Download NAUSEA AND VOMITING

40-1
NAUSEA AND VOMITING
In for a Tune-Up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level II
Kelly K. Nystrom, PharmD, BCOP
CASE SUMMARY
Mr Jones is a 57-year-old man who is admitted to the hospital for
back and abdominal pain. He is found to have metastatic small cell
lung cancer. His oxycodone ER is increased to 20 mg PO Q 12 H
for severe pain, and he is given cycle 1 of cisplatin and etoposide,
along with radiation therapy, to try to decrease his pain. The pharmacist receives chemotherapy orders, including antiemetic orders
for breakthrough and delayed nausea and vomiting. Students must
assess the antiemetic regimens and make any changes necessary
based on efficacy, side effects, and cost.
QUESTIONS
Problem Identification
1.a. Create a list of this patient’s drug therapy problems.
• Metastatic small cell lung cancer treated with etoposide and
cisplatin as well as palliative radiation therapy to the spine.
• Inappropriate dose and duration of ondansetron. The maximum single recommended dose of ondansetron is 16 mg IV
because of increased risk of QT prolongation. In addition,
etoposide has a low potential for emetogenicity, so while
ondansetron is an option for prevention of delayed nausea and
vomiting, it may be less cost effective than prochlorperazine,
metoclopramide, or dexamethasone to prevent nausea and
vomiting with etoposide on days 2 and 3.
• Inappropriate dose and duration of dexamethasone when used
with fosaprepitant.
• The dexamethasone dose prior to cisplatin should be 12 mg
because of a cytochrome P-450 3A4-mediated interaction
with most NK1 receptor antagonists, which can increase the
concentration of dexamethasone by up to 100%. To prevent
delayed nausea and vomiting, dexamethasone 8 mg PO daily
on day 2, then 8 mg bid on days 3 and 4 should also be added
to the regimen.
• Inappropriate choice of antiemetic for breakthrough treatment
of nausea and vomiting. Because ondansetron was scheduled
prior to chemotherapy, an antiemetic with a different mechanism of action would be more appropriate for breakthrough
nausea and vomiting. Prochlorperazine, metoclopramide, or
promethazine would be a reasonable choice for breakthrough
nausea and vomiting.
• Abdominal and back pain treated with scheduled and PRN
oxycodone. The patient is not on anything to prevent constipation. A scheduled stool softener and stimulant laxative should
be started.
• Liver dysfunction due to metastatic disease. The dose of etoposide
should be decreased by 50% because of the elevated bilirubin.
• Cisplatin-based chemotherapy: Guidelines classify chemotherapeutic medications as having a high, moderate, low,
or minimal emetic risk.1–3 Cisplatin is a high-emetic-risk
chemotherapy (HEC) agent. According to the National Comprehensive Cancer Network (NCCN) guidelines and the most
recent Multinational Association of Supportive Care in Cancer
(MASCC)/European Society of Medical Oncology (ESMO)
guidelines, the antiemetic combination recommendation for
HEC is a 5-HT3 receptor antagonist plus dexamethasone and
an NK1 receptor antagonist.1,3,4
• Radiation therapy to the upper abdomen and total body irradiation increase the risk of nausea and vomiting. Generally,
radiation therapy to the spine does not increase the patient’s
risk of nausea and vomiting, but when given with chemotherapy may contribute to breakthrough nausea and vomiting.1
• Anxiety (depending on the degree) may increase Mr Jones’ risk
of nausea and vomiting.1
Decreased risk factors:
• Male gender: Females have a higher risk of nausea and vomiting, particularly those with a history of morning sickness with
pregnancy or motion sickness.1,5
• Age older than 50 years: Patients under the age of 50 years may
experience significantly more postchemotherapy nausea and
vomiting than older patients.1,5
• Significant alcohol use: Patients with current heavy alcohol use
or a history of heavy alcohol use generally have less nausea and
vomiting after chemotherapy than patients who report modest
or no alcohol use.1,5 Mr Jones has a history of alcohol abuse,
which may decrease his risk of nausea and vomiting.
