Anti-Emetics

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.

Supplied: 80 mg, 125 mg capsule

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 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)

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

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

Mechanism of Action: Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.
Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 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. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on serotonin and its 5-HT3 receptors have been demonstrated to selectively stimulate the emetic response.

Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

INDICATIONS AND USAGE:  AKYNZEO is a fixed combination of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron, a serotonin-3 (5-HT3) receptor antagonist indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Oral palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

HOW SUPPLIED: Capsule: 300 mg netupitant/0.5 mg palonosetron

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.

Intravenous:

Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Adults: The recommended adult intravenous dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ZOFRAN.

Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ZOFRAN. The drug should be infused intravenously over 15 minutes.

Prevention of Postoperative Nausea and Vomiting
ZOFRAN Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.

Adults: The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

Pediatrics: For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ZOFRAN.

-------------------------------------------------------
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.

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

Mechanism of Action: Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels. Rolapitant is also active in animal models of chemotherapy-induced emesis.

INDICATIONS AND USAGE:  VARUBI™ is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.

HOW SUPPLIED: Tablets: 90 mg rolapitant; film-coated capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side.

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]