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Fosaprepitant Dimeglumine

Pronunciation: FOS-a-PRE-pi-tant di-ME-gloo-meen
Class: Antiemetic

Trade Names

Emend
- Injection, lyophilized powder for solution 115 mg
- Injection, lyophilized powder for solution 150 mg

Pharmacology

Fosaprepitant is a prodrug of aprepitant, which is a selective high-affinity antagonist of human substance P/neurokinin 1 receptors.

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Pharmacokinetics

Absorption

Following a single IV injection, mean AUC and mean C max are 31.7 mcg•h/mL and 3.27 mcg/mL, respectively, for the 115 mg injection and 37.38 mcg•h/mL and 4.15 mcg/mL, respectively, for the 150 mg injection.

Distribution

Rapidly converted to aprepitant, which is more than 95% bound to plasma proteins. Mean Vd at steady state is approximately 70 L.

Metabolism

Primarily metabolized by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19.

Elimination

Recovery in the urine and feces is 57% and 45%, respectively. Terminal half-life ranges from approximately 9 to 13 h.

Special Populations

Renal Function Impairment

In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased 21% and C max decreased 32% compared with healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC 0-∞ of total aprepitant decreased 42% and C max decreased 32%.

Hepatic Function Impairment

Following administration of a single dose of oral aprepitant 125 mg on day 1 and 80 mg once daily on days 2 and 3 to patients with mild hepatic impairment (Child-Pugh class 5 to 6), the AUC 0-24h of aprepitant was 11% lower on day 1 and 36% lower on day 3 compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh class 7 to 9), the AUC 0-24h of aprepitant was 10% higher on day 1 and 18% higher on day 3 compared with healthy subjects given the same regimen. These differences in AUC 0-24h are not considered clinically meaningful.

Elderly

Following oral administration of a single dose of aprepitant 125 mg on day 1 and 80 mg once daily on days 2 through 5, the AUC 0-24h of aprepitant was 21% higher on day 1 and 36% higher on day 5 in elderly patients 65 years of age and older, compared with younger adults. The C max was 10% higher on day 1 and 24% higher on day 5 in elderly patients compared with younger adults. These differences are not considered clinically meaningful.

Children

Fosaprepitant has not been evaluated in patients younger than 18 years of age.

Gender

The C max for aprepitant is 16% higher in women than in men. The half-life of aprepitant is 25% lower in women than in men, and T max occurs at approximately the same time. These differences are not considered clinically meaningful.

Race

Following oral administration of a single dose of aprepitant 125 mg, the AUC 0-24h is approximately 25% and 29% higher in Hispanic patients compared with white and black patients, respectively. The C max is 22% and 31% higher in Hispanic patients compared with white and black patients, respectively. These differences are not considered clinically meaningful.

Indications and Usage

In combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy, including high-dose cisplatin.

Contraindications

Coadministration of cisapride or pimozide; hypersensitivity to any component of the product.

Dosage and Administration

115 mg injection (3-day dosing regimen)
Highly emetogenic cancer chemotherapy Adults

IV Fosaprepitant 115 mg on day 1 only as an infusion over 15 minutes, 30 minutes prior to chemotherapy. Aprepitant 80 mg orally should be administered on days 2 and 3. Aprepitant 125 mg orally may be substituted for fosaprepitant 115 mg IV on day 1. Administer in conjunction with a corticosteroid (dexamethasone 12 mg orally 30 minutes prior to chemotherapy on day 1 and 8 mg orally in the morning on days 2 through 4) and a 5-HT 3 antagonist (ondansetron 32 mg IV 30 minutes prior to chemotherapy on day 1).

Moderately emetogenic cancer chemotherapy Adults

IV Fosaprepitant 115 mg on day 1 only as an infusion over 15 minutes, 30 minutes prior to chemotherapy. Aprepitant 125 mg orally may be substituted for fosaprepitant 115 mg IV on day 1. Aprepitant 80 mg orally should be administered on days 2 and 3. Administer in conjunction with a corticosteroid (dexamethasone 12 mg orally 30 minutes prior to chemotherapy on day 1) and a 5-HT 3 antagonist (ondansetron 8 mg orally 30 to 60 minutes prior to chemotherapy and 8 h after the first dose on day 1).

150 mg injection (single-dose regimen)
Highly emetogenic cancer chemotherapy Adults

IV Fosaprepitant 150 mg on day 1 only as an infusion over 20 to 30 minutes, 30 minutes prior to chemotherapy. Administer in conjunction with a corticosteroid (dexamethasone 12 mg orally 30 minutes prior to chemotherapy on day 1, 8 mg orally in the morning on day 2, and 8 mg orally twice daily on days 3 and 4) and a 5-HT 3 antagonist (ondansetron 32 mg IV 30 minutes prior to chemotherapy on day 1).

General Advice

  • Administer IV as an infusion over 15 minutes for the 115 mg injection and over 20 to 30 minutes for the 150 mg injection.
  • Fosaprepitant requires reconstitution and further dilution with sodium chloride 0.9% injection.
  • Fosaprepitant is incompatible with any solutions containing divalent cations (eg, calcium, magnesium), including Ringer's lactate solution and Hartmann's solution.
  • Long-term, continuous administration is not recommended.

Storage/Stability

Store between 36° and 46°F. Reconstituted final solution is stable for 24 h at or below 77°F.

Drug Interactions

Colchicine

Plasma concentrations of colchicine may be elevated, increasing the risk of toxicity. Use with caution and closely monitor for colchicine toxicity. Colchicine dosage adjustment may be required for patients receiving fosaprepitant.

Contraceptives, hormonal

Contraceptive efficacy may be reduced. Use alternative methods of contraception during aprepitant treatment and for 1 mo after the last dose of aprepitant.

CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin)

Plasma concentrations of these drugs may be reduced. In patients receiving warfarin, closely monitor anticoagulation parameters for 14 days after initiation of the 3-day antiemetic regimen.

CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin)

Plasma concentrations of aprepitant may be reduced, decreasing the efficacy. Use with caution and monitor the clinical response.

CYP3A4 inhibitors (eg, clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir)

Plasma concentrations of aprepitant may be elevated, increasing the pharmacologic effects and adverse reactions. Use with caution.

CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine)

Plasma concentrations of these agents may be elevated, increasing the pharmacologic effects and adverse reactions. Cisapride and pimozide are contraindicated with coadministration of aprepitant. Reduce the dexamethasone dose by 50%; reduce the oral and IV doses of methylprednisolone by 50% and 25%, respectively, when coadministering aprepitant. Use with caution.

Everolimus

Everolimus plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Closely monitor everolimus concentrations and adjust the dose as needed.

Fentanyl

Fentanyl plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Closely monitor the patient for an extended period of time and increase the fentanyl dose conservatively.

Paroxetine

Plasma concentrations of both aprepitant and paroxetine may be reduced. Monitor the clinical response.

Ranolazine

Ranolazine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Closely monitor the patient for ranolazine toxicity, including QT prolongation. Limit the ranolazine dosage to 500 mg twice daily.

Tolvaptan

Tolvaptan plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Avoid coadministration.

Adverse Reactions

CNS

Asthenia/fatigue (3%); headache (2%).

Dermatologic

Angioedema, erythema, Stevens-Johnson syndrome, urticaria.

GI

Anorexia, constipation, dyspepsia (2%); diarrhea, eructation (1%).

Lab Tests

Increased ALT (3%); increased AST (1%).

Miscellaneous

Hiccups (5%); infusion-site reactions (eg, erythema, induration, pain, pruritus, thrombophlebitis) (3%); increased blood pressure; hypersensitivity reactions (postmarketing).

Precautions

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hypersensitivity

Immediate hypersensitivity reactions, including flushing, erythema, dyspnea, and anaphylaxis, have occurred.

Hepatic Function

Use with caution in patients with severe hepatic impairment.

Long-term use

Not recommended.

Overdosage

Symptoms

None well documented.

Patient Information

  • Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Inform patients that allergic reactions, which may be sudden and/or serious, have been reported and instruct them to contact their health care provider right away if they experience an allergic reaction.
  • Instruct patients who develop an infusion-site reaction, such as erythema, edema, pain, or thrombophlebitis, on how to care for the local reaction and when to seek further evaluation.
  • Advise patient to report the use of any other prescription or nonprescription medication or herbal product to health care provider.
  • Instruct patients on long-term warfarin therapy to have their clotting status closely monitored during the 2-wk period following initiation of the 3-day regimen, particularly at 7 to 10 days after initiation.
  • Advise patient to use a nonhormonal form of contraceptive while taking fosaprepitant and for 1 mo following the last dose of the 3-day regimen.

Copyright © 2009 Wolters Kluwer Health.

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