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Recent Study Showed a 150-mg, Single-Dose Investigational Formulation of Fosaprepitant Dimeglumine Comparable to Three-Day Regimen of Oral Aprepitant for Prevention of Chemotherapy-Induced Nausea and Vomiting.

Results from Study Presented at 2010 American Society of Clinical Oncology Annual Meeting

CHICAGO -- Merck announced today results from a new non-inferiority trial of an antiemetic regimen containing fosaprepitant dimeglumine administered as a single intravenous (IV) 150-mg dose in combination with a 5-HT3 antagonist and dexamethasone compared with a three-day regimen of aprepitant with a 5-HT3 antagonist and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving a first cycle of cisplatin-based chemotherapy. The regimen containing 150 mg fosaprepitant dimeglumine was not inferior to the regimen with oral aprepitant. Results of the study, known as EASE-017, will be presented on June 8th at the 2010 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, during a discussion on the poster titled "Phase III randomized double-blind study of single-dose fosaprepitant for prevention of cisplatin-induced nausea and vomiting."

"The results of this study demonstrate that an antiemetic-regimen with a single, 150-mg injection of fosaprepitant provides similar protection against CINV as a three-day regimen of oral EMEND([R]) (aprepitant), which has become part of the standard of care for patients receiving highly emetogenic chemotherapy," said Steven Grunberg, M.D., Professor of Medicine and Pharmacology, University of Vermont. "These findings are important because prevention of CINV is a major concern, and this formulation of EMEND could potentially provide dosing flexibility to prevent CINV."

Currently, EMEND is approved as a part of a three-day regimen for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic and highly emetogenic cancer chemotherapy, including high-dose cisplatin.

In the study, 71.9 percent of patients who received an antiemetic regimen that included a single, 150 mg dose of fosaprepitant , ondansetron 32 mg IV, and dexamethasone 12 mg orally on Day 1, and dexamethasone 8 mg orally on Day 2, and dexamethasone 8 mg orally twice daily on Days 3 and 4 achieved a complete response, defined as no vomiting and no use of rescue medication, in the overall phase of chemotherapy (0 to 120 hours post-initiation of cisplatin-based chemotherapy) compared to 72.3 percent of those receiving an antiemetic regimen containing a three-day oral regimen of EMEND (EMEND 125 mg orally, ondansetron 32 mg IV, and dexamethasone 12 mg orally on Day 1, EMEND 80 mg orally once daily on Days 2 and 3, and dexamethasone 8 mg orally once daily on Days 2 through 4; 95 percent confidence interval [CI] for difference between groups = -4.1 to 3.3). In addition, 74.3 percent of patients treated with the regimen containing the single, 150 mg dose of fosaprepitant achieved a complete response in the delayed phase (25 to 120 hours post cisplatin-based chemotherapy), compared to 74.2 percent of patients treated with a regimen containing a three-day regimen of EMEND. (95 percent CI for difference between groups = -3.5 to 3.7).

The overall incidence and types of adverse events were generally consistent between the two treatment groups. The most frequently reported drug-related clinical adverse events in both the group receiving a single, 150 mg dose of fosaprepitant and the group receiving oral EMEND were asthenia (loss of strength), constipation, anorexia, diarrhea and nausea.

Study Background

Ease-017 (Evaluation of fosAprepitant in Single-dose schedulE) is a Phase III, randomized, double-blind, parallel-group, non-inferiority study involving 2,322 patients naive to cisplatin therapy and scheduled to receive cisplatin-based chemotherapy at a dose of 70 mg/m2 or higher. Of the 2,322 patients randomized, 2,247 patients were included in the analysis. The study's primary endpoint was the proportion of patients who reported no vomiting and no use of rescue therapy (complete response) in the overall phase (0-120 hours post-initiation of cisplatin-based chemotherapy) and the secondary endpoint was the proportion of patients who reported a complete response (no vomiting and no use of rescue therapy) in the delayed phase (25 to 120 hours following initiation of cisplatin-based chemotherapy).

Important Information about EMEND

EMEND, when used in combination with other medicines, is only used to help prevent nausea and vomiting caused by chemotherapy. It is not used to treat nausea and vomiting after they start. EMEND([R]) (fosaprepitant dimeglumine) for Injection may cause serious side effects, including sudden allergic reactions such as hives, rash, itching, redness of the face or skin, and difficulty breathing or swallowing. The most common side effects of EMEND are tiredness, nausea, hiccups, constipation, diarrhea, loss of appetite, headache, hair loss, injection site pain, and hardening of the site of injection. These are not all the possible side effects of EMEND.

Patients should tell their doctor about all other medicines, vitamins, or herbal supplements they are taking, if they are pregnant or plan to become pregnant, if they are breastfeeding or if they have liver problems. Patients should not take EMEND with Orap (pimozide), Seldane (terfenadine), Hismanal (astemizole), or Propulsid (cisapride) as the combination may cause serious or life-threatening problems. EMEND may also affect some medicines, including chemotherapy, causing them to work differently in your body. Patients taking Coumadin (warfarin) may need to have blood tests after taking EMEND to check their blood clotting. Women who use birth control medicines during treatment with EMEND and for up to 1 month after using EMEND should also use a backup method of contraception to avoid pregnancy.

About Merck Oncology

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Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

EMEND([R]) is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

EMEND([R]) (fosaprepitant dimeglumine) for Injection is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Before prescribing EMEND or EMEND for Injection, please read the prescribing information and the patient product information that are attached.

9985512

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use EMEND safely and effectively. See full prescribing information for EMEND.
EMEND (aprepitant) Capsules








Initial U.S. Approval: 2003


INDICATIONS AND USAGE

EMEND([R]) is a substance P/neurokinin 1 (NK1) receptor antagonist, indicated:

* in combination with other antiemetic agents 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 (1.1)

* prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1.1)

* for the prevention of postoperative nausea and vomiting (PONV) (1.2)

Limitations of Use (1.3)

* Not studied for the treatment of established nausea and vomiting.

* Chronic continuous administration is not recommended.

