Usage
Netupitant is prescribed, in combination with palonosetron and dexamethasone, for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults. It is classified as an antiemetic. More specifically, netupitant is a neurokinin-1 (NK1) receptor antagonist. It works by blocking the binding of Substance P, a neurotransmitter involved in the vomiting reflex, to the NK1 receptors in the brain and gastrointestinal tract.
Alternate Names
Netupitant is often found in a fixed-dose combination with palonosetron. This combination is marketed under the brand name Akynzeo. Fosnetupitant is a prodrug of netupitant, used in the intravenous formulation of Akynzeo.
How It Works
Pharmacodynamics: Netupitant acts as a neurokinin-1 (NK1) receptor antagonist, blocking the binding of Substance P, a key neurotransmitter involved in the emetic response. This action reduces both acute and delayed nausea and vomiting. Palonosetron, the other component of Akynzeo, is a 5-HT3 receptor antagonist, further enhancing antiemetic efficacy.
Pharmacokinetics: Following oral administration as part of the Akynzeo capsule, netupitant is absorbed and converted to its active metabolites. It is highly protein-bound (99.5%). Netupitant primarily undergoes hepatic metabolism via CYP3A4 with negligible renal excretion. The primary metabolites are also active NK1 receptor antagonists. Palonosetron undergoes metabolism via CYP2D6 primarily, and to a lesser extent, CYP3A4 and CYP1A2. It is eliminated through both renal excretion and metabolism. Fosnetupitant, given intravenously, is rapidly converted to netupitant.
Mechanism of Action: Netupitant specifically targets NK1 receptors. By competitively binding to these receptors, it prevents the binding of Substance P. This, in turn, disrupts the signaling cascade that triggers the vomiting reflex.
Elimination Pathways: Netupitant is primarily metabolized by CYP3A4 in the liver. Its metabolites are subsequently excreted. Palonosetron is eliminated through both renal and hepatic pathways.
Dosage
Standard Dosage
Adults:
The standard dose of Netupitant is 300 mg taken orally as a single capsule (Akynzeo, which also contains 0.5 mg palonosetron) approximately 1 hour before the start of each chemotherapy cycle.
Children:
The safety and effectiveness of Netupitant have not been established in pediatric patients under 18 years of age.
Special Cases:
-
Elderly Patients: No dosage adjustment is generally required, but caution is advised in patients over 75 years old due to the long half-life of netupitant and potential age-related decline in organ function.
-
Patients with Renal Impairment: No dosage adjustment is needed for mild to moderate renal impairment. Akynzeo is not recommended for patients with severe renal impairment or end-stage renal disease requiring hemodialysis.
-
Patients with Hepatic Dysfunction: No dosage adjustment is necessary for mild to moderate hepatic impairment. Akynzeo should be avoided in patients with severe hepatic impairment.
-
Patients with Comorbid Conditions: Use with caution in patients with a history of constipation or subacute intestinal obstruction. Monitor for signs and symptoms of serotonin syndrome, particularly when used concomitantly with serotonergic medications.
Clinical Use Cases
Netupitant is specifically indicated for chemotherapy-induced nausea and vomiting (CINV). It is not indicated for use in other clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose adjustments may be required based on concomitant medications, particularly those that are strong CYP3A4 inducers (e.g., rifampin) or inhibitors (e.g., ketoconazole). Concomitant use with strong CYP3A4 inducers should be avoided as they can decrease the efficacy of Netupitant.
Side Effects
Common Side Effects:
Headache, fatigue, dyspepsia, constipation, asthenia, and erythema.
Rare but Serious Side Effects:
Hypersensitivity reactions (including anaphylaxis), serotonin syndrome (especially with concomitant use of serotonergic drugs).
Long-Term Effects:
Long-term safety data are limited.
Adverse Drug Reactions (ADR):
Serotonin syndrome, hypersensitivity reactions, QTc prolongation (although generally not clinically significant).
Contraindications
Hypersensitivity to netupitant or palonosetron, pregnancy, concurrent use with pimozide, terfenadine, astemizole, or cisapride.
Drug Interactions
Netupitant is a CYP3A4 substrate and a moderate inhibitor of CYP3A4. Avoid concurrent use of CYP3A4 substrates for one week, if possible. If unavoidable, consider dose reduction of the CYP3A4 substrate. Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin). Concurrent use with strong CYP3A4 inhibitors may increase netupitant exposure, but no dosage adjustment is necessary for single-dose administration. Monitor for interactions with serotonergic drugs, digoxin, dabigatran, colchicine, and other P-gp substrates.
Pregnancy and Breastfeeding
Netupitant is contraindicated in pregnancy. It should not be used during breastfeeding.
Drug Profile Summary
- Mechanism of Action: NK1 receptor antagonist.
- Side Effects: Headache, fatigue, dyspepsia, constipation, asthenia, erythema; rarely: hypersensitivity reactions, serotonin syndrome.
- Contraindications: Hypersensitivity, pregnancy, concomitant use with certain drugs (e.g., pimozide, cisapride).
- Drug Interactions: CYP3A4 substrates and inducers, serotonergic drugs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 300 mg orally once, approximately 1 hour before chemotherapy.
- Monitoring Parameters: Signs of hypersensitivity reactions, serotonin syndrome, and severe constipation.
Popular Combinations
Netupitant is typically combined with palonosetron (as Akynzeo) and dexamethasone for the prevention of CINV.
Precautions
Pre-screening for allergies and relevant medical history (especially history of constipation), pregnancy testing in women of childbearing potential, and patient education regarding potential side effects, particularly serotonin syndrome, are crucial. Avoid driving or operating machinery if dizziness, fatigue, or somnolence occur.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Netupitant?
A: 300 mg orally as a single capsule (Akynzeo) approximately 1 hour before the start of each chemotherapy cycle, in conjunction with dexamethasone.
Q2: How does Netupitant work?
A: It’s an NK1 receptor antagonist, blocking Substance P and reducing nausea/vomiting.
Q3: Is Netupitant safe for children?
A: Safety and efficacy have not been established in children under 18.
Q4: What are the common side effects?
A: Headache, fatigue, dyspepsia, constipation, weakness, and skin redness.
Q5: Are there any serious side effects I should be aware of?
A: Yes, rare but serious side effects include hypersensitivity reactions (including anaphylaxis) and serotonin syndrome, especially when used with serotonergic drugs.
Q6: Can Netupitant be used during pregnancy or breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding.
Q7: Does Netupitant interact with other medications?
A: Yes, it can interact with CYP3A4 substrates and inducers, as well as serotonergic drugs. Consult drug interaction resources for a comprehensive list.
Q8: What should I monitor in patients taking Netupitant?
A: Monitor for signs and symptoms of hypersensitivity reactions, serotonin syndrome, and complications of constipation.
A: The IV formulation contains fosnetupitant, a prodrug of netupitant, along with palonosetron.
Q10: Should the dose of dexamethasone be adjusted when used with Netupitant/palonosetron?
A: Yes, the dexamethasone dose is typically reduced by approximately 50% when co-administered with Netupitant/palonosetron (Akynzeo).
