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Fosaprepitant

Pronunciation

(fos a PRE pi tant)

Index Terms

  • Aprepitant Injection
  • Fosaprepitant Dimeglumine
  • L-758,298
  • MK 0517

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Emend: 150 mg (1 ea) [contains disodium edta, polysorbate 80]

Brand Names: U.S.

  • Emend

Pharmacologic Category

  • Antiemetic
  • Substance P/Neurokinin 1 Receptor Antagonist

Pharmacology

Fosaprepitant is a prodrug of aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Fosaprepitant is rapidly converted to aprepitant, which prevents acute and delayed vomiting by inhibiting the substance P/neurokinin 1 (NK1) receptor; also augments the antiemetic activity of the 5-HT3 receptor antagonist and corticosteroid activity and inhibits chemotherapy-induced emesis.

Distribution

Aprepitant: Vd: ~70 L; crosses the blood-brain barrier

Metabolism

Fosaprepitant: Hepatic and extrahepatic; rapidly (within 30 minutes after the end of infusion) converted to aprepitant (nearly complete conversion)

Aprepitant: Hepatic via CYP3A4 (major); CYP1A2 and CYP2C19 (minor); forms 7 weakly-active metabolites

Excretion

Urine (57%); feces (45%)

Time to Peak

Fosaprepitant is converted to aprepitant within 30 minutes after the end of infusion

Half-Life Elimination

Aprepitant: ~9 to 13 hours

Protein Binding

Aprepitant: >95%

Special Populations: Renal Function Impairment

Following a single oral aprepitant 240 mg dose in patients with severe renal impairment (CrCl <30 mL/minute), the AUC of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32% compared with healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC of total aprepitant decreased by 42% and Cmax decreased by 32%. Hemodialysis conducted 4 or 48 hours after aprepitant dosing had no significant impact on aprepitant pharmacokinetics.

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

Following oral administration of aprepitant 125 mg on day 1 and 80 mg once daily on days 2 through 5, the AUC of aprepitant was 21% higher on day 1 and 36% higher on day 5 in elderly patients; the Cmax was 10% higher on day 1 and 24% higher on day 5 in elderly patients (relative to younger adults). These differences are not considered clinically meaningful.

Special Populations: Gender

Following a single oral aprepitant dose (ranging from 40 to 375 mg), the AUC was 9% higher and the Cmax was 17% higher in females (compared with males); the half-life of aprepitant is approximately 25% lower in females (compared with males). These differences are not considered clinically meaningful.

Special Populations: Race

Following a single oral aprepitant dose (ranging from 40 to 375 mg), the AUC of aprepitant was ~27% higher and the Cmax was ~19% higher in Hispanic patients compared with Caucasian patients; the AUC of aprepitant was 74% higher and the Cmax was 47% higher in Asian patients compared with Caucasian patients. These differences are not considered clinically meaningful.

Special Populations Note

Obesity: In an analysis of subjects with BMIs ranging from 18 kg/m2 to 36 kg/m2, for every 5 kg/m2 increase in BMI, the AUC and Cmax of aprepitant decrease by 9% and 10%, respectively. These differences are not considered clinically meaningful.

Use: Labeled Indications

Prevention of chemotherapy-induced nausea and vomiting:

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy, including high-dose cisplatin (initial and repeat courses; in combination with other antiemetics)

Prevention of delayed nausea and vomiting associated with moderately emetogenic chemotherapy (initial and repeat courses; in combination with other antiemetics)

Limitations of use: Fosaprepitant has not been studied for the management of existing nausea and vomiting.

Contraindications

Hypersensitivity to fosaprepitant or any component of the formulation; concurrent use with pimozide

Canadian labeling: Additional contraindications (not in the US labeling): Concurrent use with astemizole, terfenadine, or cisapride

Dosing: Adult

Prevention of chemotherapy-induced nausea/vomiting:

Highly emetogenic chemotherapy: IV: 150 mg ~30 minutes prior to chemotherapy on day 1 only (in combination with a 5-HT3 antagonist on day 1 only and dexamethasone on days 1 to 4 [reduce dexamethasone dose by 50% on days 1 and 2])

Moderately emetogenic chemotherapy: IV: 150 mg ~30 minutes prior to chemotherapy on day 1 only (in combination with a 5-HT3 antagonist and dexamethasone on day 1 [reduce dexamethasone dose by 50%])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, due to modest decreases in protein binding of aprepitant, the AUC of pharmacologically active unbound drug is not significantly affected in patients with renal disease.

Hemodialysis: Aprepitant is not removed by hemodialysis.

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There is no dosage adjustment provided in the manufacturer's labeling (has not been studied); additional monitoring may be needed.

Reconstitution

Reconstitute vial with 5 mL of NS, slowly directing diluent down side of vial to avoid foaming; swirl gently. Add reconstituted contents of the 150 mg vial to 145 mL NS (total volume of 150 mL), resulting in a final concentration of 1 mg/mL; gently invert bag 2 to 3 times to mix. Solutions may also be diluted to a final volume of 250 mL (0.6 mg/mL) (data on file [Merck 2013]).

