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Product Name
:
DE-VOMIT (amp)
Chemical Name
:
Ondansetron
Therapeutic Category
:
Gastro-intestinal drugs
Pharmacologic Category
:
Antiemetic - Selective 5-HT3 Receptor Antagonist
Pharmaceutical Form
:
Ampoule
Composition
:
Ondansetron 4mg / 8mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Prevention of chemotherapy-induced emesis:
I.V.:
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
Highly-emetogenic agents/single-day therapy: Oral: 24 mg given 30 minutes prior to the start of therapy
Moderately-emetogenic agents: Oral: 8 mg beginning 30 minutes before chemotherapy; repeat dose 8 hours after initial dose, then 8 mg every 12 hours for 1-2 days after chemotherapy completed
Radiation-induced emesis prophylaxis:
Total body irradiation: Oral: 8 mg 1-2 hours before each daily fraction of radiotherapy
Single high-dose fraction radiotherapy to abdomen: Oral: 8 mg 1-2 hours before irradiation, then 8 mg every 8 hours after first dose for 1-2 days after completion of radiotherapy
Daily fractionated radiotherapy to abdomen: Oral: 8 mg 1-2 hours before irradiation, then 8 mg 8 hours after first dose for each day of radiotherapy
Postoperative nausea and vomiting (PONV):
Oral: 16 mg given 1 hour prior to induction of anesthesia
I.M., I.V.: 4 mg as a single dose approximately 30 minutes before the end of anesthesia (see Note below) or as treatment if vomiting occurs after surgery (Gan, 2007).
Note: The manufacturer recommends administration immediately before induction of anesthesia; however, this has been shown not to be as effective as administration at the end of surgery (Sun, 1997). Repeat doses given in response to inadequate control of nausea/vomiting from preoperative doses are generally ineffective.
Treatment of hyperemesis gravidum (unlabeled use):
Oral: 8 mg every 12 hours
I.V.: 8 mg administered over 15 minutes every 12 hours or 1 mg/hour infused continuously for up to 24 hours

Dosing: Pediatric

Premixed injection not for use in children.
Prevention of chemotherapy-induced emesis: I.V.: Children 6 months to 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
Prevention of moderately-emetogenic chemotherapy-induced emesis: Oral:
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.
Prevention of postoperative nausea and vomiting (PONV): I.V.: Children 1 month to 12 years:
≤40 kg: 0.1 mg/kg as a single dose
>40 kg: 4 mg as a single dose

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No adjustment is necessary.

Dosing: Hepatic Impairment

Severe liver disease (Child-Pugh C): Maximum daily dose: 8 mg
Use
 
Prevention of nausea and vomiting associated with moderately- to highly-emetogenic cancer chemotherapy; radiotherapy; prevention of postoperative nausea and vomiting (PONV); treatment of PONV if no prophylactic dose of ondansetron received
Use - Unlabeled/Investigational
Hyperemesis gravidarum; breakthrough treatment of nausea and vomiting associated with chemotherapy
Adverse Reactions
 
Note: Percentages reported in adult patients.
>10%:
Central nervous system: Headache (9% to 27%), malaise/fatigue (9% to 13%)
Gastrointestinal: Constipation (6% to 11%)
1% to 10%:
Central nervous system: Drowsiness (8%), fever (2% to 8%), dizziness (4% to 7%), anxiety (6%), cold sensation (2%)
Dermatologic: Pruritus (2% to 5%), rash (1%)
Gastrointestinal: Diarrhea (2% to 7%)
Genitourinary: Gynecological disorder (7%), urinary retention (5%)
Hepatic: ALT increased (1% to 5%), AST increased (1% to 5%)
Local: Injection site reaction (4%; pain, redness, burning)
Neuromuscular & skeletal: Paresthesia (2%)
Respiratory: Hypoxia (9%)
<1% (Limited to important or life-threatening): Abnormal hepatic function, anaphylactoid reactions, anaphylaxis, angina, angioedema, arrhythmia, arthralgia, atrial fibrillation, AV block, blindness (transient/following infusion; lasting ≤48 hours), blurred vision (transient/following infusion), bradycardia, bronchospasm, cardiopulmonary arrest, chest discomfort, chills, dyspnea, dystonic reaction, ECG changes, electrocardiographic alterations (second-degree heart block and ST-segment depression), extrapyramidal symptoms, grand mal seizure, hepatic failure, hepatic necrosis, hepatitis, hypersensitivity reaction, hypokalemia, hypotension, jaundice, laryngeal edema, laryngospasm, lethargy, oculogyric crisis, palpitation, premature ventricular contractions (PVC), QT interval increased, shock, shortness of breath, stridor, supraventricular tachycardia, syncope, tachycardia, torsade de pointes, urticaria, vascular occlusive events, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia
Contraindications
 
