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Emend Tri-Pack

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Emend Tri-Pack uses


1 INDICATIONS AND USAGE

Emend Tri-Pack® is a substance P/neurokinin 1 receptor antagonist.

Emend Tri-Pack for oral suspension is indicated


Emend Tri-Pack capsules is indicated


Limitations of Use: (1.3)

1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

EMEND® for oral suspension, in combination with other antiemetic agents, is indicated in patients 6 months of age and older for the prevention of:


EMEND® capsules, in combination with other antiemetic agents, is indicated in patients 12 years of age and older for the prevention of:

1.2 Prevention of Postoperative Nausea and Vomiting

Emend Tri-Pack capsules are indicated in adults for the prevention of postoperative nausea and vomiting.

1.3 Limitations of Use

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2 DOSAGE AND ADMINISTRATION

Recommended Dosage for Prevention of Chemotherapy Induced Nausea and Vomiting (2.1)


Recommended Dosage for PONV (2.2)


Preparation and Administration (2.3, 2.4)

2.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Adults and Pediatric Patients 12 Years of Age and Older

The recommended oral dosage of Emend Tri-Pack capsules, dexamethasone, and a 5-HT3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively. For patients who cannot swallow oral capsules, Emend Tri-Pack for oral suspension can be used instead of Emend Tri-Pack capsules as shown in Table 3.

Population Day 1 Day 2 Day 3 Day 4
Emend Tri-Pack capsulesAdminister Emend Tri-Pack capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer Emend Tri-Pack capsules in the morning. Adults and

Pediatric Patients 12 Years and Older

 125 mg orally 80 mg orally 80 mg orally none
Dexamethasone Adults 12 mg orally 8 mg orally 8 mg orally 8 mg orally
Pediatric Patients 12 Years and Older If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 .Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with Emend Tri-Pack .
5-HT3 antagonist Adults and

Pediatric Patients 12 Years and Older

 See selected 5-HT3 antagonist prescribing information for the recommended dosage none none none
Population Day 1 Day 2 Day 3
EMEND capsulesAdminister Emend Tri-Pack capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer Emend Tri-Pack capsules in the morning. Adults and

Pediatric Patients 12 Years and Older

 125 mg orally 80 mg orally 80 mg orally
Dexamethasone Adults 12 mg orally none none
Pediatric Patients 12 Years and Older If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 .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 Emend Tri-Pack .
5-HT3 antagonist Adults and

Pediatric Patients 12 Years and Older

 See the selected 5-HT3 antagonist prescribing information for recommended dosage none none

Pediatric Patients 6 Months to less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow Capsules

The recommended dose of Emend Tri-Pack for oral suspension to be administered with a 5-HT3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of HEC or MEC is specified in Table 3. Dosing of Emend Tri-Pack for oral suspension is based on weight, to a maximum of 125 mg on Day 1 and 80 mg on Days 2 and 3. Dosing in pediatric patients less than 6 kg is not recommended.

Population Day 1 Day 2 Day 3 Day 4
Emend Tri-Pack for oral suspensionAfter preparation, the final concentration of Emend Tri-Pack for oral suspension is 25 mg/mL . Administer Emend Tri-Pack for oral suspension 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer Emend Tri-Pack for oral suspension in the morning. Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules 3 mg/kg orally

Maximum dose 125 mg

 2 mg/kg orally

Maximum dose 80 mg

 2 mg/kg orally

Maximum dose 80 mg

 none
Dexamethasone Adults Unable to Swallow Capsules See Table 1 or 2 See Table 1 or 2 See Table 1 or 2 See Table 1 or 2
Pediatric Patients 6 Months to Less than12 Years or Pediatric Patients Unable to Swallow Capsules If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 .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 Emend Tri-Pack .
5-HT3 antagonist Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules See selected 5-HT3 antagonist prescribing information for the recommended dosage none none none

2.2 Prevention of Postoperative Nausea and Vomiting

The recommended oral dosage of Emend Tri-Pack capsules in adults is 40 mg within 3 hours prior to induction of anesthesia.

2.3 Preparation Instructions for Emend Tri-Pack for Oral Suspension -- for Healthcare Providers

EMEND for oral suspension should be prepared by a healthcare provider.

Once prepared, it may be administered either by a healthcare provider, patient, or caregiver.

Before you prepare Emend Tri-Pack:

EMEND for oral suspension is packaged as a kit with one 1 mL oral dosing dispenser, one 5 mL oral dosing dispenser, one cap and one mixing cup.
  • Fill the mixing cup with room temperature drinking water.
  • Fill the 5 mL oral dosing dispenser with 4.6 mL of water from the mixing cup.

    Make sure no air is in the dispenser - if air is present, remove.

  • Discard all the unused water remaining in the mixing cup.
  • Add the 4.6 mL of water from the dispenser back into the mixing cup.
  • Each pouch of Emend Tri-Pack for oral suspension contains 125 mg of Emend Tri-Pack which is to be suspended in 4.6 mL of water giving a final concentration of 25 mg/mL.

    Hold the Emend Tri-Pack for oral suspension pouch upright and shake the contents to the bottom before opening the pouch.

  • Pour the entire contents of the pouch into the 4.6 mL of water in the mixing cup and snap the lid shut.
  • Mix the Emend Tri-Pack suspension gently by swirling 20 times; then gently invert the mixing cup 5 times.

    To prevent foaming, do not shake the mixing cup. The mixture will be cloudy pink to light pink.
  • Check the Emend Tri-Pack mixture for any clumps or foaming:
    • If any clumps are present, repeat Step 7 until there are no clumps.
    • If there is any foam, wait for the foam to disappear before going on to Step 9.
  • Fill the dispenser with the prescribed dose shown above in Table 3.
    • Choose the dispenser based on dose:
      • Use 1 mL dispenser if dose is 1 mL or less.
      • Use 5 mL dispenser if dose is more than 1 mL.
    • Fill the dispenser with the prescribed dose from the cup.
      • If the dose is less than 1 mL round to the nearest 0.1 mL.
      • If the dose is more than 1 mL round to the nearest 0.2 mL.
    • It is common to have medicine leftover in the cup.

Make sure no air is in the dispenser - if air is present, remove.

Make sure the dispenser contains the prescribed dose.

  • Place the cap on the dispenser until it clicks.
  • If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator [between 36°F-46°F (2°C-8°C)] for up to 72 hours prior to use. When dispensing dose(s) to the patient or caregiver, instruct them to refrigerate the oral dosing dispenser(s) until they are ready to administer the dose.
  • When ready to use, the mixture can be kept at room temperature [between 68°F-77°F (20°C-25°C)] for up to 3 hours.
  • Discard the mixing cup along with any remaining suspension.
Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

2.4 Administration Instructions

EMEND capsules and Emend Tri-Pack for oral suspension can be administered with or without food.

