CHEMOTHERAPY-INDUCED NAUSEA and VOMITING CHAPTER: 123
Pharm 2013, HP
Recommended flags in TC: 1653, 1655, 1658-1660.
TREATMENT CONSIDERATIONS/ THERAPEUTIC TIPS- Prevent/minimize and treat acute (starting within 24 hours of chemo), delayed (starting >24 hours after chemo), and anticipatory (starting before chemo as a conditioned reponse) n and v so as to increase patient comfort and avoid treatment delays.
- Controlling n/v can prevent complications: esophageal tears, dehydration, anorexia, malnutrition, weight loss, pathological bone fractures, metabolic alkalosis, chloride and potassium depletion.
- Other drugs (ie. opioids, digoxin, antibiotics) and conditions (fluid/electrolyte imbalance, bowel obstruction, CNS or hepatic metastases, infections and radiation therapy) may cause or exascerbate n/v. Ensure thorough history, exam, labs.
- Type 3 serotonin (5HT3) and neurokinin-1 (NK-1) receptors are the most implicated in chemo-induced n /v (CINV).
- 5HT3 receptor antagonists (5HT3 RA) and NK-1 receptor antagonists are the mainstay of prevention of moderate to highly emetogenic chemotherapy regimens.
- Emetogenic potential of various i.v. chemotherapeutic agents are listed on Table 1, pg 1653.
- Oral antiemetics are preferred if the patient can tolerate. With vomiting, rectally-administered agents ie.prochlorperazine (at home) and i.v. antiemetics (in hospital) are used.
PREFERRED DRUG CLASS/ DRUG (where appropriate) with INTERACTIONS, DOSING SUGGESTIONS etc.
See Figure 1, pg 1655 for Prevention and management of CINV (for regimens of various emetogenic potential).
Serotonin Antagonists:*Mainstay of prevention of moderate to highly emetogenic chemotherapy regimens
(5HT3 RA) dolasetron, granisetronand ondansetronare equivalent in efficacy and toxicity.
(SE: H/a, constipation, diarrhea, sedation, transient ↑ in liver function tests, bradycardia, dizziness. ECG interval changes have been reported. Dolasetron CI in patients <18 yoa.)
For highly emetogenic regimens: 5HT3 RA + corticosteroid + aprepitant improves results.
For moderately emetogenic regimens:5HT3RA + corticosteroid is recommended.
Well tolerated. Oral preparations are as effective and as safe as i.v. Decide based on cost.
Neurokinin-1 Receptor Antagonists:*Mainstay of prevention of moderate to highly emetogenic chemotherapy regimens
Aprepitant (oral) and fosaprepitant (i.v.) bind to substance P (brainstem and GI).
When added to a 5HT3 RA+dexamethasone for highly emetogenic chemo, NK-1 antagonists improve prevention of acute and delayed n&v.
(SE:asthenia/fatigue + hiccoughs (most common SE), diarrhea, dizziness, dyspepsia). Aprepitant is well tolerated.
Corticosteroids:
Dexamethasone (most common)though others studied (methylprednisolone).
MOA unknown. Effective as single or in combination with other antiemetics.
Particularly effective in prevention of delayed n&v.
Combination of dexamethasonewith a 5HT3RA+ aprepitantis most effective regimen for acute n&v.
(SE: mood changes, increased appetite, GI irritation, ulceration, fluid retention, weight gain, may mask signs of infection).
Dopamine Antagonists:haloperidol, metoclopramide, olanzapine, prochlorperazine
Prochlorperazineand metoclopramidemost common for management of low emetogenic regimens or as rescue agents.
At high doses,prochlorperazinemay also exhibit serotonin antagonist activity.
Prochlorperazine available in wide variety of dosage forms, facilitates use.
Similar efficacy of these 2 agents at low doses; metoclopramide has ↑ efficacy at high doses (but ↑ extrapyramidal effects).
(metoclopramide SE: sedation, dose-related diarrhea, extrapyramidal effects). Use is limited.
(prochlorperazine SE: sedation, anticholinergic effects, extrapyramidal effects, hypotension, hypersensitivity, rare pancytopenia).
Haloperidol may help refractory nausea though insufficient RCTs, but may be less effective than metoclopramide.
(SE: sedation, extrapyramidal effects).
Olanzapine antagonizes several neurotransmitters (including dopamine and 5HT). Activity in acute and delayed n&v.
(SE: Dizziness, constipation, postural hypotension, akathisia, somnolence, dry mouth).
Benzodiazepines:lorazepam, alprazolamaremost common.
Antianxiety, amnesic and sedating effects.
Anticipatory nausea. Often used in combination with other antiemetics.
(SE: Sedation).
Cannabinoids:nabilone, dronabinol
Used in refractory n&v or in combination with other antiemetics. Use limited because side effects.
(SE:Sedation, dizziness, ataxia, psychotropic effects (‘high’), hallucinations, delusions, tachycardia, orthostatic hypotension, dry mouth). Higher doses show increased risk.
Antihistamines and Anticholinergics:
Antihistamine dimenhydrinate and antimuscarinic scopolaminetreat motion sickness vomiting.
No more effective than placebo with CINV.
RED FLAGS/ COMMON INTERACTIONS ASSOCIATED WITH THIS DISEASE/ DRUGS FOR THIS DISEASE
- Intravenous dolasetronno longer available due to serious arrhythmia risk.
- Dolasetron has potential interaction with other drugs that prolong QT intervals. Blood levels ↑ when coadministered with cimetidine and ↓ when coadministered with rifampin.
- Aprepitantis moderate inhibitor of CYP3A4 and interacts with corticosteroids. Lower dose of dexamethasonewhen combined.
- Aprepitant is CI with cisapride, pimozide. ↑ levels of drugs metabolized by CYP3A4 (eg. dexamethasone, midazolam). ↓ levels of drugs metabolized by CYP2C9 (eg. phenytoin, tolbutamide, warfarin). ↑ levels of aprepitant with CYP3A4 inhibitors (eg. erythromycin, clarithromycin, ketoconazole). ↓ levels of aprepitant with CYP3A4 inducers (carbamazepine, phenytoin, rifampin). Possible ↓ of effectiveness of oral contraceptives.
- Dexamethasone is a CYP3A4 substrate. CYP3A4 inhibitors (eg. ketoconazole, erythromycin, clarithromycin) may ↓ its metabolism. Antacids and CYP3A4 inducers (eg. carbamazepine, phenobarbital, phenytoin, rifampin) may ↑ its metabolism.
- Metoclopramide + anticholinergic agentantagonizes effects of metoclopramide on GI motility.
- Olanzapine and concomitant use with benzodiazepines may cause cardiorespiratory depression and excessive sedation. Use with metoclopramide may ↑ risk of developing tardive dyskinesia. Strong CYP1A2 inhibitors (ciprofloxacin,
anti-Parkinson’s agents.
- Benzodiazepines, cannabinoids, dopamine antagonists (haloperidol, metoclopramide, prochlorperazine) interact with sedating medications. Additive sedation occurs with, for example, opioid analgesics, hypnotics, alcohol; avoid or minimize use if possible.
Pharm 2013