Zofra

FDA-Approved Indications:

• Prevention of nausea and vomiting associated with:
• Highly emetogenic chemotherapy (e.g., cisplatin-based regimens)
• Moderately emetogenic chemotherapy
• Radiotherapy-induced nausea and vomiting
• Postoperative nausea and vomiting (PONV)

Off-label/Clinically Accepted Uses:

• Treatment of established postoperative nausea and vomiting
• Hyperemesis gravidarum (severe nausea/vomiting in pregnancy)
• Gastroenteritis-induced nausea/vomiting, particularly in pediatrics
• Opioid-induced nausea
• Nausea due to migraine or vertigo
• Palliative care-related nausea

Route of Administration: Oral (tablet, orally disintegrating tablet, oral solution), IV, IM

Adults:

• Chemotherapy-induced nausea/vomiting (CINV):
• IV: 8 mg administered 30 minutes before chemotherapy; may repeat 8 mg 8 hours later, then 8 mg orally twice daily for up to 5 days.
• Oral: 8 mg twice daily starting 30 minutes before chemotherapy.
• Postoperative nausea/vomiting (PONV):
• IV: 4 mg as a single dose before induction or at end of surgery.
• Oral: 16 mg as a single dose 1 hour before anesthesia (if used orally).

Pediatrics:

• CINV:
• IV: 0.15 mg/kg/dose (max 16 mg), every 4 hours for 3 doses.
• Oral (≥4 years): 4 mg given 30 minutes before chemotherapy, then 4 mg 4 and 8 hours later.
• PONV (≥1 month): 0.1 mg/kg IV (max 4 mg) as a single dose.

Elderly:

• No dosage adjustment required.

Renal Impairment:

• No dose adjustment necessary.

Hepatic Impairment:

• In severe hepatic impairment (Child-Pugh Class C), do not exceed 8 mg/day due to reduced clearance.

Ondansetron is a selective 5-HT₃ receptor antagonist. It blocks serotonin both centrally in the chemoreceptor trigger zone (CTZ) and peripherally at vagal nerve terminals in the gastrointestinal tract. During chemotherapy, radiotherapy, or surgery, serotonin is released from enterochromaffin cells in the small intestine, stimulating vagal afferents via 5-HT₃ receptors and triggering the vomiting reflex. By inhibiting these receptors, ondansetron prevents initiation of the emetic signal, effectively controlling nausea and vomiting.

• Absorption: Rapid and well absorbed after oral administration; bioavailability ~56–60% due to first-pass metabolism.
• Distribution: Widely distributed; volume of distribution: 2.5 L/kg.
• Protein Binding: ~70–76%
• Metabolism: Extensively metabolized in the liver by CYP3A4, CYP1A2, and CYP2D6.
• Half-life:
• Adults: 3–6 hours
• Elderly: up to 9 hours
• Excretion: ~5% unchanged in urine; remainder as metabolites.
• Onset of Action: Oral: ~30 minutes; IV: ~10 minutes
• Peak Effect: 1–2 hours (oral)

• Pregnancy:
• Previously classified as FDA Category B.
• Recent data suggest potential risk of orofacial clefts in early pregnancy, but overall risk is low.
• May be used in pregnancy when benefits outweigh risks, especially for hyperemesis gravidarum.
• Lactation:
• Excreted in breast milk in small amounts.
• No reported adverse effects in nursing infants; considered compatible with breastfeeding.

• Primary Class: Antiemetic
• Subclass: Selective 5-HT₃ receptor antagonist (Serotonin antagonist)

• Known hypersensitivity to ondansetron or any component of the formulation
• Concurrent use with apomorphine (risk of profound hypotension and loss of consciousness)
• Congenital long QT syndrome (risk of arrhythmia)

• QT prolongation: Use with caution in patients with congenital long QT, bradyarrhythmias, or those taking other QT-prolonging drugs.
• Serotonin syndrome: Risk increases with concomitant serotonergic drugs (SSRIs, SNRIs, MAOIs).
• Hypokalemia or hypomagnesemia should be corrected before use.
• Hepatic impairment: Reduce dose in severe cases.
• Pediatric use: Dose appropriately and monitor for constipation and abdominal discomfort.
• Elderly patients: Slightly prolonged half-life; monitor for ECG changes.

Gastrointestinal:

• Constipation
• Diarrhea
• Dry mouth

Central Nervous System:

• Headache (most common)
• Dizziness
• Fatigue

Cardiovascular:

• QT interval prolongation
• Rare: Torsades de Pointes, bradycardia

Others:

• Hypersensitivity reactions (rash, pruritus, anaphylaxis)
• Elevated liver enzymes (transient, asymptomatic)

Onset: Side effects typically occur within the first few hours of administration; severity is generally mild to moderate and dose-dependent.

• Apomorphine: Contraindicated – risk of severe hypotension and unconsciousness.
• Serotonergic drugs (e.g., SSRIs, SNRIs, MAOIs): Risk of serotonin syndrome.
• QT-prolonging agents (e.g., amiodarone, erythromycin): Additive risk of arrhythmias.
• CYP3A4 inducers/inhibitors:
• Inhibitors (e.g., ketoconazole) may increase ondansetron levels.
• Inducers (e.g., rifampin) may reduce effectiveness.

CYP450 Enzymes Involved: CYP3A4, CYP1A2, CYP2D6

• FDA Safety Update (2012–2022): Risk of QT prolongation emphasized; ECG monitoring advised for high-risk patients.
• Updated dosing recommendations to limit maximum single IV dose to 16 mg due to arrhythmia risk.
• Guidelines (ASCO, NICE): Ondansetron remains a first-line agent for acute CINV; often used in combination with dexamethasone and NK-1 receptor antagonists.

• Tablets and ODTs (orally disintegrating tablets):
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and heat
• Oral Solution:
• Store at 2°C to 30°C
• Do not freeze
• Injection (IV/IM):
• Store at 2°C to 30°C
• Protect from light
• Do not freeze