FDA Approves Extended-Release Granisetron for CINV

August 10, 2016

The FDA has approved an extended release injection formulation of granisetron (Sustol) for use in combination with other antiemetic therapies for the prevention of chemotherapy-induced nausea and vomiting.

Ralph V. Boccia, MD

The novel formulation of the 5-HT3 receptor antagonist can maintain therapeutic levels of granisetron for 5 or more days. The approved indication is specifically for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” Ralph V. Boccia, MD, medical director, Center for Cancer and Blood Disorders, said in a statement. “In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

The efficacy data supporting the approval of extended release granisetron came from a multicenter double-blind trial that included 733 patients who received MEC or AC combination chemotherapy. Patients were randomized to 10 mg of subcutaneous granisetron (n = 371) or a single 0.25 mg intravenous dose of palonosetron hydrochloride (n = 362).

The mean patient age was 57 years (range, 22-91). Seventy-nine percent of the patients were female and 63% were white. MEC was administered to 55% of patients and 45% received AC combination chemotherapy. The most frequently used MEC regimen was carboplatin/paclitaxel (31%).

Both treatments were administered 30 minutes before chemotherapy on day 1. Intravenous dexamethasone was also administered at 8 or 20 mg on day 1, depending on the chemotherapy regimen. Those individuals who received 20 mg of intravenous dexamethasone were also given an 8 mg oral dose of the drug twice daily on days 2, 3, and 4.

The primary endpoint of the study was complete response (CR), which the trial defined as no emetic episodes or rescue medication during the acute phase (0-24 hours) and the delayed phase (>24 to 120 hours) after chemotherapy administration in cycle 1.The design of the trial also allowed for the evaluation of noninferiority of granisetron to palonosetron hydrochloride in the acute and delayed phases.

The results demonstrated that the granisetron formulation was noninferior to palonosetron. Among patients receiving MEC (n = 406) the CR in the acute phase was 83% (166/200) in the granisetron arm compared with 89% (183/206) in the palonosetron group. The CR rates in the delayed phase were 69% (137/200) and 70% (144/206), respectively.

Among patients who received AC combination chemotherapy (n = 327), the CR rate in the acute phase for the granisetron group was 70% (120/171) compared with 64% (99/156) with palonosetron. The CR rates in the delayed phase were 50% (85/171) versus 47% (74/156), respectively.

“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, CEO and director of clinical research, North Shore Hematology Oncology Associates and vice president, Community Oncology Alliance. “Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

The safety of the FDA-recommended 10-mg subcutaneous dose of extended release granisetron was evaluated in 924 patients across 2 double-blind, randomized active-controlled studies.

In the first study, 468 patients received 10 mg of subcutaneous granisetron and 463 patients received 0.25 mg of intravenous palonosetron hydrochloride. The most common all-grade adverse events (AEs) included injection site reactions (37% with granisetron vs 15% with palonosetron), constipation (14% vs 11%), fatigue (11% vs 10%), headache (9% each), diarrhea (8% vs 7%), abdominal pain (7% each), insomnia (4% vs 2%), dyspepsia (3% each), dizziness (3% vs 2%), asthenia (4% vs 6%), and gastroesophageal reflux (1% each).

The second study included 456 patients who received 10 mg of subcutaneous granisetron and 459 patients who received 0.15 mg/kg of intravenous ondansetron. Sixty-percent of patients receiving granisetron had injection site reactions. The remaining AEs that were most commonly reported matched those reported for the first trial: constipation (22% with granisetron vs 15% with palonosetron), fatigue (21% vs 24%), headache (13% vs 19%), diarrhea (9% vs 8%), abdominal pain (7% vs 4%), insomnia (5% vs 6%), dyspepsia (6% vs 7%), dizziness (5% each), asthenia (2% each), and gastroesophageal reflux (5% vs 4% each).

"The approval of Sustol is a major step in Heron’s evolution into a fully-integrated biopharmaceutical company with both development and commercial capabilities," Robert H. Rosen, president of Heron Therapeutics, said in a statement. “Our focus now turns to ensuring patients have access to this important therapy. We look forward to collaborating with the oncology community to make Sustol available in the fourth quarter of this year.”