Hypersensitivity to ondansetron, other selective 5-HT3 antagonists, or any component of the formulation; concomitant use of apomorphine
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Allergic reactions: Use with caution in patients allergic to other 5-HT3 receptor antagonists; cross-reactivity has been reported.
• ECG effects: Selective 5-HT3 antagonists, including ondansetron, have been associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT), usually occurring 1-2 hours after I.V. administration. In general, these changes are not clinically relevant, however, when used in conjunction with other agents that prolong these intervals, arrhythmia may occur. When used with agents that prolong the QT interval (eg, Class I and III antiarrhythmics), clinically relevant QT interval prolongation may occur resulting in torsade de pointes. A number of trials have shown that 5-HT3 antagonists produce QT interval prolongation to variable degrees. Use with caution in patients at risk of QT prolongation and/or ventricular arrhythmia. Reduction in heart rate may also occur with the 5-HT3 antagonists. I.V. formulations of 5-HT3 antagonists have more association with ECG interval changes, compared to oral formulations.
Disease-related concerns:
• Hepatic impairment: Dose recommendations provided for patients with severe hepatic impairment (Child-Pugh class C); use with caution in mild-moderate hepatic impairment; clearance is decreased and half-life increased in hepatic impairment.
• Long QT syndrome: Use with caution in patients with congenital long QT syndrome or other risk factors for QT prolongation (eg, medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], and cumulative high-dose anthracycline therapy).
Dosage form specific issues:
• Phenylalanine: Orally-disintegrating tablets contain phenylalanine.
Other warnings/precautions:
• Chemotherapy-related emesis: For chemotherapy, should be used on a scheduled basis, not on an “as needed” (PRN) basis, since data support the use of this drug only in the prevention of nausea and vomiting (due to antineoplastic therapy) and not in the rescue of nausea and vomiting. Should only be used in the first 24-48 hours of chemotherapy. Data does not support any increased efficacy in delayed nausea and vomiting.
• Ileus or gastric distention: Does not stimulate gastric or intestinal peristalsis; may mask progressive ileus and/or gastric distension.
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Inhibits CYP1A2 (weak), 2C9 (weak), 2D6 (weak)
Interactions
 
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Risk X: Avoid combination
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: P-glycoprotein/ABCB1 Substrates may increase the serum concentration of P-glycoprotein/ABCB1 Inhibitors. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Rifamycin Derivatives: May increase the metabolism of Antiemetics (5HT3 Antagonists). Risk C: Monitor therapy
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Pregnancy
 
B
Pregnancy Implications
Teratogenic effects were not observed in animal studies; however, there are no adequate and well-controlled studies in pregnant women. Use of ondansetron for the treatment of nausea and vomiting of pregnancy (NVP) has been evaluated. Additional studies are needed to determine safety to the fetus, particularly during the first trimester. Based on preliminary data, use is generally reserved for severe NVP (hyperemesis gravidarum) or when conventional treatments are not effective.
Lactation
 
Excretion in breast milk unknown/use caution
Mechanism of Action
 
Selective 5-HT3-receptor antagonist, blocking serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone
Pharmacodynamics / Kinetics
 
Onset of action: ~30 minutes
Absorption: Oral: Well absorbed from GI tract
Distribution: Vd: Children: 1.7-3.7 L/kg; Adults: 2.2-2.5 L/kg
Protein binding, plasma: 70% to 76%
Metabolism: Extensively hepatic via hydroxylation, followed by glucuronide or sulfate conjugation; CYP1A2, CYP2D6, and CYP3A4 substrate; some demethylation occurs
Bioavailability: Oral: 56% to 71% (some first pass metabolism); Rectal: 58% to 74%
Half-life elimination: Children <15 years: 2-7 hours; Adults: 3-6 hours
Mild-to-moderate hepatic impairment (Child-Pugh classes A and B): Adults: 12 hours
Severe hepatic impairment (Child-Pugh class C): Adults: 20 hours
Time to peak: Oral: ~2 hours; Oral soluble film: ~1 hour
Excretion: Urine (44% to 60% as metabolites, ~5% as unchanged drug); feces (~25%)
 
   
 
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