Emend Tri-Pack capsules


Emend Tri-Pack for oral suspension

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3 DOSAGE FORMS AND STRENGTHS

Emend Tri-Pack capsules: 40 mg; 80 mg; 125 mg (3)

Emend Tri-Pack for oral suspension: 125 mg (3)

Emend Tri-Pack capsules:


Emend Tri-Pack for oral suspension:

4 CONTRAINDICATIONS

Emend Tri-Pack is contraindicated in patients:

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5 WARNINGS AND PRECAUTIONS

5.1 Clinically Significant CYP3A4 Drug Interactions

Emend Tri-Pack is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4.


See Table 10 and Table 11 for a listing of potentially significant drug interactions .

5.2 Decrease in INR with Concomitant Warfarin

Coadministration of Emend Tri-Pack with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio of prothrombin time . Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Emend Tri-Pack with each chemotherapy cycle, or following administration of a single 40-mg dose of Emend Tri-Pack for the prevention of postoperative nausea and vomiting .

5.3 Risk of Reduced Efficacy of Hormonal Contraceptives

Upon coadministration with Emend Tri-Pack, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of Emend Tri-Pack . Advise patients to use effective alternative or back-up methods of contraception during treatment with Emend Tri-Pack and for 1 month following the last dose of Emend Tri-Pack .

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6 ADVERSE REACTIONS

Most common adverse reactions are :

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)


PONV


To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Emend Tri-Pack was evaluated in approximately 6800 individuals.

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

In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), Emend Tri-Pack in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) .

In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), Emend Tri-Pack in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) . The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%).

Across these 4 studies there were 1412 patients treated with the Emend Tri-Pack regimen during Cycle 1 of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 are listed in Table 5.

Emend Tri-Pack, ondansetron, and dexamethasoneEmend Tri-Pack regimen

(N=1412)

 Ondansetron and dexamethasoneStandard therapy

(N=1396)
fatigue 13% 12%
diarrhea 9% 8%
asthenia 7% 6%
dyspepsia 7% 5%
abdominal pain 6% 5%
hiccups 5% 3%
white blood cell count decreased 4% 3%
dehydration 3% 2%
alanine aminotransferase increased 3% 2%

In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the Emend Tri-Pack regimen are listed in Table 6.

Infection and Infestations oral candidiasis, pharyngitis
Blood and the Lymphatic System Disorders anemia, febrile neutropenia, neutropenia, thrombocytopenia
Metabolism and Nutrition Disorders decreased appetite, hypokalemia
Psychiatric Disorders anxiety
Nervous System Disorders dizziness, dysgeusia, peripheral neuropathy
Cardiac Disorders palpitations
Vascular Disorders flushing, hot flush
Respiratory, Thoracic and Mediastinal Disorders cough, dyspnea, oropharyngeal pain
Gastrointestinal Disorders dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting
Skin and Subcutaneous Tissue Disorders alopecia, hyperhidrosis, rash
Musculoskeletal and Connective Tissue Disorders musculoskeletal pain
General Disorders and Administration Site Condition edema peripheral, malaise
Investigations aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased

In an additional active-controlled clinical study in 1169 patients receiving Emend Tri-Pack and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with Emend Tri-Pack.

In another CINV study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving the Emend Tri-Pack regimen with cancer chemotherapy.

Adverse reactions in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age in the Prevention of Nausea and Vomiting Associated with HEC or MEC

In a pooled analysis of 2 active-controlled clinical trials in pediatric patients aged 6 months to 17 years who received highly or moderately emetogenic cancer chemotherapy (Study 5 and a safety study, Study 6), Emend Tri-Pack in combination with ondansetron with or without dexamethasone (EMEND regimen) was compared to ondansetron with or without dexamethasone (control regimen).

There were 184 patients treated with the Emend Tri-Pack regimen during Cycle 1 and 215 patients received open-label Emend Tri-Pack for up to 9 additional cycles of chemotherapy.

In Cycle 1, the most common adverse reactions reported in pediatric patients treated with the Emend Tri-Pack regimen in pooled Studies 5 and 6 are listed in Table 7.

Emend Tri-Pack and ondansetronEmend Tri-Pack regimen

(N=184)

 OndansetronControl regimen

(N=168)
neutropenia 13% 11%
headache 9% 5%
diarrhea 6% 5%
decreased appetite 5% 4%
cough 5% 3%
fatigue 5% 2%
hemoglobin decreased 5% 4%
dizziness 5% 1%
hiccups 4% 1%

Forty-nine patients were treated with ifosfamide chemotherapy in each arm. Two of the patients treated with ifosfamide in the Emend Tri-Pack arm developed behavioral changes (agitation = 1; abnormal behavior = 1), whereas no patient treated with ifosfamide in the control arm developed behavioral changes. Emend Tri-Pack has the potential for increasing ifosfamide-mediated neurotoxicity through induction of CYP3A4 .

Adverse Reactions in Adult Patients in the Prevention of PONV

In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 7 and 8), 40-mg oral Emend Tri-Pack was compared to 4-mg intravenous ondansetron .

There were 564 patients treated with Emend Tri-Pack and 538 patients treated with ondansetron.

The most common adverse reactions reported in patients treated with Emend Tri-Pack for PONV in pooled Studies 7 and 8 are listed in Table 8.

Emend Tri-Pack 40 mg

(N = 564)

 Ondansetron

(N = 538)
constipation 9% 8%
hypotension 6% 5%

In a pooled analysis of PONV studies, less common adverse reactions reported in patients treated with Emend Tri-Pack are listed in Table 9.

Infections and Infestations postoperative infection
Metabolism and Nutrition Disorders hypokalemia, hypovolemia
Nervous System Disorders dizziness, hypoesthesia, syncope
Cardiac Disorders bradycardia
Vascular Disorders hematoma
Respiratory, Thoracic and Mediastinal Disorders dyspnea, hypoxia, respiratory depression
Gastrointestinal Disorders abdominal pain, dry mouth, dyspepsia
Skin and Subcutaneous Tissue Disorders urticaria
General Disorders and Administration Site Conditions hypothermia
Investigations blood albumin decreased, bilirubin increased, blood glucose increased, blood potassium decreased
Injury, Poisoning and Procedural Complications operative hemorrhage, wound dehiscence

In addition, two serious adverse reactions were reported in PONV clinical studies in patients taking a higher than recommended dose of Emend Tri-Pack: one case of constipation, and one case of sub-ileus.

Other Studies

Angioedema and urticaria were reported as serious adverse reactions in a patient receiving Emend Tri-Pack in a non-CINV/non-PONV study (EMEND is only approved in the CINV and PONV populations).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Emend Tri-Pack. 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.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions .

Nervous system disorders: ifosfamide-induced neurotoxicity reported after Emend Tri-Pack and ifosfamide coadministration.

7 DRUG INTERACTIONS

See Full Prescribing Information for a list of clinically significant drug interactions.

