Limitations of Use

The recommended dosages in adults of CINVANTI, dexamethasone, and a 5-HT3 antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC are shown in Table 1, Table 2 and Table 3 respectively. Administer CINVANTI intravenously either by injection over a two (2) minute period or by infusion over a thirty (30) minute period on Day 1, completing the injection or infusion approximately 30 minutes prior to chemotherapy.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1. Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with HEC (Single-Dose Regimen)</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="16%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Agent</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 4</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with aprepitant <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINVANTI</td><td align="left" class="Rrule">130 mg intravenously</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dexamethasone<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">12 mg orally</td><td align="center" class="Rrule">8 mg orally</td><td align="center" class="Rrule">8 mg orally<br/>twice daily</td><td align="center" class="Rrule">8 mg orally<br/>twice daily</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule">See selected 5-HT<span class="Sub">3</span> antagonist prescribing information for recommended dosage</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2. Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with MEC (Single-Dose Regimen)</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="70%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Agent</th><th align="center" class="Rrule">Day 1</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINVANTI</td><td align="left" class="Rrule">130 mg intravenously</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dexamethasone<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></td><td align="left" class="Rrule">12 mg orally</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule">See selected 5-HT<span class="Sub">3</span> antagonist prescribing information for recommended dosage</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3. Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with MEC (3-Day Regimen with Oral Aprepitant on Days 2 and 3)</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Agent</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINVANTI</td><td align="left" class="Rrule">100 mg intravenously</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Oral Aprepitant</td><td align="left" class="Rrule">None</td><td align="center" class="Rrule">80 mg orally</td><td align="center" class="Rrule">80 mg orally</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dexamethasone<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="left" class="Rrule">12 mg orally</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule">See selected 5-HT<span class="Sub">3</span> antagonist prescribing information for recommended dosage</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> </tbody> </table></div>

Intravenous Injection over a period of 2 minutes

For intravenous injection over a period of 2 minutes, administer 130 mg of CINVANTI as part of a HEC or MEC regimen or 100 mg as part of a MEC regimen as a single dose on Day 1.

Aseptically withdraw 18 mL for the 130 mg dose or 14 mL for the 100 mg dose from the vial. Do not dilute.

The infusion line should be flushed with normal saline before and after administration of CINVANTI.

Intravenous Infusion over a period of 30 minutes

Table 4 includes preparation instructions for CINVANTI for HEC or MEC as a 130 mg single-dose regimen, and for MEC as a 100 mg single-dose followed by 2 days of oral aprepitant as a 3-day regimen. Differences in preparation for each dose are displayed as bolded text.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4. Preparation Instructions for CINVANTI Intravenous Infusion</span> </caption> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="75%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2">Note: The differences in preparation for each recommended dosage of CINVANTI are displayed in bolded text (see <a href="#table1">Table 1</a> for HEC Regimen and <a href="#table2">Table 2</a> for MEC Regimen).</td> </tr> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Use only Non-DEHP tubing, non-PVC infusion bags</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Step 1</td><td align="left" class="Rrule">Aseptically withdraw <span class="Bold">18 mL for the 130 mg dose</span> or <span class="Bold">14 mL for the 100 mg dose</span> from the vial and transfer it into an infusion bag<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> filled with <span class="Bold">100 mL</span> of 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Step 2</td><td align="left" class="Rrule">Gently invert the bag 4 to 5 times. Avoid shaking.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Step 3</td><td align="left" class="Rrule">Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed.</td> </tr> </tbody> </table></div>

Caution: Do not mix CINVANTI with solutions for which physical and chemical compatibility have not been established.

In-Use Storage Conditions for CINVANTI in Acceptable Intravenous Diluents

Diluted CINVANTI solution is stable at ambient room temperature for up to 6 hours in 0.9% Sodium Chloride Injection, USP or 12 hours in 5% Dextrose Injection, USP or up to 72 hours if stored under refrigeration in 0.9% Sodium Chloride Injection, USP or in 5% Dextrose Injection, USP.

CINVANTI is compatible with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

CINVANTI is incompatible with any solutions containing divalent cations (e.g. calcium, magnesium), including Lactated Ringer's Solution and Hartmann's Solution.

Injectable emulsion: 130 mg/18 mL (7.2 mg/mL) aprepitant as an opaque, off-white to amber emulsion, in single-dose vial

{ "type": "p", "children": [], "text": "Injectable emulsion: 130 mg/18 mL (7.2 mg/mL) aprepitant as an opaque, off-white to amber emulsion, in single-dose vial" }

CINVANTI is contraindicated in patients:

{ "type": "p", "children": [], "text": "CINVANTI is contraindicated in patients:" }

{ "type": "ul", "children": [ "who are hypersensitive to any component of the product [see Description (11)]. Hypersensitivity reactions including anaphylaxis have been reported [see Warnings and Precautions (5.2), Adverse Reactions (6.2)].", "taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of pimozide, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings and Precautions (5.1)]." ], "text": "" }

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

See Table 8 and Table 9 for a listing of potentially significant drug interactions [see Drug Interactions (7.1, 7.2)].

Serious hypersensitivity reactions, including anaphylaxis during or soon after administration of CINVANTI have occurred. Symptoms including dyspnea, eye swelling, flushing, pruritus and wheezing have been reported [see Adverse Reactions (6.2)].

Monitor patients during and after administration. If hypersensitivity reactions occur, discontinue CINVANTI and administer appropriate medical therapy. Do not reinitiate CINVANTI in patients who experience these symptoms with previous use.

Coadministration of CINVANTI with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology (12.3)]. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of CINVANTI with each chemotherapy cycle [see Drug Interactions (7.1)].

Upon coadministration with CINVANTI, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of CINVANTI [see Clinical Pharmacology (12.3)]. Advise patients to use effective alternative or back-up methods of non-hormonal contraception during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last [see Drug Interactions (7.1), Use in Specific Populations (8.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of CINVANTI was evaluated as a single-dose in healthy subjects and established from adequate and well-controlled studies of intravenous fosaprepitant and/or oral aprepitant [see Clinical Studies (14)]. Adverse reactions observed in these adequate and well-controlled studies are described below.

Safety of CINVANTI

A total of 200 healthy subjects received a single 130 mg dose of CINVANTI as a 30-minute infusion. Adverse reactions reported in at least 2% of subjects were headache (3%) and fatigue (2%). The safety profile of CINVANTI in 50 healthy subjects who received a single 2-minute injection was similar to that seen with a 30-minute infusion.

Single-Dose Intravenous Fosaprepitant -- HEC

In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single intravenous dose of fosaprepitant, a prodrug of aprepitant, compared to 1169 patients receiving a 3-day regimen of oral aprepitant [see Clinical Studies (14.1)]. When administered intravenously, fosaprepitant is converted to aprepitant within 30 minutes. The safety profile was generally similar to that seen in prior HEC studies with a 3-day regimen of oral aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the intravenous fosaprepitant group (3%) compared to those in the oral aprepitant group (0.5%). The reported infusion-site reactions included: infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration and infusion-site thrombophlebitis.

Adverse reactions associated with oral aprepitant may also be expected to occur with CINVANTI. See the full prescribing information for oral aprepitant for complete safety information.

Single-Dose Intravenous Fosaprepitant -- MEC

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of intravenous fosaprepitant in combination with ondansetron and dexamethasone (intravenous fosaprepitant regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 5.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5. Most Common Adverse Reactions in Patients Receiving MEC<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></span> </caption> <col align="left" valign="top" width="34%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Intravenous fosaprepitant, ondansetron, and dexamethasone<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> <br/>(N=504)</th><th align="center" class="Rrule">Ondansetron and dexamethasone<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> <br/>(N=497)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Reported in ≥2% of patients treated with the intravenous fosaprepitant regimen and at a greater incidence than standard therapy.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Intravenous fosaprepitant regimen</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>Standard therapy</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Fatigue</td><td align="center" class="Rrule">15%</td><td align="center" class="Rrule">13%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">13%</td><td align="center" class="Rrule">11%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Neutropenia</td><td align="center" class="Rrule">8%</td><td align="center" class="Rrule">7%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asthenia</td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Anemia</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Peripheral Neuropathy</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Leukopenia</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dyspepsia</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Urinary Tract Infection</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Pain In Extremity</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">1%</td> </tr> </tbody> </table></div>

Infusion-site reactions were reported in 2.2% of patients treated with the intravenous fosaprepitant regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and 8 infusion-site thrombophlebitis (0.6%, 0.0%), reported in the intravenous fosaprepitant regimen compared to standard therapy, respectively.

3-Day Oral Aprepitant -- MEC

In 2 active-controlled clinical trials in patients receiving MEC, 868 patients were treated with a 3-day oral aprepitant regimen during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, oral aprepitant was given in combination with ondansetron and dexamethasone (oral aprepitant regimen) and was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.2)].

In the combined analysis of Cycle 1 data for these 2 studies, adverse reactions were reported in approximately 14% of patients treated with the aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the oral aprepitant regimen with an incidence of at least 1% and greater than standard therapy are listed in Table 6.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6. Adverse Reactions (≥ 1%) in Patients Receiving MEC with a Greater Incidence in the Oral 3-Day Aprepitant Regimen Relative to Standard Therapy</span> </caption> <col align="left" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="34%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Oral Aprepitant Regimen<br/>(N = 868)</th><th align="center" class="Rrule">Standard Therapy<br/>(N = 846)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Fatigue</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">0.9</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Eructation</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">0.1</td> </tr> </tbody> </table></div>

A listing of adverse reactions reported in less than 1% in patients treated with the oral aprepitant regimen that occurred at an incidence greater than in patients treated with standard therapy are presented in the Less Common Adverse Reactions subsection below.

Less Common Adverse Reactions

Adverse reactions reported in studies in patients treated with the 3-day oral aprepitant regimen with an incidence < 1% and greater than standard therapy are listed in Table 7.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 7. Adverse Reactions (incidence &lt; 1%) in Patients Observed in Studies with a Greater Incidence in the Oral Aprepitant Regimen Relative to Standard Therapy</span> </caption> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="65%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Italics">Infection and infestations</span></td><td align="left" class="Rrule">candidiasis, staphylococcal infection</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Blood and the lymphatic system disorders</span></td><td align="left" class="Rrule">anemia, febrile neutropenia</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Metabolism and nutrition disorders</span></td><td align="left" class="Rrule">weight gain, polydipsia</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Psychiatric disorders</span></td><td align="left" class="Rrule">disorientation, euphoria, anxiety</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Nervous system disorders</span></td><td align="left" class="Rrule">dizziness, dream abnormality, cognitive disorder, lethargy, somnolence</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Eye disorders</span></td><td align="left" class="Rrule">conjunctivitis</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Ear and labyrinth disorders</span></td><td align="left" class="Rrule">tinnitus</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Cardiac disorders</span></td><td align="left" class="Rrule">bradycardia, cardiovascular disorder, palpitations</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Vascular disorders</span></td><td align="left" class="Rrule">hot flush, flushing</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Respiratory, thoracic and mediastinal disorders</span></td><td align="left" class="Rrule">pharyngitis, sneezing, cough, postnasal drip, throat irritation</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" valign="top"><span class="Italics">Gastrointestinal disorders</span></td><td align="left" class="Rrule">nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, feces hard, neutropenic colitis, flatulence, stomatitis</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Skin and subcutaneous tissue disorders</span></td><td align="left" class="Rrule">rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Musculoskeletal and connective tissue disorders</span></td><td align="left" class="Rrule">muscle cramp, myalgia, muscular weakness</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Renal and urinary disorders</span></td><td align="left" class="Rrule">polyuria, dysuria, pollakiuria</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">General disorders and administration site condition</span></td><td align="left" class="Rrule">edema, chest discomfort, malaise, thirst, chills, gait disturbance</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Investigations</span></td><td align="left" class="Rrule">alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased</td> </tr> </tbody> </table></div>

In another chemotherapy-induced nausea and vomiting study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.

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

The following adverse reactions have been identified during post-approval use of intravenous fosaprepitant and/or intravenous or oral aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis [see Warnings and Precautions (5.2)].

Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock [see Contraindications (4), Warnings and Precautions (5.2)].

Nervous system disorders: ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.

Aprepitant is a substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology (12.3)].

Some substrates of CYP3A4 are contraindicated with CINVANTI [see Contraindications (4)]. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 8.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8. Effects of Aprepitant on the Pharmacokinetics of Other Drugs</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="left" valign="middle" width="75%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP3A4 Substrates</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Pimozide</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased pimozide exposure.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">CINVANTI is contraindicated <span class="Italics">[see <a href="#S4">Contraindications (4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Benzodiazepines</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Monitor for benzodiazepine-related adverse reactions.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Dexamethasone</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased dexamethasone exposure <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Reduce the dose of oral dexamethasone by approximately 50% <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Methylprednisolone</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased methylprednisolone exposure <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.<br/>Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Chemotherapeutic Agents that are Metabolized by CYP3A4</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule"><span class="Underline">Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents</span> <br/> <ul class="Disc"> <li>Monitor for chemotherapeutic-related adverse reactions.</li> </ul> <span class="Underline">Etoposide, vinorelbine, paclitaxel, and docetaxel</span> <br/> <ul class="Disc"> <li>No dosage adjustment needed.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Hormonal Contraceptives</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>, <a href="#S8.3">Use in Specific Populations (8.3)</a>, and <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Effective alternative or back-up methods of contraception (such as condoms or spermicides) should be used during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">birth control pills, skin patches, implants, and certain IUDs</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2C9 Substrates</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">Warfarin</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Decreased warfarin exposure and decreased prothrombin time (INR) <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3)</a>, <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of CINVANTI with each chemotherapy cycle.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Other Antiemetic Agents</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold Italics">5-HT<span class="Sub">3</span> Antagonists</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">No change in the exposure of the 5-HT<span class="Sub">3</span> antagonist <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">No dosage adjustment needed.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">ondansetron, granisetron, dolasetron</td> </tr> </tbody> </table></div>

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Co-administration of CINVANTI with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 9.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9. Effects of Other Drugs on Pharmacokinetics of Aprepitant</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="left" valign="top" width="75%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Moderate to Strong CYP3A4 Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with CINVANTI <span class="Italics">[see <a href="#S6.1">Adverse Reactions (6.1)</a></span> and <span class="Italics"><a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Avoid concomitant use of CINVANTI.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule"><span class="Underline">Moderate inhibitor</span>:<br/>diltiazem<br/> <span class="Underline">Strong inhibitors</span>:<br/>ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Strong CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of CINVANTI <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Avoid concomitant use of CINVANTI.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">rifampin, carbamazepine, phenytoin</td> </tr> </tbody> </table></div>

Risk Summary

There are no available data on CINVANTI use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Avoid use of CINVANTI in pregnant women due to the alcohol content (see Clinical Considerations). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug concentrations (area under the plasma-concentration time curve [AUC]) of aprepitant approximately equivalent to the exposure at the recommended human dose (RHD) of CINVANTI 130 mg (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

CINVANTI contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. There is no safe level of alcohol exposure in pregnancy; therefore, avoid use of CINVANTI in pregnant women.

Data

Animal Data

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately equivalent to the exposure at the RHD of CINVANTI 130 mg. Aprepitant crosses the placenta in rats and rabbits.

Risk Summary

There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CINVANTI and any potential adverse effects on the breastfed infant from CINVANTI or from the underlying maternal condition.

Contraception

Upon administration of CINVANTI, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms or spermicides) during treatment with CINVANTI and for 1 month following the last dose of CINVANTI or oral aprepitant, whichever is administered last [see Warnings and Precautions (5.4), Drug Interactions (7.1), Clinical Pharmacology (12.3)].

The safety and effectiveness of CINVANTI have not been established in pediatric patients.

Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with fosaprepitant and/or oral aprepitant has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when CINVANTI is administered [see Clinical Pharmacology (12.3)].

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

{ "type": "p", "children": [], "text": "There is no specific information on the treatment of overdosage with aprepitant." }

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

{ "type": "p", "children": [], "text": "In the event of overdose, CINVANTI should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of CINVANTI, drug-induced emesis may not be effective in cases of CINVANTI overdosage." }

Aprepitant is not removed by hemodialysis.

{ "type": "p", "children": [], "text": "Aprepitant is not removed by hemodialysis." }

CINVANTI injectable emulsion contains the active ingredient, aprepitant. Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

{ "type": "p", "children": [], "text": "CINVANTI injectable emulsion contains the active ingredient, aprepitant. Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one." }

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

{ "type": "p", "children": [], "text": "Its empirical formula is C23H21F7N4O3, and its structural formula is:" }

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.

{ "type": "p", "children": [], "text": "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." }

CINVANTI (aprepitant) injectable emulsion is a sterile, opaque, off-white to amber liquid in a single-dose vial for intravenous use. Each vial contains 130 mg aprepitant in 18 mL of emulsion. The emulsion also contains the following inactive ingredients: egg lecithin (2602 mg), dehydrated alcohol (513 mg), sodium oleate (87 mg), soybean oil (1734 mg), sucrose (973 mg), and water for injection (12142 mg).

{ "type": "p", "children": [], "text": "CINVANTI (aprepitant) injectable emulsion is a sterile, opaque, off-white to amber liquid in a single-dose vial for intravenous use. Each vial contains 130 mg aprepitant in 18 mL of emulsion. The emulsion also contains the following inactive ingredients: egg lecithin (2602 mg), dehydrated alcohol (513 mg), sodium oleate (87 mg), soybean oil (1734 mg), sucrose (973 mg), and water for injection (12142 mg)." }

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. 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.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg intravenous dose of fosaprepitant, a prodrug of aprepitant, had no effect on the QTc interval. In a cross-study comparison, maximum aprepitant concentrations (Cmax) after a single 200 mg dose of fosaprepitant were 1.04- and 1.5-fold higher than that achieved with CINVANTI 130 mg dose and 100 mg dose given as a 30-minute infusion, respectively.

Pharmacokinetic parameters following administration of a single intravenous 130 mg dose of CINVANTI administered as a 2-minute injection or 100 mg or 130 mg dose of CINVANTI administered as a 30-minute infusion to healthy subjects are summarized in Table 10.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 10. Aprepitant Pharmacokinetic Parameters (Mean (± Standard Deviation)) After Single Dose Intravenous Administration of CINVANTI</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule">CINVANTI 130 mg<br/>2-minute intravenous injection</th><th align="center" class="Rrule">CINVANTI 130 mg<br/>30-minute intravenous infusion</th><th align="center" class="Rrule">CINVANTI 100 mg<br/>30-minute intravenous infusion</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Lrule Rrule">AUC<span class="Sub">0-72hr</span> (mcg∙hr/mL)</td><td align="center" class="Rrule">45.6 (± 15.5)</td><td align="center" class="Rrule">43.9 (± 12.7)</td><td align="center" class="Rrule">27.8 (± 6.5)</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">C<span class="Sub">max</span> (mcg/mL)</td><td align="center" class="Rrule">13.9 (±3.8)</td><td align="center" class="Rrule">6.1 (± 1.5)</td><td align="center" class="Rrule">4.3 (± 1.2)</td> </tr> </tbody> </table></div>

Distribution

Aprepitant is greater than 99% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.

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

Elimination

Metabolism

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

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent terminal half-life ranged from approximately 9 to 13 hours.

Specific Populations

Geriatric Patients

Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations (8.5)].

Male and Female Patients

Following oral administration of a single dose of aprepitant ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax are 9% and 17% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.

Racial or Ethnic Groups

Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful.

Patients with Renal Impairment

A single 240 mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

Patients with Hepatic Impairment

Following administration of a single 125 mg oral dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6)].

Body Mass Index (BMI)

For every 5 kg/m2 increase in BMI AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.

Drug Interactions Studies

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

Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs

CYP3A4 Substrates:

Midazolam: Fosaprepitant 150 mg (corresponding to CINVANTI 130 mg) administered as a single intravenous dose on Day 1 increased the AUC0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4.

Corticosteroids:

Dexamethasone: Fosaprepitant administered as a single 150 mg (corresponding to CINVANTI 130 mg) intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, administered as a single 8 mg oral dose on Days 1, 2, and Day 3, by approximately 2-fold on Days 1 and 2 [see Dosage and Administration (2.1), Drug Interactions (7.1)].

Methylprednisolone: When oral aprepitant as a 3-day regimen (125 mg/80 mg/80 mg) was administered with intravenous methylprednisolone 125 mg on Day 1 and oral methylprednisolone 40 mg on Days 2 and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day 1 and by 2.5-fold on Day 3 [see Drug Interactions (7.1)].

Chemotherapeutic agents:

Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125 mg/80 mg/80 mg) did not influence the pharmacokinetics of docetaxel [see Drug Interactions (7.1)].

Vinorelbine: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125 mg/80 mg/80 mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Drug Interactions (7.1)].

CYP2C9 substrates (Warfarin, Tolbutamide):

Warfarin: A single 125 mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant [see Drug Interactions (7.1)].

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.

Other Drugs:

Oral contraceptives: When oral aprepitant was administered as a 3-day regimen (125 mg/80 mg/80 mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment [see Drug Interactions (7.1)].

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

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Rifampin: When a single 375 mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)].

Ketoconazole: When a single 125 mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions (7.2)].

Diltiazem: In a study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, a moderate CYP3A4 inhibitor administered three times daily, resulted in a 1.5-fold increase in the aprepitant AUC and a 1.4-fold increase in the diltiazem AUC.

When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 ± 10.2 mm Hg with fosaprepitant versus 15.6 ± 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic blood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 ± 7.9 mm Hg with fosaprepitant versus 23.8 ± 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see Drug Interactions (7.2)].

Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant approximately equivalent to (female rats) or less than (male rats) the human exposure at the CINVANTI RHD of 130 mg. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure approximately 2 times the human exposure at the RHD of CINVANTI 130 mg. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Mutagenesis

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.

Impairment of Fertility

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 RHD of CINVANTI 130 mg and exposure in female rats approximately equivalent to the human exposure).

In a randomized, parallel, double-blind, active-controlled study, 150 mg fosaprepitant as a single intravenous infusion (N = 1147) was compared to a 3-day oral aprepitant regimen (N = 1175) in patients receiving a HEC regimen that included cisplatin (≥70 mg/m2). All patients in both groups received dexamethasone and ondansetron (see Table 11) Patient demographics were similar between the two treatment groups. Of the total 2322 patients, 63% were men, 56% White, 26% Asian, 3% American Indian/Alaska Native, 2% Black, 13% Multi-Racial, and 33% Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 11. Treatment Regimens in HEC Trial<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a></span> </caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="16%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Lrule Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 4</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Fosaprepitant placebo, aprepitant placebo and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Dexamethasone was also administered in the evenings on Days 3 and 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Day 2 reflects a dosage adjustment to account for a drug interaction with the fosaprepitant regimen <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span> </dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the clinical trial, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">§</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Days 2 through 4 reflects a dosage adjustment to account for a drug interaction with the oral aprepitant regimen <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Intravenous Fosaprepitant Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fosaprepitant</td><td align="center" class="Rrule">150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral dexamethasone<a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></td><td align="center" class="Rrule">12 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">8 mg twice daily</td><td align="center" class="Rrule">8 mg twice daily</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">Ondansetron<a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a></td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Oral Aprepitant Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Aprepitant capsules</td><td align="center" class="Rrule">125 mg</td><td align="center" class="Rrule">80 mg</td><td align="center" class="Rrule">80 mg</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral dexamethasone<a class="Sup" href="#footnote-11" name="footnote-reference-11">§</a></td><td align="center" class="Rrule">12 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">8 mg</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">Ondansetron<a class="Sup" href="#footnote-10">‡</a></td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> </tbody> </table></div>

The efficacy of a single-dose of intravenous fosaprepitant was evaluated based on the primary and secondary endpoints listed in Table 12 and was shown to be non-inferior to that of the 3-day oral aprepitant regimen with regard to complete response in each of the evaluated phases. The pre-specified non-inferiority margin for complete response in the overall phase was 7%. The pre-specified non-inferiority margin for complete response in the delayed phase was 7.3%. The pre-specified non-inferiority margin for no vomiting in the overall phase was 8.2%.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 12. Percent of Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">ENDPOINTS </th><th align="center" class="Rrule">Intravenous Fosaprepitant Regimen<br/>(N = 1106)<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> <br/>%</th><th align="center" class="Rrule">Oral aprepitant Regimen<br/>(N = 1134)<a class="Sup" href="#footnote-12">*</a> <br/>%</th><th align="center" class="Rrule">Difference<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> <br/>(95% CI)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>N: Number of patients included in the primary analysis of complete response.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for gender.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">‡</a> </dt> <dd>Complete Response = no vomiting and no use of rescue therapy.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">§</a> </dt> <dd>Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">¶</a> </dt> <dd>Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PRIMARY ENDPOINT</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Complete Response<a class="Sup" href="#footnote-14" name="footnote-reference-14">‡</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Overall<a class="Sup" href="#footnote-15" name="footnote-reference-15">§</a></td><td align="center" class="Rrule">71.9</td><td align="center" class="Rrule">72.3</td><td align="center" class="Rrule">-0.4 (-4.1, 3.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">SECONDARY ENDPOINTS</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Complete Response<a class="Sup" href="#footnote-14">‡</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">    Delayed phase<a class="Sup" href="#footnote-16" name="footnote-reference-16">¶</a></td><td align="center" class="Rrule">74.3</td><td align="center" class="Rrule">74.2</td><td align="center" class="Rrule">0.1 (-3.5, 3.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  No Vomiting</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">    Overall<a class="Sup" href="#footnote-15">§</a></td><td align="center" class="Rrule">72.9</td><td align="center" class="Rrule">74.6</td><td align="center" class="Rrule">-1.7 (-5.3, 2.0)</td> </tr> </tbody> </table></div>

Single-Dose Intravenous Fosaprepitant – MEC

In a randomized, parallel, double-blind, active comparator-controlled study, 150 mg fosaprepitant as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (intravenous fosaprepitant regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 13) in patients receiving a MEC regimen. Patient demographics were similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis, 41% were men, 84% White, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin (51%), oxaliplatin (24%), and cyclophosphamide (12%).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 13. Treatment Regimens in MEC Trial<a class="Sup" href="#footnote-17" name="footnote-reference-17">*</a></span> </caption> <col align="left" valign="middle" width="30%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-17" name="footnote-17">*</a> </dt> <dd>Fosaprepitant placebo and dexamethasone placebo (on Day 1) were used to maintain blinding.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">†</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose reflects a dosage adjustment to account for a drug interaction with the fosaprepitant regimen [<span class="Italics">see <a href="#S12.3">Clinical Pharmacology (12.3)</a></span>].</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">‡</a> </dt> <dd>The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Intravenous Fosaprepitant Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fosaprepitant </td><td align="center" class="Rrule">150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone<a class="Sup" href="#footnote-18" name="footnote-reference-18">†</a></td><td align="center" class="Rrule">12 mg</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Ondansetron<a class="Sup" href="#footnote-19" name="footnote-reference-19">‡</a></td><td align="center" class="Rrule">8 mg for 2 doses</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Standard Therapy</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone </td><td align="center" class="Rrule">20 mg</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Oral Ondansetron<a class="Sup" href="#footnote-19">‡</a></td><td align="center" class="Rrule">8 mg for 2 doses</td><td align="center" class="Rrule">8 mg twice daily</td><td align="center" class="Rrule">8 mg twice daily</td> </tr> </tbody> </table></div>

The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment group are shown in Table 14.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 14. Percent of Patients Receiving MEC Responding by Treatment Group</span> </caption> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">Intravenous Fosaprepitant Regimen<br/>(N = 502)<a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a> <br/>%</th><th align="center" class="Rrule">Standard Therapy Regimen<br/>(N = 498)<a class="Sup" href="#footnote-20">*</a> <br/>%</th><th align="center" class="Rrule">p-Value</th><th align="center" class="Rrule">Treatment Difference<br/>(95% CI)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>N: Number of patients included in the intention to treat population.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>Complete Response = no vomiting and no use of rescue therapy.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">‡</a> </dt> <dd>Delayed phase = 25 to 120 hours post-initiation of chemotherapy.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PRIMARY ENDPOINT</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response<a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">  Delayed phase<a class="Sup" href="#footnote-22" name="footnote-reference-22">‡</a></td><td align="center" class="Rrule">78.9</td><td align="center" class="Rrule">68.5</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">10.4 (5.1, 15.9)</td> </tr> </tbody> </table></div>

3-Day Oral Aprepitant -- MEC

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, a 3-day oral aprepitant regimen was compared with a standard of care therapy in patients receiving a MEC regimen that included cyclophosphamide 750 to1500 mg/m2; or cyclophosphamide 500 to1500 mg/m2 and doxorubicin (≤ 60 mg/m2) or epirubicin (≤ 100 mg/m2). Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 15.

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

Of the 438 patients who were randomized to receive the oral 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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 15. Treatment Regimens in MEC Trial<a class="Sup" href="#footnote-23" name="footnote-reference-23">*</a></span> </caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-23" name="footnote-23">*</a> </dt> <dd>Aprepitant placebo and dexamethasone placebo were used to maintain binding.</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">†</a> </dt> <dd>1 hour prior to chemotherapy.</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">‡</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">§</a> </dt> <dd>Ondansetron was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and 8 hours after first ondansetron dose.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Oral Aprepitant Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Aprepitant</td><td align="center" class="Rrule">125 mg orally<a class="Sup" href="#footnote-24" name="footnote-reference-24">†</a></td><td align="center" class="Rrule">80 mg orally</td><td align="center" class="Rrule">80 mg orally</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dexamethasone</td><td align="center" class="Rrule">12 mg orally<a class="Sup" href="#footnote-25" name="footnote-reference-25">‡</a></td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">8 mg orally × 2 doses<a class="Sup" href="#footnote-26" name="footnote-reference-26">§</a></td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Standard Therapy</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dexamethasone</td><td align="center" class="Rrule">20 mg orally</td><td align="center" class="Rrule">None</td><td align="center" class="Rrule">None</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">8 mg orally × 2 doses</td><td align="center" class="Rrule">8 mg orally twice daily</td><td align="center" class="Rrule">8 mg orally twice daily</td> </tr> </tbody> </table></div>

The antiemetic activity of oral aprepitant was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

Other prespecified endpoints:

A summary of the key results from this study is shown in Table 16.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 16. Percent of Patients Receiving MEC Responding by Treatment Group and Phase – Cycle 1</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">Oral Aprepitant Regimen<br/>(N = 433)<a class="Sup" href="#footnote-27" name="footnote-reference-27">*</a> <br/>%</th><th align="center" class="Rrule">Standard Therapy<br/>(N = 424)<a class="Sup" href="#footnote-27">*</a> <br/>%</th><th align="center" class="Rrule">p-Value</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-27" name="footnote-27">*</a> </dt> <dd>N: Number of patients included in the primary analysis of complete response.</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">†</a> </dt> <dd>Overall: 0 to 120 hours post-chemotherapy treatment.</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">‡</a> </dt> <dd>NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value &lt; 0.001.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PRIMARY ENDPOINT<a class="Sup" href="#footnote-28" name="footnote-reference-28">†</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">42</td><td align="center" class="Rrule">0.015</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">OTHER PRESPECIFIED ENDPOINTS<a class="Sup" href="#footnote-28">†</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Emesis</td><td align="center" class="Rrule">76</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-29" name="footnote-reference-29">‡</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Nausea</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Significant Nausea</td><td align="center" class="Rrule">61</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Rescue Therapy</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Complete Protection</td><td align="center" class="Rrule">43</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">NS</td> </tr> </tbody> </table></div>

In this study, a statistically significantly (p = 0.015) higher proportion of patients receiving the oral 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 oral aprepitant regimen in Cycle 1 had a complete response during the acute (0 to 24 hours) and delayed (25 to 120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

Additional Patient-Reported Outcomes: In this study, in patients receiving MEC, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the oral 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 MEC 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.

Oral Aprepitant Postmarketing Trial: In another multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the 3-day oral aprepitant regimen (N = 430) was compared with a standard of care therapy (N = 418) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; intravenous cyclophosphamide (less than 1500 mg/m2); or intravenous cytarabine (greater than 1 g/m2).

Of the 430 patients who were randomized to receive the oral 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 aprepitant 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 17.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 17. Percent of Patients Receiving MEC Responding by Treatment Group for Study 2 – Cycle 1</span> </caption> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">Oral Aprepitant Regimen<br/>(N = 430)<a class="Sup" href="#footnote-30" name="footnote-reference-30">*</a> <br/>%</th><th align="center" class="Rrule">Standard Therapy<br/>(N = 418)<a class="Sup" href="#footnote-30">*</a> <br/>%</th><th align="center" class="Rrule">p-Value</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-30" name="footnote-30">*</a> </dt> <dd>N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">No Vomiting Overall</td><td align="center" class="Rrule">76</td><td align="center" class="Rrule">62</td><td align="center" class="Rrule">&lt; 0.0001</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Complete Response Overall</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">0.0003</td> </tr> </tbody> </table></div>

In this study, a statistically significantly higher proportion of patients receiving the oral 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 to 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.

Storage

CINVANTI injectable emulsion vials must be refrigerated, store at 2°C-8°C (36°F-46°F).

CINVANTI injectable emulsion vials can remain at room temperature up to 60 days.

Do not freeze.

Hypersensitivity

Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported [see Warnings and Precautions (5.2)]. Advise patients to stop taking CINVANTI and seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, or difficulty in breathing or swallowing, or dizziness, rapid or weak heartbeat or feeling faint.

Drug Interactions

Advise patients to discuss all medications they are taking, including other prescription, non- prescription medication or herbal products [see Contraindications (4), Warnings and Precautions (5.1)].

Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following initiation of CINVANTI with each chemotherapy cycle [see Warnings and Precautions (5.3)].

Hormonal Contraceptives: Advise patients that administration of CINVANTI may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of non-hormonal contraception (such as condoms or spermicides) during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last [see Warnings and Precautions (5.4), Use in Specific Populations (8.3)].

Pregnancy

Advise pregnant women of the potential risk to a fetus and to avoid use of CINVANTI during pregnancy [see Use in Specific Populations (8.1)].

Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USAPatent: https://herontx.com/patents/CINVANTI® is a registered trademark of Heron Therapeutics, Inc.Copyright © 2017-2024 Heron Therapeutics, Inc. All rights reserved.

{ "type": "p", "children": [], "text": "Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USAPatent: https://herontx.com/patents/CINVANTI® is a registered trademark of Heron Therapeutics, Inc.Copyright © 2017-2024 Heron Therapeutics, Inc.\nAll rights reserved." }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="25%"/> <col align="right" valign="top" width="25%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="center" class="Lrule Rrule" colspan="3">PATIENT INFORMATION<br/>CINVANTI<span class="Sup">®</span> (sin van' tee)<br/>(aprepitant)<br/>injectable emulsion, for intravenous use</th> </tr> </thead> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="2">This Patient Information has been approved by the U.S. Food and Drug Administration</td><td align="right" colspan="1">Revised: September 2023</td> </tr> </tfoot> <tbody> <tr class="Botrule First First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What is CINVANTI?</span> <br/>CINVANTI is a prescription medicine used with other medicines that treat nausea and vomiting in adults to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines.<ul class="Disc"> <li>CINVANTI is not used to treat nausea and vomiting that you already have.</li> <li>It is not known if CINVANTI is safe and effective in children.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Do not receive CINVANTI if you:</span> <ul class="Disc"> <li>are allergic to aprepitant, or any of the ingredients in CINVANTI. See the end of this leaflet for a complete list of the ingredients in CINVANTI.</li> <li>are taking pimozide (ORAP).</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Before receiving CINVANTI, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have liver problems.</li> <li>are pregnant or plan to become pregnant. CINVANTI may harm your unborn baby.<ul class="Circle"> <li>Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use a backup method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with CINVANTI and for 1 month after receiving the last dose of CINVANTI.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. It is not known if CINVANTI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive CINVANTI.</li> </ul>Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.<br/>CINVANTI may affect the way other medicines work, and other medicines may affect the way CINVANTI works, causing serious side effects.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">How will I receive CINVANTI?</span> <ul class="Disc"> <li>CINVANTI is given on Day 1. It will be given to you by intravenous (IV) injection or infusion in your vein about 30 minutes before you start your chemotherapy treatment.</li> <li>If you take the blood thinner medicine warfarin sodium (COUMADIN, JANTOVEN), your healthcare provider may do blood tests after you receive CINVANTI to check your blood clotting.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What are the possible side effects of CINVANTI?<br/>CINVANTI may cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">Serious allergic reactions.</span>Serious allergic reactions can happen during your CINVANTI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during or soon after your infusion:<ul class="Circle"> <li>trouble breathing or swallowing, shortness of breath or wheezing</li> <li>swelling of your eyes, face, tongue, or throat</li> <li>flushing or redness of your face or skin</li> <li>hives, rash, itching</li> <li>dizziness, a rapid or weak heartbeat, or you feel faint</li> </ul> </li> </ul> <span class="Bold">The most common side effects of CINVANTI include:</span></td> </tr> <tr> <td align="left" class="Lrule"> <ul class="Disc"> <li>tiredness</li> <li>diarrhea</li> <li>low white blood cell and red blood cell counts</li> <li>weakness</li> <li>feeling weak or numb in your arms and legs</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>headache</li> <li>indigestion</li> <li>urinary tract infection</li> <li>belching or burping</li> <li>pain in your arms and legs</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Infusion-site side effects with CINVANTI may include:</span> pain, hardening, redness or itching at the site of infusion. Swelling (inflammation) of a vein caused by a blood clot can also happen at the infusion site. Tell your healthcare provider if you get any infusion-site side effects.<br/>Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of CINVANTI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">General information about the safe and effective use of CINVANTI.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about CINVANTI that is written for health professionals.</td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="right"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="3"> <p class="First"> <span class="Bold">What are the ingredients in CINVANTI?</span> <br/>Active ingredient: aprepitant<br/>Inactive ingredients: egg lecithin, dehydrated alcohol (3.6% alcohol by volume), sodium oleate, soybean oil, sucrose, and water for injection.<br/>Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USA<br/>Patent: https://herontx.com/patents/<br/>CINVANTI<span class="Sup">®</span> is a registered trademark of Heron Therapeutics, Inc.</p> <p>Copyright © 2017-2023 <span class="Bold">Heron Therapeutics, Inc</span>. All rights reserved.<br/>For more information about CINVANTI call 1-844-437-6611 or go to www.CINVANTI.com.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"right\" valign=\"top\" width=\"25%\"/>\n</colgroup>\n<thead>\n<tr class=\"First First Last Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"3\">PATIENT INFORMATION<br/>CINVANTI<span class=\"Sup\">®</span> (sin van' tee)<br/>(aprepitant)<br/>injectable emulsion, for intravenous use</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" colspan=\"2\">This Patient Information has been approved by the U.S. Food and Drug Administration</td><td align=\"right\" colspan=\"1\">Revised: September 2023</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What is CINVANTI?</span>\n<br/>CINVANTI is a prescription medicine used with other medicines that treat nausea and vomiting in adults to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines.<ul class=\"Disc\">\n<li>CINVANTI is not used to treat nausea and vomiting that you already have.</li>\n<li>It is not known if CINVANTI is safe and effective in children.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">Do not receive CINVANTI if you:</span>\n<ul class=\"Disc\">\n<li>are allergic to aprepitant, or any of the ingredients in CINVANTI. See the end of this leaflet for a complete list of the ingredients in CINVANTI.</li>\n<li>are taking pimozide (ORAP).</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">Before receiving CINVANTI, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have liver problems.</li>\n<li>are pregnant or plan to become pregnant. CINVANTI may harm your unborn baby.<ul class=\"Circle\">\n<li>Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use a backup method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with CINVANTI and for 1 month after receiving the last dose of CINVANTI.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if CINVANTI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive CINVANTI.</li>\n</ul>Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.<br/>CINVANTI may affect the way other medicines work, and other medicines may affect the way CINVANTI works, causing serious side effects.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">How will I receive CINVANTI?</span>\n<ul class=\"Disc\">\n<li>CINVANTI is given on Day 1. It will be given to you by intravenous (IV) injection or infusion in your vein about 30 minutes before you start your chemotherapy treatment.</li>\n<li>If you take the blood thinner medicine warfarin sodium (COUMADIN, JANTOVEN), your healthcare provider may do blood tests after you receive CINVANTI to check your blood clotting.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What are the possible side effects of CINVANTI?<br/>CINVANTI may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Serious allergic reactions.</span>Serious allergic reactions can happen during your CINVANTI infusion. Tell your healthcare provider or nurse right away if you get any of these symptoms during or soon after your infusion:<ul class=\"Circle\">\n<li>trouble breathing or swallowing, shortness of breath or wheezing</li>\n<li>swelling of your eyes, face, tongue, or throat</li>\n<li>flushing or redness of your face or skin</li>\n<li>hives, rash, itching</li>\n<li>dizziness, a rapid or weak heartbeat, or you feel faint</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">The most common side effects of CINVANTI include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\">\n<ul class=\"Disc\">\n<li>tiredness</li>\n<li>diarrhea</li>\n<li>low white blood cell and red blood cell counts</li>\n<li>weakness</li>\n<li>feeling weak or numb in your arms and legs</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>headache</li>\n<li>indigestion</li>\n<li>urinary tract infection</li>\n<li>belching or burping</li>\n<li>pain in your arms and legs</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">Infusion-site side effects with CINVANTI may include:</span> pain, hardening, redness or itching at the site of infusion. Swelling (inflammation) of a vein caused by a blood clot can also happen at the infusion site. Tell your healthcare provider if you get any infusion-site side effects.<br/>Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of CINVANTI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">General information about the safe and effective use of CINVANTI.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about CINVANTI that is written for health professionals.</td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"right\"></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in CINVANTI?</span>\n<br/>Active ingredient: aprepitant<br/>Inactive ingredients: egg lecithin, dehydrated alcohol (3.6% alcohol by volume), sodium oleate, soybean oil, sucrose, and water for injection.<br/>Manufactured for: Heron Therapeutics, Inc., San Diego, CA 92121, USA<br/>Patent: https://herontx.com/patents/<br/>CINVANTI<span class=\"Sup\">®</span> is a registered trademark of Heron Therapeutics, Inc.</p>\n<p>Copyright © 2017-2023 <span class=\"Bold\">Heron Therapeutics, Inc</span>. All rights reserved.<br/>For more information about CINVANTI call 1-844-437-6611 or go to www.CINVANTI.com.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 47426-201-01Rx Only

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CINVANTI ® (aprepitant)injectable emulsion

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130 mg/18 mL(7.2 mg/mL)

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For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

Must be refrigerated. Store at2°C-8°C (36°F-46°F). Do Not Freeze.

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1 Sterile Single-Dose VialDiscard Unused Portion

{ "type": "p", "children": [], "text": "1 Sterile Single-Dose VialDiscard Unused Portion" }

HERONTHERAPEUTICS

{ "type": "p", "children": [], "text": "HERONTHERAPEUTICS" }

NDC 47426-201-01Rx Only

{ "type": "p", "children": [], "text": "NDC 47426-201-01Rx Only" }

CINVANTI ® (aprepitant)injectable emulsion

{ "type": "p", "children": [], "text": "CINVANTI ®\n(aprepitant)injectable emulsion" }

130 mg/18 mL(7.2 mg/mL)

{ "type": "p", "children": [], "text": "130 mg/18 mL(7.2 mg/mL)" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

Must be refrigerated. Store at2°C-8°C (36°F-46°F). Do Not Freeze.

{ "type": "p", "children": [], "text": "Must be refrigerated. Store at2°C-8°C (36°F-46°F). Do Not Freeze." }

1 Sterile Single-Dose VialDiscard Unused Portion

{ "type": "p", "children": [], "text": "1 Sterile Single-Dose VialDiscard Unused Portion" }

Not For Sale

{ "type": "p", "children": [], "text": "Not For Sale" }

HERONTHERAPEUTICS

{ "type": "p", "children": [], "text": "HERONTHERAPEUTICS" }

Limitations of Use

Adults and Pediatric Patients 12 Years of Age and Older

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="15%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Population</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 4</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Administer EMEND capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND capsules in the morning.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" valign="middle">EMEND capsules<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">Adults and Pediatric Patients 12 Years and Older</td><td align="center" class="Rrule">125 mg orally</td><td align="center" class="Rrule">80 mg orally</td><td align="center" class="Rrule">80 mg orally</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2" valign="middle">Dexamethasone</td><td align="left" class="Rrule" valign="middle">Adults</td><td align="center" class="Rrule">12 mg orally</td><td align="center" class="Rrule">8 mg orally</td><td align="center" class="Rrule">8 mg orally</td><td align="center" class="Rrule">8 mg orally</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule">Pediatric Patients 12 Years and Older</td><td align="left" class="Rrule" colspan="4">If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 <span class="Italics">[see <a href="#S14.3">Clinical Studies (14.3)</a>]</span>.<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" valign="middle">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule" valign="middle">Adults and Pediatric Patients 12 Years and Older</td><td align="center" class="Rrule">See selected 5-HT<span class="Sub">3</span> antagonist prescribing information for the recommended dosage</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MEC</span> </caption> <col align="center" valign="top" width="26%"/> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule">Population</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Administer EMEND capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND capsules in the morning.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle">EMEND capsules<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="left" class="Rrule">Adults and Pediatric Patients 12 Years and Older</td><td align="center" class="Rrule">125 mg orally</td><td align="center" class="Rrule">80 mg orally</td><td align="center" class="Rrule">80 mg orally</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle">Dexamethasone</td><td align="left" class="Rrule" valign="middle">Adults</td><td align="center" class="Rrule">12 mg orally</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" valign="middle">Pediatric Patients 12 Years and Older</td><td align="left" class="Rrule" colspan="3">If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 <span class="Italics">[see <a href="#S14.3">Clinical Studies (14.3)</a>]</span>.<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule" valign="middle">Adults and Pediatric Patients 12 Years and Older</td><td align="left" class="Rrule">See the selected 5-HT<span class="Sub">3</span> antagonist prescribing information for recommended dosage</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> </tbody> </table></div>

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

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Recommended Dosing in Pediatric Patients 6 Months to Less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow Capsules</span> </caption> <col align="left" valign="top" width="21%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Population</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 4</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>After preparation, the final concentration of EMEND for oral suspension is 25 mg/mL <span class="Italics">[see <a href="#S2.3">Dosage and Administration (2.3)</a>]</span>. Administer EMEND for oral suspension 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND for oral suspension in the morning.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" valign="middle">EMEND for oral suspension<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></td><td align="left" class="Rrule">Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules</td><td align="center" class="Rrule">3 mg/kg orally Maximum dose 125 mg</td><td align="center" class="Rrule">2 mg/kg orally Maximum dose 80 mg</td><td align="center" class="Rrule">2 mg/kg orally Maximum dose 80 mg</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2" valign="middle">Dexamethasone</td><td align="left" class="Rrule">Adults Unable to Swallow Capsules</td><td align="center" class="Rrule">See <a href="#TABLE1">Table 1</a> or <a href="#S2">2</a></td><td align="center" class="Rrule">See <a href="#TABLE1">Table 1</a> or <a href="#TABLE2">2</a></td><td align="center" class="Rrule">See <a href="#TABLE1">Table 1</a> or <a href="#TABLE2">2</a></td><td align="center" class="Rrule">See <a href="#TABLE1">Table 1</a> or <a href="#TABLE2">2</a></td> </tr> <tr class="Botrule"> <td align="left" class="Rrule">Pediatric Patients 6 Months to Less than12 Years or Pediatric Patients Unable to Swallow Capsules</td><td align="left" class="Rrule" colspan="4">If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 <span class="Italics">[see <a href="#S14.3">Clinical Studies (14.3)</a>]</span>.<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" valign="middle">5-HT<span class="Sub">3</span> antagonist</td><td align="left" class="Rrule">Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules</td><td align="left" class="Rrule">See selected 5-HT<span class="Sub">3</span> antagonist prescribing information for the recommended dosage</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> </tbody> </table></div>

EMEND for oral suspension should be prepared by a healthcare provider. Once prepared, it may be administered either by a healthcare provider, patient, or caregiver.

Before preparing EMEND:

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 4: Instructions for Healthcare Providers on How to Prepare EMEND for Oral Suspension</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">EMEND for oral suspension is packaged as a kit with one 1 mL oral dosing dispenser, one 5 mL oral dosing dispenser, one cap and one mixing cup.</td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-01.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>1.</dt> <dd> Fill the mixing cup with room temperature drinking water.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-02.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>2.</dt> <dd> Fill the 5 mL oral dosing dispenser with 4.6 mL of water from the mixing cup.<br/> <span class="Bold">Make sure no air is in the dispenser - if air is present, remove.</span> </dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-03.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>3.</dt> <dd> Discard all the unused water remaining in the mixing cup.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-04.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>4.</dt> <dd> Add the 4.6 mL of water from the dispenser back into the mixing cup.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-05.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>5.</dt> <dd> Each pouch of EMEND for oral suspension contains 125 mg of aprepitant which is to be suspended in 4.6 mL of water giving a final concentration of 25 mg/mL.<br/> Hold the EMEND for oral suspension pouch upright and shake the contents to the bottom before opening the pouch.</dd> <dt>6.</dt> <dd> Pour the entire contents of the pouch into the 4.6 mL of water in the mixing cup and snap the lid shut.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-06.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>7.</dt> <dd> Mix the EMEND suspension gently by swirling 20 times; then gently invert the mixing cup 5 times.<br/> To prevent foaming, do not shake the mixing cup. The mixture will be cloudy pink to light pink.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-07.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>8.</dt> <dd> Check the EMEND mixture for any clumps or foaming:<ul class="Disc"> <li>If any clumps are present, repeat Step 7 until there are no clumps.</li> <li>If there is any foam, wait for the foam to disappear before going on to Step 9.</li> </ul> </dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-08.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <dl> <dt>9.</dt> <dd> Fill the dispenser with the prescribed dose shown above in Table 3.<ul class="Disc"> <li>Choose the dispenser based on dose:<ul class="Circle"> <li>Use 1 mL dispenser if dose is 1 mL or less.</li> <li>Use 5 mL dispenser if dose is more than 1 mL.</li> </ul> </li> <li>Fill the dispenser with the prescribed dose from the cup.<ul class="Circle"> <li>If the dose is less than 1 mL round to the nearest 0.1 mL.</li> <li>If the dose is more than 1 mL round to the nearest 0.2 mL.</li> </ul> </li> <li>It is common to have medicine leftover in the cup.</li> </ul> </dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-09.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Make sure no air is in the dispenser - if air is present, remove.<br/> Make sure the dispenser contains the prescribed dose.</span></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <dl> <dt>10.</dt> <dd> Place the cap on the dispenser until it clicks.</dd> <dt>11.</dt> <dd> If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator [between 36°F-46°F (2°C-8°C)] for up to 72 hours prior to use. When dispensing dose(s) to the patient or caregiver, instruct them to refrigerate the oral dosing dispenser(s) until they are ready to administer the dose.</dd> <dt>12.</dt> <dd> When ready to use, the mixture can be kept at room temperature [between 68°F-77°F (20°C-25°C)] for up to 3 hours.</dd> </dl> </td><td align="center" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-10.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"> <dl> <dt>13.</dt> <dd> Discard the mixing cup along with any remaining suspension.</dd> </dl> </td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

EMEND capsules and EMEND for oral suspension can be administered with or without food.

EMEND capsules

EMEND for oral suspension

EMEND capsules:

EMEND for oral suspension:

EMEND is contraindicated in patients:

{ "type": "p", "children": [], "text": "EMEND is contraindicated in patients:" }

{ "type": "ul", "children": [ "who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported [see Adverse Reactions (6.2)].", "taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of this drug which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings and Precautions (5.1)]." ], "text": "" }

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

See Table 8 and Table 9 for a listing of potentially significant drug interactions [see Drug Interactions (7.1, 7.2)].

Coadministration of EMEND with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology (12.3)]. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle [see Drug Interactions (7.1)].

Upon coadministration with EMEND, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND [see Clinical Pharmacology (12.3)]. Advise patients to use effective alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions (7.1), Use in Specific Populations (8.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety of EMEND was evaluated in approximately 6800 individuals.

Adults

In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.1)].

In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.2)]. The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%).

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <col align="left" valign="top" width="36%"/> <col align="center" valign="top" width="32%"/> <col align="center" valign="top" width="32%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EMEND, ondansetron, and dexamethasone<a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a> <br/> (N=1412)</th><th align="center" class="Rrule">Ondansetron and dexamethasone<a class="Sup" href="#footnote-9" name="footnote-reference-9">‡</a> <br/> (N=1396)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Reported in ≥ 3% of patients treated with the EMEND regimen and at a greater incidence than standard therapy.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>EMEND regimen</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">‡</a> </dt> <dd>Standard therapy</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">fatigue</td><td align="center" class="Rrule">13%</td><td align="center" class="Rrule">12%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">diarrhea</td><td align="center" class="Rrule">9%</td><td align="center" class="Rrule">8%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">asthenia</td><td align="center" class="Rrule">7%</td><td align="center" class="Rrule">6%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">dyspepsia</td><td align="center" class="Rrule">7%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">abdominal pain</td><td align="center" class="Rrule">6%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">hiccups</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">white blood cell count decreased</td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">dehydration</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">alanine aminotransferase increased</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">2%</td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 6: Less Common Adverse Reactions in EMEND-Treated Patients from a Pooled Analysis of HEC and MEC Studies<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></span> </caption> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="60%"/> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Reported in &gt; 0.5% of patients treated with the EMEND regimen, at a greater incidence than standard therapy and not previously described in Table 5.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Infection and Infestations</span></td><td align="left" class="Rrule">oral candidiasis, pharyngitis</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Blood and the Lymphatic System Disorders</span></td><td align="left" class="Rrule">anemia, febrile neutropenia, neutropenia, thrombocytopenia</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="left" class="Rrule">decreased appetite, hypokalemia</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Psychiatric Disorders</span></td><td align="left" class="Rrule">anxiety</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous System Disorders</span></td><td align="left" class="Rrule">dizziness, dysgeusia, peripheral neuropathy</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Cardiac Disorders</span></td><td align="left" class="Rrule">palpitations</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Vascular Disorders</span></td><td align="left" class="Rrule">flushing, hot flush</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td><td align="left" class="Rrule">cough, dyspnea, oropharyngeal pain</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Gastrointestinal Disorders</span></td><td align="left" class="Rrule">dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="left" class="Rrule">alopecia, hyperhidrosis, rash</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="left" class="Rrule">musculoskeletal pain</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">General Disorders and Administration Site Condition</span></td><td align="left" class="Rrule">edema peripheral, malaise</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Investigations</span></td><td align="left" class="Rrule">aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased</td> </tr> </tbody> </table></div>

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

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

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

Pediatric Patients 6 Months to 17 Years of Age

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

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

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 7: Most Common Adverse Reactions in EMEND-Treated Pediatric Patients in HEC and MEC Pooled Studies 5 and 6<a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a></span> </caption> <col align="left" valign="top" width="36%"/> <col align="center" valign="top" width="32%"/> <col align="center" valign="top" width="32%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EMEND and ondansetron<a class="Sup" href="#footnote-12" name="footnote-reference-12">†</a> <br/> (N=184)</th><th align="center" class="Rrule">Ondansetron<a class="Sup" href="#footnote-13" name="footnote-reference-13">‡</a> <br/>(N=168)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>Reported in ≥3% of patients treated with the EMEND regimen and at a greater incidence than control regimen.</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">†</a> </dt> <dd>EMEND regimen</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">‡</a> </dt> <dd>Control regimen</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">neutropenia</td><td align="center" class="Rrule">13%</td><td align="center" class="Rrule">11%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">headache</td><td align="center" class="Rrule">9%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">diarrhea</td><td align="center" class="Rrule">6%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">decreased appetite</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">cough</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">fatigue</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">hemoglobin decreased</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">dizziness</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">hiccups</td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">1%</td> </tr> </tbody> </table></div>

Forty-nine patients were treated with ifosfamide chemotherapy in each arm. Two of the patients treated with ifosfamide in the aprepitant arm developed behavioral changes (agitation = 1; abnormal behavior = 1), whereas no patient treated with ifosfamide in the control arm developed behavioral changes. Aprepitant has the potential for increasing ifosfamide-mediated neurotoxicity through induction of CYP3A4 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Non-CINV Studies

Serious adverse reactions reported in adult patients receiving a non-recommended dosage of EMEND in non-CINV studies include single cases of each of the following: angioedema and urticaria, constipation, and sub-ileus. EMEND is only approved in the CINV population.

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

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions [see Contraindications (4)].

Nervous system disorders: ifosfamide-induced neurotoxicity reported after EMEND and ifosfamide coadministration.

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology (12.3)].

Aprepitant acts as a moderate inhibitor of CYP3A4 when administered as a 3-day regimen (125-mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4. Some substrates of CYP3A4 are contraindicated with EMEND [see Contraindications (4)]. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 8.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 8: Effects of Aprepitant on the Pharmacokinetics of Other Drugs</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="80%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP3A4 Substrates</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Pimozide</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased pimozide exposure.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">EMEND is contraindicated <span class="Italics">[see <a href="#S4">Contraindications (4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Benzodiazepines</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule"> <ul class="Disc"> <li>Monitor for benzodiazepine-related adverse reactions.</li> <li>Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Dexamethasone</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased dexamethasone exposure <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Reduce the dose of oral dexamethasone by approximately 50% <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Methylprednisolone</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased methylprednisolone exposure <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule"> <ul class="Disc"> <li>Reduce the dose of intravenous methylprednisolone by approximately 25%</li> <li>Reduce the dose of oral methylprednisolone by approximately 50%</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Chemotherapeutic agents that are metabolized by CYP3A4</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule"><span class="Underline">Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents</span> <ul class="Disc"> <li>Monitor for chemotherapeutic-related adverse reactions.</li> </ul> <span class="Underline">Etoposide, vinorelbine, paclitaxel, and docetaxel</span> <ul class="Disc"> <li>No dosage adjustment needed.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Hormonal Contraceptives</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of EMEND <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3)</a>, <a href="#S8.3a">Use in Specific Populations (8.3)</a>, <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with EMEND and for 1 month following the last dose of EMEND.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">birth control pills, skin patches, implants, and certain IUDs</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2C9 Substrates</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">Warfarin</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Decreased warfarin exposure and decreased prothrombin time (INR) <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2)</a>, <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day EMEND regimen with each chemotherapy cycle.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Other</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Italics">5-HT<span class="Sub">3</span> Antagonists</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">No change in the exposure of the 5-HT<span class="Sub">3</span> antagonist <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">No dosage adjustment needed</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">ondansetron, granisetron, dolasetron</td> </tr> </tbody> </table></div>

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Co-administration of EMEND with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 9.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 9: Effects of Other Drugs on Pharmacokinetics of Aprepitant</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="80%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Moderate to Strong CYP3A4 Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with EMEND <span class="Italics">[see <a href="#S6.1">Adverse Reactions (6.1)</a> and <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Avoid concomitant use of EMEND.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule"><span class="Underline">Moderate inhibitor:</span> <br/> diltiazem<br/> <span class="Underline">Strong inhibitors:</span> <br/> ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Strong CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Clinical Impact</span></td><td align="left" class="Rrule">Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of EMEND <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="Italics">Intervention</span></td><td align="left" class="Rrule">Avoid concomitant use of EMEND.</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule"><span class="Italics">Examples</span></td><td align="left" class="Rrule">rifampin, carbamazepine, phenytoin</td> </tr> </tbody> </table></div>

Risk Summary

There are insufficient data on use of EMEND in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately 1.5 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in rabbits. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80-mg/80-mg EMEND regimen. Aprepitant crosses the placenta in rats and rabbits.

Risk Summary

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

Contraception

Upon administration of EMEND, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms and spermicides) during treatment with EMEND and for 1 month following the last dose [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

The safety and effectiveness of EMEND for oral suspension have been established in pediatric patients 6 months of age and older and EMEND capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. Use of EMEND in these age groups is supported by evidence from 302 pediatric patients in a randomized, double-blind, active comparator controlled clinical study (n = 207 patients aged 6 months to less than 12 years, n = 95 patients aged 12 through 17 years). EMEND was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician) [see Clinical Studies (14.3)]. Adverse reactions were similar to those reported in adult patients [see Adverse Reactions (6.1)].

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

Juvenile Animal Study

A study was conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs. There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory.

Of the 544 adult cancer patients treated with EMEND in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with EMEND has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

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

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when EMEND is administered [see Clinical Pharmacology (12.3)].

No specific information is available on the treatment of overdosage.

{ "type": "p", "children": [], "text": "No specific information is available on the treatment of overdosage." }

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

{ "type": "p", "children": [], "text": "Drowsiness and headache were reported in one patient who ingested 1440 mg of EMEND (approximately 11 times the maximum recommended single dose)." }

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

{ "type": "p", "children": [], "text": "In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of EMEND, drug-induced emesis may not be effective in cases of EMEND overdosage." }

Aprepitant is not removed by hemodialysis.

{ "type": "p", "children": [], "text": "Aprepitant is not removed by hemodialysis." }

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

{ "type": "p", "children": [], "text": "EMEND capsules contain the active ingredient, aprepitant. Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one." }

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

{ "type": "p", "children": [], "text": "Its empirical formula is C23H21F7N4O3, and its structural formula is:" }

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.

{ "type": "p", "children": [], "text": "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 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 125-mg capsule also contains red ferric oxide and yellow ferric oxide.

{ "type": "p", "children": [], "text": "Each capsule of EMEND for oral administration contains either 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 125-mg capsule also contains red ferric oxide and yellow ferric oxide." }

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

{ "type": "p", "children": [], "text": "Each pouch of EMEND for oral suspension 125 mg contains 125 mg of aprepitant and the following inactive ingredients: sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate." }

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.

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral EMEND doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma 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 approximately 10 ng/mL and 100 ng/mL, the NK1 receptor occupancies were approximately 50% and 90%, respectively. The oral EMEND regimen produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of EMEND has not been established.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum aprepitant concentrations after a single 200-mg dose of fosaprepitant were 4-fold higher than that achieved with oral EMEND 125 mg. QT prolongation with the recommended oral EMEND dosing regimens is not expected.

Absorption

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 to 125 mg, the mean absolute oral bioavailability of EMEND 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 were non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.

Distribution

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

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

Elimination

Metabolism

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 (2.4 times the maximum EMEND recommended dose), indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [14C]-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.

Specific Populations

Geriatric Patients

Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 through 5 (2 additional days of dosing compared to the recommended duration), the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations (8.5)].

Pediatric Patients

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

As part of a 3-day regimen, weight-based dosing of aprepitant powder for oral suspension (3-mg/kg;2-mg/kg;2-mg/kg) in 18 pediatric patients aged 6 months to less than 12 years achieved a mean AUC0-24hr of 20.9 mcg∙hr/mL on Day 1 with mean peak plasma concentration (Cmax) at 1.8 mcg/mL (N=19), occurring at approximately 6 hours. The mean concentrations at the end of Day 2 (N=18) and Day 3 (N=19) were 0.4 mcg/mL and 0.5 mcg/mL, respectively [see Dosage and Administration (2.1)].

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

Male and Female Patients

Following oral administration of a single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), the AUC0-24hr and Cmax are 9% and 17% higher in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and Tmax occurs at approximately the same time. These differences are not considered clinically meaningful.

Racial or Ethnic Groups

Following oral administration of a single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum EMEND recommended dose), the AUC0-24hr and Cmax are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC0-24hr and Cmax were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC0-24hr or Cmax between Caucasians and Blacks. These differences are not considered clinically meaningful.

Patients with Renal Impairment

A single 240-mg dose of aprepitant (approximately 1.9 times the maximum EMEND recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

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. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.7)].

Body Mass Index (BMI)

For every 5 kg/m2 increase in BMI, AUC0-24hr and Cmax of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m2 to 36 kg/m2. This change is not considered clinically meaningful.

Drug Interactions Studies

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

Effects of Aprepitant on the Pharmacokinetics of Other Drugs

CYP3A4 substrates (i.e., midazolam): Interactions between EMEND and coadministered midazolam are listed in Table 10 (increase is indicated as "↑", decrease as "↓", no change as "↔").

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 10: Pharmacokinetic Interaction Data for EMEND and Coadministered Midazolam</span> </caption> <col align="left" valign="top" width="32%"/> <col align="left" valign="top" width="27%"/> <col align="left" valign="top" width="41%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Dosage of EMEND</th><th align="left" class="Rrule">Dosage of Midazolam</th><th align="left" class="Rrule">Observed Drug Interactions</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">EMEND 125 mg on Day 1 and 80 mg on Days 2 to 5</td><td align="left" class="Rrule">oral 2 mg single dose on Days 1 and 5</td><td align="left" class="Rrule">midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 <span class="Italics">[see <a href="#S7.1">Drug Interactions (7.1)</a>]</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">EMEND 125 mg on Day 1 and 80 mg on Days 2 and 3</td><td align="left" class="Rrule">intravenous 2 mg prior to 3-day regimen of EMEND and on Days 4, 8 and 15</td><td align="left" class="Rrule">midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">EMEND 125 mg on Day 1</td><td align="left" class="Rrule">intravenous 2 mg given 1 hour after EMEND</td><td align="left" class="Rrule">midazolam AUC ↑ 1.5-fold</td> </tr> </tbody> </table></div>

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

Corticosteroids:

Dexamethasone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg dexamethasone on Day 1 and 8-mg dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5 [see Dosage and Administration (2.1)].

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, coadministered with 125 mg methylprednisolone IV on Day 1 and 40 mg methylprednisolone orally on Days 2 and 3, increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3.

Chemotherapeutic agents:

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

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

CYP2C9 substrates (Warfarin, Tolbutamide):

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 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 [see Drug Interactions (7.1)].

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. This effect was not considered clinically important.

Other Drugs

Oral contraceptives: When EMEND was administered as a 3-day regimen (125-mg/80-mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment.

P-glycoprotein substrates: 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.

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of Other Drugs on the Pharmacokinetics of Aprepitant

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 [see Drug Interactions (7.2)].

