 CELLS/ 250 BELOW REMAIN COUNTS DOSAGE AND ADMINISTRATION). AND DOSAGE (SEE month one for L µ µ

WITHHELD AND WEEKLY MONITORING INSTITUTED. AMEVIVE INSTITUTED. MONITORING WEEKLY AND WITHHELD SHOULD BE DISCONTINUED IF THE IF DISCONTINUED BE SHOULD least 50% from baseline two weeks after the 12-week treatment p treatment 12-week the after weeks two baseline from 50% least eriod. eriod. ®

DOSING SHOULD BE SHOULD DOSING CELLS/ 250 BELOW ARE COUNTS LYMPHOCYTE T CD4+ IF IMEN. L, AMEVIVE L, µ µ “clear” by Physician Global Assessment (PGA) and the proportion the and (PGA) Assessment Global Physician by “clear” of patients with a reduction in PASI of at of PASI in reduction a with patients of ®

SHOULD BE MONITORED EVERY TWO WEEKS THROUGHOUT THE COURSE OF TH OF COURSE THE THROUGHOUT WEEKS TWO EVERY MONITORED BE SHOULD E 12-WEEK DOSING REG- DOSING 12-WEEK E Other treatment responses included the proportion of patients w patients of proportion the included responses treatment Other ho achieved a scoring of “almost clear” or clear” “almost of scoring a achieved ho

COUNT BELOW NORMAL. THE CD4+ T LYMPHOCYTE COUNTS OF PATIENTS RE PATIENTS OF COUNTS LYMPHOCYTE T CD4+ THE NORMAL. BELOW COUNT CEIVING AMEVIVE CEIVING ®

THERAPY SHOULD NOT BE INITIATED IN PATIENTS WITH A CD4+ T LYMPH T CD4+ A WITH PATIENTS IN INITIATED BE NOT SHOULD THERAPY AMEVIVE OF COURSE A OCYTE

Severity Index (PASI) Index Severity of at least 75% from baseline at two weeks following the 12-wee the following weeks two at baseline from 75% least at of k treatment period. period. treatment k ® 3

both studies was defined as the proportion of patients with a r a with patients of proportion the as defined was studies both eduction in score on the Psoriasis Area and Area Psoriasis the on score in eduction

COUNTS. shows the treatment response in the first course of Stu of course first the in response treatment the shows 2 Table dy 1 and Study 2. Response to treatment in treatment to Response 2. Study and 1 dy

AMEVIVE INDUCES DOSE-DEPENDENT REDUCTIONS IN CIRCULATING CD4+ AND CD8+ CD8+ AND CD4+ CIRCULATING IN REDUCTIONS DOSE-DEPENDENT INDUCES T LYMPHOCYTE T ®

LYMPHOPENIA asis. Of these, 23% and 19%, respectively, had failed to respo to failed had respectively, 19%, and 23% these, Of asis. nd to at least one of these previous therapies. therapies. previous these of one least at to nd

In Studies 1 and 2, 77% of patients had previously received sys received previously had patients of 77% 2, and 1 Studies In temic therapy and/or phototherapy for psori- for phototherapy and/or therapy temic

WARNINGS

IM, and 168 to receive placebo. placebo. receive to 168 and IM, AMEVIVE

®

components.

hundred seventy-three patients were randomized to receive 10 mg 10 receive to randomized were patients seventy-three hundred of AMEVIVE of IM, 166 to receive 15 mg of mg 15 receive to 166 IM,

®

AMEVIVE or any of its of any or hypersensitiv known with patients to administered be not should ity to AMEVIVE to ity

Study 2 provided a basis for comparison of patients treated wit treated patients of comparison for basis a provided 2 Study IM. One IM. AMEVIVE mg 15 or mg 10 either h ® ® ®

WARNINGS, LYMPHOPENIA WARNINGS, (see WARNINGS, Serious Infections Serious WARNINGS, and

). ® counts, which might accelerate disease progression or increase increase or progression disease accelerate might which counts,

complications of disease in these patients patients these in disease of complications ®

reduces CD4+ T lymphocyte T CD4+ reduces AMEVI HIV. with infected patients to administered be not should AMEVIVE

