FDA label 41f97256-ac39-413d-8b2f-5fb7ad429143

5 WARNINGS AND PRECAUTIONS • CYP3A4 Interactions : Aprepitant is a substrate, weak-to-moderate inhibitor and inducer of CYP3A4; See Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments of aprepitant and concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 ) • Warfarin (a CYP2C9 substrate) : Risk of decreased INR of prothrombin time; monitor INR in 2-week period, particularly at 7 to 10 days, following initiation of aprepitant. ( 5.2 , 7.1 ) • Hormonal Contraceptives : Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant. Use effective alternative or back-up methods of contraception. ( 5.3 , 7.1 , 8.3 ) 5.1 Clinically Significant CYP3A4 Drug Interactions Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. • Use of aprepitant with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. o Use of pimozide with aprepitant is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see Contraindications ( 4 )]. • Use of aprepitant with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to aprepitant. • Use of aprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of aprepitant. See Table 10 and Table 11 for a listing of potentially significant drug interactions [see Drug Interactions ( 7.1 , 7.2 )]. 5.2 Decrease in INR with Concomitant Warfarin 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 )] . 5.3 Risk of Reduced Efficacy of Hormonal Contraceptives 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 )] .

6 ADVERSE REACTIONS Most common adverse reactions are ( 6.1 ): Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) • Adults (≥3%): fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased. • Pediatrics (≥3%): neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups. PONV • Adults (≥3%): constipation and hypotension. To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety of aprepitant was evaluated in approximately 6800 individuals. Adverse Reactions in Adults in the Prevention of Nausea and Vomiting Associated with HEC and MEC In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), 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 ondansetron 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 1412 patients treated with the aprepitant 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. Table 3: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies * Aprepitant, ondansetron, and dexamethasone † (N=1412) Ondansetron and dexamethasone ‡ (N=1396) fatigue 13% 12% diarrhea 9% 8% asthenia 7% 6% dyspepsia 7% 5% abdominal pain 6% 5% hiccups 5% 3% white blood cell count decreased 4% 3% dehydration 3% 2% alanine aminotransferase increased 3% 2% * Reported in ≥ 3% of patients treated with the aprepitant regimen and at a greater incidence than standard therapy. † Aprepitant regimen ‡ Standard therapy In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the aprepitant regimen are listed in Table 6. Table 4: Less Common Adverse Reactions in Aprepitant-Treated Patients from a Pooled Analysis of HEC and MEC Studies * Infection and Infestations oral candidiasis, pharyngitis Blood and the Lymphatic System Disorders anemia, febrile neutropenia, neutropenia, thrombocytopenia Metabolism and Nutrition Disorders decreased appetite, hypokalemia Psychiatric Disorders anxiety Nervous System Disorders dizziness, dysgeusia, peripheral neuropathy Cardiac Disorders palpitations Vascular Disorders flushing, hot flush Respiratory, Thoracic and Mediastinal Disorders cough, dyspnea, oropharyngeal pain Gastrointestinal Disorders dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting Skin and Subcutaneous Tissue Disorders alopecia, hyperhidrosis, rash Musculoskeletal and Connective Tissue Disorders musculoskeletal pain General Disorders and Administration Site Condition edema peripheral, malaise Investigations aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased * Reported in > 0.5% of patients treated with the aprepitant regimen, at a greater incidence than standard therapy and not previously described in Table 5. In an additional active-controlled clinical study in 1169 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 and Vomiting Associated with HEC or MEC In a pooled analysis of 2 active-controlled clinical trials in pediatric patients aged 6 months to 17 years who received highly or moderately emetogenic cancer chemotherapy (Study 5 and a safety study, Study 6), 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. Table 7: Most Common Adverse Reactions in Aprepitant -Treated Pediatric Patients in HEC and MEC Pooled Studies 5 and 6* Aprepitant and ondansetron † (N=184) Ondansetron ‡ (N=168) neutropenia 13% 11% headache 9% 5% diarrhea 6% 5% decreased appetite 5% 4% cough 5% 3% fatigue 5% 2% hemoglobin decreased 5% 4% dizziness 5% 1% hiccups 4% 1% * Reported in ≥3% of patients treated with the aprepitant regimen and at a greater incidence than control regimen. † Aprepitant regimen ‡ Control regimen 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)] . 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. Table 5: Most Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies * Aprepitant 40 mg (N = 564) Ondansetron (N = 538) constipation 9% 8% hypotension 6% 5% * Reported in ≥ 3% of patients treated with the aprepitant 40 mg and at a greater incidence than ondansetron. In a pooled analysis of PONV studies, less common adverse reactions reported in patients treated with aprepitant are listed in Table 9. Table 6: Less Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies * Infections and Infestations postoperative infection Metabolism and Nutrition Disorders hypokalemia, hypovolemia Nervous System Disorders dizziness, hypoesthesia, syncope Cardