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Aprepitant/Fosaprepitant Dimeglumine

Class: Antiemetics, Miscellaneous
VA Class: GA605
Chemical Name: 5-[[(2R,3S)-2-[(1R)-1-[3,5,bis (trifluoromethyl)phenyl]ethoxy] - 3 - (4 - fluorophenyl) - 4 - morpholinyl]methyl] - 1,2, - dihydro - 3H - 1,2,4, - triazol - 3 - one
Molecular Formula: C23H21F7N4O3C23H22F7N4O6P•2C7H17NO5
CAS Number: 170729-80-3
Brands: Emend

Introduction

Antiemetic; aprepitant is a selective, high-affinity antagonist at substance P/neurokinin-1 (NK1) receptors; fosaprepitant dimeglumine is a lyophilized prodrug of aprepitant.1 2 3 4 7 8 9 11 12 16

Uses for Aprepitant/Fosaprepitant Dimeglumine

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin therapy.1 4 7 8 9 12 16 Used in combination with other antiemetic agents.1 4 7 8 9 12 16

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Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.1 11 12 16 Used in combination with other antiemetic agents.1 11 12 16

For prevention of nausea and vomiting associated with chemotherapy with a high emetic risk (>90% incidence of emesis without antiemetics) and for combination anthracycline and cyclophosphamide chemotherapy, ASCO recommends a 3-drug antiemetic regimen consisting of aprepitant, a type 3 serotonin (5-HT3) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), and dexamethasone.7 For chemotherapy regimens of moderate emetic risk (>30% and ≤90% incidence of emesis without antiemetics), ASCO prefers a 2-drug antiemetic regimen consisting of a 5-HT3 receptor antagonist and dexamethasone.7 For chemotherapy with a low emetic risk (>10% and ≤30% incidence of emesis without antiemetics), ASCO recommends dexamethasone alone on the first day of chemotherapy.7

For prevention of delayed emesis in patients receiving cisplatin or other chemotherapy associated with a highemetic risk, ASCO recommends a 2-drug combination of aprepitant and dexamethasone.7

Safety and efficacy for chronic use or for treatment of established nausea and vomiting not established.1 2 12

Postoperative Nausea and Vomiting

Prevention of postoperative nausea and vomiting.1 2 6 14 15

Safety and efficacy for chronic use or for treatment of established nausea and vomiting not established.1 2

Aprepitant/Fosaprepitant Dimeglumine Dosage and Administration

Administration

Dispensing and Administration Precautions

Because of similarities in spelling and/or pronunciation between Emend (the trade name for aprepitant) and Amen (a former trade name for medroxyprogesterone acetate; no longer commercially available under this trade name in the US) or Vfend (the trade name for voriconazole), exercise extra care in ensuring the accuracy of prescriptions for these drugs.5 (See Possible Prescribing and Dispensing Errors under Cautions.)

Oral Administration

Administer aprepitant orally without regard to meals.1 2 4

IV Administration

Administer fosaprepitant dimeglumine by IV infusion.12

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution and Dilution

Reconstitute powder for injection with 5 mL of 0.9% sodium chloride for injection; avoid jetting saline into the vial.12 Gently swirl solution; do not shake.12

Withdraw entire volume from vial and transfer into infusion bag containing 110 mL of 0.9% sodium chloride, yielding a total volume of 115 mL (1 mg/mL).12 Mix solutions by gentle inversion of the bag 2–3 times.12

Rate of Administration

Infuse over 15 minutes.12

Dosage

Dosage of fosaprepitant dimeglumine is expressed in terms of fosaprepitant.12

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Administer as part of a regimen that includes a 5-HT3 receptor antagonist and a corticosteroid.1 2 4 12

Highly Emetogenic Cancer Chemotherapy
Oral

Administer 125 mg of aprepitant 1 hour before chemotherapy on day 1, and follow with 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.1 2 4 7

In clinical studies, aprepitant was administered with IV ondansetron (32 mg 30 minutes before chemotherapy on day 1) and oral dexamethasone (12 mg 30 minutes before chemotherapy on day 1, followed by 8 mg once daily in the morning on days 2–4).1 4

IV

Administer 115 mg of fosaprepitant over 15 minutes, 30 minutes prior to chemotherapy as an alternative to oral aprepitant (125-mg) on day 1 only of 3-day regimen.1 12 Follow fosaprepitant with oral aprepitant 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.12

