FOSAPREPITANT injection, powder, lyophilized, for solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FOSAPREPITANT DIMEGLUMINE (UNII: D35FM8T64X) (APREPITANT - UNII:1NF15YR6UY)
Available from:
MSN LABORATORIES PRIVATE LIMITED
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Fosaprepitant is contraindicated in patients: -  who are hypersensitive to any component of the product. Hypersensitivity reactions  including  anaphylactic reactio
Product summary:
No. 034 — Single-dose glass vial containing 150 mg of fosaprepitant as a white to off white lyophilized cake or powder for reconstitution. Supplied as follows: NDC 69539-034-01      1 vial per carton. Storage Fosaprepitant for injection vials must be refrigerated, store at 2°C to 8°C (36°F to 46°F). The  reconstituted final drug solution is stable for 24 hours at ambient room  temperature [at or below 25°C (77°F)].
Authorization status:
Abbreviated New Drug Application
Authorization number:
69539-034-01

FOSAPREPITANT - fosaprepitant injection, powder, lyophilized, for solution

MSN LABORATORIES PRIVATE LIMITED

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FOSAPREPITANT FOR INJECTION safely

and effectively. See full prescribing information for FOSAPREPITANT FOR INJECTION.

FOSAPREPITANT for injection, for intravenous use

Initial U.S. Approval: 2008

INDICATIONS AND USAGE

Fosaprepitant for injection is a substance P/neurokinin-1 (NK ) receptor antagonist, indicated in adults, in combination with

other antiemetic agents, for the prevention of (1):

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 (1)

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

DOSAGE AND ADMINISTRATION

Recommended Dosage (2.1)

Administer fosaprepitant for injection as an intravenous infusion; complete the infusion approximately 30 minutes prior

to chemotherapy.

Adults: 150 mg on Day 1.

Administer Fosaprepitant for injection on Day 1 as an intravenous infusion over 20 to 30 minutes (adults).

See Full Prescribing Information for dosages of concomitant antiemetic(s). (2.1)

DOSAGE FORMS AND STRENGTHS

Fosaprepitant for injection: 150 mg fosaprepitant, lyophilized cake or powder in single-dose vial for reconstitution. (3)

CONTRAINDICATIONS

Known hypersensitivity to any component of this drug. (4, 5.2)

Concurrent use with pimozide.(4)

WARNINGS AND PRECAUTIONS

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, 5.1, 7.1, 7.2)

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. (4,5.2)

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)

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, 7.1)

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, 7.1, 8.3)

ADVERSE REACTIONS

Most common adverse reactions in adults (≥2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral

neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact MSN Pharmaceuticals Inc. at 1-848-200-1906 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

See Full Prescribing Information for a list of clinically significant drug interactions. (4, 5.1,5.4, 7.1, 7.2)

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend

(fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing

exclusivity rights, this drug product is not labeled with that pediatric information.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

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

2.3 Preparation of Fosaprepitant for Injection

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Clinically Significant CYP3A4 Drug Interactions

5.2 Hypersensitivity Reactions

5.3 Infusion Site Reactions

5.4 Decrease in INR with Concomitant Warfarin

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

Sections or subsections omitted from the full prescribing information are not listed.

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.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2 DOSAGE AND ADMINISTRATION

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-HT antagonist

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 1Recommended 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

Dexamethasone

12 mg orally

8 mg orally

8 mg orally twice

daily

8 mg orally

twice daily

5-HT antagonist

See selected 5-

HT antagonist prescribing

information for the

recommended dosage

none

none

none

Administer 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)].

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

Dexamethasone

12 mg orally

5-HT antagonist

See selected 5-HT antagonist prescribing information for the

recommended dosage

Administer 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 [ see

Clinical Pharmacology (12.3)].

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Preparation of Fosaprepitant for Injection

Table 5

Preparation Instructions for Fosaprepitant for Injection (150 mg)

Step 1

Aseptically inject 5 mL 0.9% Sodium Chloride Injection, USP into the vial. Assure that 0.9%

Sodium Chloride Injection, USP is added to the vial along the vial wall in order to prevent

foaming. Swirl the vial gently. Avoid shaking and jetting 0.9% Sodium Chloride Injection, USP

into the vial.

Step 2

Aseptically prepare an infusion bag filled with 145 mL of 0.9% Sodium Chloride Injection,

Step 3

Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag

containing 145 mL of 0.9% Sodium Chloride Injection, USP to yield a total volume of 150

mLand a final concentration of 1 mg/mL.

Step 4

Gently invert the bag 2 to 3 times.

Step 5

Adults

The entire volume of the prepared infusion bag (150 mL) should be administered.

Step 6

Before administration, inspect the bag for particulate matter and discoloration. Discard the bag

if particulate and/or discoloration are observed.

Caution: Do not mix or reconstitute fosaprepitant for injection with solutions for which physical and

chemical compatibility have not been established. Fosaprepitant for injection is incompatible with any

solutions containing divalent cations (e.g., Ca

, Mg

), including Lactated Ringer’s Solution and

Hartmann's Solution.

Storage

The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below

25°C (77°F)].

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

3 DOSAGE FORMS AND STRENGTHS

Fosaprepitant for injection:150 mg fosaprepitant, White to off white lyophilized cake or powder in

single-dose glass vial for reconstitution.

4 CONTRAINDICATIONS

Fosaprepitant 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) ].

5 WARNINGS AND PRECAUTIONS

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 with other drugs that are CYP3A4 substrates, may result in increased

plasma concentration of the concomitant drug.

Use of pimozide with fosaprepitant is contraindicated due to the risk of significantly

increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT

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 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 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) ].

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 in patients who experience

these symptoms with previous use [ see contraindications (4)].

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.

5.4 Decrease in INR with Concomitant Warfarin

Coadministration of fosaprepitant 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 with each chemotherapy

cycle [see Drug Interactions (7.1)].

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives

Upon coadministration with fosaprepitant, the efficacy of hormonal contraceptives may be reduced

during administration of and for 28 days following the last dose of fosaprepitant

[see Clinical Pharmacology (12.3) ]. Advise patients to use effective alternative or back-up methods of

contraception during treatment with fosaprepitant and for 1 month following administration of

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

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

Infusion Site Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in clinical practice.

The overall safety of fosaprepitant for injection was evaluated in approximately 1600 adult patients.

Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with MEC

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients

receiving a single dose of fosaprepitant for injection in combination with ondansetron and

dexamethasone (fosaprepitant dimeglumine regimen) compared to 497 patients receiving ondansetron

and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 6.

Table 6 Most Common Adverse Reactions in Patients Receiving MEC*

Fosaprepitant for injection,

ondansetron, and

dexamethasone

(N=504)

Ondansetron and

dexamethasone

(N=497)

fatigue

diarrhea

neutropenia

asthenia

anemia

peripheral neuropathy

leukopenia

dyspepsia

urinary tract infection

pain in extremity

Reported in ≥2% of patients treated with the fosaprepitant dimeglumine regimen and at a greater

incidence than standard therapy.

fosaprepitant dimeglumine regimen

Standard therapy

Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant dimeglumine

regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions

included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site

pain (0.2%, 0.0%), and infusion-site thrombophlebitis (0.6%, 0.0%), reported in the fosaprepitant

dimeglumine regimen compared to standard therapy, respectively.

Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with HEC

In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients

receiving a single dose of fosaprepitant for injection compared to 1169 patients receiving the 3-day

regimen of oral aprepitant [ see Clinical Studies (14.1)]. The safety profile was generally similar to that

seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant. However, infusion- site

reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those

in the aprepitant group (0.5%). The following additional infusion-site reactions occurred in HEC study

and were not reported in the MEC study described above: infusion-site erythema (0.5%, 0.1%),

infusion-site pruritus (0.3%, 0.0%), and infusion-site induration (0.2%, 0.1%), reported in the

fosaprepitant group compared to the aprepitant group, respectively.

Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant

might also be expected to occur with fosaprepitant for injection. See the full prescribing information

for aprepitant capsules for complete safety information regarding studies performed with oral

aprepitant.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of fosaprepitant.

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

coadministration.

7 DRUG INTERACTIONS

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.

Table 7

Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

CYP3A4 Substrates

Pimozide

Clinical Impact

Increased pimozide exposure

Intervention

Fosaprepitant is contraindicated [see Contraindications (4)].

Benzodiazepines

Clinical Impact

Increased

exposure

midazolam

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

Monitor for chemotherapeutic-related adverse reactions.

Etoposide, vinorelbine, paclitaxel, and docetaxel

No dosage adjustment needed.

Hormonal Contraceptives

Clinical Impact

Decreased hormonal exposure during administration of and for 28

days after administration of the last dose of fosaprepitant [see

Warnings and Precautions (5.5), Use in Specific Populations (8.3), and

Clinical Pharmacology (12.3)].

Intervention

Effective

alternative

back-up

methods

contraception

(such

condoms

and spermicides)

should

used

during

treatment

with

fosaprepitant and for 1 month following administration of fosaprepitant.

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 with each chemotherapy cycle.

Other

5-HT Antagonists

Clinical Impact

change

exposure

5-HT

antagonist [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 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 [see Adverse Reactions

(6.1)and Clinical Pharmacology (12.3)].

Intervention

Avoid concomitant use of fosaprepitant

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

strong

CYP3A4

inducer

decrease

efficacy

fosaprepitant [see Clinical Pharmacology (12.3) ].

Intervention

Avoid concomitant use of fosaprepitant.

Examples

rifampin, carbamazepine, phenytoin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are insufficient data on use of fosaprepitant 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].

3

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.

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.

8.2 Lactation

Risk Summary

Lactation studies have not been conducted to assess the presence of aprepitant in human milk, the

effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat

milk. The developmental and health benefits of breastfeeding should be considered along with the

mother’s clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from

fosaprepitant or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Upon administration of fosaprepitant, 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 and for 1 month following the last dose [see Drug Interactions (7.1),

Clinical Pharmacology (12.3) ].

8.4 Pediatric Use

The safety and effectiveness of fosaprepitant dimeglumine for the prevention of nausea and vomiting

associated with HEC or MEC have not been established in patients less than 6 months of age.

Juvenile Animal Toxicity Data

In juvenile dogs treated with fosaprepitant, changes in reproductive organs were observed. In juvenile

rats treated with aprepitant, slight changes in sexual maturation were observed without an effect on

reproduction. No effects on neurobehavior, sensory and motor function, or learning and memory were

observed in rats.

In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 (equivalent to a

newborn human) to day 42 (approximately equivalent to a 2 year old human), decreased testicular weight

and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of

the uterus and cervix, and edema of vaginal tissues were seen in females from 4 mg/kg/day. A study was

also conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and

sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg

twice daily from the early postnatal period (Postnatal Day 10 (equivalent to a newborn human) through

Postnatal Day 58 (approximately equivalent to a 15 year old human)). Slight changes in the onset of

sexual maturation were observed in female and male rats; however, there were no effects on mating,

fertility, embryonic-fetal survival, or histomorphology of the reproductive organs. There were no

effects in neurobehavioral tests of sensory function, motor function, and learning and memory.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical

studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical

experience with fosaprepitant has not identified differences in responses between elderly and younger

patients. In general, use caution when dosing elderly patients as they have a greater frequency of

decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [ see Clinical

Pharmacology (12.3)].

8.6 Patients with Hepatic Impairment

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were

similar to those of healthy subjects with normal hepatic function. No dosage adjustment is

necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9).

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-

Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients

may be warranted when fosaprepitant is administered [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.

In the event of overdose, fosaprepitant should be discontinued and general supportive treatment and

monitoring should be provided. Because of the antiemetic activity of fosaprepitant, drug-induced

emesis may not be effective in cases of fosaprepitant overdosage.

Aprepitant is not removed by hemodialysis.

11 DESCRIPTION

Fosaprepitant for injection is a sterile, lyophilized formulation containing fosaprepitant dimeglumine,a

prodrug of aprepitant a substance P/neurokinin-1 (NK1) receptor antagonist, an antiemetic

agent, chemically described as 1 Deoxy-1-(methylamino)-D-glucito[3-[[(2R,3S)-2-[(1R)-1-[3,5-

bis(trifluoromethyl)phenyl]ethoxy]-3-(4- fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-

1,2,4-triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is C

H F N O P 2(C H NO ) and its structural formula is:

Fosaprepitant dimeglumine is a white to off- white powder with a molecular weight of

1004.83.It is freely soluble in water, soluble in N,N-Dimethylsulfoxide and insoluble in n-hexane.

Each vial of fosaprepitant for injection for administration as an intravenous infusion contains 245.3 mg

of fosaprepitant dimeglumine equivalent to 150 mg of fosaprepitant free acid and the

following inactive ingredients: edetate disodium (18.8 mg), lactose anhydrous (375 mg),

polysorbate 80 (75 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to

aprepitant.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK )

receptors. Aprepitant has little or no affinity for serotonin (5-HT ), dopamine, and corticosteroid

receptors, the targets of existing therapies for chemotherapy- induced nausea and

vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by

cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human

Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the

blood brain barrier and occupies brain NK receptors. Animal and human studies show that

aprepitant augments the antiemetic activity of the 5-HT -receptor antagonist ondansetron and the

corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced

emesis.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose

of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc

interval.

12.3 Pharmacokinetics

Aprepitant after Fosaprepitant Administration

Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant

administered as a 20-minute infusion to healthy subjects, the mean AUC

of aprepitant was 37.4

(±14.8)mcghr/mL and the mean maximal aprepitant concentration (C

) was 4.2 (±1.2) mcg/mL. Plasma

concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of

the completion of infusion.

Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at

steady state (Vd

) was approximately 70 L in humans.

Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1)].

Elimination

Metabolism

Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and in S9

preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that

the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the

liver.

Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that

aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19.

Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by

CYP2D6, CYP2C9, or CYP2E1 was detected.

In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over

72 hours following a single oral 300-mg dose of [

C]-aprepitant, indicating a substantial presence of

metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been

identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [

C]-fosaprepitant to healthy

subjects, 57% of the radioactivity was recovered in urine and 45% in feces.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent

terminal half-life ranged from approximately 9 to 13 hours.

Specific Populations

Age: Geriatric Population

Following oral administration of a single 125-mg dose of aprepitant 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 (65 years and older) relative to younger adults. The C

was 10% higher on Day 1 and 24%

higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically

meaningful [see Use in Specific Populations (8.5)].

Sex

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC

and C

are 9% and 17% higher in females as compared with males. The half-life of aprepitant is

approximately 25% lower in females as compared with males and T

occurs at approximately the

same time. These differences are not considered clinically meaningful.

0-∞

0-24hr

24hr

Race/Ethnicity

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC

and C

are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The

and C

were 74% and 47% higher in Asians as compared to Caucasians. There was no

difference in AUC

or C

between Caucasians and Blacks. These differences are not considered

clinically meaningful.

Renal Impairment

A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment

(creatinine clearance less than 30 mL/min/1.73 m as measured by 24-hour urinary creatinine clearance)

and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC

of total aprepitant (unbound and protein bound)

decreased by 21% and C

decreased by 32%, relative to healthy subjects (creatinine clearance

greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing

hemodialysis, the AUC

of total aprepitant decreased by 42% and C

decreased by 32%. Due to

modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of

pharmacologically active unbound drug was not significantly affected in patients with renal impairment

compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant

effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

Hepatic Impairment

Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not

expected to alter the conversion of fosaprepitant to aprepitant.

Following administration of a single 125-mg oral dose of aprepitant 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

aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given

the same regimen. 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, as compared with healthy

subjects given the same regimen. These differences in AUC

are not considered clinically

meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment

(Child-Pugh score greater than 9) [see Use in Specific Populations (8.6)]

Body Mass Index (BMI)

For every 5 kg/m increase in BMI, AUC

and C

of aprepitant decrease by 9% and 10%. BMI of

subjects in the analysis ranged from 18 kg/m to 36 kg/m . This change is not considered clinically

meaningful.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Drug Interactions Studies

Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, with no evidence of

inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for 2

days after single dose administration of fosaprepitant. Aprepitant is a substrate, an inhibitor, and an

inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein

transporter.

Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

CYP3A4 Substrates

Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the

of midazolam by approximately 1.8-fold on Day 1 and had no effect on Day 4 when midazolam

was coadministered as a single oral dose of 2 mg on Days 1 and 4 [see Drug interactions (7.1)].

Corticosteroids:

Dexamethasone: Fosaprepitant administered as a single 150 mg intravenous dose on Day 1 increased the

of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by

approximately 2-fold on Days 1 and 2 [see Dosage and Administration (2.1), Drug Interactions (7.1)].

Methylprednisolone: When oral aprepitant as a 3-day regimen (125-mg/80-mg/80-mg) was administered

with intravenous methylprednisolone 125 mg on Day 1 and oral methylprednisolone 40 mg on Days 2

and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day 1 and by 2.5-fold on Day 3

[see Drug Interactions (7.1)].

Chemotherapeutic agents:

Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125 mg/80-

24hr

0-24hr

0-24hr

0-∞

0-∞

0-24hr

24hr

0-24hr

0-24hr

0-∞

0-24hr

mg/80-mg) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125 mg/80-

mg/80-mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Oral contraceptives: When oral aprepitant was administered as a 3-day regimen (125-mg/80-mg/80 mg)

with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl

estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were

reduced by as much as 64% for 3 weeks post-treatment [see Drug Interactions (7.1)].

CYP2C9 substrates (Warfarin, Tolbutamide):

Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2

and 3 to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of

oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34%

decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time

(reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral

aprepitant [see Drug Interactions (7.1)].

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased

the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of

tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant

and on Days 4, 8, and 15. This effect was not considered clinically important.

Other Drugs

P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the P-

glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a

clinical drug interaction study.

5-HT antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects

on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of

dolasetron).

Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen

of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately

11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)].

Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day

regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased

approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see

Drug Interactions (7.2)].

Diltiazem: In a study in 10 patients with mild to moderate hypertension, administration of 100 mg of

fosaprepitant as an intravenous infusion with 120 mg of diltiazem, a moderate CYP3A4 inhibitor

administered three times daily, resulted in a 1.5-fold increase in the aprepitant AUC and a 1.4-fold

increase in the diltiazem AUC.

When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood

pressure was significantly greater than that observed with diltiazem alone [24.3 ± 10.2 mm Hg with

fosaprepitant versus 15.6 ± 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic

blood pressure was also greater after co-administration of diltiazem with fosaprepitant than

administration of diltiazem alone [29.5 ± 7.9 mm Hg with fosaprepitant versus 23.8 ± 4.8 mm Hg without

fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional

clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem

alone [see Drug Interactions (7.2)].

Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once

daily, resulted in a decrease in AUC by approximately 25% and C

by approximately 20% of both

aprepitant and paroxetine. This effect was not considered clinically important.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years.

In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to

1,000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant

3

approximately equivalent to (female rats) or less than (male rats) the adult human exposure at

the RHD of 150 mg. Treatment with aprepitant at doses of 5 to 1,000 mg/kg twice daily

caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male

rats. In female rats, it produced hepatocellular adenomas at 5 to 1,000 mg/kg twice daily and

hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000mg/kg twice daily.

In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5

to 2,000 mg/kg/day. The highest dose produced a systemic exposure approximately 2 times the

adult human exposure at the RHD of 150 mg. Treatment with aprepitant produced skin fibrosarcomas

at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with

fosaprepitant.

Mutagenesis

Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid

cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary

(CHO) cell chromosome aberration test and the mouse micronucleus test.

Impairment of Fertility

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility

studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant

were obtained following oral administration of aprepitant. Oral aprepitant did not affect the

fertility or general reproductive performance of male or female rats at doses up to the maximum

feasible dose of 1,000 mg/kg twice daily (providing exposure in male rats lower than the

exposure at the recommended adult human dose of 150 mg and exposure in female rats

approximately equivalent to the adult human exposure).

14 CLINICAL STUDIES

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

In a randomized, parallel, double-blind, active-controlled study, fosaprepitant for injection 150 mg

as a single intravenous infusion (N=1147) was compared to a 3-day oral aprepitant regimen

(N=1175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m ).All patients

in both groups received dexamethasone and ondansetron (see Table 11). Patient demographics

were similar between the two treatment groups. Of the total 2322 patients, 63% were men, 56%

White, 26% Asian, 3% American Indian/Alaska Native, 2% Black, 13% Multi-Racial, and 33%

Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of

56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil

(17%), gemcitabine (16%), paclitaxel (15%), and etoposide

(12%).

Table 11 Treatment Regimens in Adult HEC Trial*

Day 1

Day 2

Day 3

Day 4

Fosaprepitant Regimen

Fosaprepitant

for injection

150 mg

intravenously

over 20 to

30 minutes

approximately

minutes prior

chemotherapy

none

none

none

Oral

dexamethasone

12 mg

8 mg

8 mg twice

daily

8 mg twice daily

Ondansetron

Ondansetron

none

none

none

Oral aprepitant Regimen

Aprepitant capsules

125 mg

80 mg

80 mg

none

Oral dexamethasone

12 mg

8 mg

8 mg

8 mg

Ondansetron

Ondansetron

none

none

none

fosaprepitant for injection placebo, aprepitant capsules placebo and dexamethasone placebo (in the

evenings on Days 3 and 4) were used to maintain blinding.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the

morning on Days 2 through 4. Dexamethasone was also administered in the evenings on Days 3 and 4.

The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Day 2 reflects a dosage

adjustment to account for a drug interaction with the fosaprepitant for injection regimen [see Clinical

Pharmacology (12.3)].

Ondansetron 32 mg intravenous was used in the clinical trials of fosaprepitant. Although this dose was

used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron

prescribing information for the current recommended dose.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the

morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose

on Days 2 through 4 reflects a dosage adjustment to account for a drug interaction with the oral

aprepitant regimen [see Clinical Pharmacology (12.3)].

The efficacy of fosaprepitant for injection was evaluated based on the primary and secondary end

points listed in Table 12 and was shown to be non-inferior to that of the 3-day oral aprepitant regimen

with regard to complete response in each of the evaluated phases.The pre-specified non-inferiority

margin for complete response in the overall phase was 7%.The pre-specified non-inferiority margin

for complete response in the delayed phase was 7.3%. The pre -specified non - inferiority

margin for no vomiting in the overall phase was 8.2%.

Table 12 Percent of Adult Patients Receiving HEC Responding by

Treatment Group and Phase — Cycle 1

ENDPOINTS

Fosaprepitant

for Injection

Regimen

(N = 1106)

%

Oral Aprepitant

Regimen

(N = 1134)

%

Difference

(95% CI)

PRIMARY ENDPOINT

*

*

Complete Response

Overall

71.9

72.3

-0.4 (-4.1, 3.3)

SECONDARY ENDPOINTS

Complete Response

Delayed phase

74.3

74.2

0.1 (-3.5, 3.7)

No Vomiting

Overall

72.9

74.6

-1.7 (-5.3, 2.0)

N: Number of patients included in the primary analysis of complete response.

Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and

Nurminen and adjusted for Gender.

Complete Response = no vomiting and no use of rescue therapy.

Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.

Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.

14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults

In a randomized, parallel, double-blind, active comparator-controlled study, fosaprepitant for injection

150 mg as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone

(fosaprepitant dimeglumine regimen) was compared with ondansetron and dexamethasone alone (standard

therapy) (N=498) (see Table 13) in patients receiving a MEC regimen. Patient demographics were

similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis,

41% were men, 84% White, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-

Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean

age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin

(51%), oxaliplatin (24%), and cyclophosphamide (12%).

Table 13

Treatment Regimens in Adult MEC Trial*

Day 1

Day 2

Day 3

Fosaprepitant Regimen

Fosaprepitant for Injection

150 mg intravenously over 20

to 30 minutes approximately

30 minutes prior to

chemotherapy

none

none

Oral Dexamethasone

12 mg

none

none

Oral Ondansetron

8 mg for 2 doses

none

none

Standard Therapy

Oral Dexamethasone

20 mg

none

none

Oral Ondansetron

8 mg for 2 doses

8 mg twice daily

8 mg twice daily

Fosaprepitant for injection placebo and dexamethasone placebo (on Day 1) were used to maintain

blinding.

Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg

dose reflects a dosage adjustment to account for a drug interaction with the Fosaprepitant for injection

regimen [ see Clinical Pharmacology (12.3)].

The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day

1 and the second dose was administered 8 hours after first ondansetron dose.

The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the

delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment

group are shown in Table 14.

Table 14 Percent of Adult Patients Receiving MEC Responding by Treatment Group

ENDPOINTS

Fosaprepitant for

Injection Regimen

(N = 502)*

%

Standard Therapy

Regimen

(N = 498)*

%

P-Value

Treatment

Difference

(95% CI)

PRIMARY

ENDPOINT

Complete Response

Delayed phase

78.9

68.5

<0.001

10.4 (5.1, 15.9)

N: Number of patients included in the intention to treat population.

Complete Response = no vomiting and no use of rescue therapy.

Delayed phase = 25 to 120 hours post-initiation of chemotherapy.

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 034 — Single-dose glass vial containing 150 mg of fosaprepitant as a white to off white

lyophilized cake or powder for reconstitution. Supplied as follows:

NDC 69539-034-01 1 vial per carton.

Storage

Fosaprepitant for injection vials must be refrigerated, store at 2°C to 8°C (36°F to 46°F).

The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below

25°C (77°F)].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity

Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been

reported in patients taking fosaprepitant. Advise patients to seek immediate medical attention if they

experience signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin

peeling or sores, flushing, difficulty in breathing or swallowing, or dizziness, rapid or weak heartbeat

or feeling faint [see warnings and precautions (5.2)].

Infusion Site Reactions

Advise patients to seek medical attention if they experience new or worsening signs or symptoms of an

infusion site reaction, such as erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near

the infusion site [see Warnings and Precautions (5.3)].

Drug Interactions

Advise patients to discuss all medications they are taking, including other prescription, non prescription

medication or herbal products [see Contraindications (4) , Warnings and Precautions (5.1)].

Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare

provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10

days, following initiation of fosaprepitant with each chemotherapy cycle [see Warnings and Precautions

(5.4) ].

Hormonal Contraceptives: Advise patients that administration of fosaprepitant may reduce the efficacy of

hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of

contraception (such as condoms and spermicides) during treatment with fosaprepitant and for 1 month

following administration of fosaprepitant [see Warnings and Precautions (5.5) , Use in Specific

Populations (8.3)].

Manufactured by:

MSN Laboratories Private Limited

Telangana – 509 216,

INDIA

Distributed by:

MSN Pharmaceuticals Inc.

Edison, NJ 08837

Issued on:

November 2019

PATIENT INFORMATION

Fosaprepitant

(FOS a PREP i tant )

for Injection

Read this patient information before you start receiving fosaprepitant for injection and each

time you are scheduled to receive fosaprepitant for injection. There may be new information.

This information does not take the place of talking with your healthcare provider about your medical

condition or treatment.

What is fosaprepitant for injection?

Fosaprepitant for injection is a prescription medicine used with other medicines that treat nausea and

vomiting in patients 18 years of age and older to prevent nausea and vomiting caused by certain anti-cancer

(chemotherapy) medicines.

Fosaprepitant for injection is not used to treat nausea and vomiting that you already have.

It is not known if fosaprepitant for injection is safe and effective in children less than 6 months of age.

Who should not recieve fosaprepitant for injection?

Do not receive fosaprepitant for injection if you:

are allergic to fosaprepitant, aprepitant, or any of the ingredients in fosaprepitant for injection. See the

end of this leaflet for a complete list of the ingredients in fosaprepitant for injection.

are taking pimozide (ORAP®)

What should I tell my healthcare provider before receiving fosaprepitant for injection?

Before receiving fosaprepitant for injection, tell your healthcare provider if you:

have liver problem

are pregnant or plan to become pregnant. It is not known if fosaprepitant for injection can

harm your unborn baby.

Women who use birth control medicines containing hormones to prevent pregnancy (birth control

pills, skin patches, implants, and certain IUDs) should also use a backup method of birth control that

does not contain hormones, such as condoms and spermicides, during treatment with fosaprepitant

for injection and for 1 month after receiving fosaprepitant for injection.

are breastfeeding or plan to breastfeed. It is not known if fosaprepitant for injection passes into your

breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive

fosaprepitant for injection.

Tell your healthcare provider about all the medicines you take, including prescription and

over-the-counter medicines, vitamins, and herbal supplements.

Fosaprepitant for injection may affect the way other medicines work, and other medicines may affect the

way fosaprepitant for Injection works, causing serious side effects.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when

you get a new medicine.

How will I receive fosaprepitant for injection?

Adults 18 years of age and older:

Fosaprepitant for injection will be given on Day 1 of chemotherapy treatment. It will be given to you by

intravenous (IV) infusion in your vein about 50 to 60 minutes before you start your chemotherapy

treatment.

If you take the blood thinner medicine warfarin sodium (COUMADIN®, JANTOVEN®), your healthcare

provider may do blood tests after you receive fosaprepitant for injection to check your blood clotting.

What are the possible side effects of fosaprepitant for i njection?

Fosaprepitant for i njection may cause serious side effects, including:

serious allergic reactions. Allergic reactions can happen with fosaprepitant for injection and may be

serious. Tell your doctor or nurse right away if you have hives, rash, itching, flushing or redness of

your face or skin, trouble breathing or swallowing, dizziness,a rapid or weak heartbeat, or you feel

faint during or soon after you receive fosaprepitant for injection, as you may need emergency medical

care.

Severe skin reactions, which may include rash, skin peeling, or sores, may occurs,

Infusion site reactions (ISR) at or near the infusion site have happened with fosaprepitant for injection.

Most severe ISR have happened with a certain type of chemotherapy medicine that can burn or blister

your skin (vesicant) with side effects, including pain, swelling and redness. Death of skin tissue

(necrosis) has happened in some people getting this type of chemotherapy medicine. Most ISR can

happen with the first, second, or third dose and some can last up to 2 weeks or longer. Tell your

healthcare provider right away if you get any infusion site side effects.

In adults, the most common side effects of fosaprepitant for injection include:

tiredness

feeling weak or numb in your arms and legs

diarrhea

painful, difficult, or changes in your digestion (dyspepsia)

low white blood cell and red blood cell counts

urinary tract infection

weakness

pain in your arms and legs

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These

are not all of the possible side effects of fosaprepitant for injection. For more information ask your

healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

General information about the safe and effective use of fosaprepitant for injection.

If you would like more information about fosaprepitant for injection, talk with your healthcare

provider.You can ask your healthcare provider or pharmacist for information about fosaprepitant for

injection that is written for health professionals. For more information about fosaprepitant for injection

call 1-848-200-1906 or go to www.msnlabs.com

What are the ingredients in fosaprepitant for i njection?

Active ingredient : fosaprepitant dimeglumine

Inactive ingredients : edetate disodium, lactose anhydrous, polysorbate 80,sodium hydroxide and/

or hydrochloric acid (for pH adjustment).

The brands listed are trademarks or registered trademarks of their respective owners and are not affiliated

with and do not endorse MSN Pharmaceuticals Inc.

Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s

Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

MSN Laboratories Private Limited

Telangana – 509 216

INDIA

Distributed by:

MSN Pharmaceuticals Inc.

Edison, NJ 08837

Issued on:

November 2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Fos aprepitant-carton-label

Fos aprepitant-vial-label

FOSAPREPITANT

fosaprepitant injection, powder, lyophilized, for solution

MSN LABORATORIES PRIVATE LIMITED

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 9 539 -0 34

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

FO SAPREPITANT DIMEGLUMINE (UNII: D35FM8 T6 4X) (APREPITANT - UNII:1NF15YR6 UY)

FOSAPREPITANT

150 mg in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

HYDRO CHLO RIC ACID (UNII: QTT1758 2CB)

WATER (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:6 9 539 -0 34-

1 in 1 CARTON

0 9 /0 5/20 19

1

5 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 9 9 6 5

0 9 /0 5/20 19

Labeler -

MSN LABORAT ORIES PRIVAT E LIMIT ED (650786952)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

MSN LABORATORIES PRIVATE LIMITED

6 50 78 6 9 52

ANALYSIS(6 9 539 -0 34) , MANUFACTURE(6 9 539 -0 34)

Revised: 12/2019

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