when initiating therapy (e.g., monthly) and may decrease in frequency with continued treatment (e.g., every 3 months). Severe thrombocytopenia has been observed (see WARNINGS, Immune-Mediated Thrombocytopenia).

Drug Interactions

No formal drug interaction studies have been performed with RAPTIVA. RAPTIVA should not be used with other immunosuppressive drugs (see PRECAUTIONS, Immunosuppression). Live (including live-attenuated) vaccines should not be administered during RAPTIVA treatment (see PRECAUTIONS, Immunizations).

Drug/Laboratory Test Interactions

Increases in lymphocyte counts related to the pharmacologic mechanism of action are frequently observed during RAPTIVA treatment (see CLINICAL PHARMACOLOGY, Pharmacodynamics).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of RAPTIVA.

Subcutaneous injections of male and female mice with an anti-mouse CD11a antibody, a murine surrogate for efalizumab, at up to 30 times the equivalent of the 1 mg/kg clinical dose of RAPTIVA had no adverse effects on mating, fertility, or reproduction parameters. The clinical significance of this observation is uncertain. Genotoxicity studies were not conducted.

Pregnancy (Category C)

Animal reproduction studies have not been conducted with RAPTIVA. It is also not known whether RAPTIVA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RAPTIVA should be given to a pregnant woman only if clearly needed.

See Raptiva Page 12

....the incidence and severity of reactions associated with initial dosing (see DOSAGE AND ADMINISTRATION). Cases of aseptic meningitis resulting in hospitalization has been observed in association with initial dosing (see ADVERSE REACTIONS, Inflammatory/Immune-Mediated Reactions).

Information for Patients

Patients should be informed that their physician may monitor platelet counts during therapy. Patients should be advised to seek immediate medical attention if they experience any new or worsening medical problems such as a new or sudden change in thinking, balance, strength, talking, walking, or vision; if they develop any of the signs and symptoms associated with severe thrombocytopenia (such as easy bleeding from the gums, bruising, or petechiae) or with severe hemolytic anemia (such as weakness, orthostatic light-headedness, hemoglobinuria or jaundice), or with worsening of psoriasis or arthritis. Patients should also be informed that RAPTIVA is an immunosuppressant, and could increase their chances of developing an infection, including PML, or a malignancy. Patients should be advised to promptly call the prescribing doctor's office if they develop any new signs of, or receive a new diagnosis of infection, including PML, or malignancy while undergoing treatment with RAPTIVA.

Female patients should also be advised to notify their physicians if they become pregnant while taking RAPTIVA (or within 6 weeks of discontinuing RAPTIVA) and be advised of the existence of and encouraged to enroll in the RAPTIVA Pregnancy Registry by calling 1-877-RAPTIVA (1-877-727-8482).

If a patient or caregiver is to administer RAPTIVA, he/she should be instructed regarding injection techniques and how to measure the correct dose to ensure proper administration of RAPTIVA. Patients should be also referred to the RAPTIVA Patient Package Insert. In addition, patients should have available materials for and be instructed in the proper disposal of needles and syringes to comply with state and local laws. Patients should also be cautioned against reuse of syringes and needles.

Laboratory Tests

Assessment of platelet counts is recommended upon initiating and periodically while receiving RAPTIVA treatment. It is recommended that assessments be more frequent.....

See Raptiva Page 11

PRECAUTIONS

Arthritis Events

Infrequent new onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing. These arthritis events began while on treatment or following discontinuation of RAPTIVA and were uncommonly associated with flare of psoriasis. Patients improved after discontinuation of RAPTIVA with or without anti-arthritis therapy.

Immunosuppression

The safety and efficacy of RAPTIVA in combination with other immunosuppressive agents or phototherapy have not been evaluated. Patients receiving other immunosuppressive agents should not receive concurrent therapy with RAPTIVA because of the possibility of increased risk of infections and malignancies.

Immunizations

Prior to initiating therapy with RAPTIVA, psoriatic patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients on treatment with RAPTIVA should not receive live (including live-attenuated) vaccines. Vaccinations that are not live, which are received during a course of RAPTIVA, may not elicit an immune response sufficient to prevent disease. Patients receiving RAPTIVA should be cautioned if household contacts receive live vaccines, because of the potential risk for shedding and transmission.

