Anti-Emetics

Anti-Emetics:

Aprepitant (Emend®)	dolasetron (Anzemet ®):
droperidol (Inapsine ®):	granisetron (Kytril ®):
metoclopramide (Reglan ®):	ondansetron (Zofran ®):
prochlorperazine (Compazine ®):	scopolamine:
trimethobenzamide (Tigan ®):

Aprepitant (Emend®)

Mechanism of Action:
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV).

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Dosage: Adults: (Prevention of acute and delayed nausea and vomiting associated with highly-emetogenic chemotherapy in combination with a corticosteroid and 5-HT3 receptor antagonist):

125 mg on day 1, followed by 80 mg on days 2 and 3; should be used in combination with a corticosteroid and 5-HT3 receptor antagonist. In clinical trials, the following regimen was used:

Aprepitant: Oral: 125 mg day 1, followed by 80 mg on days 2 and 3.
Dexamethasone: Oral: 12 mg on day 1, followed 8 mg on days 2, 3, and 4.
Ondansetron: I.V.: 32 mg on day 1.

Supplied: 80 mg, 125 mg capsule

dolasetron (Anzemet ®):

Nausea (chemotherapy): 1.8 mg/kg up to 100mg IV/orally x 1.
Post-op: 12.5 mg IV x 1.
Prevention: 100mg orally 2 hours preop.

Mechanism of Action: Dolasetron mesylate and its active metabolite, hydrodolasetron (MDL 74,156), are selective serotonin 5-HT3 receptor antagonists not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. The serotonin 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that the released serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the vomiting reflex.

Dosage:
Nausea and vomiting prophylaxis, chemotherapy-induced (including initial and repeat courses):
Children 2-16 years:
Oral: 1.8 mg/kg within 1 hour before chemotherapy; maximum: 100 mg/dose.
I.V.: 1.8 mg/kg ~30 minutes before chemotherapy; maximum: 100 mg/dose.

Adults:
Oral: 200 mg single dose
I.V.:
0.6-5 mg/kg as a single dose.
50 mg 1-2 minute bolus.
2.4 to 3 mg/kg 20-minute infusion.

Prevention of postoperative nausea and vomiting:
Children 2-16 years:
Oral: 1.2 mg/kg within 2 hours before surgery; maximum: 100 mg/dose.
I.V.: 0.35 mg/kg (maximum: 12.5 mg) ~15 minutes before stopping anesthesia.

Adults:
Oral: 100 mg within 2 hours before surgery
I.V.: 12.5 mg ~15 minutes before stopping anesthesia

Treatment of postoperative nausea and vomiting: I.V. (only):
Children: 0.35 mg/kg (maximum: 12.5 mg) as soon as needed
Adults: 12.5 mg as soon as needed

Administration
I.V. injection may be given either undiluted IVP over 30 seconds or infused over 15 minutes. Dolasetron injection may be diluted in apple or apple-grape juice and taken orally.

Supplied
Injection, solution, as mesylate: 20 mg/mL (0.625 mL, 5 mL) [single-use ampuls and vial]; 20 mg/mL (25 mL) [multidose vial]

Tablet, as mesylate: 50 mg, 100 mg

droperidol (Inapsine ®):

Droperidol produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness.

Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period.

Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias but it does not prevent other cardiac arrhythmias.

The onset of action of single intramuscular and intravenous doses is from three to ten minutes following administration, although the peak effect may not be apparent for up to thirty minutes. The duration of the tranquilizing and sedative effects generally is two to four hours, although alteration of alertness may persist for as long as twelve hours.

INDICATIONS AND USAGE
Droperidol Injection is indicated to reduce the incidence of nausea and vomiting associated with surgical and diagnostic procedures.

CONTRAINDICATIONS
Droperidol is contraindicated in patients with known or suspected QT prolongation (i.e., QTc interval greater than 440 msec for males or 450 msec for females). This would include patients with congenital long QT syndrome.

Droperidol is contraindicated in patients with known hypersensitivity to the drug.

Droperidol is not recommended for any use other than for the treatment of perioperative nausea and vomiting in patients for whom other treatments are ineffective or inappropriate

Dosage - Adults:
Nausea and vomiting: I.M., I.V.: Initial: 2.5 mg; additional doses of 1.25 mg may be administered to achieve desired effect; administer additional doses with caution.

