Raptiva

Overdose

Doses up to 4 mg/kg/wk SC for 10 weeks following a conditioning (0.7 mg/kg) first dose have been administered without an observed increase in acute toxicity. The maximum administered single dose was 10 mg/kg IV. This was administered to one patient, who subsequently was admitted to the hospital for severe vomiting. In case of overdose, it is recommended that the patient be monitored for 24-48 hours for any acute signs or symptoms of adverse reactions or effects and appropriate treatment instituted.

Contraindications

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

Undesirable effects

The most serious adverse reactions observed during treatment with RAPTIVA (efalizumab) are serious infections, including PML, malignancies, thrombocytopenia, hemolytic anemia, arthritis events, psoriasis worsening and variants, and neurologic events (see WARNINGS).

The most common adverse reactions associated with RAPTIVA (efalizumab) were a first dose reaction complex that included headache, chills, fever, nausea, and myalgia within two days following the first two injections. These reactions are dose-level related in incidence and severity and were largely mild to moderate in severity when a conditioning dose of 0.7 mg/kg was used as the first dose. In placebo-controlled trials, 29% of patients treated with RAPTIVA (efalizumab) 1 mg/kg developed one or more of these symptoms following the first dose compared with 15% of patients receiving placebo. After the third dose, 4% and 3% of patients receiving RAPTIVA (efalizumab) 1 mg/kg and placebo, respectively, experienced these symptoms. Less than 1% of patients discontinued RAPTIVA (efalizumab) treatment because of these adverse events.

Other adverse events resulting in discontinuation of RAPTIVA (efalizumab) treatment were psoriasis (0.6%), pain (0.4%), arthritis (0.4%), and arthralgia (0.3%).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect RAPTIVA (efalizumab) exposure for 2762 adult psoriasis patients (age range 18 to 75 years), including 2400 patients exposed for three months, 904 for six months, and 218 exposed for one year or more, in all controlled and uncontrolled studies. The median age of patients receiving RAPTIVA (efalizumab) was 44 years, with 189 patients above the age of 65; 67% were men, and 89% were Caucasian. These data include patients treated at doses higher than the recommended dose of 1 mg/kg weekly.

Controlled clinical trials provide the most informative basis for estimating the frequency of RAPTIVA (efalizumab) -related adverse drug reactions. Table 3 enumerates the adverse events occurring during controlled periods of the clinical trials where the frequency of the adverse events is at least 2% greater in the RAPTIVA (efalizumab) -treated group than the placebo group.

Table 3: Adverse Events in Placebo Controlled Study Periods Reported at a ≥ 2% Higher Rate in the 1 mg/kg/wk RAPTIVA (efalizumab) Treatment than Placebo Groups

Adverse events occurring at a rate between 1 and 2% greater in the RAPTIVA (efalizumab) group compared with placebo were arthralgia, asthenia, peripheral edema, and psoriasis.

The following serious adverse reactions were observed in RAPTIVA (efalizumab) -treated patients.

In the first 12 weeks of placebo-controlled studies, the proportion of patients with serious infection was 0.4% (7/1620) in the RAPTIVA (efalizumab) -treated group (5 of these were hospitalized, 0.3%) and 0.1% (1/715) in the placebo group (see WARNINGS: Serious Infections). In the complete safety data from both controlled and uncontrolled studies, the overall incidence of hospitalization for infections was 1.6 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.2 per 100 patient-years for placebo-treated patients. Including controlled, uncontrolled, and follow-up study treatment periods there were 27 serious infections in 2475 RAPTIVA (efalizumab) -treated patients. These infections included cellulitis, pneumonia, abscess, sepsis, sinusitis, bronchitis, gastroenteritis, aseptic meningitis, Legionnaire's disease, septic arthritis, and vertebral osteomyelitis. In controlled trials, the overall rate of infections in RAPTIVA (efalizumab) -treated patients was 3% higher than in placebo-treated patients (Table 3).

In postmarketing experience, serious bacterial, viral, fungal, and opportunistic infections have occurred, including JC virus infection resulting in PML. Some of these infections have been fatal. Worsening of infection despite antimicrobial treatment has been observed (see Boxed Warnings, CONTRAINDICATIONS, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).