• History of motion sickness for males or females increases postchemotherapy risk for nausea and vomiting.1,5 Mr Jones has no
history of motion sickness.
1.c. What factors may be contributing to his nausea and vomiting?
• Chronic cholecystitis: Mr Jones is receiving scheduled ibuprofen to help with inflammation. If he is unable to eat because of
nausea and vomiting, taking ibuprofen on an empty stomach
may also be contributing to nausea and vomiting.
• Constipation: Mr Jones may benefit from the addition of a
scheduled stool softener and stimulant laxative.
• Opioid use: The recent increased opioid dose may also be contributing to Mr Jones’ nausea and vomiting.
• GERD: If Mr Jones is unable to tolerate esomeprazole due to
nausea and vomiting, he may be experiencing a flare of GERD.
Desired Outcome
2.What are the goals of therapy in this case?
• Prevent acute and delayed nausea and vomiting with appropriate antiemetic choices.
• Provide appropriate antiemetics for treatment of breakthrough
nausea and vomiting.
• Minimize adverse effects of antiemetics.
• Preserve quality of life (eg, maintain usual performance status,
appetite, ability to socialize).
• Provide cost-effective management of chemotherapy-induced
nausea and vomiting.
• Ensure adequate pain control.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Nausea and Vomiting
Amy M. Pick, PharmD, BCOP
Increased risk factors:
CHAPTER 40
40
1.b.What are this patient’s risk factors for chemotherapyinduced nausea and vomiting?
40-2
Therapeutic Alternatives
SECTION 4
3.a. Assess the patient’s antiemetic regimen for prophylaxis of
acute and delayed nausea and vomiting and for the treatment of breakthrough nausea and vomiting. Make any
changes as necessary.
Prophylactic regimen:
Gastrointestinal Disorders
• This patient has a relatively low number of emetic risk factors, but cisplatin is classified as an HEC agent.1–3 Current
guidelines recommend the combination of a 5-HT3 receptor
antagonist, dexamethasone, and an NK1 receptor antagonist to
prevent both acute and delayed nausea and vomiting.1,3,4
• Because he is taking other medications by mouth, this regimen should be administered by the oral route. Oral antiemetic
agents are recommended when patients are able to take medications by mouth because of equivalent efficacy and decreased
cost when compared with IV antiemetic agents.1,4 There is
an increased risk of QT prolongation with 5-HT3 receptor
antagonists; therefore, the maximum recommended IV dose of
ondansetron is 16 mg and oral dose of ondansetron is 24 mg.1,3
Palonosetron is the only 5-HT3 receptor antagonist without
this warning.5
• The patient should have a corticosteroid, such as dexamethasone, given with a 5-HT3 receptor antagonist to improve
efficacy.1 Because some NK1 receptor antagonists inhibit
the CYP450 3A4 metabolism of dexamethasone and increase
the dexamethasone AUC by about twofold, the dose of dexamethasone should be reduced when these agents are used
(see Table 40-1).1,4 The exception to this is rolapitant, which is
not a cytochrome P-450 3A4 inhibitor, so no dose adjustment
is needed. See Table 40-1 for dexamethasone schedules that
would be used with each of the NK1 receptor antagonists.