Moderately Emetogenic Cancer Chemotherapy
Oral

Administer 125 mg of aprepitant 1 hour before chemotherapy on day 1, and follow with 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.1 7

In a clinical study, aprepitant was administered with oral ondansetron (8 mg 30–60 minutes before chemotherapy on day 1, followed by 8 mg 8 hours after the first dose) and oral dexamethasone (12 mg 30 minutes before chemotherapy on day 1).1

IV

Administer 115 mg of fosaprepitant over 15 minutes, 30 minutes prior to chemotherapy as an alternative to oral aprepitant (125-mg) on day 1 only of 3-day regimen.1 12 Follow fosaprepitant with oral aprepitant 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.12

Postoperative Nausea and Vomiting
Oral

Administer 40 mg of aprepitant within 3 hours before induction of anesthesia.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild to moderate hepatic impairment.1 Not adequately studied in patients with severe hepatic impairment (Child-Pugh score >9).1

Renal Impairment

No dosage adjustment necessary in patients with renal impairment or end-stage renal disease requiring hemodialysis.1 4

Geriatric Patients

No dosage adjustment necessary.1 4

Cautions for Aprepitant/Fosaprepitant Dimeglumine

Contraindications

  • Concomitant use with astemizole (no longer commercially available in the US), cisapride (currently commercially available in the US only under a limited-access protocol), pimozide, or terfenadine (no longer commercially available in the US).1 2 4 12

  • Known hypersensitivity to fosaprepitant, aprepitant, polysorbate 80, or any ingredient in the formulations.1 2 4 12

Warnings/Precautions

Sensitivity Reactions

Stevens-Johnson syndrome reported in 1 patient receiving aprepitant with antineoplastic agents.1 4 Hypersensitivity reactions, including anaphylaxis, hives, rash, itching, and urticaria reported in patients receiving aprepitant or fosaprepitant; may be serious and can cause difficulty in breathing or swallowing.1 2 12 17 Angioedema reported in 1 patient.1 4

General Precautions

Drug Interaction Potential

Drug-interaction potential could be altered with chronic use (see Interactions); safety of chronic use not established.1

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling and/or pronunciation of Emend (trade name for aprepitant) and Amen (former trade name for medroxyprogesterone acetate) or Vfend (trade name for voriconazole) may result in errors.5

Specific Populations

Pregnancy

Category B.1 2 4 12

Lactation

Aprepitant is distributed into milk in rats; not known whether distributed into human milk.1 2 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy of fosaprepitant and aprepitant not established in children <18 years of age.1 4 6 12

Geriatric Use

No substantial differences in safety, efficacy, or pharmacokinetics of oral aprepitant relative to younger adults, but increased sensitivity cannot be ruled out.1 4

Hepatic Impairment

Oral aprepitant has not been adequately studied in patients with severe hepatic impairment (Child-Pugh score >9); caution advised in these patients.1 4 12

Fosaprepitant metabolized by extrahepatic tissue; hepatic insufficiency not expected to alter conversion of fosaprepitant to aprepitant.12

Common Adverse Effects

Aprepitant capsules: Asthenia and/or fatigue, dizziness, hypoesthesia, nausea, anorexia, diarrhea, constipation, heartburn, abdominal pain, epigastric discomfort, dyspepsia, gastritis, stomatitis, pharyngolaryngeal pain, hiccups, perforating duodenal ulcer, enterocolitis, neutropenia, dehydration, hot flush, pruritus, hypotension, hypertension, sinus tachycardia, neutropenic sepsis, pneumonia, alopecia, bradycardia.1 2

Fosaprepitant injection: Infusion site reactions (e.g., pain, induration), headache.12 13 16 Since fosaprepitant dimeglumine for injection is converted into aprepitant, adverse effects associated with aprepitant also may be expected to occur with the injection.12

Interactions for Aprepitant/Fosaprepitant Dimeglumine

Drug interactions following fosaprepitant administration likely to occur with agents that interact with aprepitant.12

Aprepitant is extensively metabolized, principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19.1 12 16 The drug is a weak-to-moderate, dose-dependent inhibitor and an inducer of CYP3A4;1 4 12 also an inducer of CYP2C9.1 4 12

