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Progressive Multifocal Leukoencephalopathy (PML)
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.
Immune-Mediated Hemolytic Anemia
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.
Psoriasis Worsening and Variants
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
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.
Information for Patients
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).
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
Pregnancy (Category C)
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).This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/16/2009
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