7.1 Effect of Emend Tri-Pack on the Pharmacokinetics of Other Drugs

Emend Tri-Pack is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Emend Tri-Pack is also an inducer of CYP2C9 .

Emend Tri-Pack acts as a moderate inhibitor of CYP3A4 when administered as a 3-day regimen (125-mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4. Emend Tri-Pack acts as a weak inhibitor when administered as a single 40-mg dose and has not been shown to alter the plasma concentrations of concomitant drugs that are primarily metabolized through CYP3A4. Some substrates of CYP3A4 are contraindicated with Emend Tri-Pack . Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 10.

CYP3A4 Substrates
Pimozide
Clinical Impact Increased pimozide exposure
Intervention Emend Tri-Pack is contraindicated .
Benzodiazepines
Clinical Impact Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions .
Intervention 3-day Emend Tri-Pack regimen
  • Monitor for benzodiazepine-related adverse reactions.
  • Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam

Single 40 mg dose of Emend Tri-Pack

  • No dosage adjustment of the benzodiazepine needed
Dexamethasone
Clinical Impact Increased dexamethasone exposure .
Intervention 3-day Emend Tri-Pack regimen
  • Reduce the dose of oral dexamethasone by approximately 50% .

Single 40 mg dose of Emend Tri-Pack

  • No dosage adjustment of oral dexamethasone needed
Methylprednisolone
Clinical Impact Increased methylprednisolone exposure .
Intervention 3-day Emend Tri-Pack regimen
  • Reduce the dose of intravenous methylprednisolone by approximately 25%
  • Reduce the dose of oral methylprednisolone by approximately 50%

Single 40 mg dose of Emend Tri-Pack

  • No dosage adjustment of methylprednisolone needed
Chemotherapeutic agents that are metabolized by CYP3A4
Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions .
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 Emend Tri-Pack .
Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with Emend Tri-Pack and for 1 month following the last dose of Emend Tri-Pack.
Examples birth control pills, skin patches, implants, and certain IUDs
CYP2C9 Substrates
Warfarin
Clinical Impact Decreased warfarin exposure and prolongation of prothrombin time (INR) .
Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day Emend Tri-Pack regimen with each chemotherapy cycle, or following administration of a single 40-mg dose of Emend Tri-Pack.
Other
5-HT3 Antagonists
Clinical Impact No change in the exposure of the 5-HT3 antagonist .
Intervention No dosage adjustment needed
Examples ondansetron, granisetron, dolasetron

7.2 Effect of Other Drugs on the Pharmacokinetics of Emend Tri-Pack

Emend Tri-Pack is a CYP3A4 substrate . Co-administration of Emend Tri-Pack with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of Emend Tri-Pack, respectively, as shown in Table 11.

Moderate to Strong CYP3A4 Inhibitors
Clinical Impact Significantly increased exposure of Emend Tri-Pack may increase the risk of adverse reactions associated with Emend Tri-Pack .
Intervention Avoid concomitant use of Emend Tri-Pack
Examples Moderate inhibitor:

diltiazem

Strong inhibitors:

ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir
Strong CYP3A4 Inducers
Clinical Impact Substantially decreased exposure of Emend Tri-Pack in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of Emend Tri-Pack .
Intervention Avoid concomitant use of Emend Tri-Pack
Examples rifampin, carbamazepine, phenytoin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are insufficient data on use of Emend Tri-Pack 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 approximately 1.5 times the adult human exposure at the 125-mg/80-mg/80-mg Emend Tri-Pack regimen .

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, Emend Tri-Pack was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in 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 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80-mg/80-mg Emend Tri-Pack regimen. Emend Tri-Pack crosses the placenta in rats and rabbits.

8.2 Lactation

Risk Summary

Lactation studies have not been conducted to assess the presence of Emend Tri-Pack in human milk, the effects on the breastfed infant, or the effects on milk production. Emend Tri-Pack is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Emend Tri-Pack and any potential adverse effects on the breastfed infant from Emend Tri-Pack or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Upon administration of Emend Tri-Pack, 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 during treatment with Emend Tri-Pack and for 1 month following the last dose .

8.4 Pediatric Use

Prevention of Nausea and Vomiting Associated with HEC or MEC

The safety and effectiveness of Emend Tri-Pack for oral suspension have been established in pediatric patients 6 months of age and older and Emend Tri-Pack capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. Use of Emend Tri-Pack in these age groups is supported by evidence from 302 pediatric patients in a randomized, double-blind, active comparator controlled clinical study (n = 207 patients aged 6 months to less than 12 years, n = 95 patients aged 12 through 17 years). Emend Tri-Pack was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician) . Adverse reactions were similar to those reported in adult patients .

The safety and effectiveness of Emend Tri-Pack for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months.

Prevention of Postoperative Nausea and Vomiting (PONV)

The safety and effectiveness of Emend Tri-Pack have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.

Juvenile Animal Study

A study was conducted in young rats to evaluate the effects of Emend Tri-Pack 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 rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. 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 544 adult cancer patients treated with Emend Tri-Pack in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Of the 1120 adult cancer patients treated with Emend Tri-Pack in PONV clinical studies, 7% were aged 65 and over, while 2% were aged 75 and over. Other reported clinical experience with Emend Tri-Pack 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 .

8.6 Patients with Renal Impairment

The pharmacokinetics of Emend Tri-Pack in patients with severe renal impairment and those with end stage renal disease (ESRD) requiring hemodialysis were similar to those of healthy subjects with normal renal function. No dosage adjustment is necessary for patients with any degree of renal impairment or for patients with ESRD undergoing hemodialysis.

8.7 Patients with Hepatic Impairment

The pharmacokinetics of Emend Tri-Pack 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 Emend Tri-Pack is administered .

10 OVERDOSAGE

No specific information is available on the treatment of overdosage.

Drowsiness and headache were reported in one patient who ingested 1440 mg of Emend Tri-Pack (approximately 11 times the maximum recommended single dose).

In the event of overdose, Emend Tri-Pack should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of Emend Tri-Pack, drug-induced emesis may not be effective in cases of Emend Tri-Pack overdosage.

Emend Tri-Pack is not removed by hemodialysis.

11 DESCRIPTION

Emend Tri-Pack capsules contain the active ingredient, Emend Tri-Pack. Emend Tri-Pack is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C23H21F7N4O3, and its structural formula is:

Emend Tri-Pack is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Emend Tri-Pack is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

Each capsule of Emend Tri-Pack for oral administration contains either 40 mg, 80 mg, or 125 mg of Emend Tri-Pack and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 40-mg capsule shell also contains yellow ferric oxide, and the 125-mg capsule also contains red ferric oxide and yellow ferric oxide.

Each pouch of Emend Tri-Pack for oral suspension 125 mg contains 125 mg of Emend Tri-Pack and the following inactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Emend Tri-Pack is a selective high-affinity antagonist of human substance P/neurokinin 1 receptors. Emend Tri-Pack 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) and postoperative nausea and vomiting (PONV).

