Fosaprepitant

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Fosaprepitant Prescribing Information

Fosaprepitant for injection, in combination with other antiemetic agents, is indicated in adults for the prevention of:

•acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.
•delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of Use

•Fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting.

Recommended Adult Dosage (

2.1 Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients

The recommended dosage of fosaprepitant for injection, dexamethasone, and a 5-HT₃antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC in adults is shown in Table 1 or Table 2, respectively. Administer fosaprepitant for injection as an intravenous infusion on Day 1 over 20 to 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.

Table 1 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC
	Day 1	Day 2	Day 3	Day 4
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes	none	none	none
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally	8 mg orally	8 mg orally twice daily	8 mg orally twice daily
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage	none	none	none

Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC
	Day 1
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage

)

•Fosaprepitant for injection 150 mg on Day 1 as an intravenous infusion over 20 to 30 minutes. (

2.1 Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients

Table 1 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC
	Day 1	Day 2	Day 3	Day 4
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes	none	none	none
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally	8 mg orally	8 mg orally twice daily	8 mg orally twice daily
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage	none	none	none

Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC
	Day 1
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage

)

•Complete the infusion approximately 30 minutes prior to chemotherapy.

Concomitant Antiemetics

•See Full Prescribing Information for additional information. (

2.1 Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients

Table 1 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC
	Day 1	Day 2	Day 3	Day 4
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes	none	none	none
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally	8 mg orally	8 mg orally twice daily	8 mg orally twice daily
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage	none	none	none

Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC
	Day 1
Fosaprepitant for injection	150 mg intravenously over 20 to 30 minutes
DexamethasoneAdminister dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3)] .	12 mg orally
5-HT₃antagonist	See selected 5-HT₃antagonist prescribing information for the recommended dosage

)

There are insufficient data on use of fosaprepitant for injection in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg

[see

Data

Animal Data

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 25 mg/kg/day were approximately equivalent to the exposure at the RHD of 150 mg. Aprepitant crosses the placenta in rats and rabbits.

]

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fosaprepitant for injection is contraindicated in patients:

•who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported
[see
5.2 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension and syncope have been reported
[see Adverse Reactions (6.2)]
.
Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate fosaprepitant for injection in patients who experience these symptoms with previous use
[see Contraindications (4)]
.
,
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of fosaprepitant for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders:
pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis
[see Warnings and Precautions (5.2)]
.
Immune system disorders:
hypersensitivity reactions including anaphylaxis and anaphylactic shock
[see Contraindications (4), Warnings and Precautions (5.2)]
.
Nervous system disorders:
ifosfamide-induced neurotoxicity reported after fosaprepitant and ifosfamide co-administration.
]
.
•taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide
[see
5.1 Clinically Significant CYP3A4 Drug Interactions
Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4.
•Use of fosaprepitant for injection with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.
oUse of pimozide with fosaprepitant for injection is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide
[see Contraindications (4)].
•Use of fosaprepitant for injection with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to fosaprepitant.
•Use of fosaprepitant for injection with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of fosaprepitant.
See Table 7 and Table 8 for a listing of potentially significant drug interactions
[see Drug Interactions (7.1, 7.2)].
]
.

•

CYP3A4 Interactions:

Fosaprepitant is a weak inhibitor of CYP3A4, and aprepitant, the active moiety, is a substrate, inhibitor, and inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of fosaprepitant and concomitant drugs. (

4 CONTRAINDICATIONS

Fosaprepitant for injection is contraindicated in patients:

•who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported
[see Warnings and Precautions (5.2), Adverse Reactions (6.2)]
.
•taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide
[see Warnings and Precautions (5.1)]
.

•Known hypersensitivity to any component of this drug.
•Concurrent use with pimozide.

5.1 Clinically Significant CYP3A4 Drug Interactions

Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4.

•Use of fosaprepitant for injection with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.
- oUse of pimozide with fosaprepitant for injection is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide
  [see Contraindications (4)].
•Use of fosaprepitant for injection with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to fosaprepitant.
•Use of fosaprepitant for injection with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of fosaprepitant.