Rifampin: When a single 375-mg dose of aprepitant (3 times the maximum EMEND recommended dose) was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)].

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 (approximately 1.8 times the EMEND recommended dose), 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 [see Drug Interactions (7.2)].

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

Carcinogenesis

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

Mutagenesis

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.

Impairment of Fertility

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended adult human dose and exposure in female rats at about 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen).

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

In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). See Table 11.

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

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: HEC Treatment Regimens – Studies 1 and 2<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a></span> </caption> <col align="left" valign="top" width="31%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="17%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 4</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>EMEND placebo and dexamethasone placebo were used to maintain blinding.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">§</a> </dt> <dd>Ondansetron 32 mg intravenous was used in the clinical trials of EMEND. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINV EMEND Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral EMEND<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a></td><td align="center" class="Rrule">125 mg</td><td align="center" class="Rrule">80 mg</td><td align="center" class="Rrule">80 mg</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone<a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a></td><td align="center" class="Rrule">12 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">8 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">5-HT<span class="Sub">3</span> antagonist<a class="Sup" href="#footnote-17" name="footnote-reference-17">§</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CINV Standard Therapy</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone</td><td align="center" class="Rrule">20 mg</td><td align="center" class="Rrule">8 mg twice daily</td><td align="center" class="Rrule">8 mg twice daily</td><td align="center" class="Rrule">8 mg twice daily</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">5-HT<span class="Sub">3</span> antagonist<a class="Sup" href="#footnote-17">§</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> </tbody> </table></div>

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 in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

Other prespecified endpoints:

A summary of the key study results from each individual study analysis is shown in Table 12. In both studies, a statistically significantly higher proportion of patients receiving the EMEND regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the EMEND regimen was also observed when the acute phase and the delayed phase were analyzed separately.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12: Percent of Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1</span> </caption> <col align="left" valign="top" width="22%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="13%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="13%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="3">Study 1</th><th align="center" class="Rrule" colspan="3">Study 2</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">EMEND Regimen<br/> (N=260)<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a> <br/> %</th><th align="center" class="Rrule">Standard Therapy<br/>(N=261)<a class="Sup" href="#footnote-18">*</a> <br/> %</th><th align="center" class="Rrule">p-Value</th><th align="center" class="Rrule">EMEND Regimen<br/> (N=261)<a class="Sup" href="#footnote-18">*</a> <br/> %</th><th align="center" class="Rrule">Standard Therapy<br/> (N=263)<a class="Sup" href="#footnote-18">*</a> <br/> %</th><th align="center" class="Rrule">p-Value</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="7">Visual analogue scale (VAS) score range: 0 mm=no nausea; 100 mm=nausea as bad as it could be.</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">†</a> </dt> <dd>Overall: 0 to 120 hours post-cisplatin treatment.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">‡</a> </dt> <dd>Acute phase: 0 to 24 hours post-cisplatin treatment.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">§</a> </dt> <dd>Delayed phase: 25 to 120 hours post-cisplatin treatment.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">¶</a> </dt> <dd>Not statistically significant when adjusted for multiple comparisons.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">#</a> </dt> <dd>Not statistically significant.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PRIMARY ENDPOINT</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Overall<a class="Sup" href="#footnote-19" name="footnote-reference-19">†</a></td><td align="center" class="Rrule">73</td><td align="center" class="Rrule">52</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">63</td><td align="center" class="Rrule">43</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">OTHER PRESPECIFIED ENDPOINTS</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Acute phase<a class="Sup" href="#footnote-20" name="footnote-reference-20">‡</a></td><td align="center" class="Rrule">89</td><td align="center" class="Rrule">78</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">83</td><td align="center" class="Rrule">68</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delayed phase<a class="Sup" href="#footnote-21" name="footnote-reference-21">§</a></td><td align="center" class="Rrule">75</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">68</td><td align="center" class="Rrule">47</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Protection</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Overall</td><td align="center" class="Rrule">63</td><td align="center" class="Rrule">49</td><td align="center" class="Rrule">0.001</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">41</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr> <td align="left" class="Lrule Rrule">  Acute phase</td><td align="center" class="Rrule">85</td><td align="center" class="Rrule">75</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-22" name="footnote-reference-22">¶</a></td><td align="center" class="Rrule">80</td><td align="center" class="Rrule">65</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delayed phase</td><td align="center" class="Rrule">66</td><td align="center" class="Rrule">52</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">61</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Emesis</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Overall</td><td align="center" class="Rrule">78</td><td align="center" class="Rrule">55</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">66</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr> <td align="left" class="Lrule Rrule">  Acute phase</td><td align="center" class="Rrule">90</td><td align="center" class="Rrule">79</td><td align="center" class="Rrule">0.001</td><td align="center" class="Rrule">84</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delayed phase</td><td align="center" class="Rrule">81</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">&lt;0.001</td><td align="center" class="Rrule">72</td><td align="center" class="Rrule">48</td><td align="center" class="Rrule">&lt;0.001</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Nausea</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Overall</td><td align="center" class="Rrule">48</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23" name="footnote-reference-23">#</a></td><td align="center" class="Rrule">49</td><td align="center" class="Rrule">39</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-22">¶</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delayed phase</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">48</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23">#</a></td><td align="center" class="Rrule">53</td><td align="center" class="Rrule">40</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-22">¶</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">No Significant Nausea</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Overall</td><td align="center" class="Rrule">73</td><td align="center" class="Rrule">66</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23">#</a></td><td align="center" class="Rrule">71</td><td align="center" class="Rrule">64</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23">#</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Delayed phase</td><td align="center" class="Rrule">75</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23">#</a></td><td align="center" class="Rrule">73</td><td align="center" class="Rrule">65</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-23">#</a></td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <thead> <tr> <th align="center">Figure 1: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time — Cycle 1</th> </tr> </thead> <tbody> <tr> <td align="center"><img alt="Figure 1" src="/dailymed/image.cfm?name=emend-12.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr> <td align="center">p-Value &lt;0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.</td> </tr> </tbody> </table></div>

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

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <thead> <tr> <th align="center">Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle</th> </tr> </thead> <tbody> <tr> <td align="center"><img alt="Figure 2" src="/dailymed/image.cfm?name=emend-13.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> </tbody> </table></div>

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

In Study 3, in breast cancer patients, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (less than or equal to 60 mg/m2) or epirubicin (less than or equal to 100 mg/m2). See Table 13.

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

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 13: MEC Treatment Regimens – Studies 3 and 4<a class="Sup" href="#footnote-24" name="footnote-reference-24">*</a></span> </caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-24" name="footnote-24">*</a> </dt> <dd>EMEND placebo and dexamethasone placebo were used to maintain blinding.</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">†</a> </dt> <dd>EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the mornings on Days 2 and 3.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">‡</a> </dt> <dd>Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">§</a> </dt> <dd>The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINV EMEND Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral EMEND<a class="Sup" href="#footnote-25" name="footnote-reference-25">†</a></td><td align="center" class="Rrule">125 mg</td><td align="center" class="Rrule">80 mg</td><td align="center" class="Rrule">80 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone</td><td align="center" class="Rrule">12 mg<a class="Sup" href="#footnote-26" name="footnote-reference-26">‡</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Ondansetron</td><td align="center" class="Rrule">8 mg × 2 doses<a class="Sup" href="#footnote-27" name="footnote-reference-27">§</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CINV Standard Therapy</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Dexamethasone</td><td align="center" class="Rrule">20 mg<a class="Sup" href="#footnote-26">‡</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Oral Ondansetron</td><td align="center" class="Rrule">8 mg × 2 doses<a class="Sup" href="#footnote-27">§</a></td><td align="center" class="Rrule">8 mg twice daily</td><td align="center" class="Rrule">8 mg twice daily</td> </tr> </tbody> </table></div>

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

Primary endpoint:

Other prespecified endpoints:

A summary of the key results from Study 3 is shown in Table 14. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the EMEND regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the "No Emesis Endpoint", a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the EMEND 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 14: Percent of Patients Receiving MEC Responding by Treatment Group and Phase — Cycle 1 of Study 3</span> </caption> <col align="left" valign="top" width="34%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">EMEND Regimen<br/>(N=433)<a class="Sup" href="#footnote-28" name="footnote-reference-28">*</a> <br/>%</th><th align="center" class="Rrule">Standard Therapy<br/>(N=424)<a class="Sup" href="#footnote-28">*</a> <br/>%</th><th align="center" class="Rrule">p-Value</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-28" name="footnote-28">*</a> </dt> <dd>N: Number of patients included in the primary analysis of complete response.</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">†</a> </dt> <dd>Overall: 0 to 120 hours post-chemotherapy treatment.</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">‡</a> </dt> <dd>NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value &lt;0.001.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PRIMARY ENDPOINT<a class="Sup" href="#footnote-29" name="footnote-reference-29">†</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Complete Response</td><td align="center" class="Rrule">51</td><td align="center" class="Rrule">42</td><td align="center" class="Rrule">0.015</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">OTHER PRESPECIFIED ENDPOINTS<a class="Sup" href="#footnote-29">†</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  No Emesis</td><td align="center" class="Rrule">76</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">NS<a class="Sup" href="#footnote-30" name="footnote-reference-30">‡</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  No Nausea</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">33</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  No Significant Nausea</td><td align="center" class="Rrule">61</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  No Rescue Therapy</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">NS</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Complete Protection</td><td align="center" class="Rrule">43</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">NS</td> </tr> </tbody> </table></div>

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

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

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

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

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

A summary of the key results from Study 4 is shown in Table 15. In Study 4, a statistically significantly higher proportion of patients receiving the EMEND regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the EMEND regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 15: Percent of Patients Receiving MEC Responding by Treatment Group — Cycle 1 of Study 4</span> </caption> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="24%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">ENDPOINTS</th><th align="center" class="Rrule">EMEND Regimen<br/>(N=430)<a class="Sup" href="#footnote-31" name="footnote-reference-31">*</a> <br/>%</th><th align="center" class="Rrule">Standard Therapy<br/>(N=418)<a class="Sup" href="#footnote-31">*</a> <br/>%</th><th align="center" class="Rrule">p-Value</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-31" name="footnote-31">*</a> </dt> <dd>N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">No Vomiting Overall</td><td align="center" class="Rrule">76</td><td align="center" class="Rrule">62</td><td align="center" class="Rrule">&lt;0.0001</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Complete Response Overall</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">56</td><td align="center" class="Rrule">0.0003</td> </tr> </tbody> </table></div>

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, EMEND in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting a dosage adjustment to account for a drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients who received the control regimen.

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

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

The treatment regimens in Study 5 for pediatric patients are defined in Table 16. Of the pediatric patients, 29% in the EMEND regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 16: HEC and MEC Treatment Regimens<a class="Sup" href="#footnote-32" name="footnote-reference-32">*</a> for Pediatric Patients 6 Months to 17 Years of Age— Study 5</span> </caption> <col align="left" valign="top" width="33%"/> <col align="center" valign="top" width="23%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-32" name="footnote-32">*</a> </dt> <dd>Intravenous dexamethasone was permitted at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting a dosage adjustment to account for a drug interaction <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span> No dexamethasone dose reduction was required for patients in the control regimen.</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">†</a> </dt> <dd>EMEND was administered 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days 2 and 3, EMEND was administered in the morning.</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">‡</a> </dt> <dd>Ondansetron was administered 30 minutes prior to chemotherapy on Day 1</dd> <dt> <a href="#footnote-reference-35" name="footnote-35">§</a> </dt> <dd>EMEND placebo was used to maintain blinding.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">CINV EMEND Regimen</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pediatric Patients 6 Months to less than 12 Years of Age<a class="Sup" href="#footnote-33" name="footnote-reference-33">†</a></td><td align="center" class="Rrule">3 mg/kg body weight oral suspension</td><td align="center" class="Rrule">2 mg/kg body weight oral suspension</td><td align="center" class="Rrule">2 mg/kg body weight oral suspension</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pediatric Patients 12 to 17 Years of Age<a class="Sup" href="#footnote-33">†</a></td><td align="center" class="Rrule">125 mg capsule</td><td align="center" class="Rrule">80 mg capsule</td><td align="center" class="Rrule">80 mg capsule</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">Per standard of care<a class="Sup" href="#footnote-34" name="footnote-reference-34">‡</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CINV Control Regimen<a class="Sup" href="#footnote-35" name="footnote-reference-35">§</a></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Ondansetron</td><td align="center" class="Rrule">Per standard of care<a class="Sup" href="#footnote-34">‡</a></td><td align="center" class="Rrule">none</td><td align="center" class="Rrule">none</td> </tr> </tbody> </table></div>

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

Primary endpoint:

Other prespecified endpoints:

A summary of the key study results is shown in Table 17.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 17: Percent of Patients Who Responded to Treatment by Treatment Group and Phase – Cycle 1 of Study 5</span> </caption> <col align="left" valign="top" width="60%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EMEND Regimen<br/>n/m (%)</th><th align="center" class="Rrule">Control Regimen<br/>n/m (%)</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="3">n/m = Number of patients with desired response/number of patients included in time point.</td> </tr> <tr> <td align="left" colspan="3">Acute Phase: 0 to 24 hours following initiation of chemotherapy.</td> </tr> <tr> <td align="left" colspan="3">Delayed Phase: 25 to 120 hours following initiation of chemotherapy.</td> </tr> <tr class="Last"> <td align="left" colspan="3">Overall Phase: 0 to 120 hours following initiation of chemotherapy.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-36" name="footnote-36">*</a> </dt> <dd>Complete Response = No vomiting or retching and no use of rescue medication.</dd> <dt> <a href="#footnote-reference-37" name="footnote-37">†</a> </dt> <dd>p&lt;0.01 when compared to Control Regimen</dd> <dt> <a href="#footnote-reference-38" name="footnote-38">‡</a> </dt> <dd>p&lt;0.05 when compared to Control Regimen</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3">PRIMARY ENDPOINT</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response<a class="Sup" href="#footnote-36" name="footnote-reference-36">*</a> - Delayed phase</td><td align="center" class="Rrule">77/152 (50.7)<a class="Sup" href="#footnote-37" name="footnote-reference-37">†</a></td><td align="center" class="Rrule">39/150 (26.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3">OTHER PRESPECIFIED ENDPOINTS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Complete Response<a class="Sup" href="#footnote-36">*</a> – Acute phase</td><td align="center" class="Rrule">101/152 (66.4)<a class="Sup" href="#footnote-38" name="footnote-reference-38">‡</a></td><td align="center" class="Rrule">78/150 (52.0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Complete Response<a class="Sup" href="#footnote-36">*</a> – Overall phase</td><td align="center" class="Rrule">61/152 (40.1)<a class="Sup" href="#footnote-37">†</a></td><td align="center" class="Rrule">30/150 (20.0)</td> </tr> </tbody> </table></div>

Storage and Handling

Capsules

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].

For Oral Suspension

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

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

Hypersensitivity Reactions

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

Drug Interactions

Advise patients to discuss all medications they are taking, including other prescription, non-prescription medication or herbal products [see Contraindications (4), Warnings and Precautions (5.1)].

Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle [see Warnings and Precautions (5.2)].

Hormonal Contraceptives: Advise patients that administration of EMEND may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception (such as condoms and spermicides) during treatment with EMEND and for 1 month following the last dose of EMEND [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)].

Distributed by: Merck Sharp & Dohme LLC, Rahway, NJ 07065, USA

{ "type": "p", "children": [], "text": "Distributed by:\n\t\t\t\t\t\tMerck Sharp & Dohme LLC, Rahway, NJ 07065, USA" }

For patent information: www.msd.com/research/patent

{ "type": "p", "children": [], "text": "For patent information: www.msd.com/research/patent\n" }

Copyright © 2003-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

{ "type": "p", "children": [], "text": "Copyright © 2003-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.\n\t\t\t\t\t\tAll rights reserved." }

