September 4, 2008 — The US Food and Drug Administration (FDA) has approved romiplostim subcutaneous injection for the treatment of chronic immune thrombocytopenic purpura, palonosetron HCl capsules for the prevention of chemotherapy-induced nausea and vomiting, and an expanded approval for azacitidine injection based on new overall survival rates in patients with higher-risk myelodysplastic syndromes.

Romiplostim Injection (Nplate) Approved for Thrombocytopenia in Patients With ITP

On August 22, the FDA approved romiplostim subcutaneous injection (Nplate; Amgen, Inc) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Romiplostim is a therapeutic fusion protein that combines attributes of both peptides and antibodies but is distinct from each. It mimics naturally occurring thrombopoietin (TPO), acting on TPO receptors to activate intracellular transcriptional pathways that lead to increased platelet production.

"Until now, patients suffering from chronic ITP have had limited available treatment options, many of which are often unsuitable for long-term use due to side effects and tolerability issues," said David J. Kuter, MD, chief of Hematology at Massachusetts General Hospital, Boston, in a company news release. "Nplate represents the first long-term treatment for adult chronic ITP patients, providing a new treatment approach for this chronic disease."

The approval was based on data from two 24-week double-blind, placebo-controlled, phase 3 clinical studies of 125 patients with baseline platelet counts of 30,000 x 10⁹/L or less who had completed at least 1 previous therapy.

Results showed that romiplostim therapy yielded significantly increased overall response rates relative to placebo; the difference was higher in patients without splenectomy (88% vs 14%) vs patients with splenectomy (79% vs 0%; P < .05 for both).

Moreover, 61% of patients without splenectomy and 38% of patients with splenectomy achieved a durable response while receiving romiplostim, defined as at least 6 weekly platelet counts of 50,000 x 10⁹/L or greater during the last 8 weeks in the absence of rescue medication at any time.

Combined data from both studies revealed that romiplostim therapy also significantly reduced the risk for serious (≥ grade 2 severity) bleeding events (15% vs placebo, 34%).

These findings were supported by long-term data from an open-label extension study (n = 100), in which the majority of responding patients maintained platelet counts greater than 50,000 x 10⁹/L during a median treatment period of 60 weeks (maximum, 96 weeks).

The recommended starting dose for romiplostim is 1 µg/kg administered by subcutaneous injection once weekly and then adjusted by increments of 1 µg/kg until a platelet count of 50 x 10⁹/L or greater is achieved. In clinical studies, a median dose of 2 µg/kg was required to achieve and maintain this response. Treatment should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximal weekly dose of 10 µg/kg.

In the placebo-controlled studies, headache was the most commonly reported adverse reaction (35% vs placebo, 32%). Other adverse events included arthralgia, dizziness, insomnia, myalgia, pain in the extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia.

Serious adverse events included bone marrow reticulin deposition and worsening thrombocytopenia after discontinuation of romiplostim therapy. Other risks include blood clots from excessive platelet formation and the potential for leukemia in patients with myelodysplasia.

Because of these risks, romiplostim will only be available through a restricted distribution program called the Network of Experts Understanding and Supporting Nplate and Patients, which has been developed as part of a risk evaluation and mitigation strategy that will also provide patient support and education and assist with safety data collection.

Oral Palonosetron (Aloxi) Approved for Prevention of Chemotherapy-Induced Nausea and Vomiting

On August 22, the FDA approved an oral capsule formulation of palonosetron HCl (Aloxi; Eisai Corp) for the prevention of acute nausea and vomiting after initial and repeated courses of moderately emetogenic chemotherapy.

The approval was based primarily on data from a multicenter, randomized, double-blind, active-control clinical study of 635 patients, in which complete response was defined as having no emetic episodes or requirements for rescue medication during the acute phase (0 - 24 hours) or delayed phases (24 - 120 hours).