See Table 7 and Table 8 for a listing of potentially significant drug interactions

[see Drug Interactions (7.1, 7.2)].

7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

When administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of fosaprepitant for injection are likely to occur with drugs that interact with oral aprepitant.

Fosaprepitant, given as a single 150 mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9

[see Clinical Pharmacology (12.3)]

Some substrates of CYP3A4 are contraindicated with fosaprepitant

[see Contraindications (4)]

. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.

Monitor for chemotherapeutic-related adverse reactions.

Etoposide, vinorelbine, paclitaxel, and docetaxel

No dosage adjustment needed.

Table 7 Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs
CYP3A4 Substrates
Pimozide
Clinical Impact	Increased pimozide exposure
Intervention	Fosaprepitant for injection is contraindicated [see Contraindications (4)].
Benzodiazepines
Clinical Impact	Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Monitor for benzodiazepine-related adverse reactions.
Dexamethasone
Clinical Impact	Increased dexamethasone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)].
Methylprednisolone
Clinical Impact	Increased methylprednisolone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
Chemotherapeutic agents that are metabolized by CYP3A4
Clinical Impact	Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents
Hormonal Contraceptives
Clinical Impact	Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of fosaprepitant for injection [see Warnings and Precautions (5.5), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].
Intervention	Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with fosaprepitant for injection and for 1 month following administration of fosaprepitant for injection.
Examples	birth control pills, skin patches, implants, and certain IUDs
CYP2C9 Substrates
Warfarin
Clinical Impact	Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
Intervention	In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of fosaprepitant for injection with each chemotherapy cycle.
Other
5-HT₃Antagonists
Clinical Impact	No change in the exposure of the 5-HT₃antagonist [see Clinical Pharmacology (12.3)].
Intervention	No dosage adjustment needed
Examples	ondansetron, granisetron, dolasetron

7.2 Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Aprepitant is a CYP3A4 substrate

[see Clinical Pharmacology (12.3)].

Co-administration of fosaprepitant for injection with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 8.

Table 8 Effects of Other Drugs on Pharmacokinetics of Fosaprepitant/Aprepitant
Moderate to Strong CYP3A4 Inhibitors
Clinical Impact	Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with fosaprepitant for injection [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
Intervention	Avoid concomitant use of fosaprepitant for injection
Examples	Moderate inhibitor : diltiazem Strong inhibitors : ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir
Strong CYP3A4 Inducers
Clinical Impact	Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of fosaprepitant for injection [see Clinical Pharmacology (12.3)].
Intervention	Avoid concomitant use of fosaprepitant for injection
Examples	rifampin, carbamazepine, phenytoin

)

•
Hypersensitivity Reactions (including anaphylaxis and anaphylactic shock):
May occur during or soon after infusion. If symptoms occur, discontinue the drug. Do not reinitiate fosaprepitant if symptoms occur with previous use. (
4 CONTRAINDICATIONS
Fosaprepitant for injection is contraindicated in patients:
- •who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported
  [see Warnings and Precautions (5.2), Adverse Reactions (6.2)]
  .
- •taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide
  [see Warnings and Precautions (5.1)]
  .
•Known hypersensitivity to any component of this drug.
•Concurrent use with pimozide.
,
5.2 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension and syncope have been reported
[see Adverse Reactions (6.2)]
.
Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate fosaprepitant for injection in patients who experience these symptoms with previous use
[see Contraindications (4)]
.
)
•
Infusion Site Reactions (including thrombophlebitis, necrosis, and vasculitis):
Majority of reactions reported in patients receiving vesicant chemotherapy. Avoid infusion into small veins. Discontinue infusion and administer treatment if a severe reaction develops. (
5.3 Infusion Site Reactions
Infusion site reactions (ISRs) have been reported with the use of fosaprepitant for injection
[see Adverse Reactions (6.1)]
. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of fosaprepitant for injection and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention.
Avoid infusion of fosaprepitant for injection into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment.
)

•

Warfarin (a CYP2C9 substrate):

Risk of decreased INR of prothrombin time; monitor INR in 2–week period, particularly at 7 to 10 days, following initiation of fosaprepitant. (

5.4 Decrease in INR with Concomitant Warfarin

Co-administration of fosaprepitant for injection with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time

[see Clinical Pharmacology (12.3)]

. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant for injection with each chemotherapy cycle

[see Drug Interactions (7.1)]

7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

[see Clinical Pharmacology (12.3)]

Some substrates of CYP3A4 are contraindicated with fosaprepitant

[see Contraindications (4)]

. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.

Monitor for chemotherapeutic-related adverse reactions.

Etoposide, vinorelbine, paclitaxel, and docetaxel

No dosage adjustment needed.

Table 7 Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs
CYP3A4 Substrates
Pimozide
Clinical Impact	Increased pimozide exposure
Intervention	Fosaprepitant for injection is contraindicated [see Contraindications (4)].
Benzodiazepines
Clinical Impact	Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Monitor for benzodiazepine-related adverse reactions.
Dexamethasone
Clinical Impact	Increased dexamethasone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)].
Methylprednisolone
Clinical Impact	Increased methylprednisolone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
Chemotherapeutic agents that are metabolized by CYP3A4
Clinical Impact	Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents
Hormonal Contraceptives
Clinical Impact	Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of fosaprepitant for injection [see Warnings and Precautions (5.5), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].
Intervention	Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with fosaprepitant for injection and for 1 month following administration of fosaprepitant for injection.
Examples	birth control pills, skin patches, implants, and certain IUDs
CYP2C9 Substrates
Warfarin
Clinical Impact	Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
Intervention	In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of fosaprepitant for injection with each chemotherapy cycle.
Other
5-HT₃Antagonists
Clinical Impact	No change in the exposure of the 5-HT₃antagonist [see Clinical Pharmacology (12.3)].
Intervention	No dosage adjustment needed
Examples	ondansetron, granisetron, dolasetron

)

•

Hormonal Contraceptives:

Efficacy of contraceptives may be reduced during and for 28 days following administration of fosaprepitant. Use effective alternative or back-up methods of contraception. (

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives

Upon co-administration with fosaprepitant for injection, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of fosaprepitant for injection

[see Clinical Pharmacology (12.3)]

. Advise patients to use effective alternative or back-up methods of contraception during treatment with fosaprepitant for injection and for 1 month following administration of fosaprepitant for injection

[see Drug Interactions (7.1), Use in Specific Populations (8.3)]

7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

[see Clinical Pharmacology (12.3)]

Some substrates of CYP3A4 are contraindicated with fosaprepitant

[see Contraindications (4)]

. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.

Monitor for chemotherapeutic-related adverse reactions.

Etoposide, vinorelbine, paclitaxel, and docetaxel

No dosage adjustment needed.

Table 7 Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs
CYP3A4 Substrates
Pimozide
Clinical Impact	Increased pimozide exposure
Intervention	Fosaprepitant for injection is contraindicated [see Contraindications (4)].
Benzodiazepines
Clinical Impact	Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Monitor for benzodiazepine-related adverse reactions.
Dexamethasone
Clinical Impact	Increased dexamethasone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)].
Methylprednisolone
Clinical Impact	Increased methylprednisolone exposure [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
Chemotherapeutic agents that are metabolized by CYP3A4
Clinical Impact	Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention	Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents
Hormonal Contraceptives
Clinical Impact	Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of fosaprepitant for injection [see Warnings and Precautions (5.5), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].
Intervention	Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with fosaprepitant for injection and for 1 month following administration of fosaprepitant for injection.
Examples	birth control pills, skin patches, implants, and certain IUDs
CYP2C9 Substrates
Warfarin
Clinical Impact	Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
Intervention	In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of fosaprepitant for injection with each chemotherapy cycle.
Other
5-HT₃Antagonists
Clinical Impact	No change in the exposure of the 5-HT₃antagonist [see Clinical Pharmacology (12.3)].
Intervention	No dosage adjustment needed
Examples	ondansetron, granisetron, dolasetron

8.3 Females and Males of Reproductive Potential

Contraception

Upon administration of fosaprepitant for injection, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms and spermicides) during treatment with fosaprepitant for injection and for 1 month following the last dose

[see Drug Interactions (7.1), Clinical Pharmacology (12.3)]

)

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