VE AMEVIVE ® ®

CONTRAINDICATIONS CONTRAINDICATIONS (alefacept)

who are candidates for systemic therapy or phototherapy. phototherapy. or therapy systemic for candidates are who

is indicated for the treatment of adult patients with moderate moderate with patients adult of treatment the for indicated is AMEVIVE to severe chronic plaque psoriasis plaque chronic severe to ing interval. A total of 553 patients were randomized into thr into randomized were patients 553 of total A interval. ing (Table 1). (Table cohorts ee ®

bolus. The first and second courses in the two-course cohort w cohort two-course the in courses second and first The bolus. ere separated by at least a 12-week post-dos- 12-week a least at by separated ere

INDICATIONS AND USAGE AND INDICATIONS

In Study 1, patients were randomized to receive one or two cour two or one receive to randomized were patients 1, Study In ses of AMEVIVE of ses 7.5 mg administered by IV by administered mg 7.5 Biogen Idec Inc. ® Drug Interactions Effect on Lymphocyte Counts AMEVIVE® 15 mg lyophilized powder for IM administration should be reconstituted with 0.6 mL of the supplied No formal interaction studies have been performed. In the intramuscular study (Study 2), 4% of patients temporarily discontinued treatment and no patients diluent (Sterile Water for Injection, USP). 0.5 mL of the reconstituted solution contains 15 mg of alefacept. permanently discontinued treatment due to CD4+ T lymphocyte counts below the specified threshold of Carcinogenesis, Mutagenesis, and Fertility 250 cells/µL. In Study 2, 10%, 28%, and 42% of patients had total lymphocyte, CD4+, and CD8+ T lympho- AMEVIVE® 7.5 mg lyophilized powder for IV administration should be reconstituted with 0.6 mL of the sup- In a chronic toxicity study, cynomolgus monkeys were dosed weekly for 52 weeks with intravenous alefacept cyte counts below normal, respectively. Twelve weeks after a course of therapy (12 weekly doses), 2%, 8%, plied diluent. 0.5 mL of the reconstituted solution contains 7.5 mg of 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 and 21% of patients had total lymphocyte, CD4+, and CD8+ T cell counts below normal. detected after 28 weeks of dosing. Additional animals in both dose groups developed B-cell hyperplasia of the Do not add other medications to solutions containing AMEVIVE®. Do not reconstitute AMEVIVE® with other spleen and lymph nodes. One-year post-treatment there was no evidence of alefacept-related lymphoma or In the first course of the intravenous study (Study 1), 10% of patients temporarily discontinued treatment and diluents. Do not filter reconstituted solution during preparation or administration. B-cell hyperplasia in any of the remaining treated monkeys. 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, All procedures require the use of aseptic technique. Using the supplied syringe and one of the supplied All animals in the study were positive for an endemic primate gammaherpes virus also known as lym- 48% had CD4+ T lymphocyte counts below normal and 59% had CD8+ T lymphocyte counts below normal. needles, withdraw only 0.6 mL of the supplied diluent, (Sterile Water for Injection, USP). Keeping the needle phocryptovirus (LCV). Latent LCV infection is generally asymptomatic, but can lead to B-cell lymphomas The maximal effect on lymphocytes was observed within 6 to 8 weeks of initiation of treatment. Twelve weeks pointed at the sidewall of the vial, slowly inject the diluent into the vial of AMEVIVE®. Some foaming will occur, when animals are immune suppressed. after a course of therapy (12 weekly doses), 4% of patients had total lymphocyte counts below normal, which is normal. To avoid excessive foaming, do not shake or vigorously agitate. The contents should be ® In a separate study, baboons given 3 doses of alefacept at 1 mg/kg every 8 weeks were found to have cen- 19% had CD4+ T lymphocyte counts below normal, and 36% had CD8+ T lymphocyte counts below normal. swirled gently during dissolution. Generally, dissolution of AMEVIVE takes less than two minutes. The solu- tion should be used as soon as possible after reconstitution. troblast proliferation in B-cell dependent areas in the germinal centers of the spleen following a 116-day For patients receiving a second course of AMEVIVE® in Study 1, 17% of patients had total lymphocyte counts washout period. below normal, 44% had CD4+ T lymphocyte counts below normal, and 56% had CD8+ T lymphocyte counts The reconstituted solution should be clear and colorless to slightly yellow. Visually inspect the solution for The role of AMEVIVE® in the development of the lymphoid malignancy and the hyperplasia observed in non- below normal. Twelve weeks after completing dosing, 3% of patients had total lymphocyte counts below particulate matter and discoloration prior to administration. The solution should not be used if discolored or human primates and the relevance to humans is unknown. Immunodeficiency-associated lymphocyte disor- normal, 17% had CD4+ T lymphocyte counts below normal, and 35% had CD8+ T lymphocyte counts below cloudy, or if undissolved material remains. normal (see WARNINGS, and PRECAUTIONS, Laboratory Tests). ders (plasmacytic hyperplasia, polymorphic proliferation, and B-cell lymphomas) occur in patients who have Following reconstitution, the product should be used immediately or within 4 hours if stored in the vial at congenital or acquired immunodeficiencies including those resulting from immunosuppressive therapy. Malignancies 2-8°C (36-46°F). AMEVIVE® NOT USED WITHIN 4 HOURS OF RECONSTITUTION SHOULD BE DISCARDED. No formal carcinogenicity or fertility studies were conducted. 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 Remove the needle used for reconstitution and attach the other supplied needle. Withdraw 0.5 mL of the ® Mutagenicity studies were conducted in vitro and in vivo; no evidence of mutagenicity was observed. AMEVIVE®-treated patients compared to 0.5% (2/413) in the placebo group. AMEVIVE solution into the syringe. Some foam or bubbles may remain in the vial.