uspi-mk0869-mf-2205r017

{ "type": "p", "children": [], "text": "uspi-mk0869-mf-2205r017" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="75%"/> <col align="left" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="2">Patient Information<br/>EMEND<span class="Sup">®</span> (EE mend)<br/>(aprepitant)<br/>capsules<br/>EMEND<span class="Sup">®</span> (EE mend)<br/>(aprepitant)<br/>for oral suspension</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: May 2022      </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2">Read this Patient Information before you start taking EMEND and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What is EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND for oral suspension</span> is a prescription medicine used:</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>with other medicines that treat nausea and vomiting in patients 6 months of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND capsules</span> is a prescription medicine used:</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>with other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2">EMEND is not used to treat nausea and vomiting that you already have.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2">EMEND should not be used continuously for a long time (chronic use).</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Who should not take EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Do not take EMEND if you:</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>are allergic to aprepitant or any of the ingredients in EMEND. See the end of this leaflet for a complete list of ingredients in EMEND.</li> <li>are taking pimozide (ORAP<span class="Sup">®</span>)</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What should I tell my healthcare provider before taking EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Before you take EMEND, tell your healthcare provider if you:</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>have liver problems</li> <li>are pregnant or plan to become pregnant. It is not known if EMEND can harm your unborn baby.<ul class="Circle"> <li>Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use a back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND and for 1 month after your last dose of EMEND.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. It is not known if EMEND passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take EMEND.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2">EMEND may affect the way other medicines work, and other medicines may affect how EMEND works causing serious side effects.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2">Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">How should I take EMEND?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>Take EMEND exactly as prescribed.</li> <li>Swallow EMEND capsules whole.</li> <li>EMEND may be taken with or without food.</li> <li>If you take too much EMEND, call your healthcare provider, or go to the nearest hospital emergency room.</li> <li>EMEND is taken as 3 doses over 3 days - starting on the day you have chemotherapy, and for the following 2 days.</li> <li> <span class="Bold">In adults, there are 2 ways your healthcare provider may prescribe EMEND for you:</span> <dl> <dt class="Bold">1.</dt> <dd> <span class="Bold">Capsules of EMEND by mouth for all 3 doses:</span> <ul class="Circle"> <li>You should get a package that has 3 capsules of EMEND.</li> <li> <span class="Bold">Day 1 (Day of chemotherapy):</span> Take one 125 mg capsule of EMEND (white and pink) by mouth 1 hour before you start your chemotherapy treatment.</li> <li> <span class="Bold">Day 2 and Day 3:</span> Take one 80 mg capsule of EMEND (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be taken in the morning.</li> </ul> </dd> <dt class="Bold">2.</dt> <dd> <span class="Bold">Oral suspension of EMEND by mouth for all 3 doses, for adults who are not able to swallow capsules:</span> <ul class="Circle"> <li>For each dose of EMEND for oral suspension, you will get a pre-filled oral dosing dispenser that contains your prescribed dose.</li> <li> <span class="Bold">See the detailed Instructions for Use that comes with EMEND for oral suspension</span> for information about the correct way to take a dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.</li> <li> <span class="Bold">Day 1 (Day of chemotherapy):</span> Take 1 dose of EMEND for oral suspension by mouth 1 hour before you start your chemotherapy treatment.</li> <li> <span class="Bold">Day 2 and Day 3:</span> Take 1 dose of EMEND for oral suspension by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND for oral suspension should be taken in the morning.</li> </ul> </dd> </dl> </li> <li> <span class="Bold">In children 12 years of age and older who can swallow capsules by mouth, EMEND is prescribed as capsules of EMEND by mouth for all 3 doses:</span> <ul class="Circle"> <li>You should get a package that has 3 capsules of EMEND.</li> <li> <span class="Bold">Day 1 (Day of chemotherapy):</span> Take one 125 mg capsule of EMEND (white and pink) by mouth 1 hour before you start your chemotherapy treatment.</li> <li> <span class="Bold">Day 2 and Day 3:</span> Take one 80 mg capsule of EMEND (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be taken in the morning.</li> </ul> </li> <li> <span class="Bold">In children 6 months to less than 12 years of age or in children 12 years of age and older who are not able to swallow capsules, EMEND is prescribed as oral suspension of EMEND by mouth for all 3 doses:</span> <ul class="Circle"> <li>For each dose of EMEND, you will get a pre-filled oral dosing dispenser that contains your child's prescribed dose.</li> <li> <span class="Bold">See the detailed Instructions for Use that comes with EMEND for oral suspension</span>, for information about the correct way to give a dose of EMEND for oral suspension. If you have questions about how to give EMEND for oral suspension, talk to your child's healthcare provider.</li> <li> <span class="Bold">Day 1 (Day of chemotherapy):</span> Give 1 dose of EMEND for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment.</li> <li> <span class="Bold">Day 2 and Day 3:</span> Give 1 dose of EMEND for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be given in the morning.</li> </ul> </li> <li>If you take the blood thinner medicine warfarin sodium (COUMADIN<span class="Sup">®</span>, JANTOVEN<span class="Sup">®</span>), your healthcare provider may do blood tests after you take EMEND to check your blood clotting.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What are the possible side effects of EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>In adults taking EMEND, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.</li> <li>In children 6 months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMEND. For more information ask your healthcare provider or pharmacist.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">How should I store EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND capsules</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>Store EMEND capsules at room temperature, between 68°F to 77°F (20°C to 25°C).</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND for oral suspension</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>Store EMEND for oral suspension in the refrigerator, between 36°F to 46°F (2°C to 8°C).</li> <li>Use EMEND for oral suspension within 2 days of getting the medicine from your healthcare provider.</li> <li>When ready to use, EMEND for oral suspension can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Keep EMEND and all medicines out of the reach of children.</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">General information about the safe and effective use of EMEND</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. 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. You can ask your healthcare provider 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.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What are the ingredients in EMEND?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND capsules:</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Active ingredient:</span> aprepitant</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Inactive ingredients:</span> 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.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">EMEND for oral suspension:</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Active ingredient:</span> aprepitant</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Inactive ingredients:</span> sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2">Distributed by: Merck Sharp &amp; Dohme LLC, Rahway, NJ 07065, USA<br/> For patent information: <span class="Underline"><a href="http://www.msd.com/research/patent">www.msd.com/research/patent</a></span> <br/> The brands listed in the above sections "Who should not take EMEND?" and "How should I take EMEND?" are the registered trademarks of their respective owners and are not trademarks of Merck Sharp &amp; Dohme LLC.<br/> Copyright © 2003-2022 Merck &amp; Co., Inc., Rahway, NJ, USA, and its affiliates.<br/> All rights reserved.<br/> usppi-mk0869-mf-2205r008</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="2"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"75%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">Patient Information<br/>EMEND<span class=\"Sup\">®</span> (EE mend)<br/>(aprepitant)<br/>capsules<br/>EMEND<span class=\"Sup\">®</span> (EE mend)<br/>(aprepitant)<br/>for oral suspension</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: May 2022      </td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Read this Patient Information before you start taking EMEND and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND for oral suspension</span> is a prescription medicine used:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>with other medicines that treat nausea and vomiting in patients 6 months of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND capsules</span> is a prescription medicine used:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>with other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">EMEND is not used to treat nausea and vomiting that you already have.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">EMEND should not be used continuously for a long time (chronic use).</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Who should not take EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Do not take EMEND if you:</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>are allergic to aprepitant or any of the ingredients in EMEND. See the end of this leaflet for a complete list of ingredients in EMEND.</li>\n<li>are taking pimozide (ORAP<span class=\"Sup\">®</span>)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What should I tell my healthcare provider before taking EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Before you take EMEND, tell your healthcare provider if you:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>have liver problems</li>\n<li>are pregnant or plan to become pregnant. It is not known if EMEND can harm your unborn baby.<ul class=\"Circle\">\n<li>Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use a back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with EMEND and for 1 month after your last dose of EMEND.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if EMEND passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take EMEND.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">EMEND may affect the way other medicines work, and other medicines may affect how EMEND works causing serious side effects.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I take EMEND?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Take EMEND exactly as prescribed.</li>\n<li>Swallow EMEND capsules whole.</li>\n<li>EMEND may be taken with or without food.</li>\n<li>If you take too much EMEND, call your healthcare provider, or go to the nearest hospital emergency room.</li>\n<li>EMEND is taken as 3 doses over 3 days - starting on the day you have chemotherapy, and for the following 2 days.</li>\n<li>\n<span class=\"Bold\">In adults, there are 2 ways your healthcare provider may prescribe EMEND for you:</span>\n<dl>\n<dt class=\"Bold\">1.</dt>\n<dd>\n<span class=\"Bold\">Capsules of EMEND by mouth for all 3 doses:</span>\n<ul class=\"Circle\">\n<li>You should get a package that has 3 capsules of EMEND.</li>\n<li>\n<span class=\"Bold\">Day 1 (Day of chemotherapy):</span> Take one 125 mg capsule of EMEND (white and pink) by mouth 1 hour before you start your chemotherapy treatment.</li>\n<li>\n<span class=\"Bold\">Day 2 and Day 3:</span> Take one 80 mg capsule of EMEND (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be taken in the morning.</li>\n</ul>\n</dd>\n<dt class=\"Bold\">2.</dt>\n<dd>\n<span class=\"Bold\">Oral suspension of EMEND by mouth for all 3 doses, for adults who are not able to swallow capsules:</span>\n<ul class=\"Circle\">\n<li>For each dose of EMEND for oral suspension, you will get a pre-filled oral dosing dispenser that contains your prescribed dose.</li>\n<li>\n<span class=\"Bold\">See the detailed Instructions for Use that comes with EMEND for oral suspension</span> for information about the correct way to take a dose of EMEND for oral suspension. If you have questions about how to take EMEND for oral suspension, talk to your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Day 1 (Day of chemotherapy):</span> Take 1 dose of EMEND for oral suspension by mouth 1 hour before you start your chemotherapy treatment.</li>\n<li>\n<span class=\"Bold\">Day 2 and Day 3:</span> Take 1 dose of EMEND for oral suspension by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND for oral suspension should be taken in the morning.</li>\n</ul>\n</dd>\n</dl>\n</li>\n<li>\n<span class=\"Bold\">In children 12 years of age and older who can swallow capsules by mouth, EMEND is prescribed as capsules of EMEND by mouth for all 3 doses:</span>\n<ul class=\"Circle\">\n<li>You should get a package that has 3 capsules of EMEND.</li>\n<li>\n<span class=\"Bold\">Day 1 (Day of chemotherapy):</span> Take one 125 mg capsule of EMEND (white and pink) by mouth 1 hour before you start your chemotherapy treatment.</li>\n<li>\n<span class=\"Bold\">Day 2 and Day 3:</span> Take one 80 mg capsule of EMEND (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be taken in the morning.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">In children 6 months to less than 12 years of age or in children 12 years of age and older who are not able to swallow capsules, EMEND is prescribed as oral suspension of EMEND by mouth for all 3 doses:</span>\n<ul class=\"Circle\">\n<li>For each dose of EMEND, you will get a pre-filled oral dosing dispenser that contains your child's prescribed dose.</li>\n<li>\n<span class=\"Bold\">See the detailed Instructions for Use that comes with EMEND for oral suspension</span>, for information about the correct way to give a dose of EMEND for oral suspension. If you have questions about how to give EMEND for oral suspension, talk to your child's healthcare provider.</li>\n<li>\n<span class=\"Bold\">Day 1 (Day of chemotherapy):</span> Give 1 dose of EMEND for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment.</li>\n<li>\n<span class=\"Bold\">Day 2 and Day 3:</span> Give 1 dose of EMEND for oral suspension to your child by mouth 1 hour before they start their chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, EMEND should be given in the morning.</li>\n</ul>\n</li>\n<li>If you take the blood thinner medicine warfarin sodium (COUMADIN<span class=\"Sup\">®</span>, JANTOVEN<span class=\"Sup\">®</span>), your healthcare provider may do blood tests after you take EMEND to check your blood clotting.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>In adults taking EMEND, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.</li>\n<li>In children 6 months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\tTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of EMEND. For more information ask your healthcare provider or pharmacist.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\tCall your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I store EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND capsules</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Store EMEND capsules at room temperature, between 68°F to 77°F (20°C to 25°C).</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND for oral suspension</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Store EMEND for oral suspension in the refrigerator, between 36°F to 46°F (2°C to 8°C).</li>\n<li>Use EMEND for oral suspension within 2 days of getting the medicine from your healthcare provider.</li>\n<li>When ready to use, EMEND for oral suspension can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Keep EMEND and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">General information about the safe and effective use of EMEND</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. 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. You can ask your healthcare provider 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.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in EMEND?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND capsules:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Active ingredient:</span> aprepitant</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Inactive ingredients:</span> 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.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">EMEND for oral suspension:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Active ingredient:</span> aprepitant</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Inactive ingredients:</span> sucrose, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, red iron oxide, and sodium stearyl fumarate.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Distributed by: Merck Sharp &amp; Dohme LLC, Rahway, NJ 07065, USA<br/> For patent information: <span class=\"Underline\"><a href=\"http://www.msd.com/research/patent\">www.msd.com/research/patent</a></span>\n<br/> The brands listed in the above sections \"Who should not take EMEND?\" and \"How should I take EMEND?\" are the registered trademarks of their respective owners and are not trademarks of Merck Sharp &amp; Dohme LLC.<br/> Copyright © 2003-2022 Merck &amp; Co., Inc., Rahway, NJ, USA, and its affiliates.<br/> All rights reserved.<br/> usppi-mk0869-mf-2205r008</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"></td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="49%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="49%"/> <tbody class="Headless"> <tr class="Botrule"> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Instructions for Use</span> <p class="First"> <span class="Bold">EMEND<span class="Sup">®</span></span> (<span class="Bold">EE-</span>mend)<br/> <span class="Bold"> (aprepitant)</span> <br/> for oral suspension</p> <p> <span class="Bold"><img alt="Warning" src="/dailymed/image.cfm?name=emend-14.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/> Read the Patient Information and Instructions for<br/>Use for EMEND for oral suspension before you take or<br/> before you give a dose to your child</span> </p> <p> <span class="Bold">Take by mouth only</span> </p> </td> </tr> <tr class="Botrule"> <td align="center" colspan="3"><span class="Bold">How to give a dose of EMEND for oral suspension</span></td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">The healthcare provider has prepared the dose of EMEND for you or your child.</span></td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> <dl> <dt class="Bold">1.</dt> <dd> <span class="Bold">You will get EMEND in an oral dosing dispenser</span> </dd> </dl> </td><td align="left"></td><td align="left" class="Lrule Rrule Toprule"> <dl> <dt class="Bold">2.</dt> <dd> <span class="Bold">Keep the oral dosing dispenser in the refrigerator until you give EMEND to yourself or your child</span> </dd> </dl> </td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-15.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td><td align="left"></td><td align="center" class="Botrule Lrule Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-16.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"></td><td align="left"></td><td align="left" class="Botrule Lrule Rrule"> <ul> <li>Store EMEND in the refrigerator between 36°F to 46°F (2°C to 8°C). </li> <li>Use EMEND within 2 days of getting the medicine from the healthcare provider.</li> <li>When ready to use, EMEND can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.</li> <li> <span class="Bold">Keep EMEND and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr> <td align="left" colspan="3"> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> <dl> <dt class="Bold">3.</dt> <dd> <span class="Bold">Give EMEND</span> </dd> </dl> </td><td align="left"></td><td align="left" class="Lrule Rrule Toprule"> <dl> <dt class="Bold">4.</dt> <dd> <span class="Bold">Throw away the oral dosing dispenser and cap</span> </dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=emend-17.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td><td align="left"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"><img alt="Figure" src="/dailymed/image.cfm?name=emend-18.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713"/></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule">The color of the medicine in the oral dosing dispenser may be different shades of pink (light pink to dark pink). This is normal and the medicine is okay to use.<ul> <li>Take the cap off the oral dosing dispenser.</li> <li>Place the tip of the oral dosing dispenser in your mouth or in your child's mouth along the inner cheek on either the right or left side.</li> <li>Slowly push the plunger all the way down to give all of the medicine in the oral dosing dispenser.</li> </ul> <p class="First">Call the healthcare provider if you or your child is not able to take the prescribed dose.</p> </td><td align="left"></td><td align="left" class="Botrule Lrule Rrule"></td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="left">For more information go to www.emend.com or call 1-800-622-4477.<br/> This Instructions for Use has been approved by the U.S. Food and Drug Administration.<br/> Distributed by:<br/> Merck Sharp &amp; Dohme LLC, Rahway, NJ 07065, USA<br/> For patent information: <span class="Underline"><a href="http://www.msd.com/research/patent">www.msd.com/research/patent</a></span> <br/> Copyright © 2015-2022 Merck &amp; Co., Inc., Rahway, NJ, USA, and its affiliates. <br/> All rights reserved.<br/> Issued: 05/2022<br/> usifu-mk0869-mf-2205r001</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"49%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"49%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Instructions for Use</span>\n<p class=\"First\">\n<span class=\"Bold\">EMEND<span class=\"Sup\">®</span></span> (<span class=\"Bold\">EE-</span>mend)<br/>\n<span class=\"Bold\"> (aprepitant)</span>\n<br/> for oral suspension</p>\n<p>\n<span class=\"Bold\"><img alt=\"Warning\" src=\"/dailymed/image.cfm?name=emend-14.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713\"/> Read the Patient Information and Instructions for<br/>Use for EMEND for oral suspension before you take or<br/> before you give a dose to your child</span>\n</p>\n<p>\n<span class=\"Bold\">Take by mouth only</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" colspan=\"3\"><span class=\"Bold\">How to give a dose of EMEND for oral suspension</span></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"3\"><span class=\"Bold\">The healthcare provider has prepared the dose of EMEND for you or your child.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\">\n<dl>\n<dt class=\"Bold\">1.</dt>\n<dd>\n<span class=\"Bold\">You will get EMEND in an oral dosing dispenser</span>\n</dd>\n</dl>\n</td><td align=\"left\"></td><td align=\"left\" class=\"Lrule Rrule Toprule\">\n<dl>\n<dt class=\"Bold\">2.</dt>\n<dd>\n<span class=\"Bold\">Keep the oral dosing dispenser in the refrigerator until you give EMEND to yourself or your child</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=emend-15.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713\"/></td><td align=\"left\"></td><td align=\"center\" class=\"Botrule Lrule Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=emend-16.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\"></td><td align=\"left\"></td><td align=\"left\" class=\"Botrule Lrule Rrule\">\n<ul>\n<li>Store EMEND in the refrigerator between 36°F to 46°F (2°C to 8°C). </li>\n<li>Use EMEND within 2 days of getting the medicine from the healthcare provider.</li>\n<li>When ready to use, EMEND can be kept at room temperature, between 68°F to 77°F (20°C to 25°C) for up to 3 hours.</li>\n<li>\n<span class=\"Bold\">Keep EMEND and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"3\"> </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\">\n<dl>\n<dt class=\"Bold\">3.</dt>\n<dd>\n<span class=\"Bold\">Give EMEND</span>\n</dd>\n</dl>\n</td><td align=\"left\"></td><td align=\"left\" class=\"Lrule Rrule Toprule\">\n<dl>\n<dt class=\"Bold\">4.</dt>\n<dd>\n<span class=\"Bold\">Throw away the oral dosing dispenser and cap</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=emend-17.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713\"/></td><td align=\"left\"></td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"middle\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=emend-18.jpg&amp;setid=696f9e80-9cae-403b-de9e-078343ce4713\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\">The color of the medicine in the oral dosing dispenser may be different shades of pink (light pink to dark pink). This is normal and the medicine is okay to use.<ul>\n<li>Take the cap off the oral dosing dispenser.</li>\n<li>Place the tip of the oral dosing dispenser in your mouth or in your child's mouth along the inner cheek on either the right or left side.</li>\n<li>Slowly push the plunger all the way down to give all of the medicine in the oral dosing dispenser.</li>\n</ul>\n<p class=\"First\">Call the healthcare provider if you or your child is not able to take the prescribed dose.</p>\n</td><td align=\"left\"></td><td align=\"left\" class=\"Botrule Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\">For more information go to www.emend.com or call 1-800-622-4477.<br/> This Instructions for Use has been approved by the U.S. Food and Drug Administration.<br/> Distributed by:<br/> Merck Sharp &amp; Dohme LLC, Rahway, NJ 07065, USA<br/> For patent information: <span class=\"Underline\"><a href=\"http://www.msd.com/research/patent\">www.msd.com/research/patent</a></span>\n<br/> Copyright © 2015-2022 Merck &amp; Co., Inc., Rahway, NJ, USA, and its affiliates.\n\t\t\t\t\t\t\t\t\t\t<br/> All rights reserved.<br/> Issued: 05/2022<br/> usifu-mk0869-mf-2205r001</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 0006-0461-02

{ "type": "p", "children": [], "text": "\nNDC 0006-0461-02\n" }

BiPack2 capsules

{ "type": "p", "children": [], "text": "\nBiPack2 capsules" }

EMEND® (aprepitant) capsules

{ "type": "p", "children": [], "text": "\nEMEND®\n\n(aprepitant) capsules" }

80 mg

{ "type": "p", "children": [], "text": "\n80 mg" }

For Adults andPediatric Patients12 years of Age and Older

{ "type": "p", "children": [], "text": "For Adults andPediatric Patients12 years of Age and Older" }

You have already been givena capsule of EMEND (aprepitant) toprevent nausea and vomiting beforeyour chemotherapy on Day 1.

{ "type": "p", "children": [], "text": "You have already been givena capsule of EMEND (aprepitant) toprevent nausea and vomiting beforeyour chemotherapy on Day 1." }

The two capsules in this packageare to be taken on Days 2 and 3.

{ "type": "p", "children": [], "text": "The two capsules in this packageare to be taken on Days 2 and 3." }

Each capsule contains 80 mgof aprepitant.

{ "type": "p", "children": [], "text": "Each capsule contains 80 mgof aprepitant." }

USUAL DOSAGE:See accompanying circular.

{ "type": "p", "children": [], "text": "USUAL DOSAGE:See accompanying circular." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Keep this and all drugs out ofthe reach of children.

{ "type": "p", "children": [], "text": "Keep this and all drugs out ofthe reach of children." }

Dist. by: Merck Sharp & Dohme LLCRahway, NJ 07065, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandAprepitant (active ingred.) Made in Switzerland.Formulated in Ireland.

{ "type": "p", "children": [], "text": "Dist. by: Merck Sharp & Dohme LLCRahway, NJ 07065, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandAprepitant (active ingred.) Made in Switzerland.Formulated in Ireland." }

NDC 0006-0462-06

{ "type": "p", "children": [], "text": "\nNDC 0006-0462-06" }

125 mg

{ "type": "p", "children": [], "text": "\n125 mg\n" }

EMEND® (APREPITANT) CAPSULES

{ "type": "p", "children": [], "text": "\nEMEND®\n(APREPITANT) CAPSULES" }

For Adults andPediatric Patients12 years of Age and Older

{ "type": "p", "children": [], "text": "For Adults andPediatric Patients12 years of Age and Older" }

Each capsule contains 125 mg aprepitant.

{ "type": "p", "children": [], "text": "Each capsule contains 125 mg aprepitant." }

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].USUAL DOSAGE: See accompanying circular.

{ "type": "p", "children": [], "text": "Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].USUAL DOSAGE: See accompanying circular." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

This is a bulk package and not intended for dispensing.Package not child resistant.

{ "type": "p", "children": [], "text": "This is a bulk package and not intended for dispensing.Package not child resistant." }

6 capsules

{ "type": "p", "children": [], "text": "6 capsules" }

NDC 0006-3862-03

{ "type": "p", "children": [], "text": "\nNDC 0006-3862-03\n" }

TriPack3 capsules

{ "type": "p", "children": [], "text": "\nTriPack3 capsules" }

EMEND® (aprepitant) capsules

{ "type": "p", "children": [], "text": "\nEMEND®\n\n(aprepitant) capsules" }

125 mg 80 mg

{ "type": "p", "children": [], "text": "\n125 mg 80 mg" }

For Adults andPediatric Patients12 years of Age and Older

{ "type": "p", "children": [], "text": "For Adults andPediatric Patients12 years of Age and Older" }

One 125-mg capsule contains125 mg aprepitant.

{ "type": "p", "children": [], "text": "One 125-mg capsule contains125 mg aprepitant." }

Two 80-mg capsules each containing80 mg of aprepitant.

{ "type": "p", "children": [], "text": "Two 80-mg capsules each containing80 mg of aprepitant." }

USUAL DOSAGE:See accompanying circular.

{ "type": "p", "children": [], "text": "USUAL DOSAGE:See accompanying circular." }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Keep this and all drugs out ofthe reach of children.

{ "type": "p", "children": [], "text": "Keep this and all drugs out ofthe reach of children." }

Dist. by: Merck Sharp & Dohme LLCRahway, NJ 07065, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandAprepitant (active ingred.) Made in Switzerland.Formulated in Ireland.

{ "type": "p", "children": [], "text": "Dist. by: Merck Sharp & Dohme LLCRahway, NJ 07065, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandAprepitant (active ingred.) Made in Switzerland.Formulated in Ireland." }

NDC 0006-0464-10

{ "type": "p", "children": [], "text": "\nNDC 0006-0464-10" }

40 mg

{ "type": "p", "children": [], "text": "\n40 mg\n" }

EMEND® (APREPITANT) CAPSULE

{ "type": "p", "children": [], "text": "\nEMEND®\n(APREPITANT) CAPSULE" }

Each capsule contains 40 mg aprepitant. Rx only

{ "type": "p", "children": [], "text": "Each capsule contains 40 mg aprepitant.\nRx only\n" }

Package not child resistant. Keep thisand all drugs out of the reach of children.

{ "type": "p", "children": [], "text": "Package not child resistant. Keep thisand all drugs out of the reach of children." }

Dist. by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandFormulated in Ireland

{ "type": "p", "children": [], "text": "Dist. by: Merck Sharp & Dohme Corp., a subsidiary of\nMERCK & CO., INC., Whitehouse Station, NJ 08889, USAManuf. by: Alkermes Pharma Ireland Limited, Athlone, IrelandFormulated in Ireland" }

1 Capsule

{ "type": "p", "children": [], "text": "1 Capsule" }

NDC 0006-3066-03

{ "type": "p", "children": [], "text": "\nNDC 0006-3066-03\n" }

EMEND® (aprepitant) for oral suspension

{ "type": "p", "children": [], "text": "\nEMEND®\n\t\t\t\t\t\t\t (aprepitant) for oral suspension\n" }

125 mg

{ "type": "p", "children": [], "text": "\n125 mg" }

Single-Dose Kit

{ "type": "p", "children": [], "text": "\nSingle-Dose Kit" }

Discard Unused Portion

{ "type": "p", "children": [], "text": "Discard Unused Portion" }

This product must be reconstituted and dose must be measured by a healthcare provider.

{ "type": "p", "children": [], "text": "\nThis product must be reconstituted and dose must be measured by a healthcare provider.\n" }

See package insert and accompanying directions.

{ "type": "p", "children": [], "text": "See package insert and accompanying directions." }

For Oral Administration Only

{ "type": "p", "children": [], "text": "For Oral Administration Only" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

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

{ "type": "p", "children": [], "text": "Aprepitant capsules, in combination with other antiemetic agents, is indicated in patients 12 years of age and older for the prevention of:" }

{ "type": "ul", "children": [ "acute and delayed nausea and vomiting associted with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.", "nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC)." ], "text": "" }

Aprepitant capsules are indicated in adults for the prevention of postoperative nausea and vomiting.

{ "type": "p", "children": [], "text": "Aprepitant capsules are indicated in adults for the prevention of postoperative nausea and vomiting." }

{ "type": "ul", "children": [ "Aprepitant has not been studied for the treatment of established nausea and vomiting.", "Chronic continuous administration of Aprepitant is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use." ], "text": "" }

Adults and Pediatric Patients 12 Years of Age and Older

The recommended oral dosage of aprepitant capsules, dexamethasone, and a 5-HT 3antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively.

