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Overview of Chemotherapy-Induced Nausea and Vomiting and Evidence-Based Therapies
Nelly Adel, PharmD, BCOP, BCPS
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Managed Care Considerations in Chemotherapy-Induced Nausea and Vomiting

Overview of Chemotherapy-Induced Nausea and Vomiting and Evidence-Based Therapies

Nelly Adel, PharmD, BCOP, BCPS
Pharmacologic and Integrative Medical Therapies for CINV
Pharmacologic Therapies
Prevention and treatment of CINV is based on its underlying subtype. The primary goal is to prevent CINV from occurring so that subsequent episodes of nausea and vomiting and the potential for anticipatory CINV are avoided. Uncontrolled nausea and vomiting have potential effects on the patient’s QOL and adherence to chemotherapy. The various antiemetic guidelines available for CINV describe in detail the numerous options for crafting a regimen to fit a patient’s needs.17,27,28 When devising an antiemetic regimen, the level of treatment is based on the chemotherapy drug with the highest potential for emesis. Therefore, if a chemotherapy regimen includes drugs with low or minimal emetic risks, as well as a drug with high emetic risk, such as anthracyclines, the antiemetic regimen should be tailored to the drug with the highest emetic risk. Emesis control should be individualized to patient need and, depending on the chemotherapeutic agents used, duration of regimen, the route of administration for the antiemetic, and considerations regarding the AEs of the antiemetic agents.

The main pharmacologic classes of drugs used in preventing and treating CINV (Table 327) are 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids; they also include, to a lesser extent, dopamine antagonists, benzodiazepines, cannabinoids, and the atypical antipsychotic, olanzapine. With different mechanisms of action, the agents are typically administered in combination protocols to provide maximum antiemetic control, particularly when patients are undergoing high or moderate emetic risk chemotherapy regimens.

5-HT3 Receptor Antagonists
The 5-HT3 receptor antagonists act on serotonin receptors both peripherally in the intestine and centrally in the CTZ.29 This class includes the first-generation 5-HT3 receptor antagonists, ondansetron, dolasetron, and granisetron, with half-lives between 3 and 9 hours. The second-generation compound in this class, palonosetron, has a half-life of approximately 40 hours.29 The differences in half-lives influence dosing and possibly indication. Ondansetron, dolasetron, and granisetron are most commonly used in acute CINV.30,31 Palonosetron demonstrates efficacy in delayed CINV as well.32-35 Common AEs for 5-HT3 antagonists include headache and gastrointestinal effects such as constipation, as well as elevation of liver aminotransferase levels.36-39 Of particular note, ondansetron and dolasetron should be given with caution in patients with long QT syndrome.36,38

NK1 Receptor Antagonists
The NK1 receptor antagonists act peripherally and centrally by blocking the binding of substance P at the NK1 receptor.40 The approved drugs in this class include aprepitant, fosaprepitant (a prodrug of aprepitant for injection), and rolapitant.41,42 Another NK1 receptor antagonist, netupitant, is formulated with the 5-HT3 receptor antagonist, palonosetron, in a fixed-dose combination product for acute and delayed CINV.43 The NK1 antagonists are not used as sole antiemetic agents in acute CINV, but rather typically in combination with a 5-HT3 antagonist and dexamethasone. Aprepitant may also be used in delayed CINV.17,27,28 AEs of NK1 receptor antagonists are generally limited to diarrhea, fatigue, and nausea,44-48 but individual agents have specialized AEs of note. Aprepitant is metabolized by and is a moderate inhibitor of CYP3A4, which may lead to drug-drug interactions. Of particular importance in CINV, aprepitant causes an increase in plasma dexamethasone levels; therefore, reduction in dexamethasone doses are necessary when used in combination antiemetic regimens.29,49-51 Aprepitant and fosaprepitant are also contraindicated in patients receiving pimozide because inhibition of metabolism can lead to increased pimozide levels that can cause severe or life-threatening reactions, including QT prolongation.41 In addition, aprepitant and fosaprepitant should be used with caution in patients receiving warfarin, due to a potential decrease in the international normalized ratio; drug-drug interactions are possible with CYP3A4 substrates, CYP3A4 inhibitors, and CYP3A4 inducers.41

Rolapitant is generally well tolerated, with fewer than 10% of patients experiencing treatment-related AEs.44,45 The most common AEs with rolapitant were similar to those of control groups and include neutropenia, hiccups, and dizziness.42 Although rolapitant is not an inhibitor or inducer of CYP3A4,52 it is metabolized by the enzyme, and CYP3A4 inducers, such as rifampin, can reduce rolapitant blood levels and efficacy.42 As a CYP2D6 inhibitor, rolapitant is contraindicated in patients receiving thioridazine and concomitant administration should be avoided with other CYP2D6 substrates, such as pimozide, but no dose adjustment is needed with dexamethasone.42

For the netupitant/palonosetron (NEPA) combination product, AEs include asthenia, dyspepsia, fatigue, hiccups, and erythema, and severe AEs reported in clinical trials include neutropenia and leukopenia.53,54 Netupitant is a moderate inhibitor of CYP3A4 and drug interactions are possible in patients receiving drugs that are metabolized by CYP3A4, but no contraindications are listed.43 NEPA, however, should be avoided in patients with severe renal or hepatic impairment.43

While the mechanism of action of corticosteroids as antiemetics is not entirely clear, their use in CINV dates to the 1980s.29 Dexamethasone is the corticosteroid of choice for CINV, and it is often used in combination with other agents to increase antiemetic efficacy in acute and delayed CINV. Dexamethasone may also be used as monotherapy in low–emetic risk chemotherapy regimens.17,27,28

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