Label: FOSAPREPITANT - fosaprepitant injection, powder, lyophilized, for solution

  • NDC Code(s): 69539-034-01
  • Packager: MSN LABORATORIES PRIVATE LIMITED
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated September 6, 2019

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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

    RECENT MAJOR CHANGES

    Warnings and  Precautions (5.2)                                   08/2017
    Warnings and Precautions (5.3)                                   03/2018


    INDICATIONS AND USAGE

    Fosaprepitant for injection is a substance  P/neurokinin-1 (NK1) 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)
    • Adults: 150 mg on Day 1.
    • Administer Fosaprepitant for injection on Day 1 as an intravenous infusion over 20 to 30 minutes (adults), completing the infusion approximately 30 minutes prior to chemotherapy.
    • 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, 5.1,5.47.1,  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: 1/2019

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 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 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.



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  • 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-HT3  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
    approximately 30 minutes prior to chemotherapy
    none
    none
    none
    Dexamethasone*
    12 mg orally
    8 mg orally
    8 mg orally twice daily
    8 mg orally twice daily
    5-HT3   antagonist
    See selected 5-HT3 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 approximately 30 minutes prior to chemotherapy
    Dexamethasone*
    12 mg orally
    5-HT3 antagonist
    See selected 5-HT3 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, 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 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., Ca2+, Mg2+), 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.


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  • 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.

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  • 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) ]. 
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  • 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 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)  ].

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  • 6 ADVERSE REACTIONS

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

    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
    15%
    13%
    diarrhea
    13%
    11%
    neutropenia
    8%
    7%
    asthenia
    4%
    3%
    anemia
    3%
    2%
    peripheral neuropathy
    3%
    2%
    leukopenia
    2%
    1%
    dyspepsia
    2%
    1%
    urinary tract infection
    2%
    1%
    pain in extremity
    2%
    1%

    *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.


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  • 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

    CYP3A4Substrates
    Pimozide
    Clinical Impact
    Increased pimozide exposure
    Intervention
    Fosaprepitant is contraindicated [see Contraindications (4)].
    Benzodiazepines
    Clinical Impact
    Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
    Intervention
    Monitor for benzodiazepine-related adverse reactions.
    Dexamethasone
    Clinical Impact
    Increased dexamethasone exposure [see Clinical Pharmacology (12.3)].
    Intervention
    Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)].
    Methylprednisolone
    Clinical Impact
    Increased methylprednisolone exposure [see Clinical Pharmacology (12.3)].
    Intervention
    Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
    Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
    Chemotherapeutic agents that are metabolized by CYP3A4
    Clinical Impact
    Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
    Intervention
    Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents
    • 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 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
    Warfarin
    Clinical Impact
    Decreased warfarin exposure and prolongation of 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-HT3  Antagonists
      Clinical Impact
      No change in the exposure of the 5-HT3 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 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
     
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  • 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].

    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) ].

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  • 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.

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  • 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   C23 H22 F7 N4 O6 P 2(C7 H17 NO5 ) and  its  structural  formula   is:

    str  

    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). 

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  • 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 (NK1)  receptors. Aprepitant has little or no affinity for serotonin (5-HT3),   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  NK1  receptors.  Animal  and  human  studies  show  that  aprepitant  augments   the  antiemetic  activity of  the  5-HT3 -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 AUC0-∞ of aprepitant was 37.4 (±14.8)mcg•hr/mL and the mean maximal aprepitant concentration (Cmax ) 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 (Vdss) 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 [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.
    Excretion
    Following 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 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 AUC0-24hr 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 Cmax 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 AUC0-24hr and Cmax 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 Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.
    Race/Ethnicity
    Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax 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 m2 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 AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax 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 AUC0-∞ of total aprepitant decreased by 42% and Cmax 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 AUC0-24hr 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 AUC0-24hr 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 AUC0-24hr 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/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. 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 AUC0-∞ 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 AUC0-24hr 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 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-HT3 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 Cmax by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.


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  • 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  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).

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  • 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/m2).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 30  minutes prior   to   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.



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  • 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)].

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  • 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: 
    January 2019

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  • 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:
    January 2019

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  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    Fosaprepitant-carton-label
    carton

    Fosaprepitant-vial-label

    vial

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  • INGREDIENTS AND APPEARANCE
    FOSAPREPITANT 
    fosaprepitant injection, powder, lyophilized, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:69539-034
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    FOSAPREPITANT DIMEGLUMINE (UNII: D35FM8T64X) (APREPITANT - UNII:1NF15YR6UY) FOSAPREPITANT 150 mg  in 5 mL
    Inactive Ingredients
    Ingredient Name Strength
    EDETATE DISODIUM (UNII: 7FLD91C86K)  
    POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:69539-034-01 1 in 1 CARTON 09/05/2019
    1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA209965 09/05/2019
    Labeler - MSN LABORATORIES PRIVATE LIMITED (650786952)
    Establishment
    Name Address ID/FEI Business Operations
    MSN LABORATORIES PRIVATE LIMITED 650786952 ANALYSIS(69539-034) , MANUFACTURE(69539-034)
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