<div class="scrollingtable"><table width="615px"> <caption> <span>Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC</span> </caption> <colgroup> <col width="115"/> <col width="99"/> <col width="122"/> <col width="98"/> <col width="104"/> <col width="77"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="6"></td> </tr> <tr class="Last"> <td align="left" colspan="6"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Population</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 1</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 2</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 3</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 4</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant <br/> capsules* </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">Adults and <br/> Pediatric <br/> Patients <br/> 12 Years and Older </td><td align="center" class="Botrule Rrule" valign="top">125 mg orally</td><td align="center" class="Botrule Rrule" valign="top">80 mg orally</td><td align="center" class="Botrule Rrule" valign="top">80 mg orally</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Dexamethasone</td><td align="center" class="Botrule Rrule" valign="top">Adults</td><td align="center" class="Botrule Rrule" colspan="2" valign="top">12 mg orally</td><td align="center" class="Botrule Rrule" valign="top">8 mg orally</td><td align="center" class="Botrule Rrule" valign="top">8 mg orally</td><td align="center" class="Botrule Rrule" valign="top">8 mg orally</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Pediatric <br/> Patients <br/> 12 Years and <br/> Older </td><td align="center" class="Botrule Rrule" colspan="5" valign="top">If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 <span class="Italics">[see Clinical Studies ( <a href="#ID57">14.3</a>)].† </span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">5-HT3 antagonist</td><td align="center" class="Botrule Rrule" colspan="2" valign="top">Adults and <br/> Pediatric <br/> Patients <br/> 12 Years and <br/> Older </td><td align="center" class="Botrule Rrule" valign="top">See selected <br/> 5-HT3 antagonist <br/> prescribing <br/> information for <br/> the <br/> recommended <br/> dosage </td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="614px"> <caption> <span>Table 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MEC</span> </caption> <colgroup> <col width="115"/> <col width="99"/> <col width="122"/> <col width="98"/> <col width="180"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5"></td> </tr> <tr class="Last"> <td align="left" colspan="5"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Population</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 1</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 2</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Day 3</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant <br/> capsules* </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">Adults and <br/> Pediatric Patients <br/> 12 Years and Older </td><td align="center" class="Botrule Rrule" valign="top">125 mg orally</td><td align="center" class="Botrule Rrule" valign="top">80 mg orally</td><td align="center" class="Botrule Rrule" valign="top">80 mg orally</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="2" valign="top">Dexamethasone</td><td align="center" class="Botrule Rrule" valign="top">Adults</td><td align="center" class="Botrule Rrule" colspan="2" valign="top">12 mg orally</td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top">Pediatric <br/> Patients <br/> 12 Years and <br/> Older </td><td align="center" class="Botrule Rrule" colspan="4" valign="top">If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 <span class="Italics">[see Clinical Studies ( <a href="#ID57">14.3</a>)].† </span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">5-HT3 antagonist</td><td align="center" class="Botrule Rrule" colspan="2" valign="top">Adults and <br/> Pediatric <br/> Patients <br/> 12 Years and <br/> Older </td><td align="center" class="Botrule Rrule" valign="top">See selected <br/> 5-HT <span class="Sub">3</span>antagonist <br/> prescribing <br/> information for <br/> the <br/> recommended <br/> dosage </td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> </tbody> </table></div>

The recommended oral dosage of aprepitant capsules is 40 mg within 30 hours prior to induction of anesthesia.

Aprepitant capsules can be administered with or without food

Aprepitant capsules

Aprepitant capsules, USP:

{ "type": "p", "children": [], "text": "\nAprepitant capsules, USP:\n" }

• 40 mg: white body and yellow cap with "40 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "• 40 mg: white body and yellow cap with \"40 mg\" printed in black ink on the body." }

• 80 mg: white body and white cap with "80 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "• 80 mg: white body and white cap with \"80 mg\" printed in black ink on the body." }

• 125 mg: white body and pink cap with "125 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "• 125 mg: white body and pink cap with \"125 mg\" printed in black ink on the body." }

Aprepitant is contraindicated in patients:

{ "type": "p", "children": [], "text": "\nAprepitant is contraindicated in patients:" }

• who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported [see Adverse Reactions ( 6.2)] . 

{ "type": "p", "children": [], "text": "• who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported\n \n [see Adverse Reactions (\n \n 6.2)]\n \n . \n\n " }

• taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of this drug which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "• taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of this drug which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n .\n\n " }

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

See table 10 and 11 for a listing of potentially significant drug interactions [see Drug Interactions ( 7.1, 7.2)] .

Coadministration of aprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology ( 12.3)] . Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant for the prevention of postoperative nausea and vomiting [see Drug Interactions ( 7.1)].

Upon coadministration with aprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant [see Clinical Pharmacology ( 12.3)]. Advise patients to use effective alternative or back-up methods of contraception during treatment with aprepitant and for 1 month following the last dose of aprepitant [see Drug Interactions ( 7.1), Use in Specific Populations ( 8.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety of aprepitant was evaluated in approximately 6,800 individuals.

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

In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy [see Clinical Studies ( 14.1)].

In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), aprepitant in combination with ondasetron and dexamethasone (aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies ( 14.2)] . The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%).

Across these 4 studies there were 1,412 patients treated with the aprepitant regimen during Cycle 1 of chemotherapy and 1,099 of these patients continued into the Mutliplwe-Cycle extension for up to 6 cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 are listed in Table 5.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies*</span> </caption> <colgroup> <col width="234"/> <col width="237"/> <col width="123"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">, ondansetron, and dexamethasone <span class="Sup">†</span></span> <br/> <span class="Bold">(N=1,412)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Ondansetron and dexamethasone <span class="Sup">‡</span></span> <br/> <span class="Bold">(N=1,396)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">fatigue</td><td align="center" class="Botrule Rrule" valign="top">13%</td><td align="center" class="Botrule Rrule" valign="top">12%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">diarrhea</td><td align="center" class="Botrule Rrule" valign="top">9%</td><td align="center" class="Botrule Rrule" valign="top">8%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">asthenia</td><td align="center" class="Botrule Rrule" valign="top">7%</td><td align="center" class="Botrule Rrule" valign="top">6%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">dyspepsia</td><td align="center" class="Botrule Rrule" valign="top">7%</td><td align="center" class="Botrule Rrule" valign="top">5%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">abdominal pain</td><td align="center" class="Botrule Rrule" valign="top">6%</td><td align="center" class="Botrule Rrule" valign="top">5%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">hiccups</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">3%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">white blood cell count decreased</td><td align="center" class="Botrule Rrule" valign="top">4%</td><td align="center" class="Botrule Rrule" valign="top">3%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">dehydration</td><td align="center" class="Botrule Rrule" valign="top">3%</td><td align="center" class="Botrule Rrule" valign="top">2%</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">alanine aminotransferase increased</td><td align="center" class="Botrule Rrule" valign="top">3%</td><td align="center" class="Botrule Rrule" valign="top">2%</td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 6: Less Common Adverse Reactions in Aprepitant-Treated Patients from a Pooled Analysis of HEC and MEC Studies*</span> </caption> <colgroup> <col width="266"/> <col width="328"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="2"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Infection and Infestations</span></td><td align="left" class="Botrule Rrule Toprule" valign="top">oral candidiasis, pharyngitis</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Blood and the Lymphatic System Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">anemia, febrile neutropenia, neutropenia, thrombocytopenia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">decreased appetite, hypokalemia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Psychiatric Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">anxiety</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Nervous System Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">dizziness, dysgeusia, peripheral neuropathy</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Cardiac Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">palpitations</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Vascular Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">flushing, hot flush</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">cough, dyspnea, oropharyngeal pain</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gastrointestinal Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">alopecia, hyperhidrosis, rash</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">musculoskeletal pain</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">General Disorders and</span> <br/> <span class="Bold">Administration Site Condition</span></td><td align="left" class="Botrule Rrule" valign="top">edema peripheral, malaise</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Investigations</span></td><td align="left" class="Botrule Rrule" valign="top">aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased</td> </tr> </tbody> </table></div>

In additional active-controlled clinical study 1,169 patients receiving aprepitant and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with aprepitant.

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

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

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

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

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

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 7: Most Common Adverse Reactions in Aprepitant-Treated Pediatric Patients in HEC and MEC Pooled Studies 5 and 6*</span> </caption> <colgroup> <col width="169"/> <col width="256"/> <col width="213"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="3"></td> </tr> <tr class="Last"> <td align="left" colspan="3"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">and ondansetron (N=184)</span></td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Ondansetron (N=168)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">neutropenia</td><td align="center" class="Botrule Rrule" valign="top">13%</td><td align="center" class="Botrule Rrule" valign="top">11%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">headache</td><td align="center" class="Botrule Rrule" valign="top">9%</td><td align="center" class="Botrule Rrule" valign="top">5%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">diarrhea</td><td align="center" class="Botrule Rrule" valign="top">6%</td><td align="center" class="Botrule Rrule" valign="top">5%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">decreased appetite</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">4%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">cough</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">3%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">fatigue</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">2%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">hemoglobin decreased</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">4%</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">dizziness</td><td align="center" class="Botrule Rrule" valign="top">5%</td><td align="center" class="Botrule Rrule" valign="top">1%</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">hiccups</td><td align="center" class="Botrule Rrule" valign="top">4%</td><td align="center" class="Botrule Rrule" valign="top">1%</td> </tr> </tbody> </table></div>

Forty-nine patients were treated with ifosfamide chemotherapy in each arm. Two of the patients treated with ifosfamide in the aprepitant are developed behavioral changes (agitation = 1; abnormal behavior = 1), whereas no patient treatesd with ifosfamide in the control arm developed behavioral changes. Aprepitant has the potential for increasing ifosfamide-mediated neurotoxicity through induction of CYP3A4 [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.3)] .

Adverse Reactions in Adult Patients in the Prevention of PONV

In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 7 and 8), 40 mg-oral aprepitant was compared to 4-mg intravenous ondansetron [see Clinical Studies (14.4)].

There were 564 patients treated with aprepitant and 538 patients treated with ondansetron.

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 8: Most Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies*</span> </caption> <colgroup> <col width="215"/> <col width="205"/> <col width="219"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="3"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">40 mg</span> <br/> <span class="Bold">(N = 564)</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Ondansetron (N = 538)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">constipation</td><td align="center" class="Botrule Rrule" valign="top">9%</td><td align="center" class="Botrule Rrule" valign="top">8%</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">hypotension</td><td align="center" class="Botrule Rrule" valign="top">6%</td><td align="center" class="Botrule Rrule" valign="top">5%</td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 9: Less Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies*</span> </caption> <colgroup> <col width="285"/> <col width="344"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="2"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Infections and Infestations</span></td><td align="left" class="Botrule Rrule Toprule" valign="top">postoperative infection</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">hypokalemia, hypovolemia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Nervous System Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">dizziness, hypoesthesia, syncope</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Cardiac Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">bradycardia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Vascular Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">hematoma</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">dyspnea, hypoxia, respiratory depression</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gastrointestinal Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">abdominal pain, dry mouth, dyspepsia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="left" class="Botrule Rrule" valign="top">urticaria</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="left" class="Botrule Rrule" valign="top">hypothermia</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Investigations</span></td><td align="left" class="Botrule Rrule" valign="top">blood albumin decreased, bilirubin increased, blood glucose increased, blood potassium decreased</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Injury, Poisoning and Procedural Complications</span></td><td align="left" class="Botrule Rrule" valign="top">operative hemorrhage, wound dehiscence</td> </tr> </tbody> </table></div>

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

Other Studies

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

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

Skin and subcutaneous tissue disorders:pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders:hypersensitivity reactions including anaphylactic reactions [see Contraindications ( 4)] .

Nervous system disorders:ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology ( 12.3)] .

Aprepitant acts as a moderate inhibitor of CYP3A4 when administered as a 3-day regimen (125mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4. Aprepitant acts as a weak inhibitor when administered as a single 40-mg dose and has not been shown to alter the plasma concentrations of concomitant drugs that are primarily metabolized through CYP3A4. Some substrates of CYP3A4 are contraindicated with aprepitant [see Contraindications ( 4)] . Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 10.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 10: Effects of Aprepitant on the Pharmacokinetics of Other Drugs</span> </caption> <colgroup> <col width="139"/> <col width="503"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">CYP3A4 Substrates</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Pimozide </span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Increased pimozide exposure</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">Aprepitant is contraindicated <span class="Italics">[see Contraindications ( <a href="#ID4">4</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Benzodiazepines</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions <span class="Italics">[see Clinical Pharmacology ( <a href="#ID53">12.3</a>)]. </span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Underline">3-day aprepitant regimen</span> <ul> <li> Monitor for benzodiazepine-related adverse reactions.</li> <li> Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam</li> </ul> <span class="Underline">Single 40 mg dose of aprepitant</span> <ul> <li> No dosage adjustment of the benzodiazepine needed</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Dexamethasone</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Increased dexamethasone exposure <span class="Italics">[see Clinical Pharmacology ( <a href="#ID53">12.3</a>)]. </span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Underline">3-day aprepitant regimen</span> <ul> <li> Reduce the dose of oral dexamethasone by approximately 50% <span class="Italics">[see Dosage and Administration ( <a href="#ID33">2.1</a>)]. </span> </li> </ul> <br/> <span class="Underline">Single 40 mg dose of aprepitant</span> <ul> <li> No dosage adjustment of oral dexamethasone needed </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Methylprednisolone</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Increased methylprednisolone exposure <span class="Italics">[see Clinical Pharmacology ( <a href="#ID53">12.3</a>)]. </span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Underline">3-day aprepitant regimen</span> <ul> <li> Reduce the dose of intravenous methylprednisolone by approximately 25% </li> <li> Reduce the dose of oral methylprednisolone by approximately 50%</li> </ul> <br/> <span class="Underline">Single 40 mg dose of aprepitant</span> <ul> <li> No dosage adjustment of methylprednisolone needed </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Chemotherapeutic agents that are metabolized by CYP3A4</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions <span class="Italics">[see Clinical Pharmacology ( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Underline">Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents</span> <ul> <li> Monitor for chemotherapeutic-related adverse reactions. </li> </ul> <br/> <span class="Underline">Etoposide, vinorelbine, paclitaxel, and docetaxel</span> <ul> <li> No dosage adjustment needed.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Hormonal Contraceptives</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant <span class="Italics">[see Warnings and Precautions ( <a href="#ID38">5.3</a>), Use in Specific Populations ( <a href="#ID45">8.3</a>), Clinical Pharmacology ( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Rrule" valign="top">birth control pills, skin patches, implants, and certain IUDs</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">CYP2C9 Substrates</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">Warfarin</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Decreased warfarin exposure and decreased prothrombin time (INR) <span class="Italics">[see Warnings and Precautions ( <a href="#ID37">5.2</a>), Clinical Pharmacology ( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day aprepitant regimen with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Other</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Italics">5-HT <span class="Sub">3 </span>Antagonists </span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">No change in the exposure of the 5-HT <span class="Sub">3 </span>antagonist <span class="Italics">[see Clinical Pharmacology ( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">No dosage adjustment needed</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Rrule" valign="top">ondansetron, granisetron, dolasetron</td> </tr> </tbody> </table></div>

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology ( 12.3)] . Co-administration of aprepitant with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 11.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 11: Effects of Other Drugs on Pharmacokinetics of Aprepitant</span> </caption> <colgroup> <col width="100"/> <col width="539"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Moderate to Strong CYP3A4 Inhibitors</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with aprepitant <span class="Italics">[see Adverse Reactions ( <a href="#ID39">6.1</a>) and Clinical Pharmacology ( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">Avoid concomitant use of aprepitant</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Underline">Moderate inhibitor:</span> <br/> diltiazem <br/> <br/> <span class="Underline">Strong inhibitors:</span> <br/> ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Strong CYP3A4 Inducers</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact</span></td><td align="left" class="Botrule Rrule" valign="top">Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of aprepitant <span class="Italics">[see Clinical Pharmacology</span> <br/> <span class="Italics">( <a href="#ID53">12.3</a>)] </span>. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention</span></td><td align="left" class="Botrule Rrule" valign="top">Avoid concomitant use of aprepitant</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Rrule" valign="top">rifampin, carbamazepine, phenytoin</td> </tr> </tbody> </table></div>

Risk Summary

There are insufficient data on use of aprepitant in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately 1.5 times the adult human exposure at the 125-mg/80-mg/ 80-mg aprepitant regimen [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 

Data

Animal Data

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1,000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in rabbits. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1,000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80mg/80-mg aprepitant regimen. Aprepitant crosses the placenta in rats and rabbits.

Risk Summary

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

Contraception

Upon administration of aprepitant, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms and spermicides) during treatment with aprepitant and for 1 month following the last dose [see Drug Interactions ( 7.1), Clinical Pharmacology ( 12.3)] .

Prevention of Nausea and Vomiting Associated with HEC or MEC

The safety and effectiveness of aprepitant capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. Use of aprepitant in these age groups is supported by evidence from 302 pediatric patients in a randomized, double-blind, active comparator controlled clinical study (n=207 patients aged 6 months to less than 12 years, n=95 patients aged 12 through 17 years). Aprepitant was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician) [see Clinical Studies ( 14.3)] . Adverse reactions were similar to those reported in adult patients [see Adverse Reactions ( 6.1)] .

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

Prevention of Postoperative Nausea and Vomiting (PONV)

The safety and effectiveness of aprepitant have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.

Juvenile Animal Study

A study was conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1,000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs. There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory.

Of the 544 adult cancer patients treated with aprepitant in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Of the 1,120 adult cancer patients treated with aprepitant in PONV clinical studies, 7% were aged 65 and over, while 2% were aged 75 and over. Other reported clinical experience with aprepitant has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3)] .

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

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when aprepitant is administered [see Clinical Pharmacology ( 12.3)] .

No specific information is available on the treatment of overdosage. 

{ "type": "p", "children": [], "text": "\nNo specific information is available on the treatment of overdosage. " }

Drowsiness and headache were reported in one patient who ingested 1,440 mg of aprepitant (approximately 11 times the maximum recommended single dose).

{ "type": "p", "children": [], "text": "Drowsiness and headache were reported in one patient who ingested 1,440 mg of aprepitant (approximately 11 times the maximum recommended single dose)." }

In the event of overdose, 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 in cases of aprepitant overdosage.

{ "type": "p", "children": [], "text": "In the event of overdose, 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 in cases of aprepitant overdosage." }

Aprepitant is not removed by hemodialysis. 

{ "type": "p", "children": [], "text": "Aprepitant is not removed by hemodialysis. " }

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

{ "type": "p", "children": [], "text": "\nAprepitant capsules, USP contain the active ingredient, aprepitant, USP. Aprepitant, USP is a substance P/neurokinin 1 (NK\n \n 1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2\n \n R,3\n \n S)-2-[(1\n \n R)-1-[3,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3\n \n H-1,2,4-triazol-3one.\n\n " }

Its empirical formula is C 23H 21F 7N 4O 3, and its structural formula is:

{ "type": "p", "children": [], "text": "Its empirical formula is C\n \n 23H\n \n 21F\n \n 7N\n \n 4O\n \n 3, and its structural formula is:\n\n " }

Aprepitant, USP is a white to off-white powder, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in alcohol and slightly soluble in acetonitrile.

{ "type": "p", "children": [], "text": "\nAprepitant, USP is a white to off-white powder, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in alcohol and slightly soluble in acetonitrile." }

Each capsule of aprepitant for oral administration contains either 40 mg, 80 mg, or 125 mg of aprepitant, USP and the following inactive ingredients: hypromellose 2910, poloxamer 407, sucrose, microcrystalline cellulose and imprinting ink (shellac glaze, iron oxide black and propylene glycol). The capsule shell excipients are gelatin, titanium dioxide and sodium lauryl sulfate. The 40-mg capsule shell also contains yellow ferric oxide, sodium lauryl sulfate and titanium dioxide, 80-mg capsule shell contains sodium lauryl sulfate and titanium dioxide and the 125-mg capsule contains red ferric oxide, sodium lauryl sulfate and titanium dioxide. 

{ "type": "p", "children": [], "text": "Each capsule of aprepitant for oral administration contains either 40 mg, 80 mg, or 125 mg of aprepitant, USP and the following inactive ingredients: hypromellose 2910, poloxamer 407, sucrose, microcrystalline cellulose and imprinting ink (shellac glaze, iron oxide black and propylene glycol). The capsule shell excipients are gelatin, titanium dioxide and sodium lauryl sulfate. The 40-mg capsule shell also contains yellow ferric oxide, sodium lauryl sulfate and titanium dioxide, 80-mg capsule shell contains sodium lauryl sulfate and titanium dioxide and the 125-mg capsule contains red ferric oxide, sodium lauryl sulfate and titanium dioxide. " }

Meets USP Dissolution Test 2.

{ "type": "p", "children": [], "text": "Meets USP Dissolution Test 2." }

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK 1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) 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 NK 1receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

NK 1Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo-controlled 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 (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK 1receptor 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 approximately 10 ng/mL and 100 ng/mL, the NK 1 receptor occupancies were approximately 50% and 90%, respectively. The oral aprepitant regimen for CINV produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK 1receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK 1receptor 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. Maximum aprepitant concentrations after a single 200-mg dose of fosaprepitant were 4- and 9-fold higher than that achieved with oral aprepitant 125 mg and 40 mg, respectively. QT prolongation with the recommended oral aprepitant dosing regimens for CINV and PONV is not expected.  

Absorption

Following oral administration of a single 40-mg dose of aprepitant in the fasted state, mean area under the plasma concentration-time curve (AUC 0- ∞) was 7.8 mcg•hr/mL and mean peak plasma concentration (C max) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (T max). The absolute bioavailability at the 40-mg dose has not been determined. 

Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC 0-24hr was approximately 19.6 mcg•hr/mL and 21.2 mcg•hr/mL on Day 1 and Day 3, respectively. The C max of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (T max) on Day 1 and Day 3, respectively. At the dose range of 80 to 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 were non-linear across the clinical dose range. In healthy young adults, the increase in AUC 0-∞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 (Vd ss) was approximately 70 L in humans. 

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

Elimination

Metabolism

Aprepitant undergoes extensive metabolism. In vitrostudies 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 (2.4 times the maximum aprepitant recommended dose), indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

Excretion

Following administration of a single intravenous 100-mg dose of [ 14C]-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 halflife ranged from approximately 9 to 13 hours.

Specific Populations

Geriatric Patients

Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5 (2 additional days of dosing compared to the recommended duration), the AUC 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The C max was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations ( 8.5)]. 

