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U.S. Department of Health and Human Services

Drugs

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Everolimus for Tuberous Sclerosis Complex (TSC)

On August 29, 2012, the U. S. Food and Drug Administration granted accelerated approval for everolimus tablets for oral suspension (Afinitor Disperz, Novartis Pharmaceuticals Corp.) for the treatment of pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. With this new dosage form, the currently approved indication for treatment of SEGA has been expanded to allow treatment of children less than 3 years of age. The application also provides, a higher starting dose, revisions to dose modifications, and additional safety and efficacy data in the SEGA population.

Afinitor Disperz is the first pediatric formulation to be approved by FDA for the treatment of a tumor occurring primarily during childhood. This new dosage form (tablets for oral suspension) is more rapidly dissolved using smaller volumes of water than the tablet dosage form used in clinical trials and provides for smaller dose increments allowing greater dosing flexibility. This formulation also provides another option for adult patients with SEGA.

On October 29, 2010, everolimus (Afinitor Tablets) received its initial accelerated approval for the treatment of patients with SEGA associated with TSC who require therapeutic intervention and are not candidates for curative surgical resection. The approval was based on demonstration of a ≥50% reduction in SEGA tumor volume in 9 of 28 patients aged 3-34 years (median age 11 years) enrolled in a single arm trial. The starting dose utilized in this clinical trial was 3 mg/m2, with therapeutic drug monitoring to achieve and maintain therapeutic trough everolimus concentrations.

Today’s approval also provides the results of a randomized, double-blind, placebo controlled trial in pediatric and adult patients with SEGA, which examined a higher starting dose (4.5 mg/m2/day) and enrolled patients less than 3 years of age. In the randomized trial, 78 patients were randomized to receive everolimus and 39 to receive placebo. The median age of enrolled patients was 9.5 years (range: 0.8 to 26 years). The primary outcome measure was “SEGA Response Rate,” as determined by an independent central radiology review panel 6 months after the last patient was randomized. SEGA response was defined as a ≥50% reduction in the sum of the volumes of SEGA target lesions relative to baseline, in the absence of worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, or new or worsening hydrocephalus.

SEGA responses were observed in 27 of 78 patients (35%, 95% CI: 24, 46) in the everolimus arm and none of the 39 patients (95% CI: 0, 9) in the placebo arm (p < 0.0001). With a median follow-up duration of 8.4 months for the overall study population, all responses were ongoing and the median response duration was 5.3 months (range: 2.1 to 8.4 months) in Afinitor-treated patients.

In the randomized trial, the most common adverse reactions in patients receiving everolimus (incidence ≥ 20%) were stomatitis, respiratory tract infection, pyrexia, vomiting, rash, and anxiety, aggression or other behavioral disturbances. The most common (≥ 2%) grade 3-4 adverse reactions were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea.

Serious adverse events were reported for 19 (24%) patients in the everolimus group and 5 (13%) patients in the placebo group during the double blind period of the randomized study. The most common serious adverse event (reported in ≥ 3 patients and occurring more frequently in the everolimus group) was pyrexia. Serious adverse events due to infections were more common in patients < 3 years of age; a total of 6 of 13 patients < 3 years who received everolimus had at least one serious adverse event due to infection, compared to 2 of 7 patients < 3 years who received placebo. No deaths occurred in either treatment group.

The recommended starting dose of Afinitor Tablets and Afinitor Disperz for adult and pediatric patients with SEGA is now 4.5 mg/m2/day, with subsequent dosing based on therapeutic drug monitoring to achieve and maintain everolimus trough levels of 5 to 15 ng/mL. Product labeling has also been revised to include more specific dosing guidance in patients requiring concomitant medications and frequency of therapeutic drug monitoring.

The long term effects of Afinitor Tablets and Afinitor Disperz on growth and pubertal development are unknown. Confirmatory studies are underway to further evaluate the long term safety and effectiveness of everolimus in adult and pediatric patients with SEGA.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203985s000lbl.pdf

 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).