Olanzapine

Olanzapine

PEP Topic 
Chemotherapy-Induced Nausea and Vomiting
Description 

Olanzapine is an antipsychotic used in the treatment of schizophrenia and bipolar disorder. It also has been evaluated as an adjunctive medication for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer.

Effectiveness Not Established

Guideline/Expert Opinion

Frame, D.G. (2010). Best practice management of CINV in oncology patients: I. Physiology and treatment of CINV. Multiple neurotransmitters and receptors and the need for combination therapeutic approaches. Journal of Supportive Oncology, 8(2, Suppl. 1), 5–9.

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Results Provided in the Reference:

  • This article reviewed the neurotransmitter and receptor systems involved with chemotherapy-induced nausea and vomiting (CINV) and a brief history of development of antiemetic therapies. CINV classifications was defined as follows.
    • Acute—occurring and resolving within 24 hours of chemotherapy
    • Delayed—occurring more than 24 hours after chemotherapy administration
    • Breakthrough—occurring despite antiemetic therapy
    • Refractory—unmanageable with current antiemetics
    • Anticipatory—conditioned response after prior inadequately controlled CINV.
  • The article stated that anticipatory CINV is the most common kind.
  • The article reviewed the mechanism of action and current knowledge regarding common antiemetic regimens and noted that given the physiology involved, optimal treatment requires a combination of therapies targeting multiple systems.

Guidelines & Recommendations:

  • Dexamethasone in combination with 5-HT3 receptor antagonists is recommended (unless contraindicated or not tolerated). The author noted that this is too often not included.
  • In delayed emesis, metoclopramide has been shown to be equivalent to ondansetron in controlling delayed CINV. Metoclopramide is also associated with extrapyramidal symptoms.
  • Differences among 5-HT3 receptor antagonists were noted.
    • Among first generation drugs, overall efficacy of the agents are similar.
    • Palonosetron is a second generation drug with a longer half-life, which appears to be associated with some preventive benefits.
    • Results of studies indicate that without some combination therapy, these drugs alone will fail in 40%–50% of patients.
    • The author noted that some individuals have a genetic tendency to metabolize these drugs differently and those with ultra-rapid metabolism have less therapeutic benefit. Palonosetron appears to have a smaller effect in this area.
  • The effects of 2 mg per day of oral granisetron and 3.1 mg per day via epidermal patch appear to be similar.
  • The addition of aprepitant (a neurokinin 1 [NK1] antagonist) to 5-HT3 receptor antagonists and dexamethasone has demonstrated success. A larger benefit has been found for women than for men. The current approved regimen for aprepitant is a three-day regimen; however, ongoing studies are under way to determine if additional doses are helpful. When using aprepitant, the dexamethasone dosage should be reduced. A potential interaction between aprepitant and chemotherapeutic agents such as ifosfamide have been noted. In one study, the combination was associated with increased neurotoxicity.
  • Olanzapine is an antipsychotic that blocks multiple neurotransmitters involved in CINV. Trials of olanzapine in combination with granisetron plus dexamethasone and palonosetron plus dexamethasone have demonstrated effectiveness in preventing CINV.

Nursing Implications:

This article demonstrated the importance of combination therapy for prevention and management of CINV. The author provides a good overview of relevant physiology, mechanism of action of current agents, and current regimens used. The article points to the need for additional research with the use of olanzapine for CINV.

Wickham, R. (2010). Best practice management of CINV in oncology patients: II. Antiemetic guidelines and rationale for use. Journal of Supportive Oncology, 8(2, Suppl. 1), 10–15.

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Type of Resource/Evidence-Based Process:

The search strategy was not applicable or stated.

Results Provided in the Reference:

This article discussed underlying shared principles in chemotherapy-induced nausea and vomiting (CINV) guidelines from the American Society of Clinical Oncology (ASCO), the Multinational Association for Supportive Care in Cancer (MASCC), and the National Comprehensive Cancer Network (NCCN).