DOSAGE AND ADMINISTRATION

Prevention of Chemotherapy Induced Nausea and Vomiting (2.1)

* EMEND is given for 3 days as part of the chemotherapy induced nausea and vomiting (CINV) regimen that includes a corticosteroid and a 5-HT3 antagonist. (2.1)

* The recommended dose of EMEND is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3. (2.1)

* EMEND (fosaprepitant dimeglumine) for Injection may be substituted for oral EMEND (125 mg) on Day 1 only as part of the CINV regimen. (2.1)

Prevention of Postoperative Nausea and Vomiting (2.2)

* The recommended oral dosage of EMEND for the postoperative nausea and vomiting (PONV) indication is 40 mg within 3 hours prior to induction of anesthesia. (2.2)

DOSAGE FORMS AND STRENGTHS

Capsules: 40 mg; 80 mg; 125 mg (3)

CONTRAINDICATIONS

* Hypersensitivity to any component of this medication. (4, 6.2)

* EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride, since inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. (4)

WARNINGS AND PRECAUTIONS

* Coadministration of aprepitant with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. (5.2)

* The efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used. (5.3, 7.1)

* EMEND is a dose-dependent inhibitor of CYP3A4, and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. (5.1)

* Caution should be exercised when administered in patients with severe hepatic impairment. (2.5, 5.4, 12.3)

ADVERSE REACTIONS

* Clinical adverse experiences for the CINV regimen in conjunction with highly and moderately emetogenic chemotherapy (incidence >10%) are: alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea. (6.1)

* Clinical adverse experiences for the PONV regimen (incidence >5%) are: constipation, hypotension, nausea, pruritus, pyrexia. (6.1)

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.

DRUG INTERACTIONS

* Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit or induce CYP3A4 activity may result in increased or reduced plasma concentrations of aprepitant, respectively. (5.1, 7.1, 7.2).

* Aprepitant is an inducer of CYP2C9; therefore, coadministration of EMEND with drugs that are metabolized by CYP2C9 (e.g. warfarin, tolbutamide), may result in lower plasma concentrations of these drugs. (5.2, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 03/2010
[TABLE OMITTED]


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

9985512

EMEND([R]) (aprepitant)

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

EMEND1, in combination with other antiemetic agents, is indicated 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

* prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) [see Dosage and Administration (2.1)].

1.2 Prevention of Postoperative Nausea and Vomiting (PONV)

EMEND is indicated for the prevention of postoperative nausea and vomiting [see Dosage and Administration (2.2)].

1.3 Limitations of Use

EMEND has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Capsules of EMEND (aprepitant) are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of EMEND is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3.

EMEND may be taken with or without food.

EMEND (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of aprepitant and may be substituted for oral EMEND (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion administered over 15 minutes.

In clinical studies with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:
[TABLE OMITTED]


In a clinical study with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:
[TABLE OMITTED]


2.2 Prevention of Postoperative Nausea and Vomiting (PONV)

The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of anesthesia.

EMEND may be taken with or without food.

2.3 Geriatric Patients

No dosage adjustment is necessary for the elderly.

2.4 Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease (ESRD) undergoing hemodialysis.

2.5 Patients with Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9).

2.6 Coadministration with Other Drugs

For additional information on dose adjustment for corticosteroids when coadministered with EMEND, see Drug Interactions (7.1).

Refer to the full prescribing information for coadministered antiemetic agents.

3 DOSAGE FORMS AND STRENGTHS

* Capsules EMEND 40 mg are opaque, hard, gelatin capsules, with white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink on the body.

* Capsules EMEND 80 mg are white, opaque, hard, gelatin capsules, with "461" and "80 mg" printed radially in black ink on the body.

* Capsules EMEND 125 mg are opaque, hard, gelatin capsules, with white body and pink cap with "462" and "125 mg" printed radially in black ink on the body.

4 CONTRAINDICATIONS

EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS

5.1 CYP3A4 Interactions

EMEND (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications.

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree.

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions (7.1)].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, EMEND (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125 mg/80 mg regimen) was co-administered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)].

5.2 Coadministration with Warfarin (a CYP2C9 substrate)

Coadministration of EMEND with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting [see Drug Interactions (7.1)].

5.3 Coadministration with Hormonal Contraceptives

Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions (7.1)].

5.4 Patients with Severe Hepatic Impairment

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)].

5.5 Chronic Continuous Use

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

6 ADVERSE REACTIONS

The overall safety of aprepitant was evaluated in approximately 5300 individuals.

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.

6.1 Clinical Trials Experience

Chemotherapy Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence 3%.
[TABLE OMITTED]


In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy

During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy.

In the combined analysis of Cycle 1 data for these 2 studies, the adverse experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Table 2 shows the percent of patients with clinical adverse experiences reported at an incidence 3%.
[TABLE OMITTED]


In a combined analysis of these two studies, isolated cases of serious adverse experiences were similar in the two treatment groups.

Highly and Moderately Emetogenic Chemotherapy

The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen in either HEC or MEC studies:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma.

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia.

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.

Eye disorders: conjunctivitis.

Cardiac disorders: myocardial infarction, palpitations, tachycardia.

Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.

Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.

Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.

Renal and urinary disorders: dysuria, renal insufficiency.

Reproductive system and breast disorders: pelvic pain.

General disorders and administrative site conditions: edema, malaise, pain, rigors.

Investigations: weight loss.

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Laboratory Adverse Experiences

Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence 3% in patients receiving highly emetogenic chemotherapy.
[TABLE OMITTED]


The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The adverse experience profiles 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.

Postoperative Nausea and Vomiting

In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV.

Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence 3% of the combined studies.
[TABLE OMITTED]


The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant:

Infections and infestations: postoperative infection

Metabolism and nutrition disorders: hypokalemia, hypovolemia.

Nervous system disorders: dizziness, hypoesthesia, syncope.

Vascular disorders: hematoma

Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression.

Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia.

Skin and subcutaneous tissue disorders: urticaria

General disorders and administrative site conditions: hypothermia, pain.