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Possible altered metabolism of CYP3A4 substrates.1 4 Aprepitant may inhibit or induce CYP3A4.1 4 Inhibition of CYP3A4 is dose-dependent and moderate with the 125-mg/80-mg aprepitant regimen and weak with the single-dose, 40-mg regimen.1 Possible increased plasma concentrations of concomitantly administered drugs, especially possible with higher aprepitant dosages (i.e., in a regimen consisting of 125 mg on day 1 followed by 80 mg on days 2 and 3) or with repeat administration at any aprepitant dose.1 4 6 16 Aprepitant (at a dosage level of 125 mg on day 1 followed by 80 mg on days 2 and 3) may increase plasma concentrations of a CYP3A4 substrate to lesser extent when the substrate is given IV rather than orally.1 6 18 Use with caution; dosage adjustment of the CYP3A4 substrate may be necessary.1 4 12

CYP2C9 substrates: Possible increased metabolism and decreased plasma concentrations of the CYP2C9 substrate.1 4 6 12

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Possible decreased aprepitant metabolism, resulting in increased plasma aprepitant concentrations.1 4 12 Use with caution.1 4 12 16

CYP3A4 inducers: Possible increased aprepitant metabolism.1 4 Potential for decreased aprepitant efficacy with strong CYP3A4 inducers.1 4 12

Specific Drugs

Drug

Interaction

Comments

Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron)

No clinically important effects on 5-HT3 receptor antagonist pharmacokinetics1 12 16

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Possible increased plasma aprepitant concentrations1 4

Use with caution1 4

Antineoplastic agents (e.g., etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine)

Possible increased plasma concentrations of antineoplastic agents metabolized by CYP3A41 4

Use caution; careful monitoring required1 4

Astemizole (no longer commercially available in US)

Increased plasma astemizole concentrations;1 4 potential for serious or life-threatening reaction1 2 4

Concomitant use contraindicated1 4

Benzodiazepines (e.g., alprazolam, midazolam, triazolam)

Possible increased plasma concentrations of benzodiazepines metabolized by CYP3A41 4

Consider potential effect of increased plasma benzodiazepine concentrations1 4 12 16

IV midazolam: Dosage adjustment may be necessary when concurrently administered with oral aprepitant regimen of 125 mg on day 1 followed by 80 mg on days 2 and 31

Interaction not clinically important when midazolam administered with single dose of fosaprepitant 100 mg or single 40-mg dose of aprepitant 1 6 12

Carbamazepine

Possible decreased plasma concentrations and decreased efficacy of aprepitant1 4

Cisapride (commercially available in US only under limited-access protocol)

Increased plasma cisapride concentrations;1 4 potential for serious or life-threatening reaction1 2 4

Concomitant use contraindicated1 4

Contraceptives, oral

Possible decreased plasma steroid concentrations and reduced contraceptive efficacy1 4

Use alternative or additional contraceptive methods during fosaprepitant or aprepitant treatment and for 1 month after last dose1 4 6 12 16

Corticosteroids (e.g., dexamethasone, methylprednisolone)

Possible increased plasma concentrations of corticosteroids metabolized by CYP3A4, particularly when given oral aprepitant regimen of 125 mg on day 1 followed by 80 mg on days 2 and 31 4 12

Decrease dosage of oral and IV corticosteroids if necessary.1 4 12 Decrease dosage of oral dexamethasone and methylprednisolone by 50% and IV methylprednisolone by 25% in patients receiving oral aprepitant regimen of 125 mg on day 1 followed by 80 mg on days 2 and 3;1 6 12 16 dosage adjustment not recommended in patients receiving the single-dose, 40-mg regimen6

Digoxin

Pharmacokinetic interaction unlikely1 4 12 16

Diltiazem

Possible increased plasma aprepitant and diltiazem concentrations; no clinically important changes in ECG, heart rate, or BP observed1 4 16

Small, but clinically meaningful, decrease in DBP, and possibly SBP, reported with concomitant fosaprepitant therapy; no clinically important changes in heart rate or PR interval observed12

Use with caution1 4 12

Docetaxel

No effects on docetaxel pharmacokinetics with oral aprepitant regimen of 125 mg on day 1 followed by 80 mg on days 2 and 31 6

