Nausea and Vomiting

School of Pharmacy
Lebanese International University
Pharmacotherapeutics VI
(Hematology/Oncology)
 Introduction
 Nausea and vomiting are unpleasant symptoms
 Uncontrolled vomiting can lead
 Dehydration & electrolyte imbalances
 Aspiration pneumonia
 Esophageal tears
 Nutrient depletion
 Anorexia
 Decline of the patient’s performance status and mental status
 Withdrawal from useful or curative chemotherapeutic
treatment

2
 Introduction
 Symptoms range from mild, short-lived nausea to
continuing severe emesis and retching

 Chemotherapy-induced nausea and vomiting can

significantly:
 Reduce patient quality-of-life
 Poor compliance

3
 Causes of Emesis
 Medications
 Cancer chemotherapy
 Opiate analgesics

 Radiation

 Central nervous system (CNS)

 Brain metastasis

 Infectious disease
 Viral gastroenteritis

4
 Causes of Emesis
 Metabolic Disorders
 Hypercalcemia
 Uremia
 Hyperglycemia
 Hyponatremia

 Gastrointestinal Disorders
 Bowel obstruction

 Psychological Factors
 Anxiety

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 Factor Affecting Severity of Emesis
Chemotherapy Related Factors
 Chemotherapeutic agent

 Route of administration

 Infusion time (with shorter infusion)

 Dose (higher dose)

 Chemotherapy cycles (more cycles)

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 Factor Affecting Severity of Emesis
Radiation Related Factors

 Radiation to whole body or upper abdomen

 Larger daily fractional doses of radiotherapy

 Larger total doses

 Larger amounts of irradiated tissue

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 Factor Affecting Severity of Emesis
Patient Related Factors
 Age <50 years
 Sex:
 Female higher risk , but RR < 20 % for male
 Poor control of symptoms in prior chemo cycles
 History of motion sickness
 Nausea with pregnancy, anxiety, or depression
 History of alcohol intake > 12 drinks/week
 Alcohol abuse has protective effect against CIE

8
 Pathophysiology
 Emetic response can be described in three phases:
 Nausea
 Retching
 Vomiting
 Nausea
 Subjective feeling of the need to vomit
 Loss of gastric tone & motility
 Unpleasant sensation in the mouth and GI with salivation,
sweating, dizziness, and tachycardia
 Persist for hours or days

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 Pathophysiology
 Retching
 Rhythmic contraction of the abdominal muscles, diaphragm,
and chest wall without actual emesis
 Accompany nausea, or occur before or after emesis

 Vomiting
 Forceful expulsion of the stomach contents through the
mouth

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 Pathophysiology
 Emetic response is initiated by
 CNS
 Peripheral nervous system
 Gastrointestinal (GI) tract

 In CNS: chemoreceptor trigger zone (CTZ)

 Senses toxins and noxious substances in the blood and
cerebrospinal fluid
 Release of neurotransmitters that travel to the vomiting
center(VC) and nucleus tractus solitarius(NTS)
 Neurotransmitters involved: serotonin, dopamine, and
neurokinin-1.

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 Pathophysiology
 In GI:
 Enterochromaffin cells in GI mucosa are damaged by
chemotherapy, radiation, or mechanical irritation
 ➔Release of serotonin
 Stimulate the vagal afferents
 Stimulate the VC and NTS

 Vomiting center propagates emetic response

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 Pathophysiology
Vomiting Center (VC)
 Located in the medulla oblongata of the brain, near the
nucleus tractus solitarius (NTS)
 Receives incoming signals from other parts of the brain
and GI tract and then coordinates the emetic response by
sending signals to the effector organ:
 Salivation center
 Abdominal muscles
 Respiratory centers
 Cranial nerves

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 Pathophysiology
Vomiting Center (VC)
 Neurotransmitter receptors associated with the emetic
response
 Serotonin (5-hydroxytryptamine type 3) receptors
 Neurokinin-1 receptors
 Dopamine receptors
 Others: corticosteroid, acetylcholine, histamine,
cannabinoid, gabaminergic, and opiate receptors

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 Types of Nausea and Vomiting
 Chemotherapy induced emesis (CIE) is commonly
classified as
 Acute
 Delayed
 Anticipatory
 Breakthrough
 Refractory

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 Types of Nausea and Vomiting
Acute Emesis
 Occurs within a few minutes to several hours after drug
administration

 Intensity peaks after 5 to 6 hours

 Resolves within the first 24 hours

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 Types of Nausea and Vomiting
Delayed Emesis
 Develops more than 24 hours after chemotherapy
administration persisting up to 5 days

 Occurs with administration of cisplatin, carboplatin,

cyclophosphamide, doxorubicin, and others.

