FDA Approvals: Supprelin LA, AzaSite, Invega

Yael Waknine

June 15, 2007

June 15, 2007 — The US Food and Drug Administration (FDA) has approved a histrelin acetate 50-mg once-yearly implant for the treatment of central precocious puberty; azithromycin 1% ophthalmic solution for the treatment of bacterial conjunctivitis caused by designated strains of susceptible micro-organisms; and an expanded indication for paliperidone extended-release tablets, allowing their use for acute and long-term maintenance treatment of schizophrenia.

Histrelin Acetate Implant (Supprelin LA) for the Treatment of CPP

On May 3, the FDA approved a histrelin acetate 50-mg subcutaneous implant (Supprelin LA, Indevus Pharmaceuticals, Inc) for the treatment of central precocious puberty (CPP).

The implant is intended for insertion in the inner aspect of the upper arm, and uses the company's patented hydrogel reservoir technology to provide approximately 65 µg per day of histrelin for 12 months of hormonal therapy. Its convenience, compared with other therapies that require injections every 3 to 4 weeks, might improve long-term patient compliance, the company said.

The approval was based on data from 2 single-arm open-label studies; the first was conducted in 11 pretreated girls aged 3.7 to 11.0 years, and the other in 16 pretreated and 20 treatment-naïve children (33 girls, 3 boys).

Results showed that the implant's therapeutic efficacy was similar in both groups. Suppression of leuteinizing hormone (defined as peak leuteinizing hormone < 4 mIU/mL following stimulation with leuprolide acetate) was induced in all treatment-naïve patients, maintained in all pretreated children at 1 month postimplantation, and continued through the 12th month.

Secondary efficacy hormone assessments (follicle stimulating hormone, estradiol, and testosterone) and additional efficacy assessments (bone-age advancement, linear growth, and clinical progression of puberty) indicated stabilization of disease. Estradiol suppression was present in all 33 girls (100%) through month 9, and in 97% at month 12; testosterone suppression was maintained in the 3 pretreated males participating in the second study.

The most commonly reported adverse events were implant-site reactions (51.1%); local reactions included bruising, pain, soreness, erythema, and swelling. A long- term follow-up study is ongoing, the company noted.

A previously approved histrelin 50-mg subcutaneous implant (Vantas, Indevus) is indicated only for the palliative treatment of advanced prostate cancer.

Azithromycin 1% Ophthalmic Solution (AzaSite) for Bacterial Conjunctivitis

On April 27, the FDA approved azithromycin 1% ophthalmic solution in 5-mL bottles (AzaSite, Inspire Pharmaceuticals, Inc [under license from InSite Vision, Inc]) for the treatment of bacterial conjunctivitis caused by CDC coryneform group G, Staphylococcus aureus, Streptococcus mitis group, Streptococcus pneumoniae, and Haemophilus influenzae.

The product offers a lower-dosage regimen than other available products, and consists of 1 drop placed twice-daily in the affected eye for 2 days, followed by 1 drop daily for 5 days (9 drops in total). According to a company news release, data from 2 phase 3 clinical trials (n > 1,400) have shown the regimen to be significantly more effective than placebo and to be as effective as tobramycin, which is applied 4 times daily for 5 days.

The approval was based on data from a double-blind multicenter clinical study (n = 279), showing that the use of azithromycin ophthalmic solution was significantly more effective than the vehicle alone for achieving clinical success (63% vs 50%; P = .03; 95% confidence interval [CI], 2% to 25%) and microbiologic eradication(88% vs 66%; P < .001; 95% CI, 13% to 31%). Eye irritation was the most commonly reported adverse event and occurred in about 1% to 2% of patients.

Azithromycin 1% ophthalmic solution is expected to be launched during the latter part of the third quarter of 2007, the company said.

Paliperidone Extended-Release Tablets (Invega) for Long-Term Use

On April 27, the FDA approved an expanded indication for paliperidone extended-release tablets (Invega, Janssen, LP), allowing their use for the long-term maintenance and acute treatment of schizophrenia.

The approval was based on data from the placebo-controlled randomized phase of a long-term study (n = 207), which was terminated early because of findings from an interim analysis that demonstrated the drug's long-term therapeutic efficacy.

Results showed that continued use of paliperidone in stabilized patients significantly improved their ability to maintain symptom control, and delayed time to relapse (relapse rate, 48.5% for paliperidone vs 77.9% for placebo). All patients had previously received paliperidone during an 8-week initiation period (3 to 15 mg flexibly dosed, with a 9-mg starting dose) and stabilized with an additional 6 weeks of therapy at the same dose.

Treatment-emergent adverse events (TEAEs) reported in 5% or more of paliperidone-treated patients and occurring at least as often as placebo included psychosis (23% vs 7%), insomnia (6% vs 5%), aggressive reactions (6% vs 1%), and extrapyramidal symptoms (7% vs 3%). Discontinuation rates because of TEAEs were 3% and 1%, respectively.

The recommended dosing regimen for paliperidone is 6 mg once daily, administered in the morning with or without food; initial dose titration is not required. For some patients, a dose of 3 mg per day can be sufficient, whereas others might benefit from higher doses (up to 12 mg/day).

Although it has not been systematically established that doses greater than 6 mg have additional benefit, a general trend for increased efficacy was observed at increased doses during clinical trials. However, the FDA advises that the potential benefit of such increased doses be weighed against similarly increased dose-related risks for adverse events. Dose increases above 6 mg per day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days and in increments of 3 mg per day.

Dosing adjustments might be required according to renal function status, particularly in elderly patients. The maximum recommended doses for those with mild (creatinine clearance, ≥ 50 to < 80 mL/minute) and moderate to severe renal impairment (creatinine clearance, 10 to < 50 mL/minute) are 6 and 3 mg per day, respectively. No dose adjustments are required for patients with mild to moderate hepatic impairment.

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