• Because etoposide has low emetic potential, ondansetron is an
option, but may not be needed on day 2 and may not be the
most cost-effective choice.3 Mr Jones could receive oral prochlorperazine or metoclopramide on a scheduled basis prior to
chemotherapy in addition to dexamethasone if dexamethasone
alone is not adequate.1,2
Appropriate antiemetic regimens include:
Day 1:
✓Ondansetron 24 mg PO (or granisetron 2 mg PO or dolasetron 100 mg PO or palonosetron 0.25 mg IV) + dexamethasone 12 mg PO + fosaprepitant 150 mg IV (or aprepitant
125 mg PO) 1 hour prior to chemotherapy OR
✓Ondansetron 24 mg PO (or granisetron 2 mg PO or dolasetron 100 mg PO or palonosetron 0.25 mg IV) + rolapitant
180 mg PO + dexamethasone 20 mg PO 1 hour prior to
chemotherapy OR
✓ Netupitant 300 mg/palonosetron 0.5 mg PO and dexamethasone 12 mg PO 1 hour prior to chemotherapy OR
✓Olanzapine 10 mg PO, palonosetron 0.25 mg IV, and dexamethasone 20 mg IV prior to chemotherapy
Days 2–4:
✓Prochlorperazine 10 mg (or metoclopramide 10 mg) PO
1 hour prior to chemotherapy on days 2 and 3, dexamethasone 8 mg PO daily for 1 day on day 2 and 8 mg PO bid on
days 3 and 4. (Please note that if palonosetron is the 5-HT3
antagonist used on day 1, only dexamethasone is needed
on days 2–4 and if aprepitant is used on day 1 then aprepitant 80 mg PO 1 hour prior to chemotherapy is needed on
days 2 and 3.) OR
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
TABLE 40-1 Dexamethasone Dosing with NK1 Receptor Antagonists
for Highly Emetic Chemotherapy (HEC)1
NK1 Receptor Antagonist
Dexamethasone Dosing
Aprepitant 125 mg PO on day 1,
then aprepitant 80 mg PO daily
on days 2 and 3
Fosaprepitant 150 mg IV on day 1
12 mg day 1 then 8 mg daily days 2–4
Rolapitant 180 mg PO on day 1
Netupitant 300 mg/palonosetron
0.5 mg PO on day 1
12 mg day 1; 8 mg daily day 2, then
8 mg bid days 3–4
20 mg day 1 then 8 mg bid days 2–4
12 mg day 1 then 8 mg daily days 2–4
✓If olanzapine was used on day 1, then olanzapine 10 mg PO
daily on days 2–4
✓While PO administration is preferred for antiemetics, giving
fosaprepitant IV on day 1 helps with non-compliance issues
of taking PO aprepitant on days 2 and 3.
✓Please see Table 40-1 for dexamethasone schedules with the
other NK1 receptor antagonist.
• Keep in mind that some of the 5-HT3 receptor antagonists are
available as a generic for both oral and IV routes and there is
no 5-HT3 antagonist of choice, so drug choice should be based
on what is most cost-effective for your institution.
Delayed nausea/vomiting regimen:
• The risk of nausea and vomiting lasts for at least 2 days for
moderate emetic chemotherapy (MEC) regimens and for
at least 3 days for HEC and selected MEC regimens.1 If a
patient receives an MEC or HEC regimen, the antiemetics
should be scheduled during this time of risk. Because of the
interaction of dexamethasone and most of the NK1 receptor
antagonists, the dexamethasone dose may need to be decreased
(see Table 40-1).1,4 Rolapitant is a moderate inhibitor of the
cytochrome P-450 2D6 pathway (for at least 7 days after a
single dose), Breast Cancer Resistant Protein (BCRP) and
P-glycoprotein.6 Numerous medications are affected by these
pathways including methotrexate, irinotecan, gefitinib, tamoxifen, digoxin, codeine, and olanzapine so drug interactions
should be checked, and patients should be monitored for
adverse effects if concomitant use cannot be avoided.6
Breakthrough regimen:
• Because a 5-HT3 receptor antagonist was used in the prechemotherapy antiemetic regimen, an agent with a different
mechanism of action would be a more desirable antiemetic
choice to control breakthrough nausea and vomiting.1,3,7
• NCCN guidelines list a number of options for breakthrough
nausea and vomiting. Prochlorperazine is a good alternative to
ondansetron, and an important benefit of this drug is that it is
available in various formulations including an injection, tablet,
syrup, and suppository.
• Lorazepam might also be a good option in conjunction with
the prochlorperazine because of the patient’s increased anxiety.
• Olanzapine is also another option that has shown efficacy and
is available as an oral tablet and an oral disintegrating tablet.1,3,5
Please see NCCN guidelines for other options.
3.b.What nondrug therapies may be useful to prevent nausea
and vomiting?
