FDA Safety Changes: Apidra, Ontak, Raptiva

Jill Taylor

January 06, 2009

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January 6, 2009 — The US Food and Drug Administration (FDA) has approved revisions to the safety labeling, adding adverse event information for use of insulin glulisine [rDNA origin] injection in pediatric patients; boxed warnings regarding serious infusion reactions, capillary leak syndrome, and loss of visual acuity associated with denileukin diftitox; and the risk for serious infections associated with efalizumab.

Insulin Glulisine [rDNA origin] Injection (Apidra) Updated for Use in Pediatric Patients

On October 24, 2008, the FDA approved safety labeling revisions for insulin glulisine [rDNA origin] injection (Apidra; sanofi-aventis, US, LLC) to include adverse event information for pediatric patients (ages 4 - 17 years) with type 1 diabetes. The safety and effectiveness of insulin glulisine [rDNA origin], a rapid-acting human insulin analogue used to improve glycemic control in patients with diabetes mellitus, had previously been established only for adults.

When administered intravenously, insulin glulisine [rDNA origin] injection is equipotent to human insulin. Insulin glulisine [rDNA origin] injection has a more rapid onset and shorter duration of action than human insulin when administered subcutaneously.

In a phase 3 clinical study of children and adolescents with type 1 diabetes comparing the safety and effectiveness of insulin glulisine [rDNA origin] injection (N = 277) vs insulin lispro injection, USP [rDNA origin] (Humalog; Eli Lilly; N = 295), adverse reactions occurring with a frequency of 5% or more included nasopharyngitis (9.0% vs 9.5%, respectively), upper respiratory tract infection (8.3% vs 10.8%, respectively), headache (6.9% vs 11.2%, respectively), and hypoglycemic seizure (6.1% vs 4.7%, respectively).

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin glulisine [rDNA origin] injection. Children and adolescents with type 1 diabetes showed a higher incidence of severe symptomatic hypoglycemia (hypoglycemia requiring third-party intervention) in the 2 treatment groups vs adults. At 26 weeks, severe symptomatic hypoglycemia occurred in 16.2% of patients taking insulin glulisine [rDNA origin] injection vs 19.3% of patients taking insulin lispro injection, USP [rDNA origin].

For patients of all ages, pramlintide and somatostatin analogues have been added as drugs that may increase the blood glucose–lowering effect of insulin glulisine [rDNA origin] injection; niacin has been added as a drug that may reduce the blood glucose–lowering effect of insulin glulisine [rDNA origin] injection.

The safety and effectiveness of insulin glulisine have not been established for pediatric patients younger than 4 years with type 1 diabetes or for pediatric patients with type 2 diabetes.

As in adults, glucose monitoring is essential for pediatric patients receiving insulin therapy. An additional warning was added to use caution in treating patients who may be at risk for hypokalemia, such as those using potassium-lowing medications or patients taking medications sensitive to serum potassium concentrations.

Denileukin Diftitox (Ontak) Linked to Serious Infusion Reactions, Capillary Leak Syndrome, and Loss of Visual Acuity

On October 15, 2008, the FDA approved safety labeling revisions for denileukin diftitox (Ontak; Eisai Medical Research, Inc) to warn about serious infusion reactions, capillary leak syndrome, and loss of visual acuity. Denileukin diftitox is a CD-25–directed cytotoxin that is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the interleukin-2 receptor.

Data regarding infusion reactions and capillary leak syndrome have been collected from 3 clinical studies in which 234 patients were treated with the approved doses and schedule of denileukin diftitox. In these studies, serious infusion reactions were reported in 8.1% of patients treated with denileukin diftitox, and capillary leak syndrome was reported in 32.5% of patients. There have also been postmarketing reports of both infusion reactions and capillary leak syndrome that resulted in death.

In case of a serious infusion reaction, resuscitative equipment should be available during administration of denileukin diftitox. Patients should be regularly assessed during the treatment period for symptoms of capillary leak syndrome such as weight gain, new-onset or worsening edema, hypotension, and changes in serum albumin levels before the initiation of each course of therapy. Treatment with denileukin diftitox should be withheld for patients with serum albumin levels of less than 3.0 g/dL.

Symptoms associated with capillary leak syndrome may be delayed for as long as 2 weeks after infusion and may persist or worsen after cessation of treatment.

Efalizumab ( Raptiva) Linked to Serious Infections

On October 16, 2008, the FDA approved safety labeling revisions for efalizumab (Raptiva; Genentech, Inc) to warn about the risk for serious infections. Efalizumab is an immunosuppressive recombinant humanized immunoglobin G1 kappa isotype monoclonal antibody that binds to human CD11a, indicated for the treatment of patients 18 years or older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Adverse reactions identified during postapproval use of efalizumab include infection with John Cunningham virus resulting in progressive multifocal leukoencephalopathy as well as bacterial sepsis, viral meningitis, invasive fungal disease, and other opportunistic infections. Worsening of infection despite antimicrobial treatment has been observed, with some infections resulting in death.

Patients with psoriasis should receive all appropriate immunizations as recommended by current immunization guidelines before initiation of efalizumab therapy. Patients being treated with efalizumab should not receive live or live-attenuated vaccines. Also, those undergoing efalizumab treatment should be cautioned about the potential risk for shedding and transmission if household contacts receive live vaccines.

Apidra Prescribing Information

Ontak Prescribing Information

Raptiva Prescribing Information


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