  • Common goals among these guidelines are to prevent CINV and to identify the risk period for CINV asscociated with at least four days of moderate- and high-intensity emetogenic treatments.
  • The guidelines report that oral and IV formulations of 5-HT3 receptor antagonists are equally effective.
  • Selection of an antiemetic regimen should be based on the emetic risk of the chemotherapy being used as well as patient factors and experience.
  • Prophylactic antiemetics should be used when the risk of CINV is 10% or more.
  • A table of chemotherapeutic medications by emetogenic risk was provided. The author noted that such risk assignment does not provide for moving up the CINV risk ladder according to differing patient experience. Current guidelines are similar in terms of antiemetic regimens but only outline this for the first course of chemotherapy.
  • The article provided a brief review of current specific antiemetic recommendations provided in guidelines. Substantial differences exist between physician and nursing assignment of patient risk for delayed CINV, and limited evidence exists regarding the best approaches for breakthrough CINV.

Guidelines & Recommendations:

Currently recommended agents for breakthrough CINV are prochlorperazine, metoclopramide with or without diphenhydramine, haloperidol, dexamethasone, dronabinol nabilone, lorazepam, alternating 5-HT3 receptor antagonists, olanzapine, and promethazine. The author noted that guidelines are useful, but guideline adherence can only go to a certain extent in preventing CINV, particularly with delayed symptoms, multiple-day chemotherapeutic regimens, high-dose chemotherapy, breakthrough CINV, and refractory CINV.

Nursing Implications:

CINV guidelines are a good clinical tool to help clinicians implement evidence-based practice; however, their use needs to be accompanied by accurate patient assessments throughout the period of CINV risk. A standard guideline may not fit the needs of all patients and recommendations need to be viewed as a starting point for individualized patient care. More study and attention needs to be given to issues of delayed, breakthrough, and refractory CINV. This article is expert opinion-based and does not provide evidence for all information provided.

Research Evidence Summaries

Mizukami, N., Yamauchi, M., Koike, K., Watanabe, A., Ichihara, K., Masumori, N., & Yamakage, M. (2014). Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: A randomized, double-blind, placebo-controlled study. Journal of Pain and Symptom Management, 47(3), 542–550.

doi: 10.1016/j.jpainsymman.2013.05.003
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Study Purpose:

To determine whether adding olanzapine to current standard antiemetic therapy could reduce the frequency of chemotherapy-induced nausea and vomiting (CINV) and improve patients’ quality of life (QOL) during chemotherapy

Intervention Characteristics/Basic Study Process:

Olanzapine 5 mg/day PO on days 0–5 versus a placebo in addition to 5-HT3RA (either granisetron, ondansetron, ramosetron, or palonosetron), dexamethasone (9.9 mg IV on day 1 followed by 6.6 mg IV on days 2–4), and NK1RA (aprepitant 125 mg orally on day 1 followed by 80 mg aprepitant orally on days 2 and 3 as a rescue drug for CINV). 10 mg of metoclopramide was administered intravenously as needed. Patients could use the rescue drug up to three times a day. The different 5-HT3 receptor antagonists used were administered as follows: granisetron 3–6 mg/day on days 1–3; ondansetron 4 mg/day on days 1–2; ramosetron 0.6 mg/day on days 1–3; and palonosetron 0.75 mg/day on day 1.

Sample Characteristics:

  • N = 44 
  • MEAN AGE = 63 years (olanzapine group), 55 years (control group), non-significant difference p = .06
  • MALES: 50%, FEMALES: 50%
  • KEY DISEASE CHARACTERISTICS: Cancer patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) with an Eastern Cooperative Oncology performance status of 0–2.
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients had not experienced NVR in the 24 hours before the start of the trial, had not scheduled to receive concurrent abdominal radiation therapy, had no history of DM, were not receiving other antipsychotic agents, and were not hypersensitive to olanzapine.

Setting:

  • SITE: Multi-site  
  • SETTING TYPE: Inpatient  
  • LOCATION: Sapporo, Hokkaido, Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

Randomized, double-blind, placebo-controlled trial

Measurement Instruments/Methods:

  • Primary endpoint: Total control (no vomiting, no use of rescue medications, and maximum nausea of < 5/100 mm)
  • Secondary endpoint: Functional Living Index–Emesis (FILE) questionnaire scores on days 0 and 6
  • Additional: QOL (FLIE), amount of diet intake during CTx, satisfaction, complete response (no vomiting, no use of rescue medication), complete control (complete response + nausea < 25 mm/100 mm), and Visual Analog Scale

Results:

The olanzapine group achieved better total control (59% overall, 86% in the acute phase, and 64% in the delayed phase) than the control group (23% overall, 55% in the acute phase, and 23% in the delayed phase). The olanzapine group also achieved better complete protection and complete response except for acute phase complete response (p < .05). Furthermore, the olanzapine group experienced better QOL (p < .01), and the olanzapine group indicated that CINV did not affect their daily activities whereas 36% of the control group reported influence of CINV on daily life activities. There were significant differences between the VAS for nausea and satisfaction scores for additional medication. Most of the olanzapine group patients (91%) wished to receive same protocol for future chemotherapy. Dietary intake was better maintained by the olanzapine group with a significant difference on day 2 and days 4–6.

Conclusions:

The addition of 5 mg/day of oral olanzapine to standard therapy can reduce the frequency of CINV and improve QOL for patients receiving highly or moderately emetogenic chemotherapy.

Limitations:

  • Small sample (< 100)
  • Baseline sample/group differences of import
  • Risk of bias (sample characteristics)
  • Other limitations/explanation: Age of the olanzapine group was higher than the control (which could have influenced less development of CINV), and other risk factors of the CINV were not taken into consideration. MEC group also received NK1, which is not a standard antiemetic. Combination of palonosetron and olanzapine need to be investigated further, with stratification of emetogenicity of chemotherapy regimen, and the use of first and second generation 5-HT3RA between the two groups (as palonosetron 0.75mg was used in the study).

Nursing Implications:

The addition of olanzapine to standard antiemetics, such as 5-HT3RA, steroids, and NK1RA, could achieve better control of CINV, especially for the delayed phase, with additional benefit in terms of QOL and less change in dietary intake. However, caution needs to be exercised in interpreting the result as the study allowed NK1 for the MEC, had age difference between the olanzapine and control group, and did not take risk factors of CINV into consideration, and the palonosetron dose of 0.75mg was higher than antiemetic recommendations.

Tan, L., Liu, J., Liu, X., Chen, J., Yan, Z., Yang, H., & Zhang, D. (2009). Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting. Journal of Experimental & Clinical Cancer Research, 28, 131.

doi: 10.1186/1756-9966-28-13
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Study Purpose:

To evaluate the efficacy and safety of olanzapine compared with 5-hydroxtryptamine3 (5-HT3) receptor antagonists for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) and to evaluate the impact of olanzapine on quality of life (QOL) of those receiving chemotherapy

Intervention Characteristics/Basic Study Process:

Patients were randomized into the test group or the control group. On day 1, the test group received 10 mg oral olanzapine, 10 mg IV azasetron, and 10 mg IV dexamethasone; the control group received 10 mg IV azasetron and 10 mg IV dexamethasone. On days 2–5, the test group received 10 mg oral olanzapine and the control group received 10 mg IV dexamethasone. Patients were permitted to take other antiemetic therapy for nausea or emesis based on clinical circumstances. Assessments occurred on days 1–5 post-treatment, and QOL was measure on day 6.

Sample Characteristics:

  • The study consisted of 229 participants.
  • Men in the test group had a mean age of 54 ± 9.23; women in the test group had a mean age of 48.25 ± 12.7. Men in the control group had a mean age of 54.5 ± 10.33; women in the control group had a mean age of 49.58 ± 12.12.
  • The test group was 40.5% female and 59.5% male. The control group was 40% was female and 60% male.
  • Cancer diagnoses were breast (24%), lung (23%), colorectal (13%), lymphoma (10%), stomach (9%), esophageal (5%), ovarian (5%), teratoma (2%), thymus (2%), cervical (1%), gingival (1%), glioblastoma (1%), laryngeal (1%), malignant melanoma (1%), and oropharyngeal (1%),
  • Chemotherapy agents were cisplatin (44%), oxaliplatin (23%), epirubicin (18%), adriamycin (8%), carboplatin (6%), and dacarbazine (1%).

Setting:

The setting was not identified.

Phase of Care and Clinical Applications:

All patients were in active treatment.

Study Design:

This was a randomized controlled trial.

Measurement Instruments/Methods:

  • The Common Terminology Criteria for Adverse Events, version 3 (CTAE v.3) observation table was used to grade CINV.
  • The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to evaluate quality of life.