Investigations: blood pressure decreased

Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence.

Other adverse experiences (incidence 0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included:

Nervous system disorders: dysarthria, sensory disturbance.

Eye disorders: miosis, visual acuity reduced.

Respiratory, thoracic and mediastinal disorders: wheezing

Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort.

There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40 mg aprepitant.

Laboratory Adverse Experiences

One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence 3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).

Other Studies

In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.

Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

7 DRUG INTERACTIONS

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

7.1 Effect of Aprepitant on the Pharmacokinetics of Other Agents

CYP3A4 Substrates:

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect.

As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications (4)]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).

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).

Corticosteroids:

Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone [see Dosage and Administration (2.1)]. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended.

Methylprednisolone: EMEND, 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, a CYP3A4 substrate, 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. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of EMEND 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. Therefore, no dose adjustment is recommended.

Chemotherapeutic agents: [see Warnings and Precautions (5.1)]

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

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

CYP2C9 Substrates (Warfarin, Tolbutamide):

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Warfarin: A single 125-mg dose of EMEND 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 on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) 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. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) 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 orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 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 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).

7.2 Effect of Other Agents on the Pharmacokinetics of Aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.

Ketoconazole: When a single 125-mg dose of EMEND 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. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of EMEND 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.

Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND.

7.3 Additional Interactions

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

Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant 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 aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects

Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg--hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg--hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of EMEND in pediatric patients have not been established.

8.5 Geriatric Use

In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

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 aprepitant.

In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.

Aprepitant cannot be removed by hemodialysis.

11 DESCRIPTION

EMEND (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist, 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:

(Graphic Omitted)

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

Each capsule of EMEND for oral administration contains either 40 mg, 80 mg, or 125 mg of aprepitant 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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) and postoperative nausea and vomiting (PONV).

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

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant 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 aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations >500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in >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 aprepitant 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. QT prolongation with the oral dosing regimens for CINV and PONV are not expected.

12.3 Pharmacokinetics

Absorption

Following oral administration of a single 40 mg dose of EMEND 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 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 80-125 mg, the mean absolute oral bioavailability of aprepitant 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 aprepitant.

The pharmacokinetics of aprepitant are 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

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

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

Metabolism

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 IV 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.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal half-life ranged from approximately 9 to 13 hours.

Special Populations

Gender

Following oral administration of a single 125-mg dose of EMEND, no difference in AUC0-24hr was observed between males and females. The Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary based on gender.

Geriatric

Following oral administration of a single 125-mg dose of EMEND 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) 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. No dosage adjustment for EMEND is necessary in elderly patients.

Pediatric

EMEND has not been evaluated in patients below 18 years of age.

Race

Following oral administration of a single 125-mg dose of EMEND, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Whites and Blacks, respectively. These differences are not considered clinically meaningful. There was no difference in AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment for EMEND is necessary based on race.

Hepatic Insufficiency

Following administration of a single 125-mg dose of EMEND 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; therefore, no dosage adjustment for EMEND is necessary in patients with mild to moderate hepatic impairment.

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) [see Warnings and Precautions (5.4)].

Renal Insufficiency

A single 240-mg dose of EMEND was administered to patients with severe renal impairment (CrCl<30 mL/min) 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. 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.

No dosage adjustment for EMEND is necessary for patients with renal impairment or for patients with ESRD undergoing hemodialysis.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 aprepitant (plasma AUC0-24hr) of 0.7 to 1.6 times the human exposure (AUC0-24hr = 19.6 mcg--hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Aprepitant 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.

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

14 CLINICAL STUDIES

14.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

Oral administration of EMEND in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy.

Highly Emetogenic Chemotherapy (HEC)

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 5.
[TABLE OMITTED]


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

The antiemetic activity of EMEND 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:

Primary endpoint:

* complete response (defined as no emetic episodes and no use of rescue therapy)

Other prespecified endpoints:

* complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)

* no emesis (defined as no emetic episodes regardless of use of rescue therapy)

* no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)

* no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)

A summary of the key study results from each individual study analysis is shown in Table 6 and in Table 7.
[TABLE OMITTED]
[TABLE OMITTED]


In both studies, a statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

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

Figure 1: Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time -- Cycle 1

(Graphic Omitted)

p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.

Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both Phase III 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 >108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant 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 aprepitant regimen is maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

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

(Graphic Omitted)

Moderately Emetogenic Chemotherapy (MEC)

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 9) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (60 mg/m2) or epirubicin (100 mg/m2).

In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%).

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-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.

Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 8.
[TABLE OMITTED]


The antiemetic activity of EMEND was evaluated based on the following endpoints:

Primary endpoint:

Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy)

Other prespecified endpoints:

* no emesis (defined as no emetic episodes regardless of use of rescue therapy)

* no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)

* no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)

* complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)

* complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 9.
[TABLE OMITTED]


In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant 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 aprepitant 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.

Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, 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 aprepitant 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: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles.

Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N=430) was compared with a standard of care therapy (N=418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m2); or cytarabine IV (>1 g/m2).

Of the 430 patients who were randomized to receive the aprepitant 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 aprepitant-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. Patients receiving the aprepitant 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.

The antiemetic activity of EMEND 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 this study is shown in Table 10.
[TABLE OMITTED]


In this study, a statistically significantly higher proportion of patients receiving the aprepitant 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 aprepitant 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 aprepitant 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 aprepitant 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 aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, the difference in complete response rates between the aprepitant 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 gender was observed for the no vomiting endpoint.

14.2 Prevention of Postoperative Nausea and Vomiting (PONV)

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant 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 125 mg dose and the 40 mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40 mg aprepitant dose recommended for PONV.

Of the 564 patients who received 40 mg aprepitant, 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 aprepitant 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 was evaluated during the 0 to 48 hour period following the end of surgery. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S.

Efficacy measures in PONV Study 1 included:

* no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)

* complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)

* no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary)

* time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory)

* time to first emesis in the 0 to 48 hours following the end of surgery (exploratory).