• Eating light meals, avoiding spicy or fatty foods, avoiding
foods with strong odors1
• Diversions such as music, reading, games, and videos
40-3
Patient Education
4.How would you educate this patient on his antiemetic regimen?
General information:
• After the chemotherapy, you will be taking some medications
to prevent nausea and vomiting that may occur 1–3 days after
your chemotherapy is given. These medications work best
when you take them at routine scheduled times to prevent
nausea and vomiting from occurring, rather than waiting until
you are very nauseated and taking them on an “as-needed”
basis.
Antiemetic regimen:
• About 60 minutes before your chemotherapy, we will give
you three medications to prevent nausea and vomiting. These
medications are ondansetron (or granisetron or dolasetron or
palonosetron), fosaprepitant (or aprepitant or rolapitant) and
dexamethasone. (A regimen using the combination product
netupitant/palonosetron and dexamethasone could also be
used.)
• You will also be taking scheduled oral dexamethasone on a
daily basis for a few days after your chemotherapy to help
prevent delayed nausea and vomiting. (Note: Additional aprepitant is also needed on days 2 and 3, if aprepitant was used
on day 1.)
✓ Ondansetron (or granisetron or dolasetron or palonosetron):
This medication sometimes causes headaches. It is okay
to take acetaminophen (Tylenol) if this occurs. Other side
effects that can occur include mild constipation or diarrhea.
This drug can interact with a number of medications, so
please let your doctor or pharmacist know you are taking
this medication if you are started on a new medication.
✓Fosaprepitant (or aprepitant): Like ondansetron, this drug
can also cause headache, constipation and diarrhea. It may
also cause some discomfort at the site of injection (if receiving IV). If this occurs during the infusion let your nurse
know. (If you are counseling a female, it is important to tell
them that fosaprepitant may make birth control pills less
effective. This effect can last for several weeks so another
form of birth control should be used until 28 days after the
last dose of fosaprepitant.)
✓Dexamethasone: This medicine can cause mood swings,
increased appetite, hyperactivity, and in some patients
increased blood sugars. These effects are only temporary
and will disappear after you finish the medication. It can
also cause stomach upset, and taking it with food will help
prevent this from occurring. Taking the dose with breakfast
will help prevent insomnia.
✓Prochlorperazine: The main side effect of this medication
is drowsiness. Make sure you know how you react to it
before you drive, use machinery, or do other things that
require you to be fully alert. It may also cause your mouth to
be dry and can make your BPH symptoms worse. Call your
doctor if you have any uncontrolled movements or unusual
restlessness.
✓Metoclopramide: This medication will be used only as
needed for nausea and vomiting. It may cause drowsiness, so
use caution if you must perform activities that require you
to be alert. Diarrhea sometimes occurs, but it is usually not
severe. Call your doctor if you have any uncontrolled movements or unusual restlessness.
✓Lorazepam: This medication will be used only as needed
for nausea and vomiting. It may cause drowsiness, so use
caution if you must perform activities that require you to
be alert. This medication is very effective when the nausea
and/or vomiting is caused or worsened by anxiety.
• When you go home, call the clinic right away if you have vomiting despite having taken your medications.
• Just to make sure that I have not left anything out, please tell
me about each of your medications for nausea and vomiting.
• If you have any problems with your medications or if you think
of additional questions, please feel free to call me or have your
nurse contact me. Here is a card with my name and phone
number on it.
■■ FOLLOW-UP QUESTIONS
1.How might you educate the nurse about using ondansetron for
breakthrough nausea and vomiting?
• As stated earlier, because the antiemetic regimen prior to chemotherapy contained ondansetron, giving more of the same
class of drugs will provide little benefit because the 5-HT3
receptors should already be saturated, meaning more of the
same drug will provide little or no benefit.1,3,5 The patient
would receive the greatest benefit from an antiemetic with a
different mechanism of action.
2.What pharmacologic alternatives may be helpful for the initial
treatment of this patient?