Among the 2762 psoriasis patients who received RAPTIVA (efalizumab) at any dose (median duration 8 months), 31 patients were diagnosed with 37 malignancies (see WARNINGS: Malignancies). The overall incidence of malignancies of any kind was 1.8 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.6 per 100 patient-years for placebo-treated patients. Malignancies observed in the RAPTIVA (efalizumab) -treated patients included non-melanoma skin cancer, non-cutaneous solid tumors, Hodgkin's lymphoma and non-Hodgkin's lymphoma, and malignant melanoma. The incidence of non-cutaneous solid tumors (8 in 1790 patient-years) and malignant melanoma were within the range expected for the general population.

The majority of the malignancies were non-melanoma skin cancers; 26 cases (13 basal, 13 squamous) in 20 patients (0.7% of 2762 RAPTIVA (efalizumab) -treated patients). The incidence was comparable for RAPTIVA (efalizumab) -treated and placebo-treated patients. However, the size of the placebo group and duration of follow-up were limited and a difference in rates of non-melanoma skin cancers cannot be excluded.

In the combined safety database of 2762 RAPTIVA (efalizumab) -treated patients, there were eight occurrences (0.3%) of thrombocytopenia of < 52,000 cells per µL reported (see WARNINGS: Immune-Mediated Thrombocytopenia). Three of the eight patients were hospitalized for thrombocytopenia, including one patient with heavy uterine bleeding; all cases were consistent with an immune-mediated thrombocytopenia. Antiplatelet antibody was evaluated in one patient and was found to be positive. Each case resulted in discontinuation of RAPTIVA (efalizumab). Based on available platelet count measurements, the onset of platelet decline was between 8 and 12 weeks after the first dose of RAPTIVA (efalizumab) in 5 of the patients. Onset was more delayed in 3 patients, occurring as late as one year in 1 patient. In these cases, the platelet count nadirs occurred between 12 and 72 weeks after the first dose of RAPTIVA (efalizumab).

Two reports of hemolytic anemia were observed in clinical trials. Additional cases were reported in the postmarketing setting. The anemia was diagnosed 4-6 months after the start of RAPTIVA (efalizumab) and in two serious cases the hemoglobin level decreased to 6 and 7 g/dl. RAPTIVA (efalizumab) treatment was discontinued, erythrocyte transfusions and other therapies were administered (see WARNINGS: Immune-Mediated Hemolytic Anemia).

In the combined safety database from all studies, serious psoriasis adverse events occurred in 19 RAPTIVA (efalizumab) -treated patients (0.7%) including hospitalization in 17 patients (see WARNINGS: Psoriasis Worsening/Variants). Most of these events (14/19) occurred after discontinuation of study drug and occurred in both patients responding and not responding to RAPTIVA (efalizumab) treatment. Serious adverse events of psoriasis included pustular, erythrodermic, and guttate subtypes. During the first 12 weeks of treatment within placebo-controlled studies, the rate of psoriasis adverse events (serious and non-serious) was 3.2% (52/1620) in the RAPTIVA (efalizumab) -treated patients and 1.4% (10/715) in the placebo-treated patients.

Infrequent new onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing (see PRECAUTIONS: Arthritis Events).

Symptoms associated with a hypersensitivity reaction (e.g., dyspnea, asthma, urticaria, angioedema, maculopapular rash) were evaluated by treatment group. In the first 12 weeks of the controlled clinical studies, the proportion of patients reporting at least one hypersensitivity reaction was 8% (95/1213) in the 1 mg/kg/wk group and 7% (49/715) of patients in the placebo group. Urticaria was observed in 1% of patients (16/1213) receiving RAPTIVA (efalizumab) and 0.4% of patients (3/715) receiving placebo during the initial 12-week treatment period. Other observed adverse events in patients receiving RAPTIVA (efalizumab) that may be indicative of hypersensitivity included: laryngospasm, angioedema, erythema multiforme, asthma, and allergic drug eruption. One patient was hospitalized with a serum sickness-like reaction.

In the entire RAPTIVA (efalizumab) clinical development program of 2762 RAPTIVA (efalizumab) -treated patients, inflammatory, potentially immune-mediated adverse events resulting in hospitalization included inflammatory arthritis (12 cases, 0.4% of patients) and interstitial pneumonitis (2 cases). One case each of the following serious adverse reactions was observed: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, sialadenitis, and sensorineural hearing loss. Myositis, eosinophilic pneumonitis, resolving after discontinuation of RAPTIVA (efalizumab) have been reported postmarketing.

The following adverse reactions have been identified during postapproval use of RAPTIVA (efalizumab). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections: serious bacterial, fungal, viral and other opportunistic infections, including JC virus resulting in PML (see Boxed Warnings, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).