HIV protease inhibitors (nelfinavir, ritonavir)

Possible increased plasma aprepitant concentrations1 4

Use with caution1 4

Macrolide antibiotics (e.g., clarithromycin, troleandomycin)

Possible increased plasma aprepitant concentrations1 4

Use with caution1 4

Nefazodone

Possible increased plasma aprepitant concentrations1 4

Use with caution1 4

Paroxetine

Possible decreased plasma aprepitant and paroxetine concentrations1 4

Phenytoin

Possible decreased plasma concentrations and decreased efficacy of aprepitant; possible decreased plasma phenytoin concentrations1 4

Pimozide

Increased plasma pimozide concentrations;1 4 potential for serious or life-threatening reaction1 2 4

Concomitant use contraindicated1 4

Rifampin

Possible decreased plasma concentrations and decreased efficacy of aprepitant1 4

Terfenadine (no longer commercially available the US)

Increased plasma terfenadine concentrations;1 4 potential for serious or life-threatening reaction1 2 4

Concomitant use contraindicated1 4

Tolbutamide

Possible decreased plasma tolbutamide concentrations1 4

Vinorelbine

No effects on vinorelbine pharmacokinetics with oral aprepitant regimen of 125 mg on day 1 followed by 80 mg on days 2 and 31

Warfarin

Possible decreased plasma S-warfarin concentrations and decreased PT1 4

Monitor PT closely for 2 weeks (particularly 7–10 days) after initiation of fosaprepitant followed by aprepitant, the 3-day oral aprepitant regimen or administration of the single-dose aprepitant regimen1 4 6 12 16

Aprepitant/Fosaprepitant Dimeglumine Pharmacokinetics

Absorption

Bioavailability

Absolute mean oral bioavailability at doses of 80–125 mg is approximately 60–65%.1 16 Absolute oral bioavailability of 40-mg dose not established.1

Peak plasma concentrations achieved approximately 3–4 hours after oral administration.1 16

Fosaprepitant undergoes hepatic and extrahepatic metabolism to aprepitant (the active moiety).12

Plasma concentrations of fosaprepitant were below limits of quantification within 30 minutes following infusion completion.12

Mean aprepitant plasma concentration 24 hours postdose similar between oral aprepitant (125-mg) dose and IV fosaprepitant (115-mg) dose.12

Food

Standard breakfast does not appreciably alter bioavailability.1 16

Special Populations

In patients with mild to moderate hepatic impairment, no clinically meaningful changes in systemic exposure relative to healthy individuals.1 Not studied in patients with severe hepatic impairment (Child-Pugh score >9).1

In patients with severe renal impairment or end-stage renal disease requiring hemodialysis, total (protein bound and unbound) aprepitant AUCs and peak plasma concentrations are decreased, but AUC of active unbound drug is unaffected.1

In geriatric patients, no clinically meaningful changes in systemic exposure relative to younger adults.1

Distribution

Extent

Crosses the placenta in animals; crosses the blood-brain barrier in humans.1

Plasma Protein Binding

>95%.1

Elimination

Metabolism

Fosaprepitant rapidly metabolized to aprepitant in liver by CYP3A4 and to lesser extent by CYP1A2 and 2C19; also metabolized in extrahepatic tissues.12 16

Aprepitant extensively metabolized to weakly active metabolites, principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19.1

Elimination Route

Eliminated principally by metabolism; not renally excreted.1

Following a single IV dose of radiolabeled fosaprepitant in healthy individuals, 57 and 45% of radioactivity recovered in urine and feces, respectively.16

Half-life

Terminal half-life is approximately 9–13 hours.1 16

Special Populations

Not removed by hemodialysis.1 4

Stability

Storage

Oral

Capsules

20–25°C.1 Desiccant should remain in original bottle.1

Parenteral

Injection

2–8°C.12

Following reconstitution and dilution to final concentration of 1 mg/mL in 0.9% sodium chloride injection, store at room temperature (≤25°C); use within 24 hours.12

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not mix or reconstitute with solutions containing divalent cations (e.g., lactated Ringer’s solution, Hartmann’s solution).12

Solution Compatibility

Incompatible

Ringer’s injection, Lactated12

Hartmann’s solution12

Actions

  • Fosaprepitant is a prodrug; pharmacologically active once metabolized to aprepitant.12 16