Fluid and electrolyte replacement:
• This could be accomplished with 2–4 L of D5NS with KCl
20–40 mEq/L IV over 4–6 hours. D5NS with KCl is chosen
because it provides fluid in addition to replacing the electrolytes that have been lost (ie, sodium, potassium, and chloride).
The dextrose is included to provide carbohydrates because this
patient has not been eating as a result of his vomiting.
• The volume of fluid, the composition of the fluid, and the rate
of infusion may vary depending on the severity of the patient’s
signs and symptoms and the extent of his laboratory abnormalities. Because he is vomiting, oral fluid and electrolyte
replacement is not an option.
Treatment of breakthrough nausea and vomiting:
• The plan for this should include the three possible etiologies of
this problem: chemotherapy, dyspepsia, and anxiety. Assuming recommendations were followed to premedicate on days
2–4 with dexamethasone, a 5-HT3 receptor antagonist may
also be a viable option for the acute episode of nausea and
vomiting.1 If palonosetron was used as the 5-HT3 receptor
antagonist on day 1, then prochlorperazine or lorazepam may
be better choices. A black box warning was added to metoclopramide in 2009 to notify healthcare professionals of the risk
of tardive dyskinesia, but this is generally after long-term or
high doses of metoclopramide. It is important to note though
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Nausea and Vomiting
• The chemotherapy medications you are receiving may cause
nausea and vomiting. We will give you medications by mouth
prior to your first dose of chemotherapy that work very well
at preventing the nausea and vomiting that may be associated
with your chemotherapy.
• At the first signs of nausea, please let your nurse know right
away, so she can give you a different medication (such as metoclopramide or lorazepam) to prevent any vomiting episodes.
CHAPTER 40
• Behavioral therapy such as relaxation, hypnosis, guided mental
imagery, music therapy, and acupuncture/acupressure1
40-4
SECTION 4
that this side effect may not reverse on discontinuation of
metoclopramide.
• It may be helpful to make a follow-up phone call the day after
chemotherapy to detect problems early.
• Examples of reasonable treatment plans for this patient include:
5.b. Describe the information you will need to assess the efficacy
and adverse effects of the prophylactic antiemetic regimen
prior to each future course of chemotherapy.
✓Metoclopramide 10–40 mg IV every 4–6 hours as needed
✓Ondansetron 8–16 mg PO or IV + dexamethasone 12 mg
PO or IV daily as needed (if palonosetron was not used)
✓Lorazepam 0.5–1 mg IV repeated in 3 hours if needed for
anxiety
Gastrointestinal Disorders
✓Olanzapine 10 mg PO daily for 3 days
• Prior to each course of chemotherapy, review the patient’s
medical record for additional information, and interview him
to assess the following parameters:
Efficacy:
• Some clinicians might add diphenhydramine 25–50 mg IV to
prevent extrapyramidal reactions from the antiemetics that
work by blocking dopamine receptors in the chemoreceptor
trigger zone.
• The presence and severity of anticipatory, acute, or delayed
nausea.
• Olanzapine is relatively well tolerated, and common side
effects include somnolence, orthostatic hypotension, constipation, and dizziness.5
• The effectiveness of “as-needed” antiemetics in relieving
nausea and/or vomiting.
■■ FOLLOW-UP QUESTIONS (Continued)
Optimal Plan
3.Design a plan for preventing delayed nausea and vomiting in
this patient for subsequent chemotherapy cycles.
• Because ondansetron was the 5-HT3 receptor antagonist used
in cycle 1, palonosetron 0.25 mg IV given prior to chemotherapy may be a better alternative in future cycles, because it
is designed to prevent both acute and delayed nausea.1 Palonosetron has a longer half-life and has shown to improve control
of delayed nausea and vomiting better than the other 5-HT3
receptor antagonists. Olanzapine 10 mg PO given with palonosetron on day 1 then on days 2–4 may replace the NK1 receptor
antagonist as well, so the regimen would contain palonosetron,
dexamethasone, and olanzapine.1 Another alternative may be
granisetron patch 32.3 mg applied 24–48 hours before the next
cycle of chemotherapy and removed on day 4 of the cycle.