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 aprepitant and 4 mg ondansetron are described in Table 11:
[TABLE OMITTED]


The use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant 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

(Graphic Omitted)

Efficacy measures in PONV Study 2 included:

* complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)

* no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary)

* no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary)

* no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary).

PONV Study 2 failed to satisfy its primary hypothesis that aprepitant 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 both dose levels of aprepitant had a clinically meaningful effect with respect to the secondary endpoint "no vomiting" during the first 24 hours after surgery and showed that the use of 40 mg aprepitant was associated with a 16% improvement over ondansetron for the no vomiting endpoint.
[TABLE OMITTED]


16 HOW SUPPLIED/STORAGE AND HANDLING

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. 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. 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.

Storage

Store at 20-25xC (68-77xF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling.]

17.1 Instructions

Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. For the prevention of chemotherapy induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For the prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40 mg capsule of EMEND) within 3 hours prior to induction of anesthesia.

Allergic reactions, which may be serious, and may include hives, rash and itching and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting.

Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

FDA-Approved Patient Labeling

9985512

EMEND([R]) (aprepitant)

U.S. Patent Nos.: 5,145,684; 5,719,147; 6,048,859; 6,096,742; 6,235,735
[TABLE OMITTED]


9985410
Patient Information








EMEND[R] (EE mend)








(aprepitant)








Capsules


Read the Patient Information that comes with EMEND before you start taking it and each time you refill your prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.

What is EMEND?

EMEND is a prescription medicine used in adults to prevent nausea and vomiting:

* caused by certain anti-cancer (chemotherapy) medicines. When used for this purpose, EMEND is always used with other medicines.

* after surgery.

EMEND is not used to treat nausea and vomiting that you already have.

EMEND should not be used continuously for a long time (chronic use).

It is not known if EMEND is safe and effective in children.

Who should not take EMEND?

Do not take EMEND if you:

* are taking any of the following medicines:

* ORAP[R] (pimozide)

* SELDANE[R] (terfenadine)

* HISMANAL[R] (astemizole)

* PROPULSID[R] (cisapride)

Taking EMEND with any of these medicines could cause serious or life-threatening problems.

* are allergic to any of the ingredients in EMEND. See the end of this leaflet for a list of all the ingredients in EMEND.

What should I tell my doctor before and during treatment with EMEND?

Before you take EMEND, tell your doctor if you:

* have liver problems

* are pregnant or plan to become pregnant. It is not known if EMEND 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 during treatment with EMEND and for up to 1 month after using EMEND to prevent pregnancy.

* are breast-feeding. It is not known if EMEND passes into your milk and if it can harm your baby.

Tell your doctor about all the medicines you are taking or plan to take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

EMEND may cause serious life-threatening reactions if used with certain medicines. See the section "Who should not take EMEND?"

EMEND may affect how other medicines work, and other medicines may affect how EMEND works. Ask your doctor or pharmacist before you take any new medicine. They can tell you if it is safe to take the medicine with EMEND.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.

How should I take EMEND?

* Take EMEND exactly as prescribed.

* If you take too much EMEND, call your doctor, local emergency department or poison control center right away.

If you are receiving cancer chemotherapy, EMEND is taken as 3 doses over 3 days - starting on the day you have chemotherapy, and the two days after chemotherapy. There are two ways that your doctor may prescribe EMEND for you:

1. Capsules of EMEND by mouth for all 3 doses:

You should get a package that has three capsules of EMEND.

* Day 1 (Day of chemotherapy): Take one 125-mg capsule of EMEND (white and pink) by mouth 1 hour before you start your chemotherapy treatment;

* Day 2 and Day 3 (the two days after chemotherapy): Take one 80-mg capsule of EMEND (white) by mouth, each morning for the 2 days after your chemotherapy treatment.

Or

2. Intravenous (IV) injection into a vein the first day, then capsules by mouth on the two days after chemotherapy:

* Day 1 (Day of chemotherapy): EMEND will be given to you by intravenous (IV) injection in your vein 30 minutes before you start your chemotherapy treatment.

* You should get a package that has two capsules of EMEND.

* Day 2 and Day 3 (the two days after chemotherapy): Take one 80-mg capsule of EMEND (white) by mouth, each morning for the 2 days after your chemotherapy treatment.

* If you are receiving chemotherapy, EMEND may be taken with or without food.

* If you are having surgery:

* Your doctor will prescribe a 40-mg capsule of EMEND for you before surgery. You take EMEND within three hours before surgery.

* Follow your doctor's instructions about restrictions on eating and drinking before surgery.

* If you take the blood thinner medicine warfarin sodium (COUMADIN[R], JANTOVEN[R]), your doctor may do blood tests after you take EMEND to check your blood clotting.

What are the possible side effects of EMEND?

EMEND may cause serious side effects, including:

* Serious allergic reactions. Allergic reactions can happen with EMEND and may be serious. Stop taking EMEND and call your doctor right away if you have any of these signs or symptoms of an allergic reaction:

* hives

* rash

* itching

* trouble breathing or swallowing.

In people taking EMEND to prevent nausea and vomiting caused by chemotherapy, the most common side effects of EMEND include:

* tiredness

* nausea

* hiccups

* constipation

* diarrhea

* loss of appetite

* headache

* hair loss

In people taking EMEND to prevent nausea and vomiting after surgery, the most common side effects are:

* constipation

* nausea

* itch

* fever

* low blood pressure

* headache

Tell your doctor 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. For more information ask your doctor or pharmacist.

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

How should I store EMEND?

* Store EMEND at room temperature, between 68xF and 77xF (20xC and 25xC).

* Keep EMEND and all medicines out of the reach of children.

General information about EMEND

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use EMEND for a condition for which it was not prescribed. Do not give EMEND to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about EMEND. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about EMEND that is written for health professionals. For more information about EMEND call 1-800-622-4477 or go to www.emend.com.

What are the ingredients in EMEND?

Active ingredient: aprepitant

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.