Acute-phase results showed that oral palonosetron (0.5 mg) was noninferior to a 0.25-mg dose of the previously approved intravenous (IV) formulation (76.3% vs 70.4%; 2-sided 98.3% confidence interval, –6.5% to 18.2%). However, statistical noninferiority was not demonstrated during the delayed phase (62.5% vs 65.4%; 98.3% confidence interval, –16.3% to 10.5%).

The recommended dose is one 0.5-mg capsule administered approximately 1 hour before the start of chemotherapy. In the study, the most commonly reported adverse events were headache (3.7% vs 0.25-mg IV, 8.6%) and constipation (0.6% vs 0.25-mg IV, 3.1%).

Palonosetron injection previously was approved by the FDA for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of moderately emetogenic chemotherapy and for the prevention of acute nausea and vomiting associated with initial and repeated courses of highly emetogenic chemotherapy. The recommended dose for the injection is 0.25 mg administered IV approximately 30 minutes before chemotherapy.

Azacitidine (Vidaza) Extends Survival in Patients With Higher-Risk Myelodysplastic Syndromes

On August 20, the FDA approved an expanded indication for azacitidine injection (Vidaza; Celgene Corp) that reflects new overall survival data achieved in the AZA-001 study of patients with higher-risk myelodysplastic syndromes (MDS).

"We are very encouraged by the Vidaza data from the AZA-001 trial. This trial showed, for the first time, a drug can extend survival for MDS patients," said John Huber, executive director of the Aplastic Anemia and MDS International Foundation, in a news release. "We are excited to see that in this trial Vidaza also reduced the need for blood transfusions."

According to a company news release, AZA-001 is the largest international randomized phase 3 controlled study ever conducted in higher-risk MDS. Results showed that use of azacitidine for a median of 9 cycles rather than conventional-care regimens (CCR) significantly improved median overall survival (24.5 months vs 15 months; P = .0001; hazard ratio, 0.58; 95% confidence interval, 0.43 - 0.77) and almost doubled the 2-year survival rate (50.8% vs 26.2%). Survival benefit was observed across relevant patient subgroups, including elderly patients (aged > 65 years), those with acute myelogenous leukemia, and patients with poor risk cytogenetics.

Furthermore, nearly half (45%) of patients who were transfusion dependent at baseline achieved transfusion independence (vs conventional-care regimens, 11.4%); results were durable, and the median duration of transfusion independence was 13.0 months.

In the study, the most commonly reported adverse events in azacitidine-treated patients were thrombocytopenia (69.7%), neutropenia (65.7%), and anemia (51.4%).

"The clinical data from this randomized Phase III controlled study demonstrated that patients with higher-risk MDS treated with VIDAZA benefit from a significant survival advantage, a critical measure of a drug's effectiveness," said Lewis Silverman, MD, of the Mount Sinai Medical Center in New York City, in a company news release. "Additionally, the efficacy and safety profile of VIDAZA allows for long-term therapy in patients with higher-risk MDS, underscoring the ability to treat until disease progression for optimal survival benefit."

Dr. Silverman was the lead author and principal investigator for the original azacitidine approval study (CALGB 9221) and an author and investigator of the international AZA-001 survival trial.

Azacitidine was approved by the FDA in May 2004 for the treatment of all 5 MDS subtypes, including refractory anemia or refractory anemia with sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

NPlate Prescribing Information

Aloxi Prescribing Information

Vidaza Prescribing Information

Pearls for Practice

• The FDA has approved romiplostim once-weekly subcutaneous injection for the treatment of refractory chronic immune thrombocytopenic purpura in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
• Palonosetron HCl capsules have been approved for the prevention of acute nausea and vomiting after initial and repeated courses of moderately emetogenic chemotherapy. The recommended dose is one 0.5-mg capsule administered approximately 1 hour before the start of chemotherapy.
• Data from a large study of higher-risk myelodysplastic syndromes have revealed that azacitidine significantly improves survival vs conventional-care regimens and almost doubles the 2-year survival rate. Nearly half of patients dependent on transfusion achieved independence.

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