• Dexamethasone and an NK1 receptor antagonist should be
continued as in cycle 1.
4.Design a plan to prevent anticipatory nausea and vomiting in
this patient for subsequent chemotherapy cycles.
• Mr Jones is at high risk for anticipatory nausea and vomiting
because of the uncontrolled nausea and vomiting he experienced with cycle 1.1,5
✓ Lorazepam 0.5–2 mg PO the night before and the morning of
treatment prior to coming to the clinic might be beneficial.1,5
✓Behavioral therapy, such as relaxation therapy, hypnosis,
guided imagery, acupuncture/acupressure, or music therapy,
may also be beneficial to prevent anticipatory nausea and
vomiting.1
Outcome Evaluation
5.a.Describe how you will determine whether the antiemetic
regimen he received was effective for preventing acute and
delayed nausea and vomiting.
• When the patient presents for subsequent cycles in the clinic,
ask him about the number of nausea and/or vomiting episodes he experienced after his previous chemotherapy cycle. It
may be helpful if the patient is asked to keep a diary of these
episodes.
• Assess the effect that nausea and/or vomiting had on the
patient’s quality of life (eg, was he able to continue normal
daily activities?).
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
• The number of episodes of anticipatory, acute, or delayed
vomiting or retching.
• Performance status (better, worse, or the same as it was prior
to chemotherapy).
• Appetite (better, worse, or the same as it was prior to
chemotherapy).
• Satisfaction with his antiemetic regimen (whether it worked as
well as he had hoped, with tolerable side effects).
• It may be helpful to make a follow-up phone call the day after
chemotherapy to detect problems early.
Adverse effects:
• 5-HT3 receptor antagonists: Headache, constipation, and
diarrhea
• Butyrophenones: Sedation and extrapyramidal effects
(akathisia and dystonia)
• Metoclopramide: Sedation, extrapyramidal effects (akathisia
and dystonia), and diarrhea
• Phenothiazines: Sedation and extrapyramidal effects (akathisia
and dystonia)
• Benzodiazepines: Sedation and memory disturbances
• Corticosteroids: Mood swings, insomnia, and increased
appetite
• NK1 receptor inhibitors: Fatigue, diarrhea, and hiccups
• Olanzapine: Sedation, extrapyramidal effects (akathisia and
dystonia), hyperglycemia, and constipation
■■ CLINICAL COURSE: ALTERNATIVE THERAPY
While discussing Mr Jones’ antiemetic regimen, he says, “I remember that my sister used to take ginger to prevent sea sickness when
she went on a cruise, and my cousin used ginger when he was
having chemotherapy a few years ago. Would that be good for
me to try?” See Section 19 in this instructor’s guide for questions
and answers about the use of ginger for treatment of nausea and
vomiting.
REFERENCES
1. Ettinger DS, Berger MJ, Aston J, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Guideline Antiemesis 2.2015.
© 2015 National Comprehensive Cancer Network, Inc. Available at:
www.NCCN.org. Accessed November 3, 2015.
2. Grunberg SM, Warr D, Grall RJ, et al. MASCC/ESMO guidelines:
evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—state of the art. Support Care Cancer
2011;19(Suppl 1):S43–S47.
40-5
6.Gold Standard, Inc. Rolapitant. Clinical Pharmacology [database
online]. Available at: http://www.clinicalpharmacology.com.cuhsl
.creighton.edu. Accessed November 3, 2015.
7. Navari RM. Treatment of breakthrough and refractory chemotherapyinduced nausea and vomiting. Biomed Res Int 2015;2015:595894.
doi:10.1155/2015/595894.
CHAPTER 40
3. Navari RM. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs
2013;73:249–262.
4. Kris MG, Tonato M, Bria E, et al. MASCC/ESMO guidelines: consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer
2011;19(Suppl 1):S25–S32.
5. Jordan K, Jahn F, Aapro M. Recent developments in the prevention of
chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Ann Oncol 2015;26:1081–1090.
Nausea and Vomiting
Copyright © 2017 by McGraw-Hill Education. All rights reserved.