 For cisplatin, emesis reaches its maximal intensity 48 to

72 hours after administration and can last 6 to 7 days

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 Types of Nausea and Vomiting
Anticipatory Emesis
 Occurs before patients receive their next chemotherapy
treatment

 Occurs after a negative past experience with

chemotherapy

 Risk factors
 Young individual
 Poor emetic control
 Treatment for more than 6 months
 Use of highly emetogenic agents

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 Types of Nausea and Vomiting
Breakthrough Emesis
 Occurs despite appropriate prophylactic treatment
 Requires “rescue” with antiemetic agents

Refractory Emesis
 Patient experience severe emesis
 Occurs during subsequent treatment cycles when antiemetic
prophylaxis and/or rescue have failed in earlier cycles

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 Emetogenicity of Chemotherapy
 Frequency of chemotherapy-induced emesis depends
primarily on the emetogenic potential of the specific
chemotherapeutic agents used

 Chemotherapeutic agents are divided into 4 levels

according to the percentage of patients not receiving
antiemetic prophylaxis who experience acute emesis

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 Emetogenicity of Chemotherapy
Agents Classification
Level of emetogenicity %

High emetic risk ≥ 90 %

Moderate emetic risk 30 – 90 %

Low emetic risk 10 – 30 %

Minimal emetic risk < 10 %

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 Emetogenicity of Chemotherapy

 High Emetic Risk Agents:

 AC combination defined as any chemotherapy
regimen that contains an anthracycline and
cyclophosphamide
 Carboplatin AUC ≥4
 Cisplatin
 Cyclophosphamide >1,500 mg/m2
 Doxorubicin ≥60 mg/m2
 Epirubicin >90 mg/m2
 Ifosfamide ≥2 g/m per dose
2

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 Emetogenicity of Chemotherapy

 Moderate Emetic Risk Agents:

 Chemotherapy with specified doses that cause high
emesis, at lower doses it causes moderate emetic risk
 Cytarabine >200 mg/m2
 Irinotecan
 Methotrexate ≥250 mg/m
 Oxaliplatin
 Daunorubicin
 Idarubicin

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 Emetogenicity of Chemotherapy

 Low Emetic Risk Agents:

 Chemotherapy with specified doses that cause
moderate emesis, at lower doses it causes low emetic
risk
 Docetaxel
 Paclitaxel
 Etoposide

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 Emetogenicity of Chemotherapy

 Minimal Emetic Risk Agents

 Vinblastine
 Vincristine
 Bleomycin

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 Emetogenicity of Chemotherapy
 Patients receiving chemotherapy are at risk for both acute
and delayed nausea/vomiting based upon the emetogenic
potential of the individual chemotherapy agents and their
sequence
 Examine using primary literature incidence of nausea and
vomiting for established chemotherapy combination
regimens
 If high risk and moderate risk, antiemetic regimen should be
appropriate for the high-risk chemotherapy agent

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 Principles of Emesis Control
 The primary goal is prevention of nausea/vomiting
 Antiemetic regimens should be chosen based on
 Drug with the highest emetic risk in the chemotherapy
regimen

 Previous experience with antiemetics

 Patient specific risk factors

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 Principles of Emesis Control
 Patients need to be protected throughout the entire period
of risk, which lasts for
 4 days for high emetic risk agents

 3 days for moderate emetic risk agents

 Only day of chemotherapy for low emetic risk

 No prevention for minimal emetic risk

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 Prevention of High Emetic Risk
Acute: day 1 of therapy Delayed: Day 2, 3, 4
 NK1 RA (choose one):
 Aprepitant 125 mg PO once  +/-Aprepitant 80 mg
 Aprepitant injectable emulsion 130 PO daily on days 2, 3
mg IV once (if aprepitant PO used
 Fosaprepitant 150 mg IV once on day 1)
 Rolapitant 180 mg PO once
 + Dexamethasone 8 mg
 + 5-HT3 RA (choose one)
 Dolasetron PO once
PO/IV daily on days 2,
 Granisetron SQ / IV/ PO/or patch
3, 4
 Ondansetron PO or IV once
 Palonosetron IV once
 + Dexamethasone 12 mg PO/IV once