Emend Tri-Pack 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 Emend Tri-Pack have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Emend Tri-Pack 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

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral Emend Tri-Pack doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma Emend Tri-Pack concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At Emend Tri-Pack plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral Emend Tri-Pack regimen for CINV produced mean trough plasma Emend Tri-Pack concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of Emend Tri-Pack has not been established.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum Emend Tri-Pack concentrations after a single 200-mg dose of fosaprepitant were 4- and 9-fold higher than that achieved with oral Emend Tri-Pack 125 mg and 40 mg, respectively. QT prolongation with the oral Emend Tri-Pack dosing regimens for CINV and PONV is not expected.

12.3 Pharmacokinetics

Absorption

Following oral administration of a single 40-mg dose of Emend Tri-Pack in the fasted state, mean area under the plasma concentration-time curve (AUC0-∞) was 7.8 mcg∙hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (Tmax). The absolute bioavailability at the 40-mg dose has not been determined.

Following oral administration of a single 125-mg dose of Emend Tri-Pack on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.6 mcg∙hr/mL and 21.2 mcg∙hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80 to 125 mg, the mean absolute oral bioavailability of Emend Tri-Pack is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of Emend Tri-Pack.

The pharmacokinetics of Emend Tri-Pack were non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.

Distribution

Emend Tri-Pack is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.

Emend Tri-Pack crosses the blood brain barrier in humans .

Elimination

Metabolism

Emend Tri-Pack undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that Emend Tri-Pack 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, Emend Tri-Pack accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant (2.4 times the maximum recommended dose), indicating a substantial presence of metabolites in the plasma. Seven metabolites of Emend Tri-Pack, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [14C]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. A study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ.

Emend Tri-Pack is eliminated primarily by metabolism; Emend Tri-Pack is not renally excreted. The apparent plasma clearance of Emend Tri-Pack ranged from approximately 62 to 90 mL/min. 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 Emend Tri-Pack on Day 1 and 80 mg once daily on Days 2 through 5 (2 additional days of dosing compared to the recommended duration), the AUC0-24hr of Emend Tri-Pack 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 .

Age: Pediatric Population

As part of a 3-day regimen, dosing of Emend Tri-Pack capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved a mean AUC0-24hr of 17 mcg∙hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.3 mcg/mL occurring at approximately 4 hours. The mean concentrations at the end of Day 2 (N=8) and Day 3 (N=16) were both at 0.6 mcg/mL

As part of a 3-day regimen, weight-based dosing of Emend Tri-Pack powder for oral suspension (3-mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged 6 months to less than 12 years achieved a mean AUC0-24hr of 20.9 mcg∙hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately 6 hours. The mean concentrations at the end of Day 2 (N=18) and Day 3 (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively .

A population pharmacokinetic analysis of Emend Tri-Pack in pediatric patients (aged 6 months through 17 years) suggests that sex and race have no clinically meaningful effect on the pharmacokinetics of Emend Tri-Pack.

Sex

Following oral administration of a single dose of Emend Tri-Pack ranging from 40 mg to 375 mg (3 times the maximum recommended dose), the AUC0-24hr and Cmax are 9% and 17% higher in females as compared with males. The half-life of Emend Tri-Pack 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 Emend Tri-Pack ranging from 40 mg to 375 mg (3 times the maximum recommended dose), 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 dose of Emend Tri-Pack (approximately 1.9 times the maximum recommended dose) 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 Emend Tri-Pack (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 Emend Tri-Pack decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of Emend Tri-Pack 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 Emend Tri-Pack; less than 0.2% of the dose was recovered in the dialysate .

Hepatic Impairment

Following administration of a single 125-mg dose of Emend Tri-Pack 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 Emend Tri-Pack 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 Emend Tri-Pack 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) .

Body Mass Index (BMI)

For every 5 kg/m2 increase in BMI, AUC0-24hr and Cmax of Emend Tri-Pack 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.

Drug Interactions Studies

Emend Tri-Pack is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Emend Tri-Pack is also an inducer of CYP2C9. Emend Tri-Pack is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

Effects of Emend Tri-Pack on the Pharmacokinetics of Other Drugs

CYP3A4 substrates (i.e., midazolam): Interactions between Emend Tri-Pack and coadministered midazolam are listed in Table 12 (increase is indicated as "↑", decrease as "↓", no change as "↔").

Dosage of Emend Tri-Pack Dosage of Midazolam Observed Drug Interactions
Emend Tri-Pack 125 mg on Day 1 and 80 mg on Days 2 to 5 oral 2 mg single dose on Days 1 and 5

 midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5

Emend Tri-Pack 125 mg on Day 1 and 80 mg on Days 2 and 3

 intravenous 2 mg prior to 3-day regimen of Emend Tri-Pack and on Days 4, 8 and 15

 midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15
Emend Tri-Pack 125 mg

 intravenous 2 mg given 1 hour after Emend Tri-Pack

 midazolam AUC ↑ 1.5-fold
Emend Tri-Pack 40 mg oral 2 mg midazolam AUC ↑ 1.2-fold on Day 1

A difference of less than 2-fold increase of midazolam AUC is not considered clinically important.

Corticosteroids:

Dexamethasone: Emend Tri-Pack, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg dexamethasone on Day 1 and 8-mg dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5 . A single dose of Emend Tri-Pack (40 mg) when coadministered with a single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant.

Methylprednisolone: Emend Tri-Pack, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. Although the concomitant administration of methylprednisolone with the single 40-mg dose of Emend Tri-Pack has not been studied, a single 40-mg dose of Emend Tri-Pack produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree.

Chemotherapeutic agents:

Docetaxel: In a pharmacokinetic study, Emend Tri-Pack (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, Emend Tri-Pack (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Oral contraceptives: When Emend Tri-Pack 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.

When a daily dosage of an oral contraceptive containing ethinyl estradiol and norgestimate was administered on Days 1 through 21, and Emend Tri-Pack 40 mg was given on Day 8, the AUC of ethinyl estradiol decreased by 4% and by 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with Emend Tri-Pack 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone .

CYP2C9 substrates (e.g., warfarin): A single 125-mg dose of Emend Tri-Pack was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of Emend Tri-Pack 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 Emend Tri-Pack .

Tolbutamide: Emend Tri-Pack, 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 Emend Tri-Pack and on Days 4, 8, and 15. This effect was not considered clinically important.

Emend Tri-Pack, when given as a 40-mg single dose on Day 1, decreased the AUC of tolbutamide by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of Emend Tri-Pack 40 mg and on Days 2, 4, 8, and 15. This effect was not considered significant.

P-glycoprotein substrates: Emend Tri-Pack is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of Emend Tri-Pack with digoxin in a clinical drug interaction study.