Results:

  • No significant difference was noted between both groups for complete response (CR) for acute periods with HEC or MEC.
  • Respective improvement in CR occurred in the test group for delayed nausea and vomiting with HEC (39%) and MEC (25%). The whole period of nausea improved 41% with HEC and 27% with MEC (p < 0.05).
  • The olanzapine regimen protected more than two-thirds of patients from emesis after receiving HEC and MEC, thus avoiding the use of rescue therapy 2–4 days after chemotherapy.

Conclusions:

Olanzapine can improve the CR of delayed nausea and vomiting and QOL in patients receiving HEC and MEC.

Limitations:

  • The study was not blinded. The test group received oral medication, which the control group did not receive.
  • Other antiemetic therapies were used as needed and not monitored or factored into the analysis.
  • Validity and reliability of the measurement tools was not included.
  • Drug safety and toxicity were not defined or monitored.
  • Reporting of statistical results was unclear; the authors reported two values with each measurement (e.g., "complete response for delayed nausea and vomiting in patients with HEC improved 39%, 22%") without explanation of what these two measurements correspond to.
  • Discrepeancies were reported with the QOL measurements.

Nursing Implications:

Olanzapine may be effective in preventing delayed CINV in patients receiving HEC or MEC, but results should be used cautiously because of poor statistical evaluation and reporting.

Systematic Review/Meta-Analysis

Wang, X.F., Feng, Y., Chen, Y., Gao, B.L., & Han, B.H. (2014). A meta-analysis of olanzapine for the prevention of chemotherapy-induced nausea and vomiting. Scientific Reports, 4, 4813. 

doi: 10.1038/srep04813
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Purpose:

STUDY PURPOSE: To determine the effectiveness of olanzapine in the prevention of chemotherapy-induced nausea and vomiting (CINV) after moderately to highly emetogenic chemotherapy
 
TYPE OF STUDY: Meta-analysis and systematic review

Search Strategy:

DATABASES USED: MEDLINE, PubMed, The China National Knowledge Infrastructure, Wanfang Data, and the Weipu Periodical Database  
 
KEYWORDS: Olanzapine, CINV, chemotherapy-induced nausea and vomiting, nausea, and vomiting 
 
INCLUSION CRITERIA: Randomized controlled trials; olanzapine use in CINV; blinded studies; published studies; cost-effective studies; published in English or Chinese; date range 1990 through October 2013
 
EXCLUSION CRITERIA: Studies that were not cost-effective; repetition with former research; retrospective studies; use in patients with incomplete bowel obstruction; and use for breakthrough emesis

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: Thirteen relevant articles
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: A flow diagram of the search strategy was developed by the investigators and used to select relevant articles. Both English and Chinese literature were searched.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 6 
  • TOTAL PATIENTS INCLUDED IN REVIEW = 726
  • KEY SAMPLE CHARACTERISTICS: All studies defined complete response as no vomiting or use of rescue medications. Five studies compared standard antiemetic regimens without olanzapine to standard antiemetic regimens with olanzapine.

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care, palliative care 

Results:

Five out of six studies demonstrated an increase in complete response in patients receiving standard antiemetic regimens plus olanzapine on day 1 of chemotherapy (odds ratio [OR] = 1.95, 95%; confidence interval [CI] = 1.17–3.23; p = 0.01). Five out of six studies showed a cumulative delay in vomiting (OR = 2.65, 95%; CI = 1.36–5.15; p = 0.004). Overall complete response relative risk was improved (4.07, 95%; CI = 1.59–10.43). Also note the following: delayed-phase antinausea effects in olanzapine-containing antiemetic regimens (OR = 2.79, 95%; CI = 1.76–4.43; p = 0.0001); antinausea effects in the overall phase (OR = 3.40, 95% CI = 2.32–5.00; p = 0.00001); and no superiority in the acute phase (RR = 1.34, 95%; CI = 0.77–2.34; p = 0.30).

Conclusions:

Complete response is more likely in patients who received antiemetic regimens containing olanzapine compared to patients who did not receive olanzapine. Olanzapine is more effective in delayed CINV than acute.

Limitations:

  • Small sample
  • Differences in what drugs were included in standard antiemetic regimens in each study
  • One study used aprepitant in the standard antiemetic regimen.

Nursing Implications:

Olanzapine may add CINV control when added to a standard antiemetic regimen during the delayed phase.


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