Pediatric Patients

As part of a 3-day regimen, dosing of aprepitant capsules (125-mg/80-mg/80-mg) in 18 pediatric patients (aged 12 through 17 years) achieved a mean AUC 0-24hr of 17 mcg•hr/mL on Day 1 with mean peak plasma concentration (C max) at 1.3 mcg/mL occurring at approximately 4 hours. The mean concentrations at the end of Day 2 (N=8) and Day 3 (N=16) were both at 0.6 mcg/mL

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

Male and Female Patients

Following oral administration of a single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum aprepitant recommended dose), the AUC 0-24hrand C max are 9% and 17% higher in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and T max occurs at approximately the same time. These differences are not considered clinically meaningful. 

Racial or Ethnic Groups

Following oral administration of a single dose of aprepitant ranging from 40 mg to 375 mg (3 times the maximum aprepitant recommended dose), the AUC 0-24hrand C max are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC 0-24hrand C max were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hror C max between Caucasians and Blacks. These differences are not considered clinically meaningful.

Patients with Renal Impairment

A single 240-mg dose of aprepitant (approximately 1.9 times the maximum aprepitant recommended dose) was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC 0-∞of total aprepitant (unbound and protein bound) decreased by 21% and C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-∞of total aprepitant decreased by 42% and C max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate [see Use in Specific Populations ( 8.6)] .

Patients with Hepatic Impairment

Following administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC 0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC 0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations ( 8.7)] .

Body Mass Index (BMI)

For every 5 kg/m 2 increase in BMI, AUC 0-24hr and C max of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m 2 to 36 kg/m 2. This change is not considered clinically meaningful. 

Drug Interactions Studies

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

Effects of Aprepitant on the Pharmacokinetics of Other Drugs

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 12: Pharmacokinetic Interaction Data for Aprepitant and Coadministered Midazolam  </span> </caption> <col width="201"/> <col width="178"/> <col width="252"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Dosage of Aprepitant</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Dosage of Midazolam</span></td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Observed Drug Interactions</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5</td><td align="center" class="Botrule Rrule" valign="top">oral 2 mg single dose on <br/> Days 1 and 5 </td><td align="left" class="Botrule Rrule" valign="top">midazolam AUC ↑  2.3-fold on Day 1 and ↑  3.3-fold on Day 5 <span class="Italics">[see Drug</span> <br/> <span class="Italics">Interactions ( <a href="#ID41">7.1</a>)] </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 125 mg on Day 1 and <br/> 80 mg on Days 2 and 3 </td><td align="center" class="Botrule Rrule" valign="top">intravenous 2 mg prior to 3-day regimen of aprepitant <br/> and on Days 4, 8 and 15 </td><td align="left" class="Botrule Rrule" valign="top">midazolam AUC ↑  25% on Day 4, AUC ↓  19% on Day 8 and AUC ↓  4% on Day <br/> 15 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 125 mg on Day 1</td><td align="center" class="Botrule Rrule" valign="top">intravenous 2 mg given 1 hour after aprepitant</td><td align="left" class="Botrule Rrule" valign="top">midazolam AUC ↑  1.5-fold</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="center" class="Botrule Rrule" valign="top">oral 2 mg</td><td align="left" class="Botrule Rrule" valign="top">midazolam AUC ↑  1.2-fold on Day 1</td> </tr> </tbody> </table></div>

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

 Corticosteroids:

Dexamethasone:Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg dexamethasone on Day 1 and 8-mg dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5 [see Dosage and Administration ( 2.1)] . A single dose of aprepitant (40 mg) when coadministered with a single dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold, which is not considered clinically significant. 

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

Chemotherapeutic agents:

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

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

CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of 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 aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with aprepitant [see Drug Interactions ( 7.1)] . 

Tolbutamide:Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.

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

Other Drugs

Oral contraceptives:When aprepitant was administered as a 3-day regimen (125-mg/80-mg/80-mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment.

When a daily dosage of an oral contraceptive containing ethinyl estradiol and norgestimate was administered on Days 1 through 21, and aprepitant 40 mg was given on Day 8, the AUC of ethinyl estradiol decreased by 4% and by 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with aprepitant 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone [see Drug Interactions ( 7.1)] .

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

5-HT 3antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of Other Drugs on the Pharmacokinetics of Aprepitant

Ketoconazole:When a single 125-mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions ( 7.2)] .

Rifampin:When a single 375-mg dose of aprepitant (3 times the maximum aprepitant recommended dose) was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions ( 7.2)] .

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 (approximately 1.8 times the aprepitant recommended dose), 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 [see Drug Interactions ( 7.2)] .

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

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1,000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (AUC) of 0.7 to 1.6 times the adult human exposure at the 125-mg/80-mg/ 80-mg aprepitant regimen. Treatment with aprepitant at doses of 5 to 1,000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1,000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1,000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2,000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the adult human exposure at the 125-mg/80-mg/80-mg aprepitant regimen. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Mutagenesis

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.

Impairment of Fertility

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1,000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended adult human dose and exposure in female rats at about 1.6 times the adult human exposure at the 125-mg/80-mg/80-mg aprepitant regimen).

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 HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.

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

In 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).

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. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 13: HEC Treatment Regimens – Studies 1 and 2*</span> </caption> <colgroup> <col width="228"/> <col width="120"/> <col width="96"/> <col width="72"/> <col width="78"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr class="Last"> <td align="left" colspan="5"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 1</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 2</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 3</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV Aprepitant Regimen</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral aprepitant <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">125 mg</td><td align="center" class="Botrule Rrule" valign="top">80 mg</td><td align="center" class="Botrule Rrule" valign="top">80 mg</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Dexamethasone <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">12 mg</td><td align="center" class="Botrule Rrule" valign="top">8 mg</td><td align="center" class="Botrule Rrule" valign="top">8 mg</td><td align="center" class="Botrule Rrule" valign="top">8 mg</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="center" class="Botrule Rrule" valign="top">5-HT <span class="Sub">3</span> <br/> antagonist <span class="Sup">§</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV Standard Therapy</td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Dexamethasone</td><td align="center" class="Botrule Rrule" valign="top">20 mg</td><td align="center" class="Botrule Rrule" valign="top">8 mg twice daily</td><td align="center" class="Botrule Rrule" valign="top">8 mg twice daily</td><td align="left" class="Botrule Rrule" valign="top">8 mg twice daily</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="center" class="Botrule Rrule" valign="top">5-HT <span class="Sub">3</span>antagonist <span class="Sup">§</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> </tbody> </table></div>

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

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries)

Other prespecified endpoints:

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

• no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)

• no significant nausea (maximum VAS less than 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 14. 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.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 14: Percent of Patients Receiving HEC Responding by Treatment Group and Phase —Cycle 1</span> </caption> <colgroup> <col width="120"/> <col width="119"/> <col width="81"/> <col width="67"/> <col width="115"/> <col width="75"/> <col width="61"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="7"></td> </tr> <tr> <td align="left" colspan="7"></td> </tr> <tr> <td align="left" colspan="7"></td> </tr> <tr> <td align="left" colspan="7"></td> </tr> <tr> <td align="left" colspan="7"></td> </tr> <tr> <td align="left" colspan="7"></td> </tr> <tr class="Last"> <td align="left" colspan="7"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Study 1</span></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Study 2</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">ENDPOINTS</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Aprepitant</span> <br/> <span class="Bold">Regimen</span> <br/> <span class="Bold">(N=260)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Standard</span> <br/> <span class="Bold">Therapy</span> <br/> <span class="Bold">(N=261)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">p-Value</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Aprepitant</span> <br/> <span class="Bold">Regimen</span> <br/> <span class="Bold">(N=261)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Standard</span> <br/> <span class="Bold">Therapy</span> <br/> <span class="Bold">(N=263)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">p-Value</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">PRIMARY ENDPOINT</td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response</td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Overall <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">73</td><td align="center" class="Botrule Rrule" valign="top">52</td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001</td><td align="center" class="Botrule Rrule" valign="top">63</td><td align="center" class="Botrule Rrule" valign="top">43</td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">OTHER PRESPECIFIED ENDPOINTS</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Acute phase <span class="Sup">‡</span> Delayed phase <span class="Sup">§</span></td><td align="center" class="Botrule Rrule" valign="top">89 <br/> 75 </td><td align="center" class="Botrule Rrule" valign="top">78 <br/> 56 </td><td align="left" class="Botrule Rrule" valign="top">&lt;0.001 <br/> &lt;0.001 </td><td align="center" class="Botrule Rrule" valign="top">83 <br/> 68 </td><td align="center" class="Botrule Rrule" valign="top">68 <br/> 47 </td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001 <br/> &lt;0.001 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Protection</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Overall <br/> Acute phase <br/> Delayed phase </td><td align="center" class="Botrule Rrule" valign="top">63 <br/> 85 <br/> 66 </td><td align="center" class="Botrule Rrule" valign="top">49 <br/> 75 <br/> 52 </td><td align="center" class="Botrule Rrule" valign="top">0.001 <br/> NS <span class="Sup">¶</span> <br/> &lt;0.001 </td><td align="center" class="Botrule Rrule" valign="top">56 <br/> 80 <br/> 61 </td><td align="center" class="Botrule Rrule" valign="top">41 <br/> 65 <br/> 44 </td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001 <br/> &lt;0.001 <br/> &lt;0.001 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Emesis</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Overall <br/> Acute phase <br/> Delayed phase </td><td align="center" class="Botrule Rrule" valign="top">78 <br/> 90 <br/> 81 </td><td align="center" class="Botrule Rrule" valign="top">55 <br/> 79 <br/> 59 </td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001 0.001 <br/> &lt;0.001 </td><td align="center" class="Botrule Rrule" valign="top">66 <br/> 84 <br/> 72 </td><td align="center" class="Botrule Rrule" valign="top">44 <br/> 69 <br/> 48 </td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001 &lt;0.001 <br/> &lt;0.001 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Nausea</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Overall <br/> Delayed phase </td><td align="center" class="Botrule Rrule" valign="top">48 <br/> 51 </td><td align="center" class="Botrule Rrule" valign="top">44 <br/> 48 </td><td align="center" class="Botrule Rrule" valign="top">NS <span class="Sup">#</span> <br/> NS <span class="Sup">#</span></td><td align="center" class="Botrule Rrule" valign="top">49 <br/> 53 </td><td align="center" class="Botrule Rrule" valign="top">39 <br/> 40 </td><td align="center" class="Botrule Rrule" valign="top">NS <span class="Sup">¶</span> <br/> NS <span class="Sup">¶</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Significant Nausea</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Overall <br/> Delayed phase </td><td align="center" class="Botrule Rrule" valign="top">73 <br/> 75 </td><td align="center" class="Botrule Rrule" valign="top">66 <br/> 69 </td><td align="center" class="Botrule Rrule" valign="top">NS <span class="Sup">#</span> <br/> NS <span class="Sup">#</span></td><td align="center" class="Botrule Rrule" valign="top">71 <br/> 73 </td><td align="center" class="Botrule Rrule" valign="top">64 <br/> 65 </td><td align="center" class="Botrule Rrule" valign="top">NS <span class="Sup">#</span> <br/> NS <span class="Sup">#</span></td> </tr> </tbody> </table></div>

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 HEC Who Remain Emesis Free Over Time — Cycle 1

Additional Patient-Reported Outcomes:The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients' daily lives is defined as a FLIE total score greater than 108. In each of the 2 studies, a higher proportion of patients receiving the 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 was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

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

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

In Study 3, in breast cancer patients, aprepitant in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750 to 1500 mg/m 2; or cyclophosphamide 500 to 1,500 mg/m 2 and doxorubicin (less than or equal to 60 mg/m 2) or epirubicin (less than or equal to 100 mg/m 2). See Table 15.

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

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 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.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 15: MEC Treatment Regimens – Studies 3 and 4*</span> </caption> <colgroup> <col width="169"/> <col width="170"/> <col width="135"/> <col width="108"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="4"></td> </tr> <tr> <td align="left" colspan="4"></td> </tr> <tr> <td align="left" colspan="4"></td> </tr> <tr class="Last"> <td align="left" colspan="4"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 1</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 2</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV APREPITANT Regimen</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral APREPITANT <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">125 mg</td><td align="center" class="Botrule Rrule" valign="top">80 mg</td><td align="center" class="Botrule Rrule" valign="top">80 mg</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Dexamethasone</td><td align="center" class="Botrule Rrule" valign="top">12 mg <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Ondansetron</td><td align="center" class="Botrule Rrule" valign="top">8 mg x 2 doses <span class="Sup">§</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV Standard Therapy</td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Dexamethasone</td><td align="center" class="Botrule Rrule" valign="top">20 mg <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Oral Ondansetron</td><td align="center" class="Botrule Rrule" valign="top">8 mg x 2 doses <span class="Sup">§</span></td><td align="center" class="Botrule Rrule" valign="top">8 mg twice daily</td><td align="center" class="Botrule Rrule" valign="top">8 mg twice daily</td> </tr> </tbody> </table></div>

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

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) 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 less than 5 mm on a 0 to 100 mm scale)

• no significant nausea (maximum VAS less than 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 less than 25 mm on a 0 to 100 mm scale)

• complete response during the acute and delayed phases.

A summary of the key results from Study 3 is shown in Table 16. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the 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 to 24 hours) and delayed (25 to 120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 16: Percent of Patients Receiving MEC Responding by Treatment Group and Phase — Cycle 1 of Study 3</span> </caption> <colgroup> <col width="235"/> <col width="156"/> <col width="122"/> <col width="123"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="4"></td> </tr> <tr> <td align="left" colspan="4"></td> </tr> <tr class="Last"> <td align="left" colspan="4"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">ENDPOINTS</span></td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">Regimen</span> <br/> <span class="Bold">(N=433)*</span> <br/> <span class="Bold">%</span></td><td align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Standard Therapy</span> <br/> <span class="Bold">(N=424)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">p-Value</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">PRIMARY ENDPOINT <span class="Sup">†</span></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response</td><td align="center" class="Botrule Rrule" valign="top">51</td><td align="center" class="Botrule Rrule" valign="top">42</td><td align="center" class="Botrule Rrule" valign="top">0.015</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">OTHER PRESPECIFIED ENDPOINTS <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Emesis</td><td align="center" class="Botrule Rrule" valign="top">76</td><td align="center" class="Botrule Rrule" valign="top">59</td><td align="center" class="Botrule Rrule" valign="top">NS <span class="Sup">‡</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Nausea</td><td align="center" class="Botrule Rrule" valign="top">33</td><td align="center" class="Botrule Rrule" valign="top">33</td><td align="center" class="Botrule Rrule" valign="top">NS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Significant Nausea</td><td align="center" class="Botrule Rrule" valign="top">61</td><td align="center" class="Botrule Rrule" valign="top">56</td><td align="center" class="Botrule Rrule" valign="top">NS</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Rescue Therapy</td><td align="center" class="Botrule Rrule" valign="top">59</td><td align="center" class="Botrule Rrule" valign="top">56</td><td align="center" class="Botrule Rrule" valign="top">NS</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Protection</td><td align="center" class="Botrule Rrule" valign="top">43</td><td align="center" class="Botrule Rrule" valign="top">37</td><td align="center" class="Botrule Rrule" valign="top">NS</td> </tr> </tbody> </table></div>

Additional Patient-Reported Outcomes:In Study 3, in patients receiving MEC, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the 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:In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the aprepitant regimen was maintained during all cycles.

In Study 4, aprepitant in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m 2); or cytarabine intravenous (greater than 1 g/m 2). See Table 15. 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.

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.

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

A summary of the key results from Study 4 is shown in Table 17. In Study 4, a statistically significantly higher proportion of patients receiving the 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 to 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 sex, 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 sex was observed for the no vomiting endpoint.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 17: Percent of Patients Receiving MEC Responding by Treatment Group — Cycle 1 of Study 4</span> </caption> <colgroup> <col width="198"/> <col width="138"/> <col width="162"/> <col width="78"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="4"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">ENDPOINTS</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Aprepitant</span> <br/> <span class="Bold">Regimen</span> <br/> <span class="Bold">(N=430)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Standard Therapy</span> <br/> <span class="Bold">(N=418)*</span> <br/> <span class="Bold">%</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">p-Value</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">No Vomiting Overall</td><td align="center" class="Botrule Rrule" valign="top">76</td><td align="center" class="Botrule Rrule" valign="top">62</td><td align="center" class="Botrule Rrule" valign="top">&lt;0.0001</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response Overall</td><td align="center" class="Botrule Rrule" valign="top">69</td><td align="center" class="Botrule Rrule" valign="top">56</td><td align="center" class="Botrule Rrule" valign="top">0.0003</td> </tr> </tbody> </table></div>

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, aprepitant in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the aprepitant group, reflecting a dosage adjustment to account for a drug interaction [see Clinical Pharmacology ( 12.3)]. No dexamethasone dose reduction was required for patients who received the control regimen.

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

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

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 18: HEC and MEC Treatment Regimens* for Pediatric Patients 6 Months to 17 Years of Age— Study 5</span> </caption> <colgroup> <col width="192"/> <col width="126"/> <col width="120"/> <col width="150"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="4"></td> </tr> <tr> <td align="left" colspan="4"></td> </tr> <tr> <td align="left" colspan="4"></td> </tr> <tr class="Last"> <td align="left" colspan="4"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 1</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 2</td><td align="center" class="Botrule Rrule Toprule" valign="top">Day 3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV Aprepitant Regimen</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Pediatric Patients 6 Months to less than 12 Years of Age <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">3 mg/kg body weight oral suspension</td><td align="center" class="Botrule Rrule" valign="top">2 mg/kg body weight oral suspension</td><td align="center" class="Botrule Rrule" valign="top">2 mg/kg body weight oral suspension</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Pediatric Patients 12 to 17 Years of Age <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">125 mg capsule</td><td align="center" class="Botrule Rrule" valign="top">80 mg capsule</td><td align="center" class="Botrule Rrule" valign="top">80 mg capsule</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">Per standard of care <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CINV Control Regimen <span class="Sup">§</span></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">Per standard of care <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">none</td><td align="center" class="Botrule Rrule" valign="top">none</td> </tr> </tbody> </table></div>

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

Primary endpoint:

• complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy)

Other prespecified endpoints:

• complete response in the acute phase (0 to 24 hours following initiation of chemotherapy)

• complete response in the overall phase (up to 120 hours following initiation of chemotherapy)

• no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase

• safety and tolerability

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

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 19: Percent of Patients Who Responded to Treatment by Treatment Group and Phase – Cycle 1 of Study 5</span> </caption> <colgroup> <col width="287"/> <col width="150"/> <col width="134"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="3"></td> </tr> <tr> <td align="left" colspan="3"></td> </tr> <tr> <td align="left" colspan="3"></td> </tr> <tr> <td align="left" colspan="3"></td> </tr> <tr> <td align="left" colspan="3"></td> </tr> <tr class="Last"> <td align="left" colspan="3"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top">Aprepitant Regimen <br/> n/m (%) </td><td align="center" class="Botrule Rrule Toprule" valign="top">Control Regimen n/m (%)</td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top">PRIMARY ENDPOINT</td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response <span class="Sup">*</span> - Delayed phase </td><td align="center" class="Botrule Rrule" valign="top">77/152 (50.7) <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">39/150 (26.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top">OTHER PRESPECIFIED ENDPOINTS</td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response <span class="Sup">*</span> – Acute phase </td><td align="center" class="Botrule Rrule" valign="top">101/152 (66.4) <span class="Sup">‡</span></td><td align="center" class="Botrule Rrule" valign="top">78/150 (52.0)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Complete Response <span class="Sup">*</span> – Overall phase </td><td align="center" class="Botrule Rrule" valign="top">61/152 (40.1) <span class="Sup">†</span></td><td align="center" class="Botrule Rrule" valign="top">30/150 (20.0)</td> </tr> </tbody> </table></div>

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies 7 and 8), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1,658 patients undergoing open abdominal surgery. These two studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. Study 7 was a multinational study including the U.S., whereas, Study 8 was conducted entirely in the U.S.

In the two studies, patients were randomized to receive 40-mg aprepitant, 125-mg aprepitant, or 4-mg ondansetron as a single dose. 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 aprepitant 125-mg dose did not demonstrate any additional clinical benefit over the 40-mg dose and is not a recommended dosage regimen [see Dosage and Administration ( 2.2)] .

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 aprepitant was evaluated during the 0 to 48 hour period following the end of surgery.

Efficacy measures in Study 7 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 20:

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 20: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) – Study 7</span> </caption> <colgroup> <col width="264"/> <col width="115"/> <col width="73"/> <col width="73"/> <col width="105"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr class="Last"> <td align="left" colspan="5"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold">Treatment</span></td><td align="center" class="Botrule Rrule Toprule" rowspan="2"><span class="Bold">n/m (%)</span></td><td class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">vs.</span> <br/> <span class="Bold">Ondansetron</span></td> </tr> <tr> <td align="center" class="Botrule Rrule">∆</td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Odds ratio</span>* </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Analysis</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">PRIMARY ENDPOINTS</span></td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">No Vomiting</span>0 to 24 hours (Superiority) (no emetic episodes) </td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">246/293 (84.0)</td><td align="center" class="Botrule Rrule" valign="top">12.6%</td><td align="center" class="Botrule Rrule" valign="top">2.1</td><td align="center" class="Botrule Rrule" valign="top">P&lt;0.001 <span class="Sup">†</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">200/280 (71.4)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">Complete Response</span>(Non-inferiority: If LB <span class="Sup">‡</span> &gt;0.65) (no emesis and no rescue therapy, 0 to 24 hours) </td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">187/293 (63.8)</td><td align="center" class="Botrule Rrule" valign="top">8.8%</td><td align="center" class="Botrule Rrule" valign="top">1.4</td><td align="center" class="Botrule Rrule" valign="top">LB=1.02</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">154/280 (55.0)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">Complete Response</span>(Superiority: If LB &gt;1.0) <br/> (no emesis and no rescue therapy, 0 to 24 hours) </td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">187/293 (63.8)</td><td align="center" class="Botrule Rrule" valign="top">8.8%</td><td align="center" class="Botrule Rrule" valign="top">1.4</td><td align="center" class="Botrule Rrule" valign="top">LB=1.02 <span class="Sup">‡</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">154/280 (55.0)</td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">SECONDARY ENDPOINT</span></td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="2" valign="top"><span class="Bold">No Vomiting</span>0 to 48 hours (Superiority) (no emetic episodes) </td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">238/292 (81.5)</td><td align="center" class="Botrule Rrule" valign="top">15.2%</td><td align="center" class="Botrule Rrule" valign="top">2.3</td><td align="center" class="Botrule Rrule" valign="top">P&lt;0.001 <span class="Sup">§</span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">185/279 (66.3)</td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

In Study 7, 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 – Study 7

Efficacy measures in Study 8 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).