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 Prevention of High Emetic Risk
Acute: day 1 of therapy Delayed: Day 2, 3, 4
 Olanzapine 5–10 mg PO
 Olanzapine 5-10 mg
 + Palonosetron 0.25 mg IV PO days 2, 3, 4
once
 + Dexamethasone 12 mg
PO/IV once

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 Prevention of High Emetic Risk
Acute: day 1 of therapy Delayed: Day 2, 3, 4
 Olanzapine 5-10 mg PO day 1
 + NK1 RA (choose one):
 Olanzapine 5-10 mg
 Aprepitant 125 mg PO once PO 2, 3, 4
 Aprepitant injectable emulsion 130  +/- Aprepitant 80 mg
mg IV once PO daily on days 2, 3
 Fosaprepitant 150 mg IV once
(if aprepitant PO used
 Rolapitant 180 mg PO once
on day 1)
 + 5-HT3 RA (choose one)
 Dolasetron PO once  + Dexamethasone 8 mg
 Granisetron SQ / IV/ PO/or patch PO/IV daily on days 2,
 Ondansetron PO or IV once 3, 4
 Palonosetron IV once
 + Dexamethasone 12 mg PO/IV once

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 Prevention of High Emetic Risk
 Fixed drug combination product (NK1-antagnosit + 5
HT3 anatagonist) given day 1 with dexamethasone and
continue dexamethasone day 2,3,4

 Netupitant 300 mg / palonosetron 0.5 mg (available as

fixed combination product only) PO once

 Fosnetupitant 235 mg / palonosetron 0.25 mg (available

as fixed combination product only) IV once

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 Prevention of High Emetic Risk
 Due to risk of dyspepsia with corticosteroid: add
H2block or PPI with above regimen

 Due to risk of anxiety and breakthrough emesis: add

lorazepam with above regimens

33
 Prevention of Moderate Emetic Risk
Acute: day 1 of therapy
 5-HT3 RA (choose one)
 Dolasetron PO once
 Granisetron SQ / IV/ PO/or patch
 Ondansetron PO or IV once
 Palonosetron IV once
 + Dexamethasone 12 mg PO/IV once
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Delayed: Day 2, 3
 Dexamethasone 8 mg PO/IV
daily on days 2, 3
OR
 5-HT3 RA monotherapy:
 Granisetron 1–2 mg PO/ IV
daily on days 2 and 3
 Ondansetron PO or IV
 Dolasetron PO
 N.B: when using
palonosetron day 1 or
granisetron SQ or patch, we
don’t continue them on day
2 and 3
 Prevention of Moderate Emetic Risk
Acute: day 1 of therapy Delayed: Day 2, 3
 Olanzapine 5–10 mg PO
 Olanzapine 5-10 mg
 + Palonosetron 0.25 mg IV PO days 2, 3
once
 + Dexamethasone 12 mg
PO/IV once

35
 Prevention of Moderate Emetic Risk
Acute: day 1 of therapy Delayed: Day 2, 3
 NK1 RA (choose one):
 Aprepitant 125 mg PO once  +/-Aprepitant 80 mg
 Aprepitant injectable emulsion 130 PO daily on days 2, 3
mg IV once (if aprepitant PO used
 Fosaprepitant 150 mg IV once on day 1)
 Rolapitant 180 mg PO once
 + Dexamethasone 8 mg
 + 5-HT3 RA (choose one)
 Dolasetron PO once
PO/IV daily on days 2,
 Granisetron SQ / IV/ PO/or patch
3
 Ondansetron PO or IV once
 Palonosetron IV once
 + Dexamethasone 12 mg PO/IV once

36 N.B: this regimen is only used in selected patients with risk factors
 Prevention of Moderate Emetic Risk
 Due to risk of dyspepsia with corticosteroid: add
H2block or PPI with above regimen