In a small clinical study with IV administered RAPTIVA, a single-dose of 0.3 mg/kg given before primary immunization with a neoantigen decreased the secondary immune response, and a dose of 1 mg/kg almost completely ablated it. A dose of 0.3 mg/kg IV has comparable pharmacodynamic effects to the recommended dose of 1 mg/kg SC. In chimpanzees exposed to RAPTIVA at > 10 times the clinical exposure level (based on mean peak plasma levels) antibody responses were decreased following immunization with tetanus toxoid compared with untreated control animals.

First Dose Reactions

First dose reactions including headache, fever, nausea, and vomiting are associated with RAPTIVA treatment and are dose-level related in incidence and severity (see ADVERSE REACTIONS). Therefore, a conditioning dose of 0.7 mg/kg is recommended to reduce

U.S. BL 125075/96 Amendment: Raptiva® (efalizumab)?Genentech, Inc. 9 of 33/Regional (PAS) (Safety Updates): Final Raptiva label-clean (3).doc June 2005; Rev. Date Oct. 16, 2008

See Page 10

follow-up (1 patient was lost to follow-up). Reports of severe thrombocytopenia have also been received postmarketing. Physicians should follow patients closely for signs and symptoms of thrombocytopenia. Assessment of platelet counts is recommended during treatment with RAPTIVA (see PRECAUTIONS, Laboratory Tests) and RAPTIVA should be discontinued if thrombocytopenia develops.

Immune-Mediated Hemolytic Anemia

Reports of hemolytic anemia, some serious, diagnosed 4-6 months after the start of RAPTIVA treatment have been received. RAPTIVA should be discontinued if hemolytic anemia occurs.

Psoriasis Worsening and Variants

Worsening of psoriasis can occur during or after discontinuation of RAPTIVA. During clinical studies, 19 of 2589 (0.7%) of RAPTIVA-treated patients had serious worsening of psoriasis during treatment (n = 5) or worsening past baseline after discontinuation of RAPTIVA (n = 14) (see ADVERSE REACTIONS, Adverse Events of Psoriasis). In some patients these events took the form of psoriatic erythroderma, pustular psoriasis, or development of new plaque lesions. Some patients required hospitalization and alternative antipsoriatic therapy to manage the psoriasis worsening. Patients, including those not responding to RAPTIVA treatment, should be closely observed following discontinuation of RAPTIVA, and appropriate psoriasis treatment instituted as necessary.

Neurologic Events

One case of transverse myelitis was observed during the clinical development program (2762 RAPTIVA-treated patients); neurologic events, including cases of Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, facial palsy, and transverse myelitis have been observed in patients receiving RAPTIVA in the postmarketing setting (see ADVERSE REACTIONS, Postmarketing Experience). Patients being treated with RAPTIVA should be instructed to report any new neurological signs or symptoms to their physician. Prescribers should exercise caution in considering the use of RAPTIVA in patients with significant existing or new onset nervous system adverse events. RAPTIVA should be discontinued in patients who develop PML.

requiring hospitalization included cellulitis, pneumonia, abscess, sepsis, bronchitis, gastroenteritis, aseptic meningitis, Legionnaire's disease, and vertebral osteomyelitis (note some patients had more than one infection).

Progressive Multifocal Leukoencephalopathy (PML) has been reported in a post-marketing study. Physicians treating patients with RAPTIVA should consider PML in any patient with new-onset neurologic manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. Patients being treated with RAPTIVA should be instructed to report any new neurological signs or symptoms to their physician. RAPTIVA should be discontinued in patients who develop PML.

In postmarketing experience, serious bacterial, viral, fungal, and opportunistic infections have occurred, including pneumonia, sepsis, meningitis, and encephalitis. Some of these infections have been fatal. Postmarketing reports include cytomegaloviral infections; blastomyces, cryptococcal and tuberculous pneumonia; serious herpes infection; severe pneumonia with neutropenia (ANC 60/mm3); sepsis with seeding of distant sites; necrotizing fasciitis; and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment.

Malignancies

RAPTIVA is an immunosuppressive agent. Many immunosuppressive agents have the potential to increase the risk of malignancy. The role of RAPTIVA in the development of malignancies is not known. Caution should be exercised when considering the use of RAPTIVA in patients at high risk for malignancy or with a history of malignancy. If a patient develops a malignancy, RAPTIVA should be discontinued (see ADVERSE REACTIONS, Malignancy).