Study 8 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 40-mg aprepitant had a clinically meaningful effect with respect to the secondary endpoint "no vomiting" during the first 24 hours after surgery and was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

<div class="scrollingtable"><table width="0px"> <caption> <span>Table 21: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) – Study 8</span> </caption> <colgroup> <col width="239"/> <col width="131"/> <col width="76"/> <col width="70"/> <col width="73"/> </colgroup> <tfoot> <tr class="First"> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr> <td align="left" colspan="5"></td> </tr> <tr class="Last"> <td align="left" colspan="5"></td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold">Treatment</span></td><td align="center" class="Botrule Rrule Toprule" rowspan="2"><span class="Bold">n/m (%)</span></td><td class="Botrule Toprule" valign="top"></td><td align="left" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Aprepitant</span><span class="Bold">vs. Ondansetron</span></td> </tr> <tr> <td align="center" class="Botrule Rrule">∆</td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Odds ratio</span>* </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Analysis</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">PRIMARY ENDPOINT</span></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">Complete Response</span> <br/> (no emesis and no rescue therapy, 0 to 24 hours) </td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">111/248 (44.8)</td><td align="center" class="Botrule Rrule" valign="top">2.5%</td><td align="center" class="Botrule Rrule" valign="top">1.1</td><td align="center" class="Botrule Rrule" valign="top">0.61</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">104/246 (42.3)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">SECONDARY ENDPOINTS</span></td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">No Vomiting</span> <br/> (no emetic episodes, 0 to 24 hours) </td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">223/248 (89.9)</td><td align="center" class="Botrule Rrule" valign="top">16.3%</td><td align="center" class="Botrule Rrule" valign="top">3.2</td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001 <span class="Sup">†</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">181/246 (73.6)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">No Use of Rescue Medication</span> <br/> (for established emesis or nausea, 0 to 24 hours) </td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">112/248 (45.2)</td><td align="center" class="Botrule Rrule" valign="top">-0.7%</td><td align="center" class="Botrule Rrule" valign="top">1.0</td><td align="center" class="Botrule Rrule" valign="top">0.83</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">113/246 (45.9)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule" colspan="3" valign="top"><span class="Bold">No Vomiting</span>0 to 48 hours (Superiority) (no emetic episodes, 0 to 48 hours) </td><td class="Botrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Aprepitant 40 mg</td><td align="left" class="Botrule Rrule" valign="top">209/247 (84.6)</td><td align="center" class="Botrule Rrule" valign="top">17.7%</td><td align="center" class="Botrule Rrule" valign="top">2.7</td><td align="center" class="Botrule Rrule" valign="top">&lt;0.001*</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Ondansetron</td><td align="left" class="Botrule Rrule" valign="top">164/245 (66.9)</td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

Aprepitant capsules, USP, 40 mg, are hard gelatin capsules with white body and yellow cap with "40 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "Aprepitant capsules, USP, 40 mg, are hard gelatin capsules with white body and yellow cap with \"40 mg\" printed in black ink on the body." }

NDC 51407-701-01 Carton of 1 capsule (containing 1 x 1 unit-dose blister)

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NDC 51407-701-05 Carton of 5 capsules (containing 5 x 1 unit-dose blisters)

{ "type": "p", "children": [], "text": "NDC 51407-701-05 Carton of 5 capsules (containing 5 x 1 unit-dose blisters)" }

Aprepitant capsules, USP, 80 mg, are hard gelatin capsules with white body and white cap with "80 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "Aprepitant capsules, USP, 80 mg, are hard gelatin capsules with white body and white cap with \"80 mg\" printed in black ink on the body." }

NDC 51407-702-02 Carton of 2 capsules (containing 2 x 1 unit-dose blisters)

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NDC 51407-702-06 Carton of 6 capsules (containing 3 x 2 dose blisters each)

{ "type": "p", "children": [], "text": "NDC 51407-702-06 Carton of 6 capsules (containing 3 x 2 dose blisters each)" }

Aprepitant capsules, USP, 125 mg, are hard gelatin capsules with white body and pink cap with "125 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "Aprepitant capsules, USP, 125 mg, are hard gelatin capsules with white body and pink cap with \"125 mg\" printed in black ink on the body." }

NDC 51407-703-06 Carton of 6 capsules (containing 6 x 1 unit-dose blister)

{ "type": "p", "children": [], "text": "NDC 51407-703-06 Carton of 6 capsules (containing 6 x 1 unit-dose blister)" }

Aprepitant capsules, USP, Tri-pack-wallet type, 3-day pack (125-mg/80-mg/80-mg)

{ "type": "p", "children": [], "text": "Aprepitant capsules, USP, Tri-pack-wallet type, 3-day pack (125-mg/80-mg/80-mg)" }

80 mg, are hard gelatin capsules with white body and white cap with "80 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "80 mg, are hard gelatin capsules with white body and white cap with \"80 mg\" printed in black ink on the body." }

125 mg, are hard gelatin capsules with white body and pink cap with "125 mg" printed in black ink on the body.

{ "type": "p", "children": [], "text": "125 mg, are hard gelatin capsules with white body and pink cap with \"125 mg\" printed in black ink on the body." }

Blister pack of 2, 80 mg Capsules and 1, 125 mg Capsule

{ "type": "p", "children": [], "text": "Blister pack of 2, 80 mg Capsules and 1, 125 mg Capsule" }

NDC 51407-704-03 Carton of 3 capsules (3-day pack blister tri-pack containing one 125 mg capsule and two 80 mg capsules)

{ "type": "p", "children": [], "text": "NDC 51407-704-03 Carton of 3 capsules (3-day pack blister tri-pack containing one 125 mg capsule and two 80 mg capsules)" }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Capsules

{ "type": "p", "children": [], "text": "Capsules" }

Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]." }

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

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information). " }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

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

{ "type": "p", "children": [], "text": "Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients taking aprepitant. Advise patients to stop taking aprepitant and seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, or difficulty in breathing or swallowing." }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

Advise patients to discuss all medications they are taking, including other prescription, nonprescription medication or herbal products [see Contraindications ( 4), Warnings and Precautions ( 5.1)].

{ "type": "p", "children": [], "text": "Advise patients to discuss all medications they are taking, including other prescription, nonprescription medication or herbal products \n [see Contraindications ( \n 4), Warnings and Precautions ( \n 5.1)]. \n \n" }

Warfarin:Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant for the prevention of postoperative nausea and vomiting [see Warnings and Precautions ( 5.2)] .

{ "type": "p", "children": [], "text": "\nWarfarin:Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant for the prevention of postoperative nausea and vomiting \n [see Warnings and Precautions ( \n 5.2)] \n .\n " }

Hormonal Contraceptives:Advise patients that administration of aprepitant may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception (such as condoms and spermicides) during treatment with aprepitant and for 1 month following the last dose of aprepitant [see Warnings and Precautions ( 5.3), Use in Specific Populations ( 8.3)] .

{ "type": "p", "children": [], "text": "\nHormonal Contraceptives:Advise patients that administration of aprepitant may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception (such as condoms and spermicides) during treatment with aprepitant and for 1 month following the last dose of aprepitant \n [see Warnings and Precautions ( \n 5.3), Use in Specific Populations \n ( \n 8.3)] \n .\n " }

Manufactured by:

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PHARMATHEN INTERNATION S.A., Rodopi 69300, GREECE (GRC)

{ "type": "p", "children": [], "text": "PHARMATHEN INTERNATION S.A., Rodopi 69300, GREECE (GRC)" }

Manufactured For:

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TORRENT PHARMA INC., Basking Ridge, NJ 07920

{ "type": "p", "children": [], "text": "TORRENT PHARMA INC., Basking Ridge, NJ 07920 " }

Revised: 06/2022

{ "type": "p", "children": [], "text": "Revised: 06/2022" }

2823402/3

{ "type": "p", "children": [], "text": "2823402/3" }

Marketed by:

{ "type": "p", "children": [], "text": "\nMarketed by:\n" }

GSMS, Inc.

{ "type": "p", "children": [], "text": "GSMS, Inc." }

Camarillo, CA 93012 USA

{ "type": "p", "children": [], "text": "Camarillo, CA 93012 USA" }

APREPITANT CAPSULES

{ "type": "p", "children": [], "text": "\nAPREPITANT CAPSULES\n" }

(a-PRE-pi-tant)

{ "type": "p", "children": [], "text": "\n(a-PRE-pi-tant)\n" }

Read this Patient Information before you start taking aprepitant and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read this Patient Information before you start taking aprepitant and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment." }

What are Aprepitant Capsules?

{ "type": "p", "children": [], "text": "\nWhat are Aprepitant Capsules?\n" }

Aprepitant capsulesare a prescription medicine used:

{ "type": "p", "children": [], "text": "\nAprepitant capsulesare a prescription medicine used:\n " }

● With other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines

{ "type": "p", "children": [], "text": "● With other medicines that treat nausea and vomiting in patients 12 years of age and older to prevent nausea and vomiting caused by certain anti-cancer (chemotherapy) medicines" }

● In adults to prevent nausea and vomiting after surgery.

{ "type": "p", "children": [], "text": "● In adults to prevent nausea and vomiting after surgery." }

Aprepitant capsules are not used to treat nausea and vomiting that you already have.

{ "type": "p", "children": [], "text": "Aprepitant capsules are not used to treat nausea and vomiting that you already have." }

Aprepitant capsules should not be used continuously for a long time (chronic use)

{ "type": "p", "children": [], "text": "Aprepitant capsules should not be used continuously for a long time (chronic use)" }

Who should not take aprepitant capsules?

{ "type": "p", "children": [], "text": "\nWho should not take aprepitant capsules?\n" }

Do not take aprepitant capsules if you:

{ "type": "p", "children": [], "text": "Do not take aprepitant capsules if you:" }

● are allergic to aprepitant or any of the ingredients in aprepitant capsules. See the end of this leaflet for a complete list of ingredients in aprepitant capsules.

{ "type": "p", "children": [], "text": "● are allergic to aprepitant or any of the ingredients in aprepitant capsules. See the end of this leaflet for a complete list of ingredients in aprepitant capsules." }

● are taking pimozide (ORAP®)

{ "type": "p", "children": [], "text": "● are taking pimozide (ORAP®)" }

What should I tell my healthcare provider before taking aprepitant capsules?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before taking aprepitant capsules?\n" }

Before you take aprepitant capsules, tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "\nBefore you take aprepitant capsules, tell your healthcare provider if you:\n" }

● have liver problems

{ "type": "p", "children": [], "text": "● have liver problems" }

● are pregnant or plan to become pregnant. It is not known if aprepitant capsules can harm your unborn baby.

{ "type": "p", "children": [], "text": "● are pregnant or plan to become pregnant. It is not known if aprepitant capsules can harm your unborn baby." }

○ Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain IUDs) should also use a back-up method of birth control that does not contain hormones, such as condoms and spermicides, during treatment with aprepitant capsules and for 1 month after your last dose of aprepitant capsules.

{ "type": "p", "children": [], "text": " ○ Women who use birth control medicines containing hormones to prevent pregnancy (birth control pills, skin patches, implants, and certain\n \n IUDs) should also use a back-up method of birth control that does not contain hormones, such as condoms and spermicides, during \n \n treatment with aprepitant capsules and for 1 month after your last dose of aprepitant capsules.\n " }

● are breastfeeding or plan to breasfeed. It is not known if aprepitant passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take aprepitant capsules.

{ "type": "p", "children": [], "text": "● are breastfeeding or plan to breasfeed. It is not known if aprepitant passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take aprepitant capsules." }

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

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take,including prescriptions and over-the-counter medicines, vitamins, and herbal supplements.\n " }

Aprepitant capsules my affect the way other medicines work, and other medicines may affect how aprepitant capsules work causing serious side effects.

{ "type": "p", "children": [], "text": "Aprepitant capsules my affect the way other medicines work, and other medicines may affect how aprepitant capsules work causing serious side effects." }

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

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine." }

How should I take aprepitant capsules?

{ "type": "p", "children": [], "text": "\nHow should I take aprepitant capsules?\n" }

● Take aprepitant capsules exactly as prescribed.

{ "type": "p", "children": [], "text": "● Take aprepitant capsules exactly as prescribed." }

● Swallow aprepitant capsules whole.

{ "type": "p", "children": [], "text": "● Swallow aprepitant capsules whole." }

● If you are receiving chemotherapy, aprepitant capsules may be taken with or without food.

{ "type": "p", "children": [], "text": "● If you are receiving chemotherapy, aprepitant capsules may be taken with or without food." }

● If you take too much aprepitant, call healthcare provider, or go to the nearest hospital emergency room.

{ "type": "p", "children": [], "text": "● If you take too much aprepitant, call healthcare provider, or go to the nearest hospital emergency room." }

● If you are receiving cancer chemotherapy, aprepitant capsules are taken as 3 doses over 3 days – starting on the day you have chemotherapy, and for the following 2 days.

{ "type": "p", "children": [], "text": "● If you are receiving cancer chemotherapy, aprepitant capsules are taken as 3 doses over 3 days – starting on the day you have chemotherapy, and for the following 2 days." }

● In adults who are receiving chemotherapy, there are 2 ways your healthcare provider may prescribe aprepitant capsules for you:

{ "type": "p", "children": [], "text": "● \n In adults who are receiving chemotherapy, there are 2 ways your healthcare provider may prescribe aprepitant capsules for you:\n" }

Capsules of aprepitant by mouth for all 3 doses:

{ "type": "p", "children": [], "text": "\nCapsules of aprepitant by mouth for all 3 doses:\n" }

○ You should get a package that has 3 capsules of aprepitant.

{ "type": "p", "children": [], "text": " ○ You should get a package that has 3 capsules of aprepitant." }

○ Day 1 (Day of chemotherapy): Take one 125 mg capsule of aprepitant (white and pink) by mouth 1 hour before you start your chemotherapy treatment.

{ "type": "p", "children": [], "text": " ○ \n Day 1 (Day of chemotherapy): Take one 125 mg capsule of aprepitant (white and pink) by mouth 1 hour before you start your\n \n chemotherapy treatment.\n " }

○ Day 2 and Day 3: Take one 80 mg capsule of aprepitant (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, aprepitant should be taken in the morning.

{ "type": "p", "children": [], "text": " ○ \n Day 2 and Day 3: Take one 80 mg capsule of aprepitant (white) by mouth 1 hour before you start your chemotherapy treatment. If no\n \n chemotherapy treatment is given on Days 2 and 3, aprepitant should be taken in the morning.\n " }

● In children 12 years of age and older who can swallow capsules by mouth, aprepitant is prescribed as capsules of aprepitant by mouth for all 3 doses:

{ "type": "p", "children": [], "text": "● \n In children 12 years of age and older who can swallow capsules by mouth, aprepitant is prescribed as capsules of aprepitant by mouth for all 3 doses:\n" }

○ You should get a package that has 3 capsules of aprepitant.

{ "type": "p", "children": [], "text": " ○ You should get a package that has 3 capsules of aprepitant." }

○ Day 1 (Day of chemotherapy): Take one 125 mg capsule of aprepitant (white and pink) by mouth 1 hour before your start your chemotherapy treatment.

{ "type": "p", "children": [], "text": " ○ \n Day 1 (Day of chemotherapy): Take one 125 mg capsule of aprepitant (white and pink) by mouth 1 hour before your start your\n \n chemotherapy treatment.\n " }

○ Day 2 and Day 3: Take one 80 mg capsule of aprepitant (white) by mouth 1 hour before you start your chemotherapy treatment. If no chemotherapy treatment is given on Days 2 and 3, aprepitant should be taken in the morning.

{ "type": "p", "children": [], "text": " ○ \n Day 2 and Day 3: Take one 80 mg capsule of aprepitant (white) by mouth 1 hour before you start your chemotherapy treatment. If no\n \n chemotherapy treatment is given on Days 2 and 3, aprepitant should be taken in the morning.\n " }

● If you are an adult and are having surgery:

{ "type": "p", "children": [], "text": "● \n If you are an adult and are having surgery:\n" }

○ Your doctor will prescribe a 40 mg capsule of aprepitant for you before surgery. Take a aprepitant capsule within 3 hours before surgery.

{ "type": "p", "children": [], "text": " ○ Your doctor will prescribe a 40 mg capsule of aprepitant for you before surgery. Take a aprepitant capsule within 3 hours before surgery." }

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

{ "type": "p", "children": [], "text": " ○ Follow your doctor's instructions about restrictions on eating and drinking before surgery." }

● If you take the blood thinner medicine warfarin sodium (COUMADIN®, JANTOVEN®), your healthcare provider may do blood tests after you take aprepitant to check your blood clotting.

{ "type": "p", "children": [], "text": "● If you take the blood thinner medicine warfarin sodium (COUMADIN®, JANTOVEN®), your healthcare provider may do blood tests after you take aprepitant to check your blood clotting." }

What are the possible side effects of aprepitant capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of aprepitant capsules?\n" }

● In adults taking aprepitant capsules, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests.

{ "type": "p", "children": [], "text": "● In adults taking aprepitant capsules, the most common side effects include tiredness, diarrhea, weakness, indigestion, stomach (abdominal) pain, hiccups, decrease in white blood cell count, dehydration, and changes in liver function tests." }

● In adults taking aprepitant capsules to prevent nausea and vomiting after surgery, the most common side effect include constipation, low blood pressure (hypotension).

{ "type": "p", "children": [], "text": "● In adults taking aprepitant capsules to prevent nausea and vomiting after surgery, the most common side effect include constipation, low blood pressure (hypotension)." }

● In children 6 months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups.

{ "type": "p", "children": [], "text": "● In children 6 months to 17 years of age, the most common side effects include decrease in white blood cell count, headache, diarrhea, decreased appetite, cough, tiredness, decrease in red blood cell count, dizziness, and hiccups." }

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of aprepitant capsules. For more information ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of aprepitant capsules. For more information ask your healthcare provider or pharmacist." }

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

{ "type": "p", "children": [], "text": "Call our healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store aprepitant capsules?

{ "type": "p", "children": [], "text": "\nHow should I store aprepitant capsules?\n" }

● Store at room temperature, between 68° to 77°F (20° to 25°C).

{ "type": "p", "children": [], "text": "● Store at room temperature, between 68° to 77°F (20° to 25°C)." }

Keep aprepitant capsules and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep aprepitant capsules and all medicines out of the reach of children.\n" }

General information about the safe and effective use of aprepitant capsules

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of aprepitant capsules\n" }

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use aprepitant capsules for a condition for which it was not prescribed. Do not give aprepitant capsules to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about aprepitant capsules that is written for health professionals. For more information about aprepitant call 1-800-912-9561.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use aprepitant capsules for a condition for which it was not prescribed. Do not give aprepitant capsules to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about aprepitant capsules that is written for health professionals. For more information about aprepitant call 1-800-912-9561." }

What are the ingredients in aprepitant capsules?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in aprepitant capsules?\n" }

Active ingredient: aprepitant

{ "type": "p", "children": [], "text": "\nActive ingredient: aprepitant\n " }

Inactive ingredients: hypromellose 2910, poloxamer 407, sucrose, microcrystalline cellulose. The imprinting Ink: shellac glaze, iron oxide black and propylene glycol. The capsule shell excipients gelatin, titanium dioxide, and sodium lauryl sulfate. The 40 mg capsule shell contains yellow ferric oxide, sodium lauryl sulfate and titanium dioxide, 80 mg capsule shell contains sodium lauryl sulfate and titanium dioxide, 125 mg capsules contains red ferric oxide, sodium lauryl sulfate and titanium dioxide.

{ "type": "p", "children": [], "text": "\nInactive ingredients: hypromellose 2910, poloxamer 407, sucrose, microcrystalline cellulose. The imprinting Ink: shellac glaze, iron oxide black and propylene glycol. The capsule shell excipients gelatin, titanium dioxide, and sodium lauryl sulfate. The 40 mg capsule shell contains yellow ferric oxide, sodium lauryl sulfate and titanium dioxide, 80 mg capsule shell contains sodium lauryl sulfate and titanium dioxide, 125 mg capsules contains red ferric oxide, sodium lauryl sulfate and titanium dioxide.\n " }

Manufactured by:

{ "type": "p", "children": [], "text": "\nManufactured by:\n" }

PHARMATHEN INTERNATION S.A., Rodopi 69300, GREECE (GRC)

{ "type": "p", "children": [], "text": "PHARMATHEN INTERNATION S.A., Rodopi 69300, GREECE (GRC)" }

Manufactured For:

{ "type": "p", "children": [], "text": "\nManufactured For:\n" }

TORRENT PHARMA INC. Basking Ridge, NJ 07920

{ "type": "p", "children": [], "text": "TORRENT PHARMA INC. Basking Ridge, NJ 07920" }

Revised: 06/2022

{ "type": "p", "children": [], "text": " Revised: 06/2022" }

Marketed by:

{ "type": "p", "children": [], "text": "\nMarketed by:\n" }

GSMS, Inc.

{ "type": "p", "children": [], "text": "GSMS, Inc." }

Camarillo, CA 93012 USA

{ "type": "p", "children": [], "text": "Camarillo, CA 93012 USA" }

Carton of Aprepitant Capsule, USP 40 mg

{ "type": "p", "children": [], "text": "\nCarton of Aprepitant Capsule, USP 40 mg" }

Carton of Aprepitant Capsule, USP 80 mg

{ "type": "p", "children": [], "text": "\nCarton of Aprepitant Capsule, USP 80 mg\n" }

Carton of Aprepitant Capsule, USP 125 mg

{ "type": "p", "children": [], "text": "\nCarton of Aprepitant Capsule, USP 125 mg\n" }

Carton of Aprepitant Capsule, USP (80 mg and 125 mg Kit)

{ "type": "p", "children": [], "text": "\nCarton of Aprepitant Capsule, USP (80 mg and 125 mg Kit)\n" }