® Pregnancy (Category B) Among 1869 patients who received AMEVIVE at any dose in clinical trials, 43 patients were diagnosed with Administration Instructions Women of childbearing potential make up a considerable segment of the patient population affected by pso- 63 treatment-emergent malignancies. The majority of the malignancies were non-melanoma skin cancers: For intramuscular use, inject the full 0.5 mL of solution. Rotate injection sites so that a different site is used riasis. Since the effect of AMEVIVE® on pregnancy and fetal development, including immune system devel- 46 cases (20 basal cell, 26 squamous cell carcinomas) in 27 patients. Other malignancies observed in for each new injection. New injections should be given at least 1 inch from an old site and never into areas ® opment, is not known, health care providers are encouraged to enroll patients currently taking AMEVIVE® who AMEVIVE -treated patients included melanoma (n=3), solid organ malignancies (n=12 in 11 patients), and where the skin is tender, bruised, red, or hard. become pregnant into the Biogen Idec Pregnancy Registry by calling 1-866-AMEVIVE (1-866-263-8483). lymphomas (n=5); the latter consisted of two Hodgkin’s and two non-Hodgkin’s lymphomas, and one cuta- neous T cell lymphoma (mycosis fungoides). For intravenous use, Reproductive toxicology studies have been performed in cynomolgus monkeys at doses up to 5 mg/kg/week • Prepare 2 syringes with 3.0 mL Normal Saline, USP for pre- and post-administration flush. (about 62 times the human dose based on body weight) and have revealed no evidence of impaired fertility or Infections • Prime the winged infusion set with 3.0 mL saline and insert the set into the vein. harm to the fetus due to AMEVIVE®. No abortifacient or teratogenic effects were observed in cynomolgus In the 24-week period constituting the first course of placebo-controlled studies, serious infections (infections • Attach the AMEVIVE®-filled syringe to the infusion set and administer the solution over no more than ® monkeys following intravenous bolus injections of AMEVIVE® administered weekly during the period of requiring hospitalization) were seen at a rate of 0.9% (8/876) in AMEVIVE -treated patients and 5 seconds. ® organogenesis to gestation. AMEVIVE® underwent trans-placental passage and produced in utero exposure 0.2% (1/413) in the placebo group. In patients receiving repeated courses of AMEVIVE therapy, the • Flush the infusion set with 3.0 mL saline, USP. in the developing monkeys. In utero, serum levels of exposure in these monkeys were 23% of maternal serum rates of serious infections remained similar across courses of therapy. Serious infections among ® levels. No evidence of fetal toxicity including adverse effects on immune system development was observed 1869 AMEVIVE -treated patients included cellulitis, abscesses, wound infections, toxic shock, pneumonia, HOW SUPPLIED in any of these animals. appendicitis, cholecystitis, gastroenteritis and herpes infections. AMEVIVE® for IV administration is supplied in either a carton containing four administration dose packs, or in Animal reproduction studies, however, are not always predictive of human response and there are no adequate Hypersensitivity Reactions a carton containing one administration dose pack. Each dose pack contains one 7.5-mg single-use vial of and well-controlled studies in pregnant women. Because the risk to the development of the fetal immune sys- In clinical studies, 4 of 1869 (0.2%) patients were reported to experience angioedema: two of these patients AMEVIVE®, one 10 mL single-use diluent vial (Sterile Water for Injection, USP), one syringe, one 23 gauge, tem and postnatal immune function in humans is unknown, AMEVIVE® should be used during pregnancy only were hospitalized. In the 24-week period constituting the first course of placebo-controlled studies, urticaria 3/4 inch winged infusion set, and two 23 gauge, 1 1/4 inch needles. The NDC number for the four administra- ® if clearly needed. If pregnancy occurs while taking AMEVIVE®, continued use of the drug should be assessed. was reported in 6 (<1%) AMEVIVE -treated patients vs. 1 patient in the control group. Urticaria resulted in tion dose pack carton is 59627-020-01. The NDC number for the one administration dose pack carton is discontinuation of therapy in one of the AMEVIVE®-treated patients. 