FDA Approvals: FluLaval and Fentora


October 12, 2006 — The US Food and Drug Administration (FDA) has a trivalent, inactivated split-virion influenza vaccine for the active immunization of adults against disease caused by viral strains likely to cause influenza this season; and fentanyl buccal tablets for the management of breakthrough pain in cancer patients who are tolerant to opioid therapy for their underlying persistent cancer pain.

Trivalent, Inactivated, Split-Virion Influenza Vaccine (FluLaval) for Use in Adults

On October 5, the FDA approved a trivalent, inactivated split-virion influenza vaccine (FluLaval, made by GlaxoSmithKline) for the active immunization of adults aged 18 years and older against disease caused by viral strains judged likely to cause seasonal influenza in the Northern Hemisphere in 2006-2007.

Each 0.5-mL dose for intramuscular injection contains 15 µg each of influenza virus hemagglutinin (HA) of A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. The vaccine is packaged in a 10-dose vial with thimerosal (25 µg per dose) as a preservative. According to an FDA news release, thimerosal-reduced or thimerosal-free formulations are planned for use in pediatric studies.

The approval was based on an accelerated review of data from randomized controlled, comparative clinical trials in 1000 healthy US adults aged 18 to 64 years, and 658 Canadian adults aged 50 years and older. Results showed the vaccine to be safe and capable of generating an immune response within 7 days of injection. The FDA notes that as part of the approval process, the maker will conduct further studies to verify the decrease in influenza disease after vaccination.

The majority of adverse events reported by vaccine recipients were mild and self-limiting, with the most commonly reported adverse events including injection-site pain, erythema, and/or swelling (incidence, ≥ 10%). The most commonly observed systemic adverse events occurring in 10% or more of recipients were headache, fatigue, myalgia, low-grade fever, and malaise.

Because the vaccine is prepared from virus propagated in the allantoic cavity of embryonated hens' eggs and may contain trace amounts of residual egg protein, it should not be administered to individuals with known systemic hypersensitivity reactions to egg proteins (eggs or egg products), chicken proteins, or other product components, such as thimerosal.

Vaccine use is contraindicated also in those who have had a life-threatening reaction to any previously administered influenza vaccine and patients with an acute evolving neurologic disorder. Caution is advised when considering vaccine use in patients who have developed Guillain-Barré syndrome within 6 weeks of receipt of prior influenza vaccine.

Also, the potential for drug interactions leading to decreased clearance of warfarin, theophylline, and phenytoin should be considered in patients receiving these drugs.

The influenza vaccine previously was approved for use in Canada, where it is marketed under the name Fluviral.

Fentanyl Buccal Tablets (Fentora) for Breakthrough Cancer Pain in Opioid-Tolerant Patients

On September 25, the FDA approved fentanyl buccal tablets (Fentora, made by Cephalon, Inc) for the management of breakthrough pain in cancer patients who are tolerant to current opioid therapy for their underlying persistent cancer pain. The tablets are available in 100-, 200-, 400-, 600-, and 800-µg strengths.

Patients considered opioid tolerant are those who are taking at least 60 mg/day of oral morphine, 25 µg/hour of transdermal fentanyl, 30 mg/day of oxycodone, 8 mg/day of oral hydromorphone, or an equianalgesic dose of another opioid for a week or longer.

Unlike conventional short-acting oral opioids that require 30 to 45 minutes to take effect, the tablet's proprietary drug delivery technology (OraVescent) allows approximately 50% of the active ingredient to be absorbed quickly into the bloodstream via the buccal mucosa. When placed in contact with saliva, the delivery system generates a reaction that leads to the release of carbon dioxide. According to a company news release, it is thought that transient pH changes accompanying this reaction may optimize tablet dissolution and fentanyl absorption rate.

The approval was based on data from placebo-controlled clinical trials, showing that use of the fentanyl buccal tablets achieved significant improvement on the Sum of Pain Intensity Differences scale (P < .01); some patients experienced clinically significant decreases in pain intensity and greater pain relief within 15 minutes, the first time point measured.

Fentanyl buccal tablets were well-tolerated in these studies. Most adverse events were mild to moderate in severity, and the most commonly reported of these (incidence, ≥ 10%) consisted of nausea, vomiting, application site abnormalities, fatigue, anemia, dizziness, constipation, edema, asthenia, dehydration, and headache. No attempt was made to correct for concomitant use of around-the-clock opioids or cancer-related symptoms.

Serious adverse events were related to opioid use and included respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. The FDA advises that all patients receiving fentanyl buccal therapy be monitored for symptoms of respiratory depression; opioid adverse effects should be expected and managed accordingly.

The recommended initial dose of fentanyl buccal tablets is one 100-µg tablet; titration should involve multiples of this dose. Patients requiring more than 100 µg can be instructed to use two 100-µg tablets (1 on each side of the mouth in the buccal cavity). If this dose is not successful in controlling the breakthrough pain episode, the patient may use two 100-µg tablets on each side of the mouth in the buccal cavity (4 tablets).

The FDA notes that while not bioequivalent, four 100-µg tablets have been found to deliver approximately 12% and 13% higher values for Cmax and area under the curve, respectively, vs one 400-µg tablet. Hence, patients converting from four 100-µg tablets to one 400-µg tablet would be expected to experience a decrease in plasma concentration; however, the impact of this decrease on pain relief has not been evaluated.

According to pharmacokinetic data, systemic exposure to fentanyl occurs earlier and is approximately 30% greater with the buccal tablets compared with oral transmucosal fentanyl citrate (Actiq, made by Cephalon, Inc), thereby delivering therapeutic benefit at a lower dose.

Because of these differences in bioavailability, the 2 products are not interchangeable on a microgram-to-microgram basis, and dosages should be adjusted appropriately when converting patients from one to the other. Dosing conversion recommendations for patients transferring from oral transmucosal fentanyl citrate to fentanyl buccal tablets include a reduction from 200 to 100 µg, 400 to 100 µg, 600 to 200 µg, 800 to 200 µg, 1200 to 400 µg, and 1600 to 400 µg.

Fentanyl buccal tablets should be used with caution at the lowest possible dose in patients with hepatic and/or renal impairment and in those receiving CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, and ritonavir). No dose adjustments appear to be necessary for patients with grade 1 mucositis; the product's efficacy has not been evaluated in patients with more severe disease.