Supplied
Injection, solution: 2.5 mg/mL (1 mL, 2 mL)

WARNINGS
Droperidol should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI's), 5) concomitant treatment with other drug products known to prolong the QT interval (see PRECAUTIONS, Drug Interactions), and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.

Effects on Cardiac Conduction: A dose-dependent prolongation of the QT interval was observed within 10 minutes of droperidol administration in a study of 40 patients without known cardiac disease who underwent extracranial head and neck surgery. Significant QT prolongation was observed at all three dose levels evaluated, with 0.1, 0.175, and 0.25 mg/kg associated with prolongation of median QTc by 37,44, and 59 msec, respectively.

Cases of QT prolongation and serious arrhythmias (e.g., torsade de pointes, ventricular arrhythmias, cardiac arrest, and death) have been observed during post-marketing treatment with droperidol. Some cases have occurred in patients with no known risk factors and at doses at or below recommended doses. There has been at least one case of nonfatal torsade de pointes confirmed by rechallenge.

Based on these reports, all patients should undergo a 12-lead ECG prior to administration of droperidol to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, droperidol should NOT be administered. For patients in whom the potential benefit of droperidol treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2-3 hours after completing treatment to monitor for arrhythmias.

FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD BE READILY AVAILABLE.

As with other CNS depressant drugs, patients who have received droperidol should have appropriate surveillance.

It is recommended that opioids, when required, initially be used in reduced doses.

As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received droperidol.

Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur.

granisetron (Kytril ®):

Mechanism of Action:
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for alpha1-, alpha2- or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.

Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal volunteers.

Dosage
Oral: Adults:
Prophylaxis of chemotherapy-related emesis: 2 mg once daily up to 1 hour before chemotherapy or 1 mg twice daily; the first 1 mg dose should be given up to 1 hour before chemotherapy.

Prophylaxis of radiation therapy-associated emesis: 2 mg once daily given 1 hour before radiation therapy.

I.V.:
Children >/= 2 years and Adults:
Prophylaxis of chemotherapy-related emesis:
10 mcg/kg/dose (or 1 mg/dose) administered IVPB over 5 minutes given within 30 minutes of chemotherapy: for some drugs (eg, carboplatin, cyclophosphamide) with a later onset of emetic action, 10 mcg/kg every 12 hours may be necessary.

Breakthrough: Repeat the dose 2-3 times within the first 24 hours as necessary (not based on controlled trials, or generally recommended)

Adults: PONV:
Prevention: 1 mg given undiluted over 30 seconds; administer before induction of anesthesia or before reversal of anesthesia

Treatment: 1 mg given undiluted over 30 seconds

Supplied
Injection, solution: 1 mg/mL (4 mL) [contains benzyl alcohol]
Injection, solution [preservative free]: 0.1 mg/mL (1 mL); 1 mg/mL (1 mL)
Solution, oral: 2 mg/10 mL (30 mL) [contains sodium benzoate; orange flavor]
Tablet: 1 mg

metoclopramide (Reglan ®):

Mechanism of Action: The antiemetic properties of metoclopramide appear to be a result of its antagonism of central and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying caused by apomorphine.

Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide produces sedation and may produce extrapyramidal reactions, although these are comparatively rare. Metoclopramide inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels, which may be associated with transient fluid retention.

The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.

Dosage - Children:
Gastroesophageal reflux: Oral: 0.1-0.2 mg/kg/dose up to 4 times/day; efficacy of continuing metoclopramide beyond 12 weeks in reflux has not been determined; total daily dose should not exceed 0.5 mg/kg/day

Gastrointestinal hypomotility (gastroparesis): Oral, I.M., I.V.: 0.1 mg/kg/dose up to 4 times/day, not to exceed 0.5 mg/kg/day

Antiemetic (chemotherapy-induced emesis) (unlabeled): I.V.: 1-2 mg/kg 30 minutes before chemotherapy and every 2-4 hours, for a total of 5 doses (5-10 mg/kg) daily

Post-pyloric feeding tube placement (unlabeled):
I.V.:
<6 years: 0.1 mg/kg.
6-14 years: 2.5-5 mg.

Dosage - Adults:
Gastroesophageal reflux: Oral: 10-15 mg/dose up to 4 times/day 30 minutes before meals or food and at bedtime; single doses of 20 mg are occasionally needed for provoking situations

Gastrointestinal hypomotility (gastroparesis):
Oral: 10 mg 30 minutes before each meal and at bedtime for 2-8 weeks.

