FDA Approvals: Kadian, Depocyt, Reclast

Yael Waknine

June 12, 2007

June 12, 2007 — The US Food and Drug Administration (FDA) has approved a 10-mg formulation for morphine sulfate extended-release capsules for the treatment of chronic pain; cytarabine liposome injection for the intrathecal treatment of lymphomatous meningitis; and zoledronic acid 5-mg infusion for the treatment of Paget's disease of the bone.

New 10-mg Morphine Sulfate Extended-Release Capsules ( Kadian) for Chronic Pain

On April 30, the FDA approved a 10-mg formulation for morphine sulfate extended-release capsules (Kadian, Alpharma, Inc).

The capsules were previously approved in 20-, 30-, 50-, 60-, 80-, 100-, and 200-mg strengths. According to a company news release, the addition of the 10-mg formulation is intended to facilitate individualized pain therapy. Its launch in the US market is expected during 2007.

Morphine sulfate extended-release capsules are indicated for once- or twice-daily use in the management of moderate to severe pain when a continuous, 24-hour analgesic is needed for an extended period. The 100- and 200-mg capsules are for use in opioid-tolerant patients only.

Although the capsules should not generally be used during the immediate postoperative period (12 - 24 hours after surgery), they can be administered in settings of prior (preoperative) use or if the pain is expected to be moderate or severe and to persist for an extended period.

Cytarabine Liposome Injection (Depocyt) for Lymphomatous Meningitis

On April 19, the FDA granted full approval to cytarabine liposome injection (Depocyt) for the intrathecal treatment of lymphomatous meningitis, a life-threatening complication of lymphoma.

Cytarabine was previously granted accelerated approval by the FDA on the basis of preliminary data showing a better complete response rate than unencapsulated cytarabine in this population.

The approval was based on data from 2 randomized controlled clinical trials of patients with neoplastic meningitis. Patients in both studies received concurrent treatment with dexamethasone to minimize symptoms associated with chemical arachnoiditis, a syndrome that can be fatal if left untreated and manifests primarily with symptoms of nausea, vomiting, and headache.

Results from the first study (n = 33 lymphoma patients) showed that cytarabine liposome injection administered every 2 weeks yielded a significantly better complete response rate (41%) than unencapsulated cytarabine therapy (6%) given twice weekly, as defined by conversion at all initially positive sites and an absence of neurologic disease progression during the 4-week treatment period (95% confidence interval [CI], 18% to 67% vs 0% to 30%).

These findings are supported by data from the second study (n = 24 lymphoma patients), in which patients were randomized to receive cytarabine liposome injection for 6 2-week induction cycles followed by 4 weekly maintenance cycles (complete response rate, 33%) or cytarabine 50-mg twice weekly followed by 4 weekly maintenance cycles (complete response rate, 17%) (95% CI, 10% to 65% vs 2% to 48%).

Cytarabine liposome injection therapy should be initiated with an induction phase of 50 mg (1 vial) administered intrathecally (intraventricular or lumbar puncture) every 14 days for 2 doses (weeks 1 and 3). Patients should be started on dexamethasone 4-mg twice daily either by mouth or intravenously beginning on the day of each injection.

For the consolidation phase, the 50-mg dose should be administered every 14 days for 3 doses (weeks 5, 7, and 9), followed by 1 additional dose at week 13. The maintenance dose is 50 mg every 28 days for 4 doses (weeks 17, 21, 25, and 29). If neurotoxicity occurs, the dosage should be reduced to 25 mg; if it persists, therapy should be discontinued.

Zoledronic Acid Infusion (Reclast) for Paget's Disease

On April 16, the FDA approved zoledronic acid 5-mg solution for infusion (Reclast, Novartis Pharma AG) to treat Paget's disease of the bone. The single-dose bisphosphonate is administered by intravenous infusion for 15 minutes.

The approval is based on data from clinical studies linking zoledronic acid to a greater therapeutic response, faster onset of action, and longer remission period than risedronate therapy.

Results showed that a significantly greater proportion of patients given a single dose of zoledronic acid showed therapeutic response at 6 months, compared with those given a 60-day oral regimen of risedronate, 30 mg per day (96% vs 74%). A great majority of those responding to the zoledronic acid infusion remained in remission for 1 year or longer.

Normalization of serum alkaline phosphatase levels (a key marker for bone turnover) at 6 months was also achieved in a significantly greater proportion of patients receiving single-dose zoledronic acid than those receiving the 60-day risedronate regimen (89% vs 58%). The overall frequency of adverse events was similar in both groups.

Use of the product is expected to increase compliance because it eliminates the complicated daily regimens and gastrointestinal tract discomfort associated with standard oral bisphosphonate therapies, the company said in a news release.

Zoledronic acid 4-mg infusion (Zometa, Novartis.) was previously approved by the FDA for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases of solid tumors. The 5-mg infusion (marketed as Aclasta) was previously approved by the European Commission for use in the European Union.


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