U.S. Patent Nos.: 5,145,684; 5,719,147; 6,048,859; 6,096,742; 6,235,735

The brands listed in the above sections "Who should not take EMEND?" and "What should I tell my doctor before and during treatment with EMEND?" are the registered trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
[TABLE OMITTED]


Issued March 2010
[TABLE OMITTED]


HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use EMEND for Injection safely and effectively. See full prescribing information for EMEND for Injection.
EMEND (fosaprepitant dimeglumine) for Injection








Initial U.S. Approval: 2008


INDICATIONS AND USAGE

EMEND for Injection, in combination with other antiemetic agents, is indicated 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 (1)

* prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) (1)

Limitations of Use (1.1)

* Not studied for the treatment of established nausea and vomiting.

* Chronic continuous administration is not recommended.

DOSAGE AND ADMINISTRATION

* EMEND for Injection (115 mg) may be substituted for oral EMEND (125 mg) on Day 1 only as part of the chemotherapy induced nausea and vomiting (CINV) regimen that includes a corticosteroid and a 5-HT3 antagonist. (2.1)

* The 3-day CINV regimen includes EMEND for Injection (115 mg) given 30 minutes prior to chemotherapy as an infusion administered over 15 minutes or EMEND (125 mg orally) on Day 1; EMEND (80 mg orally) on Days 2 and 3. (2.1)

DOSAGE FORMS AND STRENGTHS

One single dose per 10 mL glass vial supplied as sterile lyophilized powder for intravenous use only after reconstitution and dilution: 115 mg (3)

CONTRAINDICATIONS

* Hypersensitivity to any component of this medication. (4, 6.2)

* Fosaprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride, since inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. (4)

WARNINGS AND PRECAUTIONS

* Immediate hypersensitivity reactions may occur during infusion. Patients have generally responded to discontinuation. It is not recommended to reinitiate the infusion. (5.2, 6.2)

* Coadministration of aprepitant with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. (5.3)

* The efficacy of hormonal contraceptives during and for 28 days following the last dose of fosaprepitant or aprepitant may be reduced. Alternative or back-up methods of contraception should be used. (5.4, 7.1)

* Fosaprepitant, when administered as a 3-day antiemetic regimen for CINV is a moderate inhibitor of CYP3A4, and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. (5.1)

* Caution should be exercised when administered in patients with severe hepatic impairment. (2.5, 5.5, 12.3)

ADVERSE REACTIONS

* Clinical adverse experiences for the CINV regimen in conjunction with highly and moderately emetogenic chemotherapy (incidence >10%) are: alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea. (6.1)

* Clinical adverse experiences reported for EMEND for Injection (incidence >1%) are: infusion site pain, infusion site induration, headache. (6.1)

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.

DRUG INTERACTIONS

* Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant.

* Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit or induce CYP3A4 activity may result in increased or reduced plasma concentrations of aprepitant, respectively. (5.1, 7.1, 7.2)

* Aprepitant is an inducer of CYP2C9; therefore, coadministration of EMEND for Injection with drugs that are metabolized by CYP2C9 (e.g. warfarin, tolbutamide), may result in lower plasma concentrations of these drugs. (5.3, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 03/2010
[TABLE OMITTED]


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

9840005

EMEND([R]) (fosaprepitant dimeglumine) for Injection

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

EMEND for Injection1 is a substance P/neurokinin-1 (NK1) receptor antagonist indicated for use in combination with other antiemetic agents 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

* prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) [see Dosage and Administration (2.1)].

1.1 Limitations of Use

EMEND for Injection has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)

EMEND for Injection is a sterile prodrug of aprepitant to be administered intravenously as an infusion. Aprepitant is available as capsules (EMEND2) for oral administration.

EMEND for Injection (115 mg) may be substituted for EMEND (125 mg) 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an infusion administered over 15 minutes.

EMEND for Injection should not be mixed or reconstituted with solutions for which physical and chemical compatibility have not been established. EMEND for Injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Solution and Hartmann's Solution.

EMEND for Injection may be administered with or without food.

The 3-day CINV regimen includes EMEND for Injection (115 mg) or EMEND (125 mg orally) on Day 1; EMEND (80 mg orally) on Days 2 and 3; in addition to a corticosteroid and a 5-HT3 antagonist as specified in the tables below.

In clinical studies with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:
[TABLE OMITTED]


In a clinical study with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:
[TABLE OMITTED]


2.2 Preparation of EMEND for Injection

1. Aseptically inject 5 mL 0.9% Sodium Chloride for Injection (saline) into the vial. Assure that saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial.

2. Aseptically prepare an infusion bag filled with 110 mL of saline.

3. Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 110 mL of saline to yield a total volume of 115 mL and a final concentration of 1 mg/1 mL.

4. Gently invert the bag 2-3 times.

The reconstituted final drug solution is stable for 24 hours at ambient room temperature (at or below 25xC).

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Caution: EMEND for Injection should not be mixed or reconstituted with solutions for which physical and chemical compatibility have not been established. EMEND for Injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Solution and Hartmann's Solution.

2.3 Geriatric Patients

No dosage adjustment is necessary for the elderly.

2.4 Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease (ESRD) undergoing hemodialysis.

2.5 Patients with Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9).

2.6 Coadministration with Other Drugs

For additional information on dose adjustment for corticosteroids when coadministered with EMEND for Injection, [see Drug Interactions (7.1)].

Refer to the full prescribing information for coadministered antiemetic agents.

3 DOSAGE FORMS AND STRENGTHS

One 115 mg single dose per 10 mL glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).

4 CONTRAINDICATIONS

EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80 or any other components of the product.

Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, fosaprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS

5.1 CYP3A4 Interactions

Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions (7.1)].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was co-administered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)].

5.2 Hypersensitivity Reactions

Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and dyspnea have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.

5.3 Coadministration with Warfarin (a CYP2C9 substrate)

Coadministration of aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of fosaprepitant followed by oral aprepitant with each chemotherapy cycle [see Drug Interactions (7.1)].