I.V. (for severe symptoms): 10 mg over 1-2 minutes; 10 days of I.V. therapy may be necessary for best response

Antiemetic (chemotherapy-induced emesis) (unlabeled): I.V.: 1-2 mg/kg 30 minutes before chemotherapy and every 2-4 hours, for a total of 5 doses (5-10 mg/kg) daily

Postoperative nausea and vomiting (unlabeled): I.M., I.V.: 10 mg near end of surgery; 20 mg doses may be used

Post-pyloric feeding tube placement (unlabeled): I.M., I.V.: 10 mg

Elderly:
Gastroesophageal reflux: Oral: 5 mg 4 times/day (30 minutes before meals and at bedtime); increase dose to 10 mg 4 times/day if no response at lower dose

Gastrointestinal hypomotility: Oral: Initial: 5 mg 30 minutes before meals and at bedtime for 2-8 weeks; increase if necessary to 10 mg doses. I.V.: Initiate at 5 mg over 1-2 minutes; increase to 10 mg if necessary

Postoperative nausea and vomiting (unlabeled): I.M.: 5 mg near end of surgery; may repeat dose if necessary

Dosing adjustment in renal impairment:
Clcr 10-40 mL/minute: Administer at 50% of normal dose
Clcr<10 mL/minute: Administer at 25% of normal dose
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Supplied
Injection, solution, as hydrochloride (Reglan®): 5 mg/mL (2 mL, 10 mL, 30 mL).
Syrup, as hydrochloride: 5 mg/5 mL (10 mL, 480 mL) [some products contain sodium benzoate; sugar free]
Tablet, as hydrochloride (Reglan®): 5 mg, 10 mg

ondansetron (Zofran ®):

Mechanism of Action: Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron's mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.

Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's antiemetic action in chemotherapy-induced nausea and vomiting is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of vomiting. The released serotonin may stimulate the vagal afferents through the 5-TH3 receptors and initiate the vomiting reflex.

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Children: I.V.:
Chemotherapy-induced emesis: 4-18 years: 0.15 mg/kg/dose administered 30 minutes prior to chemotherapy, 4 and 8 hours after the first dose or 0.45 mg/kg/day as a single dose

Postoperative nausea and vomiting: 2-12 years:
</= 40 kg: 0.1 mg/kg
>40 kg: 4 mg

Oral: Chemotherapy-induced emesis:
4-11 years: 4 mg 30 minutes before chemotherapy; repeat 4 and 8 hours after initial dose, then 4 mg every 8 hours for 1-2 days after chemotherapy completed
>/= 12 years: Refer to adult dosing.
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Adults: I.V.: Chemotherapy-induced emesis:
0.15 mg/kg 3 times/day beginning 30 minutes prior to chemotherapy or
0.45 mg/kg once daily or
8-10 mg 1-2 times/day or
24 mg or 32 mg once daily

I.M., I.V.: Postoperative nausea and vomiting: 4 mg as a single dose approximately 30 minutes before the end of anesthesia, or as treatment if vomiting occurs after surgery

Oral: Chemotherapy-induced emesis:
Highly-emetogenic agents/single-day therapy: 24 mg given 30 minutes prior to the start of therapy.
Moderately-emetogenic agents: 8 mg every 12 hours beginning 30 minutes before chemotherapy, continuously for 1-2 days after chemotherapy completed.

Total body irradiation: 8 mg 1-2 hours before daily each fraction of radiotherapy

Single high-dose fraction radiotherapy to abdomen: 8 mg 1-2 hours before irradiation, then 8 mg every 8 hours after first dose for 1-2 days after completion of radiotherapy

Postoperative nausea and vomiting: 16 mg given 1 hour prior to induction of anesthesia
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Elderly: No dosing adjustment required

Dosage adjustment in renal impairment: No dosing adjustment required.
Dosage adjustment in hepatic impairment: Maximum daily dose: 8 mg in patients with severe liver disease (Child-Pugh score >/= 10)

Supplied:
Infusion [premixed in D5W] (Zofran®): 32 mg (50 mL).
Injection solution (Zofran®): 2 mg/mL (2 mL, 20 mL).
Oral Soln (Zofran®): 4 mg/5 mL (50 mL) .
Tablet (Zofran®): 4 mg, 8 mg, 24 mg
Tablet, orally-disintegrating (Zofran® ODT): 4 mg, 8 mg.

prochlorperazine (Compazine ®):

Prochlorperazine is a propylpiperazine derivative of phenothiazine. Like other phenothiazines, it exerts an antiemetic effect through a depressant action on the chemoreceptor trigger zone. It also has a clinically useful antipsychotic effect. Following intramuscular administration of prochlorperazine edisylate, the drug has an onset of action within ten to twenty minutes and a duration of action of three to four hours.

