fosaprepitant

Action and Spectrum

Mechanism of action

A neurokinin-1 (NK1) receptor antagonist blocks the action of substance P, a neuropeptide that regulates emesis (vomiting). The mechanism of action of fosaprepitant results in a reduction of chemotherapy-induced nausea and vomiting (CINV)

Spectrum

The spectrum of activity of fosaprepitant includes the prevention of acute and delayed CINV caused by highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). It is given intravenously and is typically used with other antiemetics for maximum efficacy

Drug Interaction

Adverse Reaction

Frequency defined:

>10%

Diarrhea

Asthenia

Fatigue

Neutropenia

1-10%

Asthenia

Peripheral neuropathy

Leukopenia

UTI

Neutropenia

Anemia

Infusion site reactions

Dyspepsia

Pain in extremity

Post-marketing reports

Anaphylactic reactions

Pruritis

Rash

Black Box Warning

Contraindication / Caution

Contraindications

• Allergy to fosaprepitant or its components
• Severe liver dysfunction
• Pregnancy and breastfeeding
• Concomitant use of aprepitant with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)
• Concomitant use of aprepitant with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin)
• Concomitant use of aprepitant with drugs is known to prolong the QT interval.

Caution

• Use with caution in patients with moderate liver dysfunction.
• Monitor for increased adverse reactions when used with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, fluconazole)
• Monitor for decreased efficacy when used with moderate CYP3A4 inducers (e.g., efavirenz, nevirapine)
• It may cause dizziness, drowsiness, and decreased alertness, so caution should be exercised when operating machinery or driving a vehicle.
• It may cause QT prolongation, so ECG monitoring is recommended in patients with a history of the prolonged QT interval, congenital long QT syndrome, or electrolyte imbalances.
• Use caution in patients with a history of substance P-mediated disorders (e.g., IgE-mediated hypersensitivity reactions)

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available

Lactation: Excretion of the drug in human breast milk is unknown

Pregnancy category:

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women.

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.

Category N: There is no data available for the drug under this category.

Pharmacology

Pharmacology

It is a prodrug of aprepitant, and its antiemetic effects are due to aprepitant’s actions as a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has limited or no affinity for other receptors such as serotonin (5-HT3), dopamine, and corticosteroid receptors. It is demonstrated to be effective in both animal and human studies for inhibiting emesis induced by cisplatin and other chemotherapeutic agents, as well as augmenting the efficacy of 5-HT3 receptor antagonists and corticosteroids in reducing chemotherapy-induced nausea and vomiting.

Pharmacodynamics

It is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors, which regulate emesis (vomiting). Blocking these receptors effectively reduces the severity of chemotherapy-induced nausea and vomiting.

It has limited or no affinity for other receptors, such as serotonin (5-HT3), dopamine, and corticosteroid receptors. This selective targeting of the NK1 receptors minimizes the potential for drug interactions and adverse effects associated with non-selective drugs.

The pharmacodynamics of fosaprepitant contributes to its efficacy as an antiemetic drug, particularly in combination with other antiemetics such as 5-HT3 receptor antagonists and corticosteroids

Pharmacokinetics

• Absorption: It is rapidly converted to aprepitant in vivo after intravenous administration, with peak plasma concentration of aprepitant reaching 4.2 mcg/mL and AUC of 37.4 mcg·hr/mL. Fosaprepitant plasma concentrations are below the limits of quantification within 30 minutes after the completion of the infusion.
• Distribution: It is highly protein-bound (>95%) with a volume of distribution (Vd) of 70 L.
• Metabolism: It undergoes extensive metabolism, primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C19. It also exhibits moderate inhibition of CYP3A4 and weak induction of CYP2C9 and CYP3A4.
• Elimination/Excretion: The half-life of the aprepitant is 9-13 hours, with total body clearance ranging from 62-90 mL/min. After intravenous administration, aprepitant is excreted primarily in urine (57%) and feces (45%) and is not dialyzable

Adminstartion

Administration

It is administered intravenously (IV) and is usually given as a dose of 115 mg infused over 15 minutes, followed by oral administration of aprepitant. The oral form of aprepitant is typically given in a 3-day regimen (40 mg on day 1, followed by 80 mg on days 2 and 3) in combination with other antiemetics, such as 5-HT3 receptor antagonists and corticosteroids, to prevent chemotherapy-induced nausea and vomiting.

The dosing and administration schedule of fosaprepitant and aprepitant may vary depending on the specific chemotherapy regimen, patient factors, and other factors

Patient Information Leaflet

Patient information leaflet

Generic Name: fosaprepitant

Pronounced:  [ FOS-a-PREP-i-tan-t ]

Why do we use fosaprepitant?

The primary use of fosaprepitant and its active form aprepitant is to prevent chemotherapy-induced nausea and vomiting. It is typically used in combination with other antiemetics, such as 5-HT3 receptor antagonists and corticosteroids, to enhance its efficacy.

Fosaprepitant and aprepitant are indicated for the prevention of:

• Acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy, such as cisplatin
• Nausea and vomiting associated with moderately emetogenic chemotherapy