5-HT3 antagonists: In clinical drug interaction studies, Emend Tri-Pack 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 Emend Tri-Pack

Ketoconazole: When a single 125-mg dose of Emend Tri-Pack was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of Emend Tri-Pack increased approximately 5-fold and the mean terminal half-life of Emend Tri-Pack increased approximately 3-fold .

Rifampin: When a single 375-mg dose of Emend Tri-Pack (3 times the maximum recommended dose) was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of Emend Tri-Pack decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold .

Diltiazem: In patients with mild to moderate hypertension, administration of Emend Tri-Pack once daily, as a tablet formulation comparable to 230 mg of the capsule formulation (approximately 1.8 times the recommended dose), with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of Emend Tri-Pack AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone .

Paroxetine: Coadministration of once daily doses of Emend Tri-Pack, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation (approximately 0.7 and 1.4 times the maximum recommended dose), with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both Emend Tri-Pack and paroxetine. This effect was not considered clinically important.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to Emend Tri-Pack (AUC) of 0.7 to 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg Emend Tri-Pack regimen. Treatment with Emend Tri-Pack 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 of about 2.8 to 3.6 times the adult human exposure at the 125-mg/80-mg/80-mg Emend Tri-Pack regimen. Treatment with Emend Tri-Pack produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Mutagenesis

Emend Tri-Pack was 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

Emend Tri-Pack 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 and exposure in female rats at about 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg Emend Tri-Pack regimen).

14 CLINICAL STUDIES

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

Oral administration of Emend Tri-Pack in combination with ondansetron and dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.

In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, Emend Tri-Pack in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). See Table 13.

In these studies, 95% of the patients in the Emend Tri-Pack group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of Emend Tri-Pack patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).

Of the 550 patients who were randomized to receive the Emend Tri-Pack regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The EMEND-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older.

Day 1 Day 2 Day 3 Day 4
CINV Emend Tri-Pack Regimen
Oral Emend Tri-PackEmend Tri-Pack was administered 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3. 125 mg 80 mg 80 mg none
Oral DexamethasoneDexamethasone 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 reflects a dosage adjustment to account for a drug interaction with the Emend Tri-Pack regimen . 12 mg 8 mg 8 mg 8 mg
Ondansetron 5-HT3 antagonistOndansetron 32 mg intravenous was used in the clinical trials of Emend Tri-Pack. 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
CINV Standard Therapy
Oral Dexamethasone 20 mg 8 mg twice daily 8 mg twice daily 8 mg twice daily
Ondansetron 5-HT3 antagonist none none none

The antiemetic activity of Emend Tri-Pack was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:


Other prespecified endpoints:


A summary of the key study results from each individual study analysis is shown in Table 14. In both studies, a statistically significantly higher proportion of patients receiving the Emend Tri-Pack regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the Emend Tri-Pack regimen was also observed when the acute phase and the delayed phase were analyzed separately.

Study 1 Study 2
ENDPOINTS Emend Tri-Pack Regimen

(N=260)N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation.

%

 Standard Therapy

(N=261)

%

 p-Value Emend Tri-Pack Regimen (N=261)

%

 Standard Therapy

(N=263)

%

 p-Value
Visual analogue scale (VAS) score range: 0 mm=no nausea; 100 mm=nausea as bad as it could be.
PRIMARY ENDPOINT
Complete Response
OverallOverall: 0 to 120 hours post-cisplatin treatment. 73 52 <0.001 63 43 <0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phaseAcute phase: 0 to 24 hours post-cisplatin treatment. 89 78 <0.001 83 68 <0.001
Delayed phaseDelayed phase: 25 to 120 hours post-cisplatin treatment. 75 56 <0.001 68 47 <0.001
Complete Protection
Overall 63 49 0.001 56 41 <0.001
Acute phase 85 75 NSNot statistically significant when adjusted for multiple comparisons. 80 65 <0.001
Delayed phase 66 52 <0.001 61 44 <0.001
No Emesis
Overall 78 55 <0.001 66 44 <0.001
Acute phase 90 79 0.001 84 69 <0.001
Delayed phase 81 59 <0.001 72 48 <0.001
No Nausea
Overall 48 44 NSNot statistically significant. 49 39 NS
Delayed phase 51 48 NS 53 40 NS
No Significant Nausea
Overall 73 66 NS 71 64 NS
Delayed phase 75 69 NS 73 65 NS

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the Emend Tri-Pack regimen, and the incidence of first emesis was reduced in the Emend Tri-Pack regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.

Figure 1: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time - Cycle 1
p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.
Figure 1

Additional Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients' daily lives is defined as a FLIE total score greater than 108. In each of the 2 studies, a higher proportion of patients receiving the Emend Tri-Pack regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).

Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the Emend Tri-Pack regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle
Figure 2

14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults

Emend Tri-Pack was studied in two randomized, double-blind, parallel-group studies (Studies 3 and 4) in adult patients receiving MEC.

In Study 3, in breast cancer patients, Emend Tri-Pack in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). See Table 15.

In this study, the most common combinations were cyclophosphamide + doxorubicin (61%); and cyclophosphamide + epirubicin + fluorouracil (22%).

Of the 438 patients who were randomized to receive the Emend Tri-Pack regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The EMEND-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

Day 1 Day 2 Day 3
CINV Emend Tri-Pack Regimen
Oral Emend Tri-PackEmend Tri-Pack was administered 1 hour prior to chemotherapy treatment on Day 1 and in the mornings on Days 2 and 3. 125 mg 80 mg 80 mg
Oral Dexamethasone 12 mgDexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the Emend Tri-Pack regimen . none none
Oral Ondansetron 8 mg × 2 dosesThe 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. none none
CINV Standard Therapy
Oral Dexamethasone 20 mg none none
Oral Ondansetron 8 mg × 2 doses 8 mg twice daily 8 mg twice daily

The antiemetic activity of Emend Tri-Pack was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:


Other prespecified endpoints:


A summary of the key results from Study 3 is shown in Table 16. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the Emend Tri-Pack regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the "No Emesis Endpoint", a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the Emend Tri-Pack regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

ENDPOINTS Emend Tri-Pack Regimen

(N=433)N: Number of patients included in the primary analysis of complete response.

%

 Standard Therapy

(N=424)

%

 p-Value
PRIMARY ENDPOINTOverall: 0 to 120 hours post-chemotherapy treatment.
Complete Response 51 42 0.015
OTHER PRESPECIFIED ENDPOINTS
No Emesis 76 59 NSNS when adjusted for prespecified multiple comparisons rule; unadjusted p-value <0.001.
No Nausea 33 33 NS
No Significant Nausea 61 56 NS
No Rescue Therapy 59 56 NS
Complete Protection 43 37 NS

Additional Patient-Reported Outcomes: In Study 3, in patients receiving MEC, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the Emend Tri-Pack regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the "No Vomiting Domain" of this composite endpoint.

