When First-Line Antiemetics Aren’t Enough: Considering Olanzapine in Palliative Care

When patients with advanced cancer come to our palliative care clinic, they’re often struggling with symptoms like weight loss, and nausea and vomiting—especially when they are receiving treatment with a moderate- or high-risk emetogenic chemotherapy regimen.

Most palliative care clinicians regularly prescribe typical first-line antiemetics like ondansetron and prochlorperazine for chemotherapy-induced nausea and vomiting (CINV). But now clinicians are increasingly turning to an atypical antipsychotic medication as an add-on treatment or even as a first-line antiemetic: olanzapine.

Consider how this second-generation antipsychotic medication could help a patient, such as a 62-year-old woman experiencing CINV from her treatment for stage IV non-small cell lung cancer (NSCLC), which includes cisplatin, pemetrexed, and pembrolizumab.

On the day of chemotherapy, she receives ondansetron and dexamethasone. A few hours after treatment, she feels nauseous and starts vomiting. She vomits three or four times in the subsequent 24-hour period. The nausea and vomiting pattern lingers over the next two weeks, gradually dissipating, until it’s time for her next treatment cycle. Even with her taking ondansetron 4 mg ODT several times per day, the vomiting and poor appetite has caused her to lose twelve pounds in the past month. She presents to the palliative care clinic asking for help.

This patient is experiencing acute, persistent CINV that is refractory to her current antiemetic regimen, and the significant weight loss has negatively impacted her quality of life. She would likely be an excellent candidate for a trial of olanzapine.

Despite its growing popularity in the palliative care sphere, many clinicians are still unfamiliar with olanzapine and may be uncomfortable prescribing it for patients without conditions like bipolar disorder or schizophrenia. However, palliative care clinicians, especially those working in the oncology setting, have found that olanzapine may help with multiple symptoms, including nausea, poor appetite, anxiety, and insomnia. In fact, the latest National Comprehensive Cancer Network (NCCN) guidelines consider olanzapine as part of several different first-line antiemetic regimens. (For those who cannot access the clinician-facing NCCN guidelines, you can view the patient-facing guidelines.)

Here’s why: olanzapine is a high-yield drug. It’s a single medication that can often address multiple issues. As a result, your patients may experience several benefits from just one daily dose.

Olanzapine is a potent serotonin and dopamine receptor antagonist (among other receptors). Serotonin and dopamine are the two neurotransmitters that are most active in the chemoreceptor trigger zone (CTZ), a region in the caudal portion of the brainstem. The CTZ is outside of the blood-brain barrier, and so it detects emetogenic agents (e.g., chemotherapy, opioids) in the bloodstream and plays a major role in triggering the nausea and vomiting reflex.

Research has shown that olanzapine reduces chemotherapy-related nausea and vomiting in patients with advanced cancer, with the added benefit of stimulating appetite. One of the noted side effects of olanzapine is weight gain, so essentially, we are harnessing that for our patients with cachexia. Olanzapine may also allow patients to use fewer doses of antiemetics for breakthrough symptoms.

Notably, all the symptoms we typically treat with olanzapine are considered off-label use for this medication.

As with any medication, we always must consider the potential risks associated with olanzapine.

One such risk is drug-induced QT prolongation—a concern associated with many psychotropic drugs. QT prolongation can lead to torsades de pointes (TdP), a serious and potentially fatal arrhythmia.

And while olanzapine does demonstrate a prolonging effect on the QT interval, the degree of prolongation is dose-dependent, and the clinically significant prolongation may not be as serious as you might fear. Typically, we use lower doses of olanzapine (2.5-10 mg daily) in the palliative care setting. In our group, it is not routine practice to check an electrocardiogram (ECG) when initiating a patient on olanzapine. However, we do exercise caution with ECG monitoring in certain clinical situations, such as patients concurrently receiving multiple QT prolonging medications (e.g. methadone, selective serotonin reuptake inhibitors, tricyclic antidepressants, fluoroquinolones, etc.). Additionally, it is prudent to obtain a baseline ECG in patients with a history of cardiac disease.

Extrapyramidal symptoms (EPS), such as drug-induced parkinsonism, tardive dyskinesia, and akathisia, are also associated with olanzapine use due to excessive dopamine receptor antagonism. First-generation antipsychotics (e.g., haloperidol) typically carry higher risk for these effects than second-generation drugs (e.g., olanzapine and risperidone). So, generally speaking, the risk for extrapyramidal side effects is low and EPS is typically associated with higher doses of olanzapine, as such would be used to treat a psychiatric condition such as schizophrenia. When we do see EPS in patients taking olanzapine, they are typically also taking another dopamine-blocking medication, such prochlorperazine or metoclopraminde for breakthrough nausea. In such cases, discontinuation of the dopamine antagonist and rotation to a different antiemetic drug class typically allows for EPS resolution.

A growing body of research now highlights the benefits that olanzapine can provide to seriously ill patients, including individuals with cancer. And while its use as an antiemetic for CINV has become commonplace, patients with serious illness often have overlapping symptoms that may be addressed with a trial of olanzapine. Its effects on mood, appetite, and sleep are all generally attributed to the blockade of 5-HT receptors in the cerebral cortex, which may help relieve these symptoms.

If you’re considering a trial of olanzapine for your patient, I recommend starting with a daily dose of 2.5 to 5 mg PO or ODT. The oral-dissolving tablets can be especially useful in patients who are having problems with swallowing. Intramuscular and intravenous preparations of olanzapine do exist but are typically used for psychiatric indications, including schizophrenia and acute agitation. In the palliative care setting, we typically use only the oral tablets and oral-dissolving tablets. After initiation, I re-evaluate the patient several weeks later. If they are tolerating well but without notable improvement in their symptoms, I up-titrate, slowly, and typically to a maximum dose of 10 mg daily.

I also recommend the patient take olanzapine prior to bedtime to harness the benefit of its sedative effect, especially if the patient is already struggling with insomnia. Bedtime administration will also mitigate daytime drowsiness.

If I had to summarize my approach to using olanzapine in patients with serious illness, it would be: start low and go slow.

Olanzapine can be very useful for addressing multiple symptoms—especially nausea and vomiting—in patients with serious illness, including those undergoing cancer treatment. Administration near bedtime is advisable, and even low doses can achieve positive results while minimizing risks such as QT prolongation and extrapyramidal symptoms. If the patient has sub-optimal results, thoughtful dose escalation is key to maximizing benefit while limiting harm.

Palliative care clinicians should feel comfortable considering olanzapine as a treatment option for patients with nausea, poor appetite, anxiety, and insomnia. When used appropriately, it can meaningfully improve quality of life.

Explore these additional resources on nausea and vomiting:

• Nausea/Vomiting, a course that teaches practical skills to identify, manage, and reduce nausea and vomiting in people living with serious illness.
• How to Manage Nausea and Vomiting in Patients with Serious Illness, a blog covering the ins and outs of nausea and vomiting in people living with serious illness, including causes, treatment, and patient-education.

Edited by Melissa Baron. Clinical review by Andrew Esch, MD, MBA.