Administration

Infuse over 20 to 30 minutes ~30 minutes prior to chemotherapy

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Solutions diluted to 1 mg/mL for infusion are stable for 24 hours at room temperature at ≤25°C (≤77°F). Solutions diluted in NS to a final volume of 250 mL (0.6 mg/mL) should be administered within 24 hours (data on file [Merck 2013]).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Astemizole: Fosaprepitant may increase the serum concentration of Astemizole. The active metabolite aprepitant is likely responsible for this effect. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Cisapride: Fosaprepitant may increase the serum concentration of Cisapride. The active metabolite aprepitant is likely responsible for this effect. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Corticosteroids (Systemic): Fosaprepitant may increase the serum concentration of Corticosteroids (Systemic). The active metabolite aprepitant is likely responsible for this effect. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

CYP3A4 Substrates (High risk with Inhibitors): Fosaprepitant may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DilTIAZem: Fosaprepitant may increase the serum concentration of DilTIAZem. The active metabolite aprepitant is likely responsible for this effect. DilTIAZem may increase the serum concentration of Fosaprepitant. Specifically, diltiazem may increase the concentration of the active metabolite aprepitant. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Estrogen Derivatives (Contraceptive): Fosaprepitant may decrease the serum concentration of Estrogen Derivatives (Contraceptive). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with fosaprepitant or aprepitant and for at least one month following the last fosaprepitant/aprepitant dose. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ifosfamide: Fosaprepitant may increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PARoxetine: May decrease serum concentrations of the active metabolite(s) of Fosaprepitant. Fosaprepitant may decrease the serum concentration of PARoxetine. Monitor therapy

Pimozide: Fosaprepitant may increase the serum concentration of Pimozide. The active metabolite aprepitant is likely responsible for this effect. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Progestins (Contraceptive): Fosaprepitant may decrease the serum concentration of Progestins (Contraceptive). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

RifAMPin: May decrease the serum concentration of Fosaprepitant. More specifically, rifampin may decrease concentrations of the active metabolite aprepitant. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sirolimus: Fosaprepitant may increase the serum concentration of Sirolimus. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Terfenadine: Fosaprepitant may increase the serum concentration of Terfenadine. The active metabolite aprepitant is likely responsible for this effect. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

TOLBUTamide: Fosaprepitant may decrease the serum concentration of TOLBUTamide. Monitor therapy

Warfarin: Fosaprepitant may decrease the serum concentration of Warfarin. The active metabolite aprepitant is likely responsible for this effect. Monitor therapy

Adverse Reactions

Adverse reactions reported with aprepitant and fosaprepitant (as part of a combination chemotherapy regimen) occurring at a higher frequency than standard antiemetic therapy:

>10%:

Central nervous system: Fatigue (1% to 15%)

Gastrointestinal: Diarrhea (13%)

1% to 10%:

Central nervous system: Peripheral neuropathy (3%), headache (2%)

Gastrointestinal: Hiccups (5%), anorexia (2%), constipation (2%), dyspepsia (2%), eructation (1%)

Genitourinary: Urinary tract infection (2%)

Hematologic & oncologic: Neutropenia (8%), anemia (3%), leukopenia (2%)

Hepatic: Increased serum ALT (1% to 3%), increased serum AST (1%)

Local: Infusion-site reaction (2%; includes induration at injection site, infusion-site pain, local pruritus, local thrombophlebitis, or localized erythema)

Neuromuscular & skeletal: Weakness (4%), limb pain (2%)

<1% (Limited to important or life-threatening): Abdominal distention, abdominal pain, abnormal dreams, abnormal gait, acne vulgaris, anaphylactic shock, anaphylaxis, anemia, angioedema, anxiety, bradycardia, candidiasis, cardiovascular signs and symptoms, chest discomfort, chills, cognitive dysfunction, colitis (neutropenic), conjunctivitis, cough, decreased visual acuity, diaphoresis, disorientation, dizziness, drowsiness, dysarthria, dysgeusia, dyspnea, dysuria, edema, epigastric distress, erythema, euphoria, febrile neutropenia, fecal impaction, flatulence, flushing, gastroesophageal reflux, gastroesophageal reflux disease, hallucination, hematuria (microscopic), hot flash, hyperglycemia, hypersensitivity reaction, hypertension, hypoesthesia, hyponatremia, impaired consciousness, increased serum alkaline phosphatase, insomnia, intestinal obstruction, lethargy, loss of consciousness, malaise, miosis, muscle cramps, myalgia, myasthenia, nausea, obstipation, oily skin, palpitations, paresthesia, perforated duodenal ulcer, pharyngitis, pollakiuria, polydipsia, polyuria, post nasal drip, pruritus, seizure, sensory disturbance, SIADH (syndrome of inappropriate antidiuretic hormone secretion), skin lesion, skin photosensitivity, skin rash, sneezing, staphylococcal infection, Stevens-Johnson syndrome, stomatitis, throat irritation, tinnitus, toxic epidermal necrolysis, urticaria, vomiting, weight changes (gain/loss), wheezing, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions, including dyspnea, erythema, flushing, and anaphylaxis have been reported during infusions; if symptoms occur, stop infusion; do not reinitiate.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

• Nausea/vomiting: Not studied for treatment of existing nausea and vomiting.

Concurrent drug therapy issues:

• Drug-drug interactions: Fosaprepitant is rapidly converted to aprepitant, which has a high potential for drug interactions. Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Due to a drug interaction, a 50% reduction in the day 1 and 2 dexamethasone dose is recommended.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Chronic continuous administration is not recommended.

Monitoring Parameters

Monitor INR in patients on chronic warfarin therapy in the 2-week period (particularly at 7 to 10 days) following fosaprepitant administration; monitor for signs/symptoms of hypersensitivity reactions.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies for aprepitant. Efficacy of hormonal contraceptive may be reduced; alternative or additional methods of contraception should be used both during treatment with fosaprepitant or aprepitant and for at least 1 month following the last fosaprepitant/aprepitant dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, painful extremities, abdominal pain, or heartburn. Have patient report immediately to prescriber signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of infection, flushing, difficulty swallowing, dizziness, passing out, tachycardia, abnormal heartbeat, injection site pain or irritation, burning or numbness feeling, severe loss of strength and energy, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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