5.4 Coadministration with Hormonal Contraceptives

Upon coadministration with aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant [see Drug Interactions (7.1)].

5.5 Patients with Severe Hepatic Impairment

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)].

5.6 Chronic Continuous Use

Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

6 ADVERSE REACTIONS

The overall safety of aprepitant was evaluated in approximately 4900 individuals.

Since EMEND for Injection is converted to aprepitant, those adverse experiences associated with aprepitant might also be expected to occur with EMEND for Injection.

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.

6.1 Clinical Trials Experience

Fosaprepitant (intravenous formulation)

In a randomized, open-label, incomplete crossover, bioequivalence study, 66 subjects were dosed with 115 mg of EMEND for Injection intravenously and 72 subjects received 125 mg of aprepitant orally. Systemic exposure of 115 mg of intravenous EMEND for Injection is equivalent to 125 mg oral aprepitant. The following clinical adverse experiences, regardless of causality, were reported in subjects dosed with EMEND for Injection: infusion site pain, 5 (7.6%); infusion site induration, 1 (1.5%); headache, 2 (3%).

Oral Aprepitant

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence 3%.
[TABLE OMITTED]


In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy

During Cycle 1 of a moderately emetogenic chemotherapy study, 438 patients were treated with the aprepitant regimen and 385 of these patients continued into the Multiple-Cycle extension for up to 4 cycles of chemotherapy. In Cycle 1, clinical adverse experiences were reported in approximately 73% of patients treated with the aprepitant regimen compared with approximately 75% of patients treated with standard therapy. Table 2 shows the percent of patients with clinical adverse experiences reported at an incidence 3%.
[TABLE OMITTED]


Isolated cases of serious adverse experiences, regardless of causality, of dehydration, enterocolitis, febrile neutropenia, hypertension, hypoesthesia, neutropenic sepsis, pneumonia, and sinus tachycardia were reported in the moderately emetogenic CINV clinical study.

Highly and Moderately Emetogenic Chemotherapy

The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma.

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia.

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.

Eye disorders: conjunctivitis.

Cardiac disorders: myocardial infarction, palpitations, tachycardia.

Vascular disorders: deep venous thrombosis, flushing, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.

Gastrointestinal disorders: acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.

Skin and subcutaneous tissue disorders: acne, diaphoresis, rash.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.

Renal and urinary disorders: dysuria, renal insufficiency.

Reproductive system and breast disorders: pelvic pain.

General disorders and administrative site conditions: edema, malaise, rigors.

Investigations: weight loss.

Laboratory Adverse Experiences

Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence 3% in patients receiving highly emetogenic chemotherapy.
[TABLE OMITTED]


The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The following laboratory adverse experiences were reported at an incidence 3% during Cycle 1 of the moderately emetogenic chemotherapy study in patients treated with the aprepitant regimen or standard therapy, respectively: decreased hemoglobin (2.3%, 4.7%) and decreased white blood cell count (9.3%, 9.0%).

The adverse experience profiles in the Multiple-Cycle extensions for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Other Studies with Postoperative Nausea and Vomiting

In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron I.V. Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron I.V.

Additional adverse experiences were observed in patients receiving general anesthesia. In the patients treated with aprepitant (40 mg) for postoperative nausea and vomiting, the following additional adverse experiences were reported, regardless of causality, at an incidence 3%: anemia, bradycardia, flatulence, hypotension, pruritus, pyrexia.

The following adverse experiences were reported, regardless of causality, in patients treated with aprepitant for postoperative nausea and vomiting at an incidence of >0.5% and greater than with ondansetron: abdominal pain, abdominal pain upper, blood pressure decreased, dizziness, dyspepsia, hematoma, hypoesthesia, hypothermia, hypovolemia, hypoxia, operative hemorrhage, pain, postoperative infection, respiratory depression, syncope, urticaria, wound dehiscence.

Other adverse experiences (incidence 0.5%) reported, regardless of causality, in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: bowel sounds abnormal, dysarthria, miosis, sensory disturbance, stomach discomfort, visual acuity reduced, wheezing.

Laboratory Adverse Experiences with Postoperative Nausea and Vomiting

One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant), was reported, regardless of causality, at an incidence 3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant as in patients treated with ondansetron.

Other Studies

In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.

Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-marketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

Immediate hypersensitivity reactions have been observed during the infusion of fosaprepitant, which may include the following: flushing, erythema, dyspnea [see Warnings and Precautions (5.2)].

7 DRUG INTERACTIONS

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from data with oral aprepitant and one study conducted with fosaprepitant and oral midazolam.

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.

7.1 Effect of Aprepitant on the Pharmacokinetics of Other Agents

CYP3A4 Substrates:

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications (4)].

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of fosaprepitant or oral aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Fosaprepitant or 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).

Corticosteroids:

Dexamethasone: Oral aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and oral aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant followed by aprepitant, to achieve exposures of dexamethasone similar to those obtained when dexamethasone is given without aprepitant. The daily dose of dexamethasone administered in clinical CINV studies with oral aprepitant reflects an approximate 50% reduction of the dose of dexamethasone [see Dosage and Administration (2.1)].

Methylprednisolone: Oral aprepitant, 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, a CYP3A4 substrate, 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. The I.V. methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant followed by aprepitant to achieve exposures of methylprednisolone similar to those obtained when it is given without aprepitant.

Chemotherapeutic agents: See Warnings and Precautions (5.1).

Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

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 healthy 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 (a CYP2C9 substrate) 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. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of fosaprepitant followed by aprepitant with each chemotherapy cycle.

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 (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and oral aprepitant was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg I.V. on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of oral aprepitant on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of either. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant or aprepitant and for 1 month following the last dose.

Midazolam: A study was completed with fosaprepitant and oral midazolam. Fosaprepitant was given at a dose of 100 mg over 15 minutes along with a single dose of midazolam 2 mg. The plasma AUC of midazolam was increased by 1.6-fold. This effect was not considered clinically important.

