FDA Approvals: Rozerem, Synera, Avelox IV

Yael Waknine

July 28, 2005

July 28, 2005 — The U.S. Food and Drug Administration (FDA) has approved ramelteon 8-mg tablets for the treatment of insomnia characterized by difficulty with sleep onset; a lidocaine-tetracaine 70-mg/70-mg topical patch to provide local dermal analgesia for superficial venous access and dermatologic procedures; and moxifloxacin intravenous infusion for the treatment of complicated skin and skin structure infections caused by methicillin-susceptible bacteria.

Ramelteon (Rozerem) Sleeping Pills Offer New Mechanism of Action, Fewer Adverse Effects

On July 22, the FDA approved ramelteon 8-mg tablets (Rozerem [TAK-375], made by Takeda Pharmaceuticals North America, Inc.) for the treatment of insomnia characterized by difficulty with sleep onset.

Unlike current therapies that broadly target gamma-aminobutyric acid receptors in the brain, ramelteon acts as a selective agonist at two melatonin receptors (Mella 1a/1b; MT1/MT2) in the suprachiasmatic nucleus, also known as the "circadian clock." Ramelteon has demonstrated a greater affinity, selectivity, and potency than melatonin at MT1 receptors that are thought to regulate sleepiness.

Ramelteon has shown no evidence of abuse or dependence potential and is the only prescription sleep aid not designated as a Schedule IV controlled substance. Also, it can be prescribed for long-term use, and its selective mechanism of action avoids adverse events such as impairment of memory and motor ability.

The approval was based on safety and efficacy data from clinical trials in more than 4,200 patients aged 18 to 93 years, including those with mild-to-moderate chronic obstructive pulmonary disease and sleep apnea. Patients received single daily doses for various periods of up to a year.

The most commonly reported (> 2% over placebo) adverse events associated with ramelteon use were somnolence, fatigue, and dizziness.

Because ramelteon is metabolized by the liver by the cytochrome P450 1A2 (CYP 1A2) enzyme, it should not be administered to patients with severe hepatic impairment or those receiving therapy with a strong CYP 1A2 inhibitor such as fluvoxamine.

Ramelteon is currently undergoing phase 2 and 3 trials for this indication in Japan and Europe, respectively, and phase 2 U.S. trials for the treatment of circadian rhythm sleep disorders.

Heating Component in Lidocaine-Tetracaine Patch (Synera) Enhances Analgesia

On July 23, the FDA approved a lidocaine-tetracaine 70-mg/70-mg topical patch (Synera [S-Caine], made by Zars, Inc.) for use on intact skin to provide local dermal analgesia for superficial venous access and dermatologic procedures such as excision electrodessication and shave biopsy of skin lesions.

The patch consists of a thin, uniform layer of local anesthetic emulsion with an integrated, oxygen-activated heating component that has been shown to enhance analgesic delivery.

The approval was based in part on data from randomized, double-blind trials showing that use of the patch was significantly more effective than placebo for reducing pain associated with superficial dermatologic procedures in adults and the elderly (age, > 65 years), as assessed by visual analog scale (VAS) scores (median score, adults, 5 vs 31; elderly, 10 vs 23).

Similar results were observed in two adult studies and one geriatric study of the patch's analgesic efficacy relative to placebo for venipuncture (median VAS score, 1 vs 9; 5 vs 28; 8 vs 14).

Additional pediatric trials demonstrated the patch's efficacy across all age groups for reducing pain associated with lidocaine injection.

Local skin reactions (erythema, blanching, edema) were the most commonly reported patch-related adverse events.

Moxifloxacin HCl Injection (Avelox IV) Approved for Treating Complicated SSSI

On June 13, the FDA approved a new indication for moxifloxacin HCl intravenous infusion (Avelox IV, made by Bayer Pharmaceuticals Corp. and marketed by Schering-Plough Corp.), allowing its use for the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae.

The approval was based in part on data from a randomized, double-blind, North American trial in 617 patients (335 available for analysis), showing that sequential intravenous/oral use of 400 mg per day of moxifloxacin for one to two weeks yielded overall success rates comparable to that of beta-lactam/beta-lactamase inhibitor (control) therapy (77.2% vs 81.5%; 95% confidence interval [CI] for difference, -14.4% to 2.0%).

Overall results achieved in a one- to three-week open-label international trial were also comparable between groups (80.6% vs 84.5%; 95% CI for the difference, -9.4% to 2.2%).

Success rates varied similarly between the moxifloxacin and comparator groups with respect to diagnosis (infected ulcers, 61%; complicated erysipelas, 90%) and certain pathogens (S. aureus, 82.2% vs 87.6%; E. coli, 81.6% vs 84.8%; K. pneumoniae, 91.7% vs 70.0%; E. cloacae, 81.8% vs 57.1%).

This indication for moxifloxacin HCl injection (Avalox IV) was approved by the European Commission (EC) on July 18, 2005. Moxifloxacin HCl was previously approved by the FDA and EC for the treatment of community acquired pneumonia, acute bacterial sinusitis, and acute exacerbations of chronic bronchitis, and by the FDA for the treatment of uncomplicated skin and skin structure infections.

Reviewed by Gary D. Vogin, MD

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