Malignancies: lymphoma

Skin: toxic epidermal necrolysis and photosensitivity reactions

Neurologic: Guillain-Barré Syndrome, chronic inflammatory demyelinating

polyneuropathy, transverse myelitis, and facial palsy (see WARNINGS: Neurologic Events).

In RAPTIVA (efalizumab) -treated patients, a mean elevation in alkaline phosphatase (5 Units/L) was observed; 4% of RAPTIVA (efalizumab) -treated patients experienced a shift to above normal values compared with 0.6% of placebo-treated patients. The clinical significance of this change is unknown. Higher numbers of RAPTIVA (efalizumab) -treated patients experienced elevations above normal in two or more liver function tests than placebo (3.1% vs. 1.5%).

Other laboratory adverse reactions that were observed included thrombocytopenia (see WARNINGS, and ADVERSE REACTIONS: Immune-Mediated Thrombocytopenia), lymphocytosis (40%) (including three cases of transient atypical lymphocytosis), and leukocytosis (26%).

In patients evaluated for antibodies to RAPTIVA (efalizumab) after RAPTIVA (efalizumab) treatment ended, predominantly low-titer antibodies to RAPTIVA (efalizumab) or other protein components of the RAPTIVA (efalizumab) drug product were detected in 6.3% (67/1063) of patients. The long-term immunogenicity of RAPTIVA (efalizumab) is unknown.

The data reflect the percentage of patients whose test results were considered positive for antibodies to RAPTIVA (efalizumab) in the ELISA assay, and 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 RAPTIVA (efalizumab) with the incidence of antibodies to other products may be misleading.

Therapeutic indications

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.

Pharmacokinetic properties

In patients with moderate to severe plaque psoriasis, following an initial SC RAPTIVA (efalizumab) dose of 0.7 mg/kg followed by 11 weekly SC doses of 1 mg/kg/wk, serum concentrations reached a steady-state at 4 weeks with a mean trough concentration of approximately 9 µg/mL (n = 26). After the last dose, the mean peak concentration was approximately 12 µg/mL (n = 25). Mean steady-state clearance was 24 mL/kg/day (range = 5-76 mL/kg/day, n = 25). Mean time to eliminate RAPTIVA (efalizumab) after the last steady-state dose was 25 days (range = 13-35 days, n = 17). The mean estimated RAPTIVA (efalizumab) SC bioavailability was 50%. In a population pharmacokinetic analysis of 1088 patients, body weight was found to be the most significant covariate affecting RAPTIVA (efalizumab) clearance. In patients receiving weekly SC doses of 1 mg/kg, RAPTIVA (efalizumab) exposure was similar across body weight quartiles. RAPTIVA (efalizumab) clearance was not significantly affected by gender or race. The pharmacokinetics of RAPTIVA (efalizumab) in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of RAPTIVA (efalizumab) have not been studied.

Date of revision of the text

Name of the medicinal product

Qualitative and quantitative composition

RAPTIVA (efalizumab) is supplied as a lyophilized, sterile powder to deliver 125 mg of efalizumab per single-use vial.

Each RAPTIVA (efalizumab) carton contains four trays. Each tray contains one single-use vial designed to deliver 125 mg of efalizumab, one single-use prefilled diluent syringe containing 1.3 mL sterile water for injection (non-USP), two 25 gauge × 5/8 inch needles, two alcohol prep pads, a package insert with an accompanying patient information insert. The NDC number for the four administration dose pack carton is 50242-058-04.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990. Revised: 3/13/09

Special warnings and precautions for use

PML is a rapidly progressive infection of the central nervous system caused by the JC virus that leads to death or severe disability.

RAPTIVA (efalizumab) increases the risk for PML and this risk may markedly increase with longer duration of RAPTIVA (efalizumab) exposure. Post-marketing cases of PML have been reported with RAPTIVA (efalizumab) used as monotherapy. Three reports of confirmed PML were associated with exposure for greater than 3 years. At the time of these 3 reports, it is estimated that approximately 46,000 patients had been exposed to RAPTIVA (efalizumab) worldwide; however, relatively few patients had been exposed beyond 2 years. Approximately 14,000 patients have been exposed for greater than 1 year, 5,100 patients have been exposed for greater then 2 years and 1,900 patients have been exposed for greater than 3 years. The time dependent threshold when the risk for PML increases is unknown since additional cases may have been misdiagnosed and/or not reported.