Oral aprepitant increased the AUC of midazolam by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of oral aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with a 3-day regimen of fosaprepitant followed by aprepitant. In another study with intravenous administration of midazolam, oral aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg I.V. was given prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Oral aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of oral aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and oral aprepitant. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of oral aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold.

7.2 Effect of Other Agents on the Pharmacokinetics of Aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.

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. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

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.

Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

7.3 Additional Interactions

Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure [mean (SD) of 24.3 (+/- 10.2) mm Hg with fosaprepitant versus 15.6 (+/- 4.1) mm Hg without fosaprepitant] and resulted in a small further maximum decrease in systolic blood pressure [mean (SD) of 29.5 (+/- 7.9) mm Hg with fosaprepitant versus 23.8 (+/- 4.8) mm Hg without fosaprepitant], which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval, beyond those changes induced by diltiazem alone.

In the same study, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant 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 aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg--hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg--hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

10 OVERDOSAGE

No specific information is available on the treatment of overdosage.

In the event of overdose, oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.

Aprepitant cannot be removed by hemodialysis.

11 DESCRIPTION

EMEND (fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant, a substance P/neurokinin-1 (NK1) receptor antagonist, and is chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[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 C23H22F7N4O6P - 2(C7H17NO5) and its structural formula is:

(Graphic Omitted)

Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.

EMEND for Injection is a lyophilized prodrug of aprepitant containing polysorbate 80 (PS80), to be administered intravenously as an infusion.

Each vial of EMEND for Injection for intravenous administration contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant and the following inactive ingredients: edetate disodium (14.4 mg), polysorbate 80 (57.5 mg), lactose anhydrous (287.5 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). Fosaprepitant dimeglumine hereafter will be referred to as fosaprepitant.

Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, 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:

(Graphic Omitted)

12 CLINICAL PHARMACOLOGY

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion [see Clinical Pharmacology (12.3)]. Upon conversion of 115 mg of fosaprepitant to aprepitant, 18.3 mg of phosphate and 73 mg of meglumine are liberated from fosaprepitant.

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

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK-1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK-1 receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations >500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in >95% brain NK-1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK-1 receptor occupancy and the clinical efficacy of aprepitant 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.

12.3 Pharmacokinetics

Aprepitant after Fosaprepitant Administration

Following a single intravenous dose of fosaprepitant administered as a 15-minute infusion to healthy volunteers the mean AUC0- of aprepitant was 31.7 (+/- 14.3) mcg--hr/mL and the mean maximal aprepitant concentration (Cmax) was 3.27 (+/- 1.16) mcg/mL. The mean aprepitant plasma concentration at 24 hours postdose was similar between the 125-mg oral aprepitant dose and the 115-mg intravenous fosaprepitant dose (See Figure 1).

Figure 1: Mean Plasma Concentration of Aprepitant Following 125-mg Oral Aprepitant and 115-mg I.V. Fosaprepitant

(Graphic Omitted)

Distribution

Fosaprepitant is rapidly converted to aprepitant. Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans.

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

Metabolism

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from nonclinical species (rat and dog) and humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant 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. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.

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 I.V. 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.

Special Populations

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant.

Gender

Following oral administration of a single 125-mg dose of aprepitant, no difference in AUC0-24hr was observed between males and females. The Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on gender.

Geriatric

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) 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. No dosage adjustment is necessary in elderly patients.

Pediatric

Fosaprepitant has not been evaluated in patients below 18 years of age.

Race

Following oral administration of a single 125-mg dose of aprepitant, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Whites and Blacks, respectively. These differences are not considered clinically meaningful. There was no difference in AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment is necessary based on race.

Hepatic Insufficiency

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 dose of oral 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; therefore, no dosage adjustment is necessary in patients with mild to moderate hepatic impairment.

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) [see Warnings and Precautions (5.5)].

Renal Insufficiency

A single 240-mg dose of oral aprepitant was administered to patients with severe renal impairment (CrCl<30 mL/min) 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. 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.

No dosage adjustment is necessary for patients with renal impairment or for patients with ESRD undergoing hemodialysis.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 aprepitant (plasma AUC0-24hr) of 0.7 to 1.6 times the human exposure (AUC0-24hr = 19.6 mcg--hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.

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.

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 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

14 CLINICAL STUDIES

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant. Fosaprepitant 115 mg I.V. infused over 15 minutes can be substituted for 125 mg oral aprepitant on Day 1 [see Dosage and Administration (2.1)]. Pivotal efficacy studies were conducted with oral aprepitant.

Oral administration of aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy.

14.1 Highly Emetogenic Chemotherapy (HEC)

In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older.

Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 4.
[TABLE OMITTED]


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

The antiemetic activity of oral aprepitant 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:

Primary endpoint:

* complete response (defined as no emetic episodes and no use of rescue therapy)

Other prespecified endpoints:

* complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)

* no emesis (defined as no emetic episodes regardless of use of rescue therapy)

* no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)

* no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)

A summary of the key study results from each individual study analysis is shown in Table 5 and in Table 6.
[TABLE OMITTED]
[TABLE OMITTED]


In both studies, a statistically significantly higher proportion of patients (both p<0.001) receiving the aprepitant 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 aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 2.

Figure 2: Percent of Patients Receiving Highly Emetogenic Chemotherapy Who Remain Emesis Free Over Time -- Cycle 1

(Graphic Omitted)

p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.

Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both Phase III 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 >108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant 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 3.

Figure 3: Proportion of Patients Receiving Highly Emetogenic Chemotherapy with No Emesis and No Significant Nausea by Treatment Group and Cycle

(Graphic Omitted)

14.2 Moderately Emetogenic Chemotherapy (MEC)

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 7) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (60 mg/m2) or epirubicin (100 mg/m2).

In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%).

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-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.

Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 7.
[TABLE OMITTED]


The antiemetic activity of oral aprepitant was evaluated based on the following endpoints:

Primary endpoint:

Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy)

Other prespecified endpoints:

* no emesis (defined as no emetic episodes regardless of use of rescue therapy)

* no nausea (maximum VAS <5 mm on a 0 to 100 mm scale)

* no significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale)

* complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale)

* complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 8.
[TABLE OMITTED]


In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy. 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 aprepitant 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.

Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, 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 aprepitant 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: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles.

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 3884 -- One 115 mg single dose per 10 mL glass vial: White to off-white lyophilized solid. Supplied as follows:

NDC 0006-3884-32 1 vial per carton.

Storage

Vials: Store at 2-8xC (36-46xF).

Sterile lyophilized powder for intravenous use only after reconstitution and dilution.

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling.]

17.1 Instructions

Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed.

Patients should follow the physician's instructions for the EMEND for Injection regimen.

For the prevention of CINV, patients should be given their dose of EMEND for Injection as an infusion over 15 minutes, 30 minutes prior to chemotherapy on Day 1.

Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin and may cause difficulty in breathing or swallowing, have been reported in general use. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction.

EMEND for Injection may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of fosaprepitant followed by aprepitant, with each chemotherapy cycle.

Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or back-up methods of contraception during treatment with EMEND for Injection and for 1 month following the last dose of the 3-day aprepitant regimen.

FDA-Approved Patient Labeling
[TABLE OMITTED]


9840005

U.S. Patent Nos.: 5,512,570; 5,691,336

1 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright [c] 2008 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All Rights Reserved

2 Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

9840005
Patient Information








EMEND[R]








(fosaprepitant dimeglumine)








for Injection


Read the Patient Information that comes with EMEND (fosaprepitant dimeglumine) for Injection before you are given the injection each time you refill your prescription. The information may have changed. This leaflet provides only a summary of certain information about EMEND for Injection. Your doctor or pharmacist can give you an additional leaflet that is written for health professionals that contains more complete information. This leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss EMEND for Injection when you start taking your medicine.

What is EMEND for Injection?

EMEND for Injection is a prescription medicine used in adults to prevent nausea and vomiting caused by certain cancer chemotherapy medicines. EMEND for Injection is always used WITH OTHER MEDICINES. EMEND for Injection is not used to treat nausea and vomiting that you already have.

Who should not take EMEND for Injection?

Do not take EMEND for Injection if you:

* are taking any of the following medicines:

* ORAP([R]) (pimozide)

* SELDANE([R]) (terfenadine)

* HISMANAL([R]) (astemizole)

* PROPULSID([R]) (cisapride)

Taking EMEND for Injection with any of these medicines could cause serious or life-threatening problems.

* are allergic to fosaprepitant or any of the ingredients in EMEND for Injection. See the end of this leaflet for a list of all the ingredients in EMEND for Injection.

What should I tell my doctor before and during treatment with EMEND for Injection?

Tell your doctor about all your medical conditions, including if you:

* have liver problems

* are pregnant or plan to become pregnant. It is not known if EMEND for Injection can harm your unborn baby. Women who use birth control medicines containing hormones to prevent pregnancy (these can include birth control pills, skin patches, implants, and certain IUDs) during treatment with EMEND for Injection and for up to 1 month after using EMEND for Injection should also use a back-up method of birth control to prevent pregnancy.

* are breast-feeding. It is not known if EMEND for Injection passes into your milk and if it can harm your baby.

Tell your doctor about all the medicines you are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements. EMEND for Injection may cause serious life-threatening reactions if used with certain medicines. (See the section "Who should not take EMEND for Injection?")

Some medicines can affect EMEND for Injection. EMEND for Injection may also affect some medicines, including chemotherapy, causing them to work differently in your body.

Your doctor may check to make sure your other medicines are working correctly while you are taking EMEND for Injection. People who take warfarin (COUMADIN([R]), JANTOVEN([R])) may need to have blood tests after each 3-day treatment to check their blood clotting.

How should I take EMEND for Injection?

EMEND for Injection is given intravenously on Day 1 only of a 3-day regimen, then EMEND capsules are taken by mouth on the two days after chemotherapy:

* Day 1 (Day of chemotherapy): EMEND will be given to you by intravenous (IV) injection in your vein 30 minutes before you start your chemotherapy treatment.

* You should get a package that has two capsules of EMEND.

* Day 2 and Day 3 (the two days after chemotherapy): Take one 80-mg capsule of EMEND (white) by mouth, each morning for the 2 days after your chemotherapy treatment.

EMEND for Injection may be given with or without food.

What are the possible side effects of EMEND for Injection?

EMEND for Injection may cause serious side effects, including:

* Allergic reactions, which may occur suddenly and may include hives, rash, itching, redness of the face or skin and may cause you to have difficult breathing or swallowing. If you have an allergic reaction, call your doctor or seek medical attention right away.

In people taking EMEND for Injection the most common side effects are:

* tiredness

* nausea

* hiccups

* constipation

* diarrhea

* loss of appetite

* headache

* hair loss

* injection site pain

* hardening of site of injection

Tell your doctor 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 for Injection. For more information ask your doctor 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 use of EMEND for Injection

This leaflet summarizes the most important information about EMEND for Injection. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about EMEND for Injection that is written for health professionals. For more information about EMEND for Injection call 1-800-622-4477 or go to www.emend.com.

What are the ingredients in EMEND for Injection?

Active ingredient: fosaprepitant

Inactive ingredients: edetate disodium, polysorbate 80, lactose anhydrous, sodium hydroxide and/or hydrochloric acid (for pH adjustment).

U.S. Patent Nos.: 5,512,570; 5,691,336

The brands listed in the above sections "Who should not take EMEND for Injection?" and "What should I tell my doctor before and during treatment with EMEND for Injection?" are the registered trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
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Issued March 2010
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Comment:Recent Study Showed a 150-mg, Single-Dose Investigational Formulation of Fosaprepitant Dimeglumine Comparable to Three-Day Regimen of Oral Aprepitant for Prevention of Chemotherapy-Induced Nausea and Vomiting.
Publication:Business Wire
Article Type:Clinical report
Geographic Code:1U3IL
Date:Jun 2, 2010
Words:21777
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