Multiple-Cycle Extension: In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the Emend Tri-Pack regimen was maintained during all cycles.

In Study 4, Emend Tri-Pack in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m2); or cytarabine intravenous (greater than 1 g/m2). See Table 15. Patients receiving the Emend Tri-Pack regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers.

Of the 430 patients who were randomized to receive the Emend Tri-Pack regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The EMEND-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years.

The antiemetic activity of Emend Tri-Pack was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period.

A summary of the key results from Study 4 is shown in Table 17. In Study 4, a statistically significantly higher proportion of patients receiving the Emend Tri-Pack regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the Emend Tri-Pack regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving Emend Tri-Pack compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving Emend Tri-Pack compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).

In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving Emend Tri-Pack were observed to have no vomiting and complete response compared to patients receiving standard therapy. For sex, the difference in complete response rates between the Emend Tri-Pack and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for sex was observed for the no vomiting endpoint.

ENDPOINTS Emend Tri-Pack Regimen

(N=430)N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.

%

 Standard Therapy

(N=418)

%

 p-Value
No Vomiting Overall 76 62 <0.0001
Complete Response Overall 69 56 0.0003

14.3 Prevention of Nausea and Vomiting Associated with HEC or MEC in Pediatric Patients

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, Emend Tri-Pack in combination with ondansetron was compared to ondansetron alone for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the Emend Tri-Pack group, reflecting a dosage adjustment to account for a drug interaction . No dexamethasone dose reduction was required for patients who received the control regimen.

Eligible patients had documented malignancy at either an original diagnosis or relapse and were scheduled to receive emetogenic chemotherapy or a chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen.

Of the 152 pediatric patients randomized to receive the Emend Tri-Pack regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the Emend Tri-Pack regimen were osteosarcoma (11%), Ewing's sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of Emend Tri-Pack patients exposed were: vincristine sulfate (65), etoposide (59), doxorubicin (48), ifosfamide (45), carboplatin (39), and cisplatin (35).

The treatment regimens in Study 5 for pediatric patients are defined in Table 18. Of the pediatric patients, 29% in the Emend Tri-Pack regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.

Day 1 Day 2 Day 3
CINV Emend Tri-Pack Regimen
Pediatric Patients 6 Months to less than 12 Years of AgeEmend Tri-Pack was administered 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days 2 and 3, Emend Tri-Pack was administered in the morning. 3 mg/kg body weight oral suspension 2 mg/kg body weight oral suspension 2 mg/kg body weight oral suspension
Pediatric Patients 12 to 17 Years of Age 125 mg capsule 80 mg capsule 80 mg capsule
Ondansetron Per standard of careOndansetron was administered 30 minutes prior to chemotherapy on Day 1 none none
CINV Control RegimenEmend Tri-Pack placebo was used to maintain blinding.
Ondansetron Per standard of care none none

The antiemetic activity of Emend Tri-Pack was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study 5 was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 1. Patients had the opportunity to receive open-label Emend Tri-Pack in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints:

Primary endpoint:


Other prespecified endpoints:


A summary of the key study results are shown in Table 19.

Emend Tri-Pack Regimen

n/m (%)

 Control Regimen

n/m (%)
n/m = Number of patients with desired response/number of patients included in time point.
Acute Phase: 0 to 24 hours following initiation of chemotherapy.
Delayed Phase: 25 to 120 hours following initiation of chemotherapy.
Overall Phase: 0 to 120 hours following initiation of chemotherapy.
PRIMARY ENDPOINT
Complete ResponseComplete Response = No vomiting or retching and no use of rescue medication. - Delayed phase 77/152 (50.7)p<0.01 when compared to Control Regimen 39/150 (26.0)
OTHER PRESPECIFIED ENDPOINTS
Complete Response – Acute phase 101/152 (66.4)p<0.05 when compared to Control Regimen 78/150 (52.0)
Complete Response – Overall phase 61/152 (40.1) 30/150 (20.0)

14.4 Prevention of PONV in Adults

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies 7 and 8), Emend Tri-Pack was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. These two studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. Study 7 was a multinational study including the U.S., whereas, Study 8 was conducted entirely in the U.S.

In the two studies, patients were randomized to receive 40-mg Emend Tri-Pack, 125-mg Emend Tri-Pack, or 4-mg ondansetron as a single dose. Emend Tri-Pack was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the Emend Tri-Pack 125-mg dose did not demonstrate any additional clinical benefit over the 40-mg dose and is not a recommended dosage regimen .

Of the 564 patients who received 40-mg Emend Tri-Pack, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40-mg Emend Tri-Pack ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older.

The antiemetic activity of Emend Tri-Pack was evaluated during the 0 to 48 hour period following the end of surgery.

Efficacy measures in Study 7 included:


A closed testing procedure was applied to control the type I error for the primary endpoints.

The results of the primary and secondary endpoints for 40-mg Emend Tri-Pack and 4-mg ondansetron are described in Table 20:

Treatment n/m (%) Emend Tri-Pack vs. Ondansetron
Δ Odds ratioEstimated odds ratio for Emend Tri-Pack versus Ondansetron. A value of >1 favors Emend Tri-Pack over Ondansetron. Analysis
n/m = Number of responders/number of patients in analysis.
Δ Difference (%):EMEND 40 mg minus Ondansetron.
PRIMARY ENDPOINTS
No Vomiting 0 to 24 hours (Superiority)

(no emetic episodes)
Emend Tri-Pack 40 mg 246/293 (84.0) 12.6% 2.1 P<0.001P-value of two-sided test <0.05.
Ondansetron 200/280 (71.4)
Complete Response (Non-inferiority: If LBLB = lower bound of 1-sided 97.5% confidence interval for the odds ratio. >0.65)

(no emesis and no rescue therapy, 0 to 24 hours)
Emend Tri-Pack 40 mg 187/293 (63.8) 8.8% 1.4 LB=1.02
Ondansetron 154/280 (55.0)
Complete Response (Superiority: If LB >1.0)

(no emesis and no rescue therapy, 0 to 24 hours)
Emend Tri-Pack 40 mg 187/293 (63.8) 8.8% 1.4 LB=1.02
Ondansetron 154/280 (55.0)
SECONDARY ENDPOINT
No Vomiting 0 to 48 hours (Superiority)

(no emetic episodes)
Emend Tri-Pack 40 mg 238/292 (81.5) 15.2% 2.3 P<0.001Based on the prespecified fixed sequence multiplicity strategy, Emend Tri-Pack 40 mg was not superior to Ondansetron.
Ondansetron 185/279 (66.3)

In Study 7, the use of Emend Tri-Pack did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of Emend Tri-Pack delayed the time to first vomiting, as depicted in Figure 3.

Figure 3: Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery – Study 7

Efficacy measures in Study 8 included:


Study 8 failed to satisfy its primary hypothesis that Emend Tri-Pack is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery.