The effect of intermittent use of RAPTIVA (efalizumab) , or the concomitant or sequential use of other immunosuppressant drugs, on the risk of PML is not known (see Boxed Warnings, CONTRAINDICATIONS). There are no known screening tests or medical interventions that can reliably predict, prevent, or treat PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and may include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and/or changes in thinking, memory, and orientation leading to confusion and personality changes.

Healthcare providers treating patients with RAPTIVA (efalizumab) should consider PML in any patient with new-onset neurologic manifestations. Patients being treated with RAPTIVA (efalizumab) should be instructed to immediately report to their healthcare provider any new neurological signs or symptoms that they or anyone close to them notices. RAPTIVA (efalizumab) should be withheld immediately at the first sign or symptom suggestive of PML (see WARNINGS: Psoriasis Worsening and Variants). It is not known whether early detection of PML and discontinuation of RAPTIVA (efalizumab) will mitigate risk of irreversible neurological damage and death associated with the disease. Consultation with a neurologist, brain MRI and cerebrospinal fluid analysis for JC viral DNA should be considered. Patients should be evaluated frequently to ensure they are receiving significant clinical benefit that justifies continued treatment in light of the risks, to ensure they understand the significance of the risk of PML, and for any sign or symptom that is suggestive of PML. Patients who discontinue RAPTIVA (efalizumab) should continue to be carefully monitored for the onset of neurologic symptoms that may represent PML and for worsening of psoriasis (see Boxed Warnings).

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

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 (see Boxed Warnings).

The immunosuppression caused by RAPTIVA (efalizumab) may have the potential to increase the risk of malignancy. The role of RAPTIVA (efalizumab) in the development of malignancies is not known. Caution should be exercised when considering the use of RAPTIVA (efalizumab) 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: Malignancies).

RAPTIVA (efalizumab) causes immunosuppression. The safety and efficacy of RAPTIVA (efalizumab) in combination with other immunosuppressive agents or phototherapy have not been evaluated. Patients receiving other systemic immunosuppressive agents should not receive concurrent therapy with RAPTIVA (efalizumab) because of the possibility of increased risk of infections and malignancies. RAPTIVA (efalizumab) should not be administered to patients with compromised immune systems, for example, due to HIV infection or AIDS, leukemia, or lymphoma.

Platelet counts at or below 52,000 cells per µL were observed in 8 (0.3%) RAPTIVA (efalizumab) -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 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 (efalizumab) (see PRECAUTIONS: Laboratory Tests) and RAPTIVA (efalizumab) should be discontinued if thrombocytopenia develops.

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

Worsening of psoriasis can occur during or after discontinuation of RAPTIVA (efalizumab). During clinical studies, 19 of 2589 (0.7%) of RAPTIVA (efalizumab) -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 (efalizumab) treatment, should be closely observed following discontinuation of RAPTIVA (efalizumab) , and appropriate psoriasis treatment instituted as necessary.

One case of transverse myelitis was observed during the clinical development program (2762 RAPTIVA (efalizumab) -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 (efalizumab) in the postmarketing setting (see ADVERSE REACTIONS: Postmarketing Experience). Patients being treated with RAPTIVA (efalizumab) should be instructed to immediately report any new neurological signs or symptoms to their physician. Prescribers should not use RAPTIVA (efalizumab) in patients with significant existing or new onset nervous system adverse events. RAPTIVA (efalizumab) should be discontinued in patients who develop PML

First dose reactions including headache, fever, nausea, and vomiting are associated with RAPTIVA (efalizumab) 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 the incidence and severity of reactions associated with initial dosing (see DOSAGE AND ADMINISTRATION). Cases of aseptic meningitis resulting in hospitalization have been observed in association with initial dosing (see ADVERSE REACTIONS; Inflammatory/Immune-Mediated Reactions).

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 (efalizumab) and were uncommonly associated with flare of psoriasis. Patients improved after discontinuation of RAPTIVA (efalizumab) with or without anti-arthritis therapy.