 Due to risk of anxiety and breakthrough emesis: add

lorazepam with above regimens

37
 Prevention of Low Emetic Risk
 Start before chemotherapyi,j,y
 Repeat daily for multiday doses of chemotherapy
 Dexamethasone 8–12 mg PO/IV oncel,y
 or
 Metoclopramide 10–20 mg PO/IV once
 or
 Prochlorperazine 10 mg PO/IV once
 or
 5-HT3 Ral (select one):
 Dolasetron PO
 Granisetron PO
 Ondansetron PO

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 Antiemetic Therapies
To provide maximal protection against, antiemetic therapy
 Initiated before chemotherapy 30 min before
 Continued for the same length of time as the duration of
the emetic activity of the chemotherapeutic agent being
used

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 Antiemetic Therapies
Serotonin (5-HT3) Receptor Antagonists
 Dolasetron 100 mg PO
 Granisetron 10 mg SQ once,t or 2 mg PO once, or 0.01
mg/kg (max 1 mg) IV or 3.1 mg/24-h transdermal
patch applied 24–48 h
 Ondansetron 16–24 mg PO once, or 8–16 mg IV
 Palonosetron 0.25 mg IV

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 Antiemetic Therapies
Serotonin (5-HT3) Receptor Antagonists
 IV Palonosetron
 100 fold higher binding affinity
 Half life 40 hrs
 Prolonged inhibition
 A single intravenous palonosetron dose of 0.25 mg may be sufficient prior
to the start of a 3-day chemotherapy regimen instead of multiple
 Daily doses of another oral or intravenous serotonin antagonist.
 When palonosetron is used as part of an antiemetic regimen that does NOT
contain an NK-1 antagonist, palonosetron is the preferred
 serotonin antagonist.2
 Repeat dosing of palonosetron 0.25 mg IV is likely to be safe, based on
available evidence.
 In terms of efficacy, limited data are available for multiday dosing

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 Antiemetic Therapies
Serotonin (5-HT3) Receptor Antagonists
 Ondansetron, granisetron PO/IV, and dolasetron are
effective in preventing acute emesis but appear to be less
effective for delayed emesis

 IV dolasetron is no longer recommended for the

prevention of nausea and vomiting due to risk of cardiac
arrhythmias. Only use PO

 Granisetron SQ/ or patch has longer durationthat PO/IV

and effective in preventing acute and delayed emesis

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 Antiemetic Therapies
Serotonin (5-HT3) Receptor Antagonists
 QT prolongation has occurred in patient with cardiac diseases, CHF,
bradycardia, and electrolyte abnormalities (Hypokalemia,
Hypomagnesemia), and those taking medications that cause QT
prolongation
 Recommend ECG monitoring

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 Antiemetic Regimen
 The addition of dexamethasone improves the efficacy of
the antiemetic regimen containing 5-HT3 antagonists

 Dexamethasone should be administered once daily (either

orally or intravenously) for moderately or highly emetogenic
chemotherapy and continued after chemotherapy for regimens
that are likely to cause significant delayed emesis
 It shouldn’t be added when chemotherapy regimen already
includes a corticosteroid
 Contraindicated with IL-2 and aldesleukin (immunotherapy and
cellular therapy)

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 Antiemetic Therapies
Neurokinin-1–Receptor Antagonist
 Aprepitant
 Fosaprepitant
 Rolapitant
 Selectively blocks the binding of substance P at the NK-1
receptor in the central nervous system

 Augment the antiemetic activity of the 5-HT3–receptor

antagonists and the corticosteroid dexamethasone to prevent
both acute and delayed emesis

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 Antiemetic Therapies
Neurokinin-1–Receptor Antagonist
 Oral aprepitant is FDA approved for the prevention of nausea
and vomiting in patients receiving highly and selected
moderately emetogenic chemotherapy

 Fosaprepitant dimeglumine, an IV version of aprepitant, can be

given on day 1 only 30 minutes before chemotherapy

 When using high dose of fosaprepitant (150 mg IV) on day

 ➔then it is not necessary to give oral aprepitant on days 2-3

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 Antiemetic Therapies
Neurokinin-1–Receptor Antagonist
 A meta-analysis (of 7 randomized controlled trials) in
patients receiving highly emetogenic chemotherapy found

 NK-1 receptor antagonists used alone or with standard

therapy did not significantly increase protection from acute
emesis
 However, for delayed emesis, it was associated with
significantly increased protection