The study demonstrated that 40-mg Emend Tri-Pack had a clinically meaningful effect with respect to the secondary endpoint "no vomiting" during the first 24 hours after surgery and was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

Treatment n/m (%) Emend Tri-Pack vs. Ondansetron
Δ Odds ratioEstimated odds ratio: Emend Tri-Pack 40 mg versus Ondansetron. Analysis
n/m = Number of responders/number of patients in analysis.
Δ Difference (%):EMEND 40 mg minus Ondansetron.
PRIMARY ENDPOINT
Complete Response

(no emesis and no rescue therapy, 0 to 24 hours)
Emend Tri-Pack 40 mg 111/248 (44.8) 2.5% 1.1 0.61
Ondansetron 104/246 (42.3)
SECONDARY ENDPOINTS
No Vomiting

(no emetic episodes, 0 to 24 hours)
Emend Tri-Pack 40 mg 223/248 (89.9) 16.3% 3.2 <0.001Not statistically significant after pre-specified multiplicity adjustment.
Ondansetron 181/246 (73.6)
No Use of Rescue Medication

(for established emesis or nausea, 0 to 24 hours)
Emend Tri-Pack 40 mg 112/248 (45.2) -0.7% 1.0 0.83
Ondansetron 113/246 (45.9)
No Vomiting 0 to 48 hours (Superiority)

(no emetic episodes, 0 to 48 hours)
Emend Tri-Pack 40 mg 209/247 (84.6) 17.7% 2.7 <0.001
Ondansetron 164/245 (66.9)
Figure 3

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 3855 - 125-mg capsules: Opaque, hard gelatin capsule with white body and pink cap with "462" and "125 mg" printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0462-06 unit-dose package of 6.

No. 3854 - 80-mg capsules: White, opaque, hard gelatin capsule with "461" and "80 mg" printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0461-02 unit-of-use BiPack of 2

NDC 0006-0461-06 unit-dose package of 6.

No. 3862 - Unit-of-use TriPack containing one 125-mg capsule and two 80-mg capsules.

NDC 0006-3862-03.

No. 6741 - 40-mg capsules: Opaque, hard gelatin capsule with white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink on the body. They are supplied as follows:

NDC 0006-0464-10 unit-of-use package of 1

NDC 0006-0464-05 unit-dose package of 5.

No. 3066 - 125 mg for oral suspension: Pink to light pink powder, in a single-use pouch, packaged as a kit with one 1 mL oral dosing dispenser, one 5 mL oral dosing dispenser, one cap and one mixing cup. It is supplied as follows:

NDC 0006-3066-03 – unit of use carton.

Storage and Handling

Capsules

Store at 20-25°C (68-77°F).

For Oral Suspension

Store unopened pouch at 20-25°C (68-77°F); excursions permitted between 15-30°C (between 59-86°F). Store in the original container. Do not open pouch until ready for use.

Once prepared, if suspension is not used immediately, store refrigerated [between 36°F-46°F (2°C-8°C)] for up to 72 hours prior to use. When ready to use, the mixture can be kept at room temperature [between 68°F-77°F (20°C-25°C)] for up to 3 hours.

17 PATIENT COUNSELING INFORMATION

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

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients taking Emend Tri-Pack. Advise patients to stop taking Emend Tri-Pack and seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, or difficulty in breathing or swallowing.

Drug Interactions

Advise patients to discuss all medications they are taking, including other prescription, non-prescription medication or herbal products .

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 the 3-day regimen of Emend Tri-Pack with each chemotherapy cycle, or following administration of a single 40-mg dose of Emend Tri-Pack for the prevention of postoperative nausea and vomiting .

Hormonal Contraceptives: Advise patients that administration of Emend Tri-Pack 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 Emend Tri-Pack and for 1 month following the last dose of Emend Tri-Pack .

Distributed by:

Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

For patent information: www.merck.com/product/patent/home.html

Copyright © 2003-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

uspi-mk0869-mf-1705r011

Patient Information

Emend Tri-Pack® (EE mend)

(aprepitant)

capsules

Emend Tri-Pack® (EE mend)

(aprepitant)

for oral suspension
This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: December 2015
Read this Patient Information before you start taking Emend Tri-Pack and each time you get a refill. 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 Emend Tri-Pack?

Emend Tri-Pack for oral suspension 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

Emend Tri-Pack capsules is a prescription medicine used:

  • with other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines
  • in adults to prevent nausea and vomiting after surgery

Emend Tri-Pack is not used to treat nausea and vomiting that you already have.

Emend Tri-Pack should not be used continuously for a long time (chronic use).

Who should not take Emend Tri-Pack?

Do not take Emend Tri-Pack if you:

  • are allergic to Emend Tri-Pack or any of the ingredients in Emend Tri-Pack. See the end of this leaflet for a complete list of ingredients in Emend Tri-Pack.
  • are taking pimozide (ORAP®)
What should I tell my healthcare provider before taking Emend Tri-Pack?

Before you take Emend Tri-Pack, tell your healthcare provider if you:

  • have liver problems
  • are pregnant or plan to become pregnant. It is not known if Emend Tri-Pack 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 back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with Emend Tri-Pack and for 1 month after your last dose of Emend Tri-Pack.
  • are breastfeeding or plan to breastfeed. It is not known if Emend Tri-Pack passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Emend Tri-Pack.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Emend Tri-Pack may affect the way other medicines work, and other medicines may affect how Emend Tri-Pack 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 should I take Emend Tri-Pack?
  • Take Emend Tri-Pack exactly as prescribed.
  • Swallow Emend Tri-Pack capsules whole.
  • If you are receiving chemotherapy, Emend Tri-Pack may be taken with or without food.
  • If you take too much Emend Tri-Pack, call your healthcare provider, or go to the nearest hospital emergency room.
  • If you are receiving cancer chemotherapy, Emend Tri-Pack is taken as 3 doses over 3 days - starting on the day you have chemotherapy, and for the following 2 days.
  • In adults who are receiving chemotherapy, there are 2 ways your healthcare provider may prescribe Emend Tri-Pack for you:
    • Capsules of Emend Tri-Pack by mouth for all 3 doses:
      • You should get a package that has 3 capsules of Emend Tri-Pack.
      • Day 1 (Day of chemotherapy): Take one 125 mg capsule of Emend Tri-Pack (white and pink) by mouth 1 hour before you start your chemotherapy treatment.
      • Day 2 and Day 3: Take one 80 mg capsule of Emend Tri-Pack (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, Emend Tri-Pack should be taken in the morning.
    • Oral suspension of Emend Tri-Pack by mouth for all 3 doses, for adults who are not able to swallow capsules:
      • For each dose of Emend Tri-Pack for oral suspension, you will get a pre-filled oral dosing dispenser that contains your prescribed dose.
      • See the detailed Instructions for Use that comes with Emend Tri-Pack for oral suspension for information about the correct way to take a dose of Emend Tri-Pack for oral suspension. If you have questions about how to take Emend Tri-Pack for oral suspension, talk to your healthcare provider.
      • Day 1 (Day of chemotherapy): Take 1 dose of Emend Tri-Pack for oral suspension by mouth 1 hour before you start your chemotherapy treatment.
      • Day 2 and Day 3: Take 1 dose of Emend Tri-Pack for oral suspension by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, Emend Tri-Pack for oral suspension should be taken in the morning.
  • In children 12 years of age and older, who can swallow capsules by mouth, and who are receiving chemotherapy, Emend Tri-Pack is prescribed as capsules of Emend Tri-Pack by mouth for all 3 doses:
    • You should get a package that has 3 capsules of Emend Tri-Pack.
    • Day 1 (Day of chemotherapy): Take one 125 mg capsule of Emend Tri-Pack (white and pink) by mouth 1 hour before you start your chemotherapy treatment.
    • Day 2 and Day 3: Take one 80 mg capsule of Emend Tri-Pack (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, Emend Tri-Pack should be taken in the morning.
  • In children 6 months to less than 12 years of age who are receiving chemotherapy, or in children 12 years of age and older who are not able to swallow capsules and who are receiving chemotherapy, Emend Tri-Pack is prescribed as oral suspension of Emend Tri-Pack by mouth for all 3 doses:
    • For each dose of Emend Tri-Pack, you will get a pre-filled oral dosing dispenser that contains your child's prescribed dose.
    • See the detailed Instructions for Use that comes with Emend Tri-Pack for oral suspension, for information about the correct way to give a dose of Emend Tri-Pack for oral suspension. If you have questions about how to give Emend Tri-Pack for oral suspension, talk to your child's healthcare provider.
    • Day 1 (Day of chemotherapy): Give 1 dose of Emend Tri-Pack for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment.
    • Day 2 and Day 3: Give 1 dose of Emend Tri-Pack for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, Emend Tri-Pack should be given in the morning.
  • If you are an adult and are having surgery:
    • Your healthcare provider will prescribe a 40 mg capsule of Emend Tri-Pack for you before surgery. Take Emend Tri-Pack within 3 hours before surgery.
    • Follow your healthcare provider's instructions about restrictions on eating and drinking before surgery.
  • If you take the blood thinner medicine warfarin sodium (COUMADIN®, JANTOVEN®), your healthcare provider may do blood tests after you take Emend Tri-Pack to check your blood clotting.
What are the possible side effects of Emend Tri-Pack?
  • In adults taking Emend Tri-Pack to prevent nausea and vomiting caused by chemotherapy, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.
  • In adults taking Emend Tri-Pack to prevent nausea and vomiting after surgery, the most common side effects include constipation and low blood pressure (hypotension).
  • In children 6 months to 17 years of age, who are taking Emend Tri-Pack to prevent nausea and vomiting caused by chemotherapy, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.

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 Emend Tri-Pack. For more information ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Emend Tri-Pack?

EMEND capsules

  • Store Emend Tri-Pack capsules at room temperature, between 68°F to 77°F (20°C to 25°C).

Emend Tri-Pack for oral suspension

  • Store Emend Tri-Pack for oral suspension in the refrigerator, between 36°F to 46°F (2°C to 8°C).
  • Use Emend Tri-Pack for oral suspension within 2 days of getting the medicine from your healthcare provider.
  • When ready to use, Emend Tri-Pack for oral suspension can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.

Keep Emend Tri-Pack and all medicines out of the reach of children.

General information about the safe and effective use of Emend Tri-Pack

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Emend Tri-Pack for a condition for which it was not prescribed. Do not give Emend Tri-Pack to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Emend Tri-Pack that is written for health professionals. For more information about Emend Tri-Pack call 1-800-622-4477 or go to www.emend.com.

What are the ingredients in Emend Tri-Pack?

Emend Tri-Pack capsules:

Active ingredient: Emend Tri-Pack

Inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 125 mg capsule shell also contains red ferric oxide and yellow ferric oxide. The 40 mg capsule shell also contains yellow ferric oxide.

Emend Tri-Pack for oral suspension:

Active ingredient: Emend Tri-Pack

Inactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

For patent information: www.merck.com/product/patent/home.html

The brands listed in the above sections "Who should not take Emend Tri-Pack?" and "How should I take Emend Tri-Pack?" are the registered trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Copyright © 2003-2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

usppi-mk0869-mf-1512r006
Instructions for Use

Emend Tri-Pack® (EE-mend)

(aprepitant)

for oral suspension

Read the Patient Information and Instructions for

Use for Emend Tri-Pack for oral suspension before you take or

before you give a dose to your child

Take by mouth only

How to give a dose of Emend Tri-Pack for oral suspension
The healthcare provider has prepared the dose of Emend Tri-Pack for you or your child.
  • You will get Emend Tri-Pack in an oral dosing dispenser
  • Keep the oral dosing dispenser in the refrigerator until you give Emend Tri-Pack to yourself or your child
  • Store Emend Tri-Pack in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • Use Emend Tri-Pack within 2 days of getting the medicine from the healthcare provider.
  • When ready to use, Emend Tri-Pack can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.
  • Keep Emend Tri-Pack and all medicines out of the reach of children.
  • Give Emend Tri-Pack
  • Throw away the oral dosing dispenser and cap
The color of the medicine in the oral dosing dispenser may be different shades of pink (light pink to dark pink). This is normal and the medicine is okay to use.
  • Take the cap off the oral dosing dispenser.
  • Place the tip of the oral dosing dispenser in your mouth or in your child's mouth along the inner cheek on either the right or left side.
  • Slowly push the plunger all the way down to give all of the medicine in the oral dosing dispenser.

Call the healthcare provider if you or your child is not able to take the prescribed dose.
For more information go to www.emend.com or call 1-800-622-4477.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by:

Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

For patent information: www.merck.com/product/patent/home.html

Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

Issued: 12/2015

usifu-mk0869-mf-1512r000
Figure Figure Figure Figure Warning

Emend Tri-Pack pharmaceutical active ingredients containing related brand and generic drugs:


Emend Tri-Pack available forms, composition, doses:


Emend Tri-Pack destination | category:


Emend Tri-Pack Anatomical Therapeutic Chemical codes:


Emend Tri-Pack pharmaceutical companies:


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References

  1. Dailymed."EMEND (APREPITANT) CAPSULE EMEND (APREPITANT) KIT EMEND (APREPITANT) POWDER, FOR SUSPENSION [MERCK SHARP & DOHME CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."APREPITANT: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Aprepitant". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Emend Tri-Pack?

Depending on the reaction of the Emend Tri-Pack after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Emend Tri-Pack not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Emend Tri-Pack addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Emend Tri-Pack, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Emend Tri-Pack consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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