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

Healthcare providers should counsel patients about the risks and benefits of RAPTIVA (efalizumab) before an initial prescription, including the risks of PML and other serious infections. Prescribers should monitor patients frequently while on therapy to ensure significant clinical benefit that justifies continued treatment in light of the risks, to ensure they understand the significance of the risk of PML, to assess for any sign or symptom that is suggestive of PML, to assess for adverse events, and to continue patient education about the risks and benefits of RAPTIVA (see Boxed Warnings, CONTRAINDICATIONS, WARNINGS: Progressive Multifocal Leukoencephalopathy)

Patients should be instructed to:

• Read the Medication Guide before starting RAPTIVA (efalizumab) and before each RAPTIVA (efalizumab) injection. They should be encouraged to ask questions about what they have read.
• Have frequent follow-up with their health care provider while on therapy (see Boxed Warnings, WARNINGS: Progressive Multifocal Leukoencephalopathy)
• Report and seek immediate medical attention if they experience any new or worsening medical problems, such as an infection that does not go away, or if they or people close to them notice a new or sudden change in the patient's thinking; if they develop a new or sudden change in 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 (see Boxed Warnings, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS)

Patients should also be informed that RAPTIVA (efalizumab) is an immunosuppressant, and should not be used with other systemic immunosuppressive therapies due to the potential for an increased risk of developing an infection (including PML) or a malignancy that could lead to hospitalization, disability, or death.

Patients should be advised to inform all of their healthcare providers that they are receiving RAPTIVA (efalizumab) and to immediately call their physician's office if they develop any signs of, or receive a diagnosis of infection, including PML, or malignancy while undergoing treatment with RAPTIVA (efalizumab). Patients should also be informed that their physician may monitor platelet counts during therapy.

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

If a patient or caregiver is to administer RAPTIVA (efalizumab) , he/she should be instructed regarding injection techniques and how to measure the correct dose to ensure proper administration of RAPTIVA (efalizumab). Patients should be also referred to the RAPTIVA (efalizumab) Medication Guide. 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.

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

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

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 (efalizumab) had no adverse effects on mating, fertility, or reproduction parameters. The clinical significance of this observation is uncertain.

Genotoxicity studies were not conducted.

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

In a developmental toxicity study conducted in mice using an anti-mouse CD11a antibody at up to 30 times the equivalent of the recommended clinical dose of RAPTIVA (efalizumab) , no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when administered during organogenesis. No adverse effects on behavioral, reproductive, or growth parameters were observed in offspring of female mice subcutaneously treated with an anti-mouse CD11a antibody during gestation and lactation using doses 3- to 30-times the equivalent of the recommended clinical dose of RAPTIVA (efalizumab). At 11 weeks of age, the offspring of these females exhibited a significant reduction in their ability to mount an antibody response, which showed evidence of partial reversibility by 25 weeks of age. Animal studies, however, are not always predictive of human response, and there are no adequate and well-controlled studies in pregnant women.

Since the effects of RAPTIVA (efalizumab) on pregnant women and fetal development, including immune system development are not known, healthcare providers are encouraged to enroll patients who become pregnant while taking RAPTIVA (efalizumab) (or within 6 weeks of discontinuing RAPTIVA (efalizumab) ) in the RAPTIVA (efalizumab) Pregnancy Registry by calling 1-877 RAPTIVA (efalizumab) (1-877-727-8482).

It is not known whether RAPTIVA (efalizumab) is excreted in human milk. An anti-mouse CD11a antibody was detected in milk samples of lactating mice exposed to anti-mouse CD11a antibody and the offspring of the exposed females exhibited significant reduction in antibody responses (see PRECAUTIONS: Pregnancy). Since maternal immunoglobulins are known to be present in the milk of lactating mothers, and animal data suggest the potential for adverse effects in nursing infants from RAPTIVA (efalizumab) , 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.

FDA has not required pediatric studies in ages 0 to 17 because of the potential risk of non-recoverable suppression of humoral immunity with repeat dose administration of RAPTIVA (efalizumab) in pediatric patients, based on data from juvenile animal studies.

An immunotoxicity study was conducted in juvenile mice dosed from 3 to 11 weeks of age (human age equivalent approximately 1-14 years) using an anti-mouse CD11a antibody. Immediately following 8 weekly doses at 3 to 30 times the human equivalent dose of RAPTIVA (efalizumab) , the mice exhibited a significant reduction in the ability to mount a humoral antibody response consistent with the mechanism of action of blocking LFA-1/ICAM interactions. Complete reversibility of the treatment related suppression of humoral immunity was not achieved following a 13 week recovery period.

Of the 1620 patients who received RAPTIVA (efalizumab) in controlled trials, 128 were ≥ 65 years of age, and 2 were ≥ 75 years of age. Although no differences in safety or efficacy were observed between older and younger patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. Because the incidence of infections is higher in the elderly population, in general, caution should be used in treating the elderly. There have been postmarketing reports of PML occurring in elderly patients who received RAPTIVA for more than three years (see Boxed Warnings, WARNINGS: Progressive Multifocal Leukoencephalopathy).

