Chemotherapy-induced nausea and vomiting

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting.

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BACKGROUND: We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy.

METHODS: In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (≥70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point.

RESULTS: In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2.

CONCLUSIONS: Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy.

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

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2016-07-08_11-11-05

Patients are fearful of nausea and vomiting during the course of cancer treatment, as it is an expected side effect of chemotherapy. Senior oncology physicians describe the early days of cancer treatment when large bowls lined the ward, positioned close to each patient. In the present age, we are still concerned about chemotherapy-induced nausea and vomiting (CINV). New agents such as 5-hydroxytryptamine-3 (5HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists, and long-established drugs such as dexamethasone are within the oncologist’s armamentarium. Despite a combination of these agents, patients can still suffer from severe nausea and vomiting, which may lead to hospital admissions, delays in treatment and plenty of misery.

Olanzapine, an antipsychotic drug that blocks several neurotransmitters, is not licensed for use in CINV. However, small single center studies have suggested that this drug is a useful treatment in cases of poorly controlled emesis. Olanzapine received approval for use in 1996, and since 2011 it has been available in a generic formulation. In a double-blind phase III study published in this week’s NEJM, Navari and colleagues investigated the role of olanzapine in CINV. All eligible patients were administered highly emetogenic chemotherapy regimens that included cisplatin (>70mg/m2), or doxorubicin (60mg/m2) and cyclophosphamide (600mg/m2). Patients who were chemotherapy naïve were randomly assigned to receive olanzapine (10mg/day, oral) or placebo over the first four days of one treatment cycle. All patients were also treated with 5-HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone in accordance with international anti-emetic guidelines.

The primary endpoint compared the number of patients with no nausea in the acute (0-24 hours post chemotherapy), delayed (24-120 hours post-chemotherapy) and the overall (0-120 hours post-chemotherapy) periods among those receiving highly emetogenic chemotherapy.

The trial participants were from 46 academic or community practice institutions within the United States. The final analysis included 186 patients in the olanzapine arm and 183 patients in the placebo group. The proportion of patients with no nausea was significantly higher in the olanzapine arm compared to placebo arm in the acute (74% vs. 45% p=0.0015), delayed (42% vs. 25%, p=0.0015) and overall periods (37% vs. 22%, p=0.0015). Complete responses, which measured the absence of emesis and no use of rescue anti-emetics, were also significantly higher among patients treated with olanzapine in all three time periods. Among adverse events, patients receiving olanzapine reported more undesired sedation on day 2 post-chemotherapy; however, patients did not discontinue treatment and these side effects resolved.

This placebo-controlled trial shows the benefit of olanzapine in the treatment of CINV in combination with other anti-emetics. However, the study protocol was only used in one cycle of highly emetogenic chemotherapy. Optimal dosing, safety and efficacy in multiple chemotherapy cycles have not yet been determined, and the authors suggest future clinical trials address these issues.

In an era of enormous costs of cancer care, this is a useful trial that demonstrates a new use for an available, inexpensive drug. Oncology is continuing to apply new agents with novel mechanisms of action to the treatment of cancers; however, chemotherapy is likely to remain a foundation of cancer treatment. Management of CINV will continue to be a difficult problem for patients receiving intense, multi drug chemotherapy.

Ondansetron (Zofran) 32 mg, Single Intravenous (IV) Dose: Updated Safety Communication – Product Removal due to Potential For Serious Cardiac Risks

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AUDIENCE: Oncology, Surgery, Health Professional

ISSUE: FDA is notifying health care professionals that the 32 mg, single intravenous (IV) dose of the anti-nausea drug Zofran (ondansetron hydrochloride) will no longer be marketed because of the potential for serious cardiac risks.

BACKGROUND: The 32 mg, single IV dose of Zofran had been used to prevent chemotherapy-induced nausea and vomiting. A previous Drug Safety Communication (DSC), issued on June 29, 2012, communicated that the 32 mg, single IV dose should be avoided due to the risk of a specific type of irregular heart rhythm called QT interval prolongation, which can lead to Torsades de Pointes, an abnormal, potentially fatal heart rhythm.  These drugs are sold pre-mixed in solutions of either dextrose or sodium chloride in plastic containers.

FDA anticipates these products will be removed from the market through early 2013.  FDA does not anticipate that removal of the 32 mg intravenous dose of ondansetron currently sold as pre-mixed injections will contribute to a drug shortage of IV ondansetron, as the 32 mg dose makes up a very small percentage of the current market

RECOMMENDATION: FDA continues to recommend the intravenous regimen of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting. Oral dosing of Ondansetron remains effective for the prevention of chemotherapy-induced nausea and vomiting. At this time, there is not enough information available for FDA to recommend an alternative single IV dose regimen.