Antiemetic: Adults:
Oral: 5-10 mg 3-4 times/day; usual maximum: 40 mg/day.
I.M.: 5-10 mg every 3-4 hours; usual maximum: 40 mg/day. (injected deeply into the upper outer quadrant of the buttock.)
I.V.: 2.5 to 10 mg; maximum 10 mg/dose or 40 mg/day; may repeat dose every 3-4 hours as needed. (Rate not to exceed 5 mg per minute. Compazine Injection may be administered either undiluted (administered over 5 to 10 minutes) or diluted in isotonic solution (administered over approximately 30 minutes) . A single dose of the drug should not exceed 10 mg.
Rectal: 25 mg twice daily

Surgical nausea/vomiting: Adults:

I.M.: 5-10 mg 1-2 hours before induction; may repeat once if necessary.
I.V.: 5-10 mg 15-30 minutes before induction; may repeat once if necessary.

Antipsychotic: Adults:
Oral: 5-10 mg 3-4 times/day; doses up to 150 mg/day may be required in some patients for treatment of severe disturbances

I.M.: 10-20 mg every 4-6 hours may be required in some patients for treatment of severe disturbances; change to oral as soon as possible

Nonpsychotic anxiety: Oral: Adults: Usual dose: 15-20 mg/day in divided doses; do not give doses >20 mg/day or for longer than 12 weeks

Elderly: Behavioral symptoms associated with dementia (unlabeled use): Initial: 2.5-5 mg 1-2 times/day; increase dose at 4- to 7-day intervals by 2.5-5 mg/day; increase dosing intervals (twice daily, 3 times/day, etc) as necessary to control response or side effects; maximum daily dose should probably not exceed 75 mg in elderly; gradual increases (titration) may prevent some side effects or decrease their severity

Hemodialysis: Not dialyzable (0% to 5%)

Supplied
Injection, solution, as edisylate: 5 mg/mL (2 mL, 10 mL) [contains benzyl alcohol]
Suppository, rectal: 2.5 mg (12s), 5 mg (12s), 25 mg (12s) [may contain coconut and palm oil]
Tablet, as maleate: 5 mg, 10 mg

scopolamine:

Mechanism of Action
The sole active agent of Transderm Scóp is scopolamine, a belladonna alkaloid with well-known pharmacological properties. It is an anticholinergic agent which acts: i) as a competitive inhibitor at postganglionic muscarinic receptor sites of the parasympathetic nervous system, and ii) on smooth muscles that respond to acetylcholine but lack cholinergic innervation. It has been suggested that scopolamine acts in the central nervous system (CNS) by blocking cholinergic transmission from the vestibular nuclei to higher centers in the CNS and from the reticular formation to the vomiting center. Scopolamine can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress motor function.

Scopolamine hydrobromide:
Preoperative:
Adults:
I.M., I.V., SubQ: 0.3 to 0.65 mg; may be repeated every 4 to 6 hours

Transdermal patch: Apply 2.5 cm 2 patch to hairless area behind ear the night before surgery or 1 hour prior to cesarean section (the patch should be applied no sooner than 1 hour before surgery for best results and removed 24 hours after surgery)

Motion sickness: Transdermal: Adults: Apply 1 disc behind the ear at least 4 hours prior to exposure and every 3 days as needed; effective if applied as soon as 2-3 hours before anticipated need, best if 12 hours before

Supplied
Injection, solution, as hydrobromide: 0.4 mg/mL (1 mL)
Transdermal system (Transderm Scop®): 1.5 mg (4s) [releases ~1 mg over 72 hours]

trimethobenzamide (Tigan ®):

Oral: 250 mg orally every 6 to 8 hours
IM / Rectal: 200mg IM or rectally every 6 to 8 hours.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.

David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.