Dosage (Posology) and method of administration

The recommended dose of RAPTIVA (efalizumab) is a single 0.7 mg/kg SC conditioning dose followed by weekly SC doses of 1 mg/kg (maximum single dose not to exceed a total of 200 mg).

RAPTIVA (efalizumab) is intended for use under the guidance and supervision of a physician. If it is determined to be appropriate, patients may self-inject RAPTIVA (efalizumab) after proper training in the preparation and injection technique and with medical follow-up (see PRECAUTIONS: Information for Patients).

RAPTIVA (efalizumab) should be administered using the sterile, disposable syringe and needles provided (see HOW SUPPLIED section). Remove the cap from the pre-filled syringe containing sterile water for injection (non-USP) and attach the needle to the syringe. Remove the plastic cap protecting the rubber stopper of the RAPTIVA (efalizumab) vial and wipe the top of the rubber stopper with one of the provided alcohol swabs. After cleaning with the alcohol swab, do not touch the top of the vial. To prepare the RAPTIVA (efalizumab) solution, using the provided pre-filled diluent syringe slowly inject the 1.3 mL of sterile water for injection (non-USP) into the RAPTIVA (efalizumab) vial. Swirl the vial with a GENTLE rotary motion to dissolve the product. DO NOT SHAKE. Shaking will cause foaming of the RAPTIVA (efalizumab) solution. Generally, dissolution of RAPTIVA (efalizumab) takes less than 5 minutes. RAPTIVA (efalizumab) is provided as a single-use vial and contains no antibacterial preservatives. Reconstitute immediately before use and use only once. If the reconstituted RAPTIVA (efalizumab) is not used immediately, store the RAPTIVA (efalizumab) vial at room temperature and use within 8 hours. The reconstituted solution should be clear to pale yellow and free of particulates.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to subcutaneous administration. If particulates or discolorations are noted, the product should not be used.

Insert the needle into the vial containing the RAPTIVA (efalizumab) solution, invert the vial, and keeping the needle below the level of the liquid, withdraw the dose to be given into the syringe. Replace the needle on the syringe with a new needle.

No other medications should be added to solutions containing RAPTIVA (efalizumab) , and RAPTIVA (efalizumab) should not be reconstituted with other diluents.

Sites for injection include thigh, abdomen, buttocks, or upper arm. Injection sites should be rotated.

Following administration, discard any unused reconstituted RAPTIVA (efalizumab) solution.

Do not use a vial beyond the expiration date stamped on the carton or vial label. RAPTIVA (efalizumab) (lyophilized powder) must be refrigerated at 2-8°C (36-46°F). Protect the vial from exposure to light. Store in original carton until time of use.

Interaction with other medicinal products and other forms of interaction

The most serious adverse reactions observed during treatment with RAPTIVA (efalizumab) are serious infections, including PML, malignancies, thrombocytopenia, hemolytic anemia, arthritis events, psoriasis worsening and variants, and neurologic events (see WARNINGS).

The most common adverse reactions associated with RAPTIVA (efalizumab) were a first dose reaction complex that included headache, chills, fever, nausea, and myalgia within two days following the first two injections. These reactions are dose-level related in incidence and severity and were largely mild to moderate in severity when a conditioning dose of 0.7 mg/kg was used as the first dose. In placebo-controlled trials, 29% of patients treated with RAPTIVA (efalizumab) 1 mg/kg developed one or more of these symptoms following the first dose compared with 15% of patients receiving placebo. After the third dose, 4% and 3% of patients receiving RAPTIVA (efalizumab) 1 mg/kg and placebo, respectively, experienced these symptoms. Less than 1% of patients discontinued RAPTIVA (efalizumab) treatment because of these adverse events.

Other adverse events resulting in discontinuation of RAPTIVA (efalizumab) treatment were psoriasis (0.6%), pain (0.4%), arthritis (0.4%), and arthralgia (0.3%).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect RAPTIVA (efalizumab) exposure for 2762 adult psoriasis patients (age range 18 to 75 years), including 2400 patients exposed for three months, 904 for six months, and 218 exposed for one year or more, in all controlled and uncontrolled studies. The median age of patients receiving RAPTIVA (efalizumab) was 44 years, with 189 patients above the age of 65; 67% were men, and 89% were Caucasian. These data include patients treated at doses higher than the recommended dose of 1 mg/kg weekly.