Immune-Mediated Thrombocytopenia

Platelet counts at or below 52,000 cells per ìL were observed in 8 (0.3%) RAPTIVA-treated patients during clinical trials compared with none among the placebo-treated patients (see ADVERSE REACTIONS, Immune-Mediated Thrombocytopenia). Five of the 8 patients received a course of systemic steroids for thrombocytopenia. Thrombocytopenia resolved in the 7 patients receiving adequate....

See: Raptiva Page 8

....treatment period with RAPTIVA maintained PASI-75 response compared with 8 of 40 patients (20%) re-randomized to placebo. Sustained responses to RAPTIVA have also been observed in uncontrolled, open-label extension treatment trials when patients received RAPTIVA without interruption for 24 weeks.

In Study 2, response to intermittent RAPTIVA treatment was evaluated among patients who achieved PASI-75 response with 12 weeks of RAPTIVA treatment and were followed off-treatment until relapse of psoriasis (50% loss of treatment response). In patients who resumed RAPTIVA treatment upon relapse of psoriasis, 31% (17/55) re-established a PASI-75 response (compared with the initial baseline). After 12 weeks of treatment, the median duration of a PASI-75 response after RAPTIVA discontinuation was between 1 and 2 months. The safety and efficacy of RAPTIVA therapy beyond 1 year have not been established.

INDICATIONS AND USAGE

RAPTIVA® (efalizumab) is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

CONTRAINDICATIONS

RAPTIVA should not be administered to patients with known hypersensitivity to RAPTIVA or any of its components.

WARNINGS

Serious Infections

RAPTIVA is an immunosuppressive agent and has the potential to increase the risk of infection and reactivate latent, chronic infections. RAPTIVA should not be administered to patients with clinically important infections. Caution should be exercised when considering the use of RAPTIVA in patients with a chronic infection or history of recurrent infections. If a patient develops a serious infection, RAPTIVA should be discontinued. New infections developing during RAPTIVA treatment should be monitored closely. During the first 12 weeks of controlled trials, serious infections occurred in 7 of 1620 (0.4 %) RAPTIVA-treated patients compared with 1 of 715 (0.1%) placebo-treated patients (see ADVERSE REACTIONS, Infections). Serious infections

See Raptiva Page 7

All three components of the PASI (plaque induration, scaling, and erythema) contributed comparably to the improvement in PASI. Other clinical responses evaluated (Table 2) included the proportion of patients who achieved minimal or clear status by a static Physician Global Assessment (sPGA) and the proportion of patients with a reduction in PASI of at least 50% from baseline (PASI-50) 1 week following the 12-week treatment period. The sPGA is a 6 category scale ranging from "very severe" to "clear" indicating the physician's overall assessment of the psoriasis severity focusing on plaque, scaling and erythema. Treatment success of minimal or clear consisted of none or slight elevation in plaque, none or minimal white color in scaling, and up to moderate definite red coloration in erythema. Across all four studies, the percentage of patients with baseline sPGA classifications of moderate was 48−56%, severe 33−43%, and 3−6% were classified as very severe.

previously received systemic therapy or phototherapy (PUVA) for psoriasis. Patients with clinically significant flares and patients with guttate, erythrodermic, or pustular psoriasis as the sole form of psoriasis were excluded from the studies. Patients were randomized to receive doses of 1 mg/kg or 2 mg/kg of RAPTIVA or placebo administered once a week for 12 weeks. Patients randomized to RAPTIVA received 0.7 mg/kg as the first dose prior to receiving the full assigned dose in subsequent weeks. During the studies, patients could receive concomitant low potency topical steroids. No other concomitant psoriasis therapies were allowed during treatment or the follow-up period.

Patients were evaluated using the Psoriasis Area and Severity Index (PASI) during the study. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of the psoriatic changes within the affected regions (erythema, infiltration/plaque thickness, and desquamation). Both treatment groups in all four studies had baseline median PASI scores of 17. Both treatment groups across all four studies had baseline median body surface area involvement ranging between 22−28%. Compared with placebo, more patients randomized to RAPTIVA had at least a 75% reduction from baseline PASI score (PASI-75) 1 week after the 12-week treatment period (Table 1). RAPTIVA 2 mg/kg was not superior to RAPTIVA 1 mg/kg.