59627-020-02. Nursing Mothers Hepatic Injury ® ® AMEVIVE for IM administration is supplied in either a carton containing four doses, or in a carton contain- It is not known whether AMEVIVE is excreted in human milk. Because many drugs are excreted in human In post-marketing experience there have been reports of asymptomatic transaminase elevation, fatty infiltra- milk, and because there exists the potential for serious adverse reactions in nursing infants from AMEVIVE®, ing one dose. Each four-dose carton contains one removable drug/diluent pack for refrigeration, four 1 mL tion of the liver, hepatitis, and severe liver failure (see PRECAUTIONS, Hepatic Injury). 1 a decision should be made whether to discontinue nursing while taking the drug or to discontinue the use of syringes, and eight 23 gauge, 1 /4 inch needles. Each four-dose drug/diluent pack for refrigeration contains: ® the drug, taking into account the importance of the drug to the mother. In the 24-week period constituting the first course of placebo-controlled studies, 1.7% (15/876) of four 15-mg single-use vials of AMEVIVE and four 10 mL single-use diluent vials of Sterile Water for Injection, ® USP. Each single-dose carton contains one removable drug/diluent pack for refrigeration, one syringe and two AMEVIVE -treated patients and 1.2% (5/413) of the placebo group experienced ALT and/or AST elevations of 1 Geriatric Use 23 gauge, 1 /4 inch needles. Each single-dose drug/diluent pack for refrigeration contains: one 15-mg at least 3 times the upper limit of normal. ® Of the 1869 patients who received AMEVIVE® in clinical trials, a total of 129 patients were ≥ 65 years of age single-use vial of AMEVIVE and one 10 mL single-use diluent vial of Sterile Water for Injection, USP. and 16 patients were ≥ 75 years of age. No differences in safety or efficacy were observed between older and Injection Site Reactions The NDC number for the four-dose carton is 59627-021-03. The NDC number for the single-dose carton is younger patients, but there were not sufficient data to exclude important differences. Because the incidence In the intramuscular study (Study 2), 16% of AMEVIVE®-treated patients and 8% of placebo-treated patients 59627-021-04. reported injection site reactions. In patients receiving repeated courses of AMEVIVE® IM therapy, the inci- of infections and certain malignancies is higher in the elderly population, in general, caution should be used AMEVIVE® is reconstituted with 0.6 mL of the 10 mL single-use diluent. in treating the elderly. dence 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%), Storage Pediatric Use bleeding (4%), edema (2%), non-specific reaction (2%), mass (1%), or skin hypersensitivity (<1%). In the The safety and efficacy of AMEVIVE® in pediatric patients have not been studied. AMEVIVE® is not indicated clinical trials, a single case of injection site reaction led to the discontinuation of AMEVIVE®. The dose pack (IV) and drug/diluent pack (IM) containing AMEVIVE® (lyophilized powder) should be stored for pediatric patients. Immunogenicity in a refrigerator between 2-8°C/36-46°F. PROTECT FROM LIGHT. Retain in carton (IV) or drug/diluent pack Approximately 3% (50/1357) of patients receiving AMEVIVE® developed low-titer antibodies to alefacept. (IM) until time of use. ADVERSE REACTIONS No apparent correlation of antibody development and clinical response or adverse events was observed. The long-term immunogenicity of AMEVIVE® is unknown. Rx only The most serious adverse reactions were: The data reflect the percentage of patients whose test results were considered positive for antibodies to REFERENCES • Lymphopenia (see WARNINGS) alefacept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. • Malignancies (see WARNINGS) Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors 1. Bos JD, Hagenaars C, Das PK, et al. Predominance of “memory” T cells (CD4+, CDw29+) over “naïve” • Serious Infections requiring hospitalization (see WARNINGS) including sample handling, timing of sample collection, concomitant medications, and underlying disease. For T cells (CD4+, CD45R+) in both normal and diseased human skin. Arch Dermatol Res 1989; 281:24-30. • Hypersensitivity