Controlled clinical trials provide the most informative basis for estimating the frequency of RAPTIVA (efalizumab) -related adverse drug reactions. Table 3 enumerates the adverse events occurring during controlled periods of the clinical trials where the frequency of the adverse events is at least 2% greater in the RAPTIVA (efalizumab) -treated group than the placebo group.

Table 3: Adverse Events in Placebo Controlled Study Periods Reported at a ≥ 2% Higher Rate in the 1 mg/kg/wk RAPTIVA (efalizumab) Treatment than Placebo Groups

Adverse events occurring at a rate between 1 and 2% greater in the RAPTIVA (efalizumab) group compared with placebo were arthralgia, asthenia, peripheral edema, and psoriasis.

The following serious adverse reactions were observed in RAPTIVA (efalizumab) -treated patients.

In the first 12 weeks of placebo-controlled studies, the proportion of patients with serious infection was 0.4% (7/1620) in the RAPTIVA (efalizumab) -treated group (5 of these were hospitalized, 0.3%) and 0.1% (1/715) in the placebo group (see WARNINGS: Serious Infections). In the complete safety data from both controlled and uncontrolled studies, the overall incidence of hospitalization for infections was 1.6 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.2 per 100 patient-years for placebo-treated patients. Including controlled, uncontrolled, and follow-up study treatment periods there were 27 serious infections in 2475 RAPTIVA (efalizumab) -treated patients. These infections included cellulitis, pneumonia, abscess, sepsis, sinusitis, bronchitis, gastroenteritis, aseptic meningitis, Legionnaire's disease, septic arthritis, and vertebral osteomyelitis. In controlled trials, the overall rate of infections in RAPTIVA (efalizumab) -treated patients was 3% higher than in placebo-treated patients (Table 3).

In postmarketing experience, serious bacterial, viral, fungal, and opportunistic infections have occurred, including JC virus infection resulting in PML. Some of these infections have been fatal. Worsening of infection despite antimicrobial treatment has been observed (see Boxed Warnings, CONTRAINDICATIONS, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).

Among the 2762 psoriasis patients who received RAPTIVA (efalizumab) at any dose (median duration 8 months), 31 patients were diagnosed with 37 malignancies (see WARNINGS: Malignancies). The overall incidence of malignancies of any kind was 1.8 per 100 patient-years for RAPTIVA (efalizumab) -treated patients compared with 1.6 per 100 patient-years for placebo-treated patients. Malignancies observed in the RAPTIVA (efalizumab) -treated patients included non-melanoma skin cancer, non-cutaneous solid tumors, Hodgkin's lymphoma and non-Hodgkin's lymphoma, and malignant melanoma. The incidence of non-cutaneous solid tumors (8 in 1790 patient-years) and malignant melanoma were within the range expected for the general population.

The majority of the malignancies were non-melanoma skin cancers; 26 cases (13 basal, 13 squamous) in 20 patients (0.7% of 2762 RAPTIVA (efalizumab) -treated patients). The incidence was comparable for RAPTIVA (efalizumab) -treated and placebo-treated patients. However, the size of the placebo group and duration of follow-up were limited and a difference in rates of non-melanoma skin cancers cannot be excluded.

In the combined safety database of 2762 RAPTIVA (efalizumab) -treated patients, there were eight occurrences (0.3%) of thrombocytopenia of < 52,000 cells per µL reported (see WARNINGS: Immune-Mediated Thrombocytopenia). Three of the eight patients were hospitalized for thrombocytopenia, including one patient with heavy uterine bleeding; all cases were consistent with an immune-mediated thrombocytopenia. Antiplatelet antibody was evaluated in one patient and was found to be positive. Each case resulted in discontinuation of RAPTIVA (efalizumab). Based on available platelet count measurements, the onset of platelet decline was between 8 and 12 weeks after the first dose of RAPTIVA (efalizumab) in 5 of the patients. Onset was more delayed in 3 patients, occurring as late as one year in 1 patient. In these cases, the platelet count nadirs occurred between 12 and 72 weeks after the first dose of RAPTIVA (efalizumab).

Two reports of hemolytic anemia were observed in clinical trials. Additional cases were reported in the postmarketing setting. The anemia was diagnosed 4-6 months after the start of RAPTIVA (efalizumab) and in two serious cases the hemoglobin level decreased to 6 and 7 g/dl. RAPTIVA (efalizumab) treatment was discontinued, erythrocyte transfusions and other therapies were administered (see WARNINGS: Immune-Mediated Hemolytic Anemia).