  • Aprepitant occupies NK1 receptors in the brain.1 3 4 Acts in the CNS to inhibit cancer chemotherapy-induced nausea and vomiting (including both acute and delayed emesis induced by cisplatin) and postoperative nausea and vomiting.1 3 4

  • Augments the antiemetic activity of ondansetron and dexamethasone.1 3 4

Advice to Patients

  • Importance of reading the fosaprepitant and aprepitant patient information provided by the manufacturer before beginning therapy and rereading each time the prescription is renewed.1 2 12

  • Importance of using fosaprepitant and aprepitant only as directed by the clinician.1 2 12

  • Importance of taking first oral aprepitant (125-mg) dose 1 hour before initiation of antineoplastic chemotherapy.1 2

  • Advise patients that aprepitant may be taken with or without food.2 12 17

  • Importance of taking aprepitant (40-mg) dose within 3 hours prior to induction of anesthesia for prevention of postoperative nausea and vomiting.1

  • Importance of discontinuing aprepitant and promptly contacting a clinician if symptoms of an allergic reaction occur.2 12 17

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Importance of women using alternative or additional contraceptive methods during fosaprepitant or aprepitant use (and for 1 month after last dose) if oral contraceptives are being taken.1 2 12

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products.1 2 12 Importance of closely monitoring prothrombin time in patients receiving chronic warfarin therapy during the 2 weeks (particularly 7–10 days) after initiation of fosaprepitant followed by aprepitant, or the 3-day oral aprepitant regimen for each antineoplastic chemotherapy cycle, or administration of aprepitant for prevention of postoperative emesis.1 2 12

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Aprepitant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

40 mg

Emend

Merck

80 mg

Emend

Merck

125 mg

Emend

Merck

Fosaprepitant Dimeglumine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For IV infusion only

115 mg (of fosaprepitant)

Emend

Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Emend 125MG Capsules (MERCK SHARP &amp; DOHME): 6/$944.00 or 18/$2,707.09

Emend 40MG Capsules (MERCK SHARP &amp; DOHME): 5/$297.63 or 15/$844.55

Emend 80MG Capsules (MERCK SHARP &amp; DOHME): 2/$217.03 or 6/$624.97

Emend 80MG Capsules (MERCK SHARP &amp; DOHME): 6/$632.97 or 18/$1,780.89

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck. Emend (aprepitant) capsules prescribing information. Whitehouse Station, NJ; 2008 Feb.

2. Merck. Emend (aprepitant) capsules patient information. Whitehouse Station, NJ; 2008 Apr.

3. Sorbera LA, Castaner J, Bayes M at al. Aprepitant and L-758298. Drugs Fut. 2002; 27:211-22.

4. Merck. Emend (aprepitant) product information form for the American Hospital Formulary Service. 2003.

5. Merck. Dear pharmacist letter regarding Emend (aprepitant). 2003 Apr.

6. Merck, Whitehouse Station, NJ: Personal communication.

7. Kris MG, Hesketh PJ, Somerfield MR et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006; 24:2932-2947. [PubMed 16717289]

8. Hesketh PJ, Grunberg SM, Gralla RJ et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003; 21:4112-9. [PubMed 14559886]

9. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003; 97:3090-8. [PubMed 12784346]

11. Warr DG, Hesketh PJ, Gralla RJ. et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005; 23:2822-30. [PubMed 15837996]

12. Merck. Emend (fosaprepitant dimeglumine) for injection prescribing information. Whitehouse Station, NJ; 2008 Feb.

13. Lasseter KC, Gambale J, Jin B et al. Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol. 2007; 47:834-40. [PubMed 17525168]

14. Diemunsch P, Gan TJ, Philip BK et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery. Br J Anesth. 2007; 99:202-11.

15. Gan TJ, Apfel CC, Kovac A et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Anal. 2007; 104:1082-9.

16. Navari RM. Fosaprepitant (MK-0517): a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin. Investig. Drugs. 2007; 16:1977-85.

17. Merck. Emend (fosaprepitant dimeglumine) for injection patient information. Whitehouse Station, NJ; 2009 Feb.

18. Merck. Whitehouse Station, NJ: Personal communication.

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