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. 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 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). Postmarketing reports of serious infections include necrotizing fasciitis and tuberculous pneumonia. Bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia (ANC 60/mm³), and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment have been observed.

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 RAPTIVAin 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 nL were observed in 8 (0.3%) RAPTIVA-treated patients during clinical trials compared with none among the placebo-treated patients (see ADVERSE REACTIONS, 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 (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.

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

The safety and efficacy of vaccines, administered to patients being treated with RAPTIVA have not been studied. 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. Acellular, live and live-attenuated vaccines should not be administered during RAPTIVA treatment.

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 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)

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 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 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 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) to enroll into the Registry.

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 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.

Subcutaneous injections of male and female mice with an anti-mouse CD11a antibody 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.

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, 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. 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 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 (or within 6 weeks of discontinuing RAPTIVA) in the RAPTIVA Pregnancy Registry by calling 1-877-RAPTIVA (1-877-727-8482).

Nursing Mothers

It is not known whether RAPTIVA 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, 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.

Pediatric Use

The safety and efficacy of RAPTIVA in pediatric patients have not been studied.

Geriatric Use

Of the 1620 patients who received RAPTIVA 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.

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