In the combined safety database from all studies, serious psoriasis adverse events occurred in 19 RAPTIVA (efalizumab) -treated patients (0.7%) including hospitalization in 17 patients (see WARNINGS: Psoriasis Worsening/Variants). Most of these events (14/19) occurred after discontinuation of study drug and occurred in both patients responding and not responding to RAPTIVA (efalizumab) treatment. Serious adverse events of psoriasis included pustular, erythrodermic, and guttate subtypes. During the first 12 weeks of treatment within placebo-controlled studies, the rate of psoriasis adverse events (serious and non-serious) was 3.2% (52/1620) in the RAPTIVA (efalizumab) -treated patients and 1.4% (10/715) in the placebo-treated patients.

Infrequent new onset or recurrent severe arthritis events, including psoriatic arthritis events, have been reported in clinical trials and postmarketing (see PRECAUTIONS: Arthritis Events).

Symptoms associated with a hypersensitivity reaction (e.g., dyspnea, asthma, urticaria, angioedema, maculopapular rash) were evaluated by treatment group. In the first 12 weeks of the controlled clinical studies, the proportion of patients reporting at least one hypersensitivity reaction was 8% (95/1213) in the 1 mg/kg/wk group and 7% (49/715) of patients in the placebo group. Urticaria was observed in 1% of patients (16/1213) receiving RAPTIVA (efalizumab) and 0.4% of patients (3/715) receiving placebo during the initial 12-week treatment period. Other observed adverse events in patients receiving RAPTIVA (efalizumab) that may be indicative of hypersensitivity included: laryngospasm, angioedema, erythema multiforme, asthma, and allergic drug eruption. One patient was hospitalized with a serum sickness-like reaction.

In the entire RAPTIVA (efalizumab) clinical development program of 2762 RAPTIVA (efalizumab) -treated patients, inflammatory, potentially immune-mediated adverse events resulting in hospitalization included inflammatory arthritis (12 cases, 0.4% of patients) and interstitial pneumonitis (2 cases). One case each of the following serious adverse reactions was observed: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, sialadenitis, and sensorineural hearing loss. Myositis, eosinophilic pneumonitis, resolving after discontinuation of RAPTIVA (efalizumab) have been reported postmarketing.

The following adverse reactions have been identified during postapproval use of RAPTIVA (efalizumab). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections: serious bacterial, fungal, viral and other opportunistic infections, including JC virus resulting in PML (see Boxed Warnings, WARNINGS: Serious Infections, Progressive Multifocal Leukoencephalopathy).

Malignancies: lymphoma

Skin: toxic epidermal necrolysis and photosensitivity reactions

Neurologic: Guillain-Barré Syndrome, chronic inflammatory demyelinating

polyneuropathy, transverse myelitis, and facial palsy (see WARNINGS: Neurologic Events).

In RAPTIVA (efalizumab) -treated patients, a mean elevation in alkaline phosphatase (5 Units/L) was observed; 4% of RAPTIVA (efalizumab) -treated patients experienced a shift to above normal values compared with 0.6% of placebo-treated patients. The clinical significance of this change is unknown. Higher numbers of RAPTIVA (efalizumab) -treated patients experienced elevations above normal in two or more liver function tests than placebo (3.1% vs. 1.5%).

Other laboratory adverse reactions that were observed included thrombocytopenia (see WARNINGS, and ADVERSE REACTIONS: Immune-Mediated Thrombocytopenia), lymphocytosis (40%) (including three cases of transient atypical lymphocytosis), and leukocytosis (26%).

In patients evaluated for antibodies to RAPTIVA (efalizumab) after RAPTIVA (efalizumab) treatment ended, predominantly low-titer antibodies to RAPTIVA (efalizumab) or other protein components of the RAPTIVA (efalizumab) drug product were detected in 6.3% (67/1063) of patients. The long-term immunogenicity of RAPTIVA (efalizumab) is unknown.

The data reflect the percentage of patients whose test results were considered positive for antibodies to RAPTIVA (efalizumab) in the ELISA assay, and 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 RAPTIVA (efalizumab) with the incidence of antibodies to other products may be misleading.

No formal drug interaction studies have been performed with RAPTIVA (efalizumab). RAPTIVA (efalizumab) should not be used with other immunosuppressive drugs (see WARNINGS: Immunosuppression).

Live (including live-attenuated) vaccines should not be administered during RAPTIVA treatment (see PRECAUTIONS: Immunizations).

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