Reactions (see PRECAUTIONS, Allergic Reactions) these reasons, comparison of the incidence of antibodies to alefacept with the incidence of antibodies to other 2. Ellis C, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345:248-255. Commonly observed adverse events seen in the first course of placebo-controlled clinical trials with at least a products may be misleading. ® 3. Fredriksson T, Pettersson U. Severe psoriasis—oral therapy with a new retinoid. Dermatologica 1978; 2% higher incidence in the AMEVIVE -treated patients compared to placebo-treated patients were: pharyngi- 157:238-244. tis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflamma- OVERDOSAGE tion, and accidental injury. The only adverse event that occurred at a 5% or higher incidence among The highest dose tested in humans (0.75 mg/kg IV) was associated with chills, headache, arthralgia, and Issued: September/2005 AMEVIVE®-treated patients compared to placebo-treated patients was chills (1% placebo vs. 6% AMEVIVE®), sinusitis within one day of dosing. Patients who have been inadvertently administered an excess of the rec- which occurred predominantly with intravenous administration. ommended dose should be closely monitored for effects on total lymphocyte count and CD4+ T lymphocyte AMEVIVE® (alefacept) The adverse reactions which most commonly resulted in clinical intervention were cardiovascular events count. Manufactured by: including coronary artery disorder in <1% of patients and myocardial infarct in <1% of patients. These events BIOGEN IDEC INC. were not observed in any of the 413 placebo-treated patients. The total number of patients hospitalized for DOSAGE AND ADMINISTRATION 14 Cambridge Center cardiovascular events in the AMEVIVE®-treated group was 1.2% (11/876). ® Cambridge, MA 02142 USA AMEVIVE should only be used under the guidance and supervision of a physician. ©2005 Biogen Idec Inc. All rights reserved. The most common events resulting in discontinuation of treatment with AMEVIVE® were CD4+ T lymphocyte The recommended dose of AMEVIVE® is 7.5 mg given once weekly as an IV bolus or 15 mg given once week- 1-866-263-8483 levels below 250 cells/µL (see WARNINGS, and ADVERSE REACTIONS, Effect on Lymphocyte Counts), ly as an IM injection. The recommended regimen is a course of 12 weekly injections. Retreatment with an headache (0.2%), and nausea (0.2%). additional 12-week course may be initiated provided that CD4+ T lymphocyte counts are within the normal U.S. Patents: range, and a minimum of a 12-week interval has passed since the previous course of treatment. 4,956,281 Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the 5,547,853 clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not The CD4+ T lymphocyte counts of patients receiving AMEVIVE® should be monitored before initiating dosing 5,728,677 reflect the rates observed in practice. The adverse reaction information does, however, provide a basis for and every two weeks throughout the course of the 12-week dosing regimen. If CD4+ T lymphocyte counts are 5,914,111 identifying the adverse events that appear to be related to drug use and a basis for approximating rates. below 250 cells/µL, AMEVIVE® dosing should be withheld and weekly monitoring instituted. AMEVIVE® 5,928,643 µ The data described below reflect exposure to AMEVIVE® in a total of 1869 psoriasis patients, of whom should be discontinued if the counts remain below 250 cells/ L for one month (see PRECAUTIONS, 6,162,432 1315 (70%) received 1 to 2 courses of therapy and 554 (30%) received 3 or more courses. The median dura- Laboratory Tests). Additional U.S. Patents Pending I63007-5 tion 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 Preparation Instructions ® placebo-controlled studies. The population studied ranged in age from 16 to 84 years, and included 69% men AMEVIVE should be reconstituted by a health care professional using aseptic technique. Each vial is intend- and 31% women. The patients were mostly Caucasian (88%), reflecting the general psoriatic population. ed for single patient use only. Disease severity at baseline was moderate to severe psoriasis. Do not use AMEVIVE® beyond the date stamped on the carton, dose pack lid (IV), drug/diluent pack (IM), AMEVIVE® vial label, or diluent container label.