Usage
Netupitant + Palonosetron is prescribed for the prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy, including highly emetogenic chemotherapy (e.g., cisplatin-based regimens) and moderately emetogenic chemotherapy. It is an antiemetic.
It acts by dual antagonism of neurokinin-1 (NK1) and serotonin-3 (5-HT3) receptors, effectively targeting two distinct pathways implicated in chemotherapy-induced nausea and vomiting.
Alternate Names
The combination is commonly referred to as NEPA. It is marketed under the brand name Akynzeo (for both oral capsules and intravenous formulations). The intravenous formulation contains fosnetupitant, a prodrug of netupitant.
How It Works
Pharmacodynamics: Netupitant + Palonosetron exerts its antiemetic effect by blocking the activity of substance P at NK1 receptors in the central nervous system and serotonin at 5-HT3 receptors both centrally and peripherally. This dual mechanism addresses both the acute and delayed phases of chemotherapy-induced nausea and vomiting.
Pharmacokinetics:
- Absorption: Netupitant is well absorbed orally, with peak plasma concentrations reached in approximately 5 hours after a single dose. Fosnetupitant, the prodrug in the IV formulation, is rapidly converted to netupitant. Palonosetron also reaches peak plasma concentrations in about 5 hours after oral administration.
- Metabolism: Netupitant is primarily metabolized by CYP3A4, while palonosetron is mainly metabolized by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2.
- Elimination: Netupitant has a long elimination half-life of approximately 88 hours, contributing to its sustained antiemetic effect. Palonosetron has a shorter half-life of around 48 hours. Both drugs are excreted primarily in feces.
Mode of Action: Netupitant acts centrally by blocking NK1 receptors, preventing substance P from binding and initiating the vomiting reflex. Palonosetron blocks 5-HT3 receptors, inhibiting serotonin-induced nausea and vomiting signals.
Dosage
Standard Dosage
Adults:
- Highly Emetogenic Chemotherapy: One 300 mg/0.5 mg capsule orally approximately 1 hour before chemotherapy OR one vial (235 mg fosnetupitant/0.25 mg palonosetron) IV over 30 minutes starting 30 minutes before chemotherapy. Administer in conjunction with dexamethasone (12 mg orally 30 minutes before chemotherapy on Day 1, followed by 8 mg orally once daily on Days 2-4).
- Moderately Emetogenic Chemotherapy: One 300 mg/0.5 mg capsule orally approximately 1 hour before chemotherapy. Administer in conjunction with dexamethasone (12 mg orally 30 minutes before chemotherapy on Day 1).
Children: Safety and efficacy have not been established in patients younger than 18 years.
Special Cases:
- Elderly Patients: Use with caution due to age-related changes in hepatic, renal, or cardiac function.
- Patients with Renal Impairment: No dosage adjustment is necessary for mild to moderate impairment. Avoid use in severe renal impairment or end-stage renal disease.
- Patients with Hepatic Dysfunction: No dosage adjustment is necessary for mild to moderate impairment. Avoid use in severe hepatic impairment.
- Patients with Comorbid Conditions: Exercise caution in patients with a history of constipation or cardiac conditions, especially those associated with QT prolongation.
Clinical Use Cases
Netupitant + Palonosetron is specifically indicated for chemotherapy-induced nausea and vomiting (CINV) and is not routinely used in clinical settings like intubation, surgical procedures, mechanical ventilation, or ICU care outside the context of chemotherapy. Its use in emergency situations like status epilepticus or cardiac arrest is not established.
Dosage Adjustments
Dosage adjustments are primarily based on renal and hepatic function as outlined above. Concomitant medications metabolized by or affecting CYP3A4 may necessitate dosage adjustments or avoidance.
Side Effects
Common Side Effects
Headache, fatigue, dyspepsia, constipation, asthenia, erythema.
Rare but Serious Side Effects
Hypersensitivity reactions (including anaphylaxis), serotonin syndrome (especially with concomitant serotonergic drugs).
Long-Term Effects
Long-term safety data are limited.
Adverse Drug Reactions (ADR)
Serious hypersensitivity reactions, serotonin syndrome, QT prolongation (rare).
Contraindications
Hypersensitivity to netupitant, palonosetron, or any component of the formulation. Pregnancy.
Drug Interactions
- CYP3A4 Inhibitors: Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) may increase netupitant exposure. Concomitant use is not recommended or requires careful monitoring.
- CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampin, phenytoin) may decrease netupitant exposure, potentially reducing efficacy. Avoid concomitant use.
- Serotonergic Drugs: Concomitant use with serotonergic drugs (e.g., SSRIs, SNRIs, MAOIs) may increase the risk of serotonin syndrome. Use with caution and monitor closely.
Pregnancy and Breastfeeding
Netupitant + Palonosetron is contraindicated in pregnancy. It is unknown whether netupitant or palonosetron is excreted in human milk. Caution should be exercised when administering to breastfeeding mothers.
Drug Profile Summary
- Mechanism of Action: Dual NK1 and 5-HT3 receptor antagonist.
- Side Effects: Headache, fatigue, dyspepsia, constipation, asthenia, erythema; rarely, hypersensitivity reactions, serotonin syndrome.
- Contraindications: Hypersensitivity, pregnancy.
- Drug Interactions: CYP3A4 inhibitors and inducers, serotonergic drugs.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; caution during breastfeeding.
- Dosage: See detailed dosage guidelines above.
- Monitoring Parameters: Monitor for hypersensitivity reactions, serotonin syndrome, and potential drug interactions. Liver function tests and ECG may be considered in specific cases.
Popular Combinations
Netupitant + Palonosetron is typically administered in combination with dexamethasone for enhanced antiemetic efficacy.
Precautions
- Evaluate patients for history of hypersensitivity to NK1 or 5-HT3 receptor antagonists.
- Monitor for signs and symptoms of serotonin syndrome, especially when co-administered with serotonergic drugs.
- Monitor patients with a history of constipation.
- Correct electrolyte imbalances (hypokalemia, hypomagnesemia) before administration.
- Exercise caution in elderly patients and those with hepatic or renal impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Netupitant + Palonosetron?
A: See detailed dosage guidelines above.
Q2: What are the most common side effects?
A: Headache, fatigue, dyspepsia, constipation, asthenia, and skin redness (erythema) are the most common side effects.
Q3: How does Netupitant + Palonosetron work?
A: It works by blocking NK1 and 5-HT3 receptors, which are involved in the vomiting reflex.
Q4: Can this drug be used in children?
A: The safety and efficacy of Netupitant + Palonosetron have not been established in pediatric patients.
Q5: Can Netupitant + Palonosetron be used during pregnancy?
A: No, it is contraindicated during pregnancy.
Q6: What if a patient has renal impairment?
A: No dosage adjustment is needed for mild to moderate renal impairment. It should be avoided in patients with severe renal impairment or end-stage renal disease.
Q7: What are the potential drug interactions?
A: Significant drug interactions can occur with strong CYP3A4 inhibitors and inducers and serotonergic drugs.
Q8: What should I monitor for in patients taking Netupitant + Palonosetron?
A: Monitor for signs and symptoms of serotonin syndrome, hypersensitivity reactions, QT prolongation, and worsening of pre-existing constipation.
A: Yes, Akynzeo is available as an intravenous formulation containing fosnetupitant, a prodrug of netupitant, and palonosetron.
Q10: Can Netupitant/Palonosetron be taken with food?
A: Yes, it can be taken with or without food.