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 Antiemetic Therapies
Aprepitant
 Drug Interactions
 Substrate, moderate inducer, and moderate inhibitor of
cytochrome P450 enzyme 3A4 (CYP3A4);
 Affected by CYP inducers and inhibitors

 Induces CYP2C9

 CI with pimozide, terfenadine, astemizole, or cisapride

 Life-threatening reaction

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 Antiemetic Therapies
Aprepitant /Fosaprepitant
 Drug Interactions
 Caution with chemotherapeutic agents known to be
metabolized by CYP3A4 include docetaxel, paclitaxel,
etoposide, irinotecan, ifosfamide, imatinib,vinorelbine,
vinblastine, and vincristine

 Caution with warfarin: induce metabolism and reduce INR

 Caution with OC: decreases the AUC, other methods of birth

control should be used

49
 Antiemetic Therapies
Aprepitant / Fosaprepitant
 Drug Interactions
 Increase AUC of dexamethasone

 Consider to decrease the dose of Dexamethasone

 But if CS (Dexamethasone, Prednisone) are already in
chemotherapy regimen
 Don’t consider decreasing the dose

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 Antiemetic Therapies
Rolapitant
Newly approved agent
Compared to aprepitant, given rolapitant has been studied
as a one-time dose on day 1 of chemotherapy, while
aprepitant is recommended to be given on days 1 through 3
 Rolapitant does not inhibit CYP 2C9 or 3A4 enzymes,
whereas aprepitant induces CYP 2C9 and 3A4 and
moderately inhibits 3A4, thus Rolapitant does not share this
interaction with dexamethasone.

51
 Antiemetic Therapies
 Netupitant and Fosnetupitant:
 Available only as fixed combination regimen with palonosetron
 Not available as monotherapy

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 Antiemetic Therapies
Olanzapine
 MOA
 Antipsychotic in the thienobenzodiazepine drug class that
blocks multiple neurotransmitters: dopamine at D1, D2, D3,
and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3,
and 5-HT6 receptors; catecholamines at alpha-1 adrenergic
receptors; acetylcholine at muscarinic receptors; and
histamine at H1 receptors.

 Side effects:
 Sedation, dry mouth, increased appetite
 Weight gain, postural hypotension
 Dizziness
 Increased risk of hyperlipidemia, hyperglycemia, new-onset
diabetes
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 Anticipatory Emesis
Prevention
 Use optimal antiemetic therapy during every cycle of
treatment

 Benzodiazepines
 Alprazolam 0.5 - 2 mg PO TID beginning on the night before
treatment or
 Lorazepam 0.5 - 2 mg PO on the night before and morning
of treatment

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 Anticipatory Emesis
Prevention
 Behavioral therapy:
 Relaxation/systematic desensitization
 Hypnosis/guided imagery
 Music therapy

 Acupuncture/ acupressure

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 Breakthrough Emesis
Treatment
 Switch to rectal or IV therapy

 Ensure adequate hydration or fluid repletion since PO

route is not likely to be feasible due to ongoing vomiting

 Add one agent from a different drug class to the current

regimen

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 Breakthrough Emesis
Example on drugs to be added
 Olanzapine
 Lorazepam
 Phenothiazine
 Serotonin (5-HT3) antagonists
 Haloperidol
 Metoclopramide
 Scopolamine transdermal patch
 Dexamethasone
 Promethazine
 Prochlorperazine
 Canabinoids: Dronabinol or Nabilone

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 Breakthrough Emesis
After a breakthrough emesis:
 Consider adjustment in the antiemetic regimen before the
subsequent cycle:
 Consider changing antiemetic therapy to higher level
primary treatment for next cycle
 If minimal, so prevent for next cycle as low
 If low, so prevent for next cycle as moderate
 If moderate, so prevent next cycle as high thus NK1-antagonist
 If high
 Consider changing from NK-1 antagonist to olanzapine containing regime
or vice versa
 Consider administration of NK-1 antagonist with olanzapine for very high
risk patients

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 Radiation Induced Emesis
 All patient undergoing total body irradiation, radiation
upper abdomen/localized sites must:
 Start pretreatment for each day of RT treatment:
 Granisetron 2 mg PO daily or
 Ondansetron 8 mg PO BID
 ± Dexamethasone 4 mg PO daily
 If patient receiving concurrent radiation therapy with
chemotherapy
 Same as prevention for chemotherapy-induced
nausea/vomiting

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