NDC 70625-311 Fosaprepitant

Fosaprepitant

NDC Product Code 70625-311

NDC CODE: 70625-311

Proprietary Name: Fosaprepitant What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Fosaprepitant What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF-WHITE)

NDC Code Structure

  • 70625 - Praxgen Pharmaceuticals Llc

NDC 70625-311-01

Package Description: 1 VIAL in 1 CARTON > 5 mL in 1 VIAL

NDC Product Information

Fosaprepitant with NDC 70625-311 is a a human prescription drug product labeled by Praxgen Pharmaceuticals Llc. The generic name of Fosaprepitant is fosaprepitant. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Fosaprepitant Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • EDETATE DISODIUM (UNII: 7FLD91C86K)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Neurokinin 1 Antagonists - [MoA] (Mechanism of Action)
  • Substance P/Neurokinin-1 Receptor Antagonist - [EPC] (Established Pharmacologic Class)
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2C9 Inducers - [MoA] (Mechanism of Action)
  • Cytochrome P450 3A4 Inducers - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Praxgen Pharmaceuticals Llc
Labeler Code: 70625
FDA Application Number: ANDA213199 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-03-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Fosaprepitant Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

  • Fosaprepitant for injection, in combination with other antiemetic agents, is indicated in adults and pediatric patients 6 months of age and older 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 UseFosaprepitant has not been studied for the treatment of established nausea and vomiting.

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


3 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 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 Dexamethasone


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 [see Clinical Pharmacology (12.3)]. 12 mg orally 8 mg orally 8 mg orally twice daily 8 mg orally twice daily 5-HT


3 antagonist


 See selected 5-HT


3 antagonist prescribing information for the recommended dosage


 none none noneTable 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MECDay 1 Fosaprepitant for injection 150 mg intravenously over 20 to 30 minutes approximately 30 minutes Dexamethasone


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)]. 12 mg orally 5-HT


3 antagonist


 See selected 5-HT


3 antagonist prescribing information for the recommended dosage

2.2 Prevention Of Nausea And Vomiting Associated With Hec And Mec In Pediatric Patients

  • The recommended pediatric dose regimens of fosaprepitant, to be administered with a 5-HT
  • 3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of single or multi-day chemotherapy regimens of HEC or MEC, are shown in Tables 3 and 4. Single-day chemotherapy regimens include those regimens in which HEC or MEC is administered for a single day only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for 2 or more days.
  • Fosaprepitant Dosage Regimens for Use with Single-Day Chemotherapy RegimensFor pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, fosaprepitant may be administered as:a single dose regimen of fosaprepitant for injection infused through a central venous catheter on Day 1, as shown in Table 3; oras a 3-day fosaprepitant regimen consisting of fosaprepitant for injection as an intravenous infusion through a central venous catheter on Day 1 and fosaprepitant capsules or fosaprepitant for oral suspension on Days 2 and 3, as shown in Table 4.Administer fosaprepitant for injection on Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.Table 3 Single Dose Regimen of fosaprepitant for injection for Pediatric Patients 6 Months
  • Dosing in pediatric patients less than 6 kg is not recommended to 17 Years for the Prevention of Nausea and Vomiting Associated with Single-Day Regimens of HEC or MEC
  • Drug    Age RegimenFosaprepitant for injection    12 Years to 17 Years 150 mg intravenously over 30 minutes 2 Years to less than 12 Years 4 mg/kg (maximum dose 150 mg)
  • Intravenously over 60 minutes
  • 6 Months to less than 2 Years 5 mg/kg (maximum dose 150 mg)
  • Intravenously over 60 minutes
  • Dexamethasone
  • Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 6 Months to 17 Years If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 and 2. 5-HT3 antagonist 6 Months to 17 Years See selected 5-HT3 antagonist prescribing information for the recommended dosageFosaprepitant Dosage Regimen for Use with Multi-Day Chemotherapy RegimensFor pediatric patients weighing at least 6 kg receiving multi-day regimens of HEC or MEC, administer fosaprepitant on Days 1, 2, and 3. Administer fosaprepitant for injection as an intravenous infusion through a central venous catheter on Day 1 and fosaprepitant capsules or fosaprepitant for oral suspension on Days 2 and 3, as shown in Table 4.Administer fosaprepitant for injection on Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.Table 4 Pediatric Patients 6 Months
  • Dosing in pediatric patients less than 6 kg is not recommended to 17 Years Recommended 3-Day fosaprepitant Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC
  • Age Group Drug Day 1 Day 2 Day 312 Years to 17 Years Fosaprepitant for injection 115 mg intravenously over 30 minutes -- -- Fosaprepitant capsules
  • For patients 12 years to 17 years who cannot swallow oral capsules, fosaprepitant for oral suspension can be used instead. -- 80 mg orally 80 mg orally6 Months to
  • Less than 12 Years
  • Fosaprepitant for injection3 mg/kg (maximum dose 115 mg)
  • Intravenously over 60 minutes
  • -- --Fosaprepitant for oral suspension --2 mg/kg orally
  • (maximum 80 mg)
  • 2 mg/kg orally
  • (maximum 80 mg)
  • 6 Months to 17 Years Dexamethasone
  • Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4   6 Months to 17 Years 5-HT3 antagonistSee selected 5-HT3 antagonist prescribing information for the recommended dosage

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, USP. 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 mL and a final concentration of 1 mg/mL. Step 4 Gently invert the bag 2 to 3 times. Step 5Determine the volume to be administered from this prepared infusion bag, based on the recommended dose [see Dosage and Administration (2.1, 2.2)].
  • AdultsThe entire volume of the prepared infusion bag (150 mL) should be administered.
  • PediatricsIn patients 12 years and older, the volume to be administered is calculated as follows:
  • Volume to administer (mL) equals the recommended dose (mg)In patients 6 months to less than 12 years, the volume to be administered is calculated as follows:Volume to administer (mL) = recommended dose (mg/kg) x weight (kg)      o
  • Note: Do not exceed the maximum dose[see Dosage and Administration (2.2)]In pediatric patients, the entire volume in the infusion bag may not be required. Step 6 If necessary, for volumes less than 150 mL, the calculated volume can be transferred to an appropriate size bag or syringe prior to administration by infusion. Step 7 Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed.The recommended dose of fosaprepitant for injection is based on the patient’s age and weight.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
  • 2+, Mg
  • 2+), including Lactated Ringers Solution and Hartmann's Solution.
  • StorageThe reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)].

3 Dosage Forms And Strengths

Fosaprepitant for injection: 150 mg fosaprepitant, white to off-white lyophilized 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)].

5.1 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.o 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 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 1800 adult and pediatric patients.

Other

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


Reported in 2% of patients treated with the fosaprepitant regimen and at a greater incidence than standard therapy.Fosaprepitant for injection, ondansetron, and dexamethasone 


fosaprepitant regimen(N=504)Ondansetron and dexamethasone


Standard therapy(N=497)  fatigue 15% 13% diarrhea 13% 11% neutropenia 8% 7% asthenia 4% 3% anemia 3% 2% peripheral neuropathy3% 2% leukopenia 2% 1% dyspepsia 2% 1% urinary tract infection 2% 1% pain in extremity 2% 1%Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant 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 regimen compared to standard therapy, respectively.

Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with HECIn 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 fosaprepitant (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 the 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.

Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MECSingle-Dose fosaprepitant for Injection RegimenThe safety of a single dose fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and a single-arm clinical study in patients who received either HEC or MEC. Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults. The safety analysis included 69 pediatric patients who received the recommended dose. An additional 70 patients received a single, higher-than-recommended dose. The most common adverse reactions that occurred in >15% of patients who received the recommended dose were anemia, neutropenia, thrombocytopenia, and febrile neutropenia.3-Day IV/Oral/Oral fosaprepitant RegimenIn pediatric patients (12 to 17 years), the safety of the 3-day IV/oral/oral fosaprepitant regimen was evaluated in a single-arm clinical study including 12 patients who received a regimen of either HEC or MEC. In pediatric patients 6 months to 12 years of age, the safety of the 3-day IV/oral/oral fosaprepitant regimen was not directly evaluated. The safety of a single-dose of fosaprepitant for injection (3 mg/kg) administered on day 1 of the 3-day IV/oral/oral regimen was evaluated in one active-controlled and one single-arm study including 48 patients who received a regimen of either HEC or MEC. Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults and pediatric patients receiving a single dose of fosaprepitant for injection.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 fosaprepitant capsules for complete safety information regarding studies performed with oral aprepitant.

CarcinogenesisCarcinogenicity 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 1000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant 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 1000 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  1000 mg/kg twice daily and hepatocellular carcinomas  and thyroid follicular cell adenomas at 125 to  1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from  2.5 to 2000 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.

MutagenesisAprepitant 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 FertilityFosaprepitant, 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  1000 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).

Manufactured for:Peterson Pharmaceuticals


303C College Rd East


Princeton


NJ 085406608


Manufactured by:Cangene BioPharma, LLC


1111 South Paca Street,


Baltimore, Maryland (MD) 21230, USA

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.

7.1 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)].


BenzodiazepinesClinical 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.DexamethasoneClinical ImpactIncreased 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)].


 InterventionVinblastine, vincristine, or ifosfamide or other chemotherapeutic agentsMonitor for chemotherapeutic-related adverse reactions.


Etoposide, vinorelbine, paclitaxel, and docetaxelNo dosage adjustment needed.


Harmonal 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 or back-up methods of contraception (such as condoms and spermicides) should be 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 WarfarinClinical 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


3 Antagonists


 Clinical Impact No change in the exposure of the 5-HT


3 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),


Clinical Pharmacology (12.3)].


 Intervention Avoid concomitant use of fosaprepitant ExamplesModerate 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


[see


Clinical Pharmacology (12.3)].


 Intervention Avoid concomitant use of fosaprepitant Examples rifampin, carbamazepine, phenytoin

8.1 Pregnancy

Risk SummaryThere 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].


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.DataAnimal DataIn 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 SummaryLactation 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

ContraceptionUpon 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 a single dose regimen of fosaprepitant for injection and a 3-day IV/oral/oral fosaprepitant regimen have been established in pediatric patients 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC.Use of fosaprepitant in this age group is supported by evidence from adequate and well-controlled studies of fosaprepitant for injection in adults, with additional safety, efficacy and pharmacokinetic data in pediatric patients 6 months to 17 years. Efficacy was also supported by data from an adequate and well- controlled study of a 3-day oral aprepitant regimen in pediatric patients 6 months to 17 years. See the full prescribing information for fosaprepitant capsules for complete clinical information regarding studies performed with oral aprepitant. Adverse reactions were similar to those reported in adult patients.


[See


Dosage and Administration (2.2),


Adverse Reactions (6.1),


Clinical Pharmacology (12.3)].


The safety of fosaprepitant for injection administered on consecutive days has not been established in pediatric patients 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC.The safety and effectiveness of fosaprepitant 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 DataIn 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 (providing exposure in male and female rats lower than the exposure at the recommended pediatric human dose) 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.

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 (NK
1) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2
R,3
S)-2-[(1
R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1
H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).
Its empirical formula is C
23H
22F
7N
4O
6P ∙ 2(C
7H
17NO
5) and its structural formula is:
Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.Each vial of fosaprepitant for injection for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: edetate disodium (5.4 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).

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


1) receptors. Aprepitant has little or no affinity for serotonin (5-HT


3), 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


1 receptors. Animal and human studies have shown that aprepitant augments the antiemetic activity of the 5-HT


3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

12.2 Pharmacodynamics

Cardiac ElectrophysiologyIn 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 AdministrationFollowing 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


0- of aprepitant was 37.4 (± 14.8) mcg·hr/mL and the mean maximal aprepitant concentration (C


max) 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.


DistributionAprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd


ss) was approximately 70 L in humans.


Aprepitant crosses the blood brain barrier in humans


[see


Clinical Pharmacology (12.1)]


.


EliminationMetabolismFosaprepitant 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 [


14C]-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.


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


14C]-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 PopulationsAge: Geriatric PopulationFollowing 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


0-24hr 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


max 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)]


.


Age: Pediatric PopulationSingle-Dose fosaprepitant for Injection Regimen: Simulated systemic exposures of aprepitant in patients 2 years to less than 12 years and observed systemic exposures in patients 6 months to less than 2 years and 12 to 17 years are shown in Table 9, including AUC


0-24hr, peak plasma concentration (C


max) on Day 1 and concentrations at the end of Day 1 (C


24), Day 2 (C


48) and Day 3 (C


72).


Table 9 Systemic Exposures of Aprepitant for Single-Dose fosaprepitant for Injection Regimen in Pediatric Patients Population  Single-Dose of fosaprepitant


for Injection Regimen 


     Geometric Mean AUC


0-24hr.(mcg


ND = Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest hr/mL)


 C


max (mcg/mL)


C


24(mcg/mL) 


 C


48(mcg/mL)


 C


72(mcg/mL)


 12 Years to 17 Years 150 mg 29.4 3.4 0.7 ND* ND* 6 Years to less than 12 Years 4 mg/kg 35.2 3.6 0.7 0.2 0.05 2 Years to less than 6 Years 28.2 3.1 0.4 0.1 0.02 6 Months to less than 2 Years 5 mg/kg 32.7 3.3 0.4 NE


NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. ND*3-Day IV/Oral/Oral fosaprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to less than 12 years and observed systemic exposures in patients 12 to 17 years are shown in Table 10, including AUC


0-24hr, peak plasma concentration (C


max) on Day 1 and concentrations at the end of Day 1 (C


24), Day 2 (C


48) and Day 3 (C


72).


Table 10 Systemic Exposures of Aprepitant for 3-Day IV/Oral/Oral Regimen in Pediatric Patients Population  3-Day Dose of fosaprepitant (IV/Oral/Oral


IV on Day 1, Oral on Day 2, and Oral on Day 3) 


    Geometric Mean  AUC


0-24hr.(mcg* hr/mL)


 C


max (mcg/mL)


 C


24(mcg/mL)


 C


48(mcg/mL)


 C


72(mcg/mL)


 12 Years to 17 Years 115/80/80 mg 18.0 3.0 0.4 0.2 NE


NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. 6 Years to less than 12 Years   3/2/2 mg/kg 25.7 2.7 0.5 0.3 0.3 2 Years to less than 6 Years 20.2 2.3 0.3 0.2 0.2 6 Months to less than 2 Years 16.6 1.9 0.2 0.1 0.1Plasma concentrations of fosaprepitant are negligible within 15 30 minutes after the completion of the infusion in pediatric patients.SexFollowing oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC


0-24hr and C


max 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


max occurs at approximately the same time. These differences are not considered clinically meaningful. A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that sex has no clinically meaningful effect on the pharmacokinetics of aprepitant.


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


0-24hr and C


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


0-24hr and C


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


0-24hr or C


max between Caucasians and Blacks. These differences are not considered clinically meaningful. A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that race has no clinically meaningful effect on the pharmacokinetics of aprepitant.


Renal ImpairmentA 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


2 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


0-¥ of total aprepitant (unbound and protein bound) decreased by 21% and C


max 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


0-¥ of total aprepitant decreased by 42% and C


max 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 ImpairmentFosaprepitant 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


0-24hr of 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


0-24hr 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


0-24hr 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


2 increase in BMI, AUC


0-24hr and C


max of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m


2 to 36 kg/m


2. This change is not considered clinically meaningful.


Drug Interactions StudiesFosaprepitant, 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 DrugsCYP3A4 SubstratesMidazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC


0- 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 AUC


0-24hr 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-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 DrugsP-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


3 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/AprepitantRifampin: 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


max by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

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


2). 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


Fosaprepitant for injection placebo, fosaprepitant capsules placebo and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blindingDay 1Day 2 Day 3 Day 4  Fosaprepitant Regimen Fosaprepitant for injection 150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy none none none Oral dexamethasone


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)]. 12 mg 8 mg 8 mg twice daily 8 mg twice daily Ondansetron Ondansetron


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. none none none Oral fosaprepitant Regimen Fosaprepitant capsules 125 mg 80 mg 80 mg none Oral dexamethasone


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 fosaprepitant regimen [
see
Clinical Pharmacology (12.3)]
.
 12 mg 8 mg 8 mg 8 mg OndansetronOndansetron none none noneThe efficacy of fosaprepitant for injection was evaluated based on the primary and secondary endpoints 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)


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


 Oral fosaprepitant Regimen


(N = 1134)*%


Difference


Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender. (95% CI) 


PRIMARY


ENDPOINT


 Complete Response


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


Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy. 71.9 72.3 -0.4 (-4.1, 3.3) SECONDARY


ENDPOINTS


 Complete Response Delayed phase


Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy 74.3 74.2 0.1 (-3.5, 3.7) No Vomiting Overall


§ 72.9 74.6 -1.7 (-5.3, 2.0)

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 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


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


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)].
 12 mg none none Oral Ondansetron


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. 8 mg for 2 doses none none Standard Therapy Oral Dexamethasone 20 mg none noneOral Ondansetron


‡ 8 mg for 2 doses 8 mg twice daily 8 mg twice dailyThe 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)


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


 Standard Therapy Regimen


(N = 498)*


%


 P-Value Treatment Difference (95% CI) PRIMARY ENDPOINT Complete Response


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


Delayed phase = 25 to 120 hours post-initiation of chemotherapy. 78.9 68.5 <0.001 10.4 (5.1, 15.9)

16 How Supplied/Storage And Handling

Single-dose glass vial containing 150 mg of fosaprepitant as a white to off-white lyophilized powder for reconstitution. Supplied as follows:NDC 70625-311-01          1 vial per carton.

Storage And Handling

StorageFosaprepitant for injection vials must be refrigerated, store at 2°C-8°C (36°F-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).HypersensitivityAdvise 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 ReactionsAdvise 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 InteractionsAdvise 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)]


.

Spl Patient Package Insert

  • Patient Information Fosaprepitant for injectionRead 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 6 months 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 receive 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 problems • are pregnant or plan to become pregnant. It is not known if fosaprepitant for injection can harm your unborn baby.o 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.Children 6 months to 17 years of age:Fosaprepitant for injection will be given on Day 1 of chemotherapy treatment. It will be given to your child by intravenous (IV) infusion into a large vein through a type of IV line called a central venous catheter, about 1 hour to 1 ½ hours before the start of their chemotherapy treatment. • Your child may also receive:o capsules of fosaprepitant or an oral suspension of fosaprepitant on Days 2 and 3. If your child will receive either of these, see the Patient Information for fosaprepitant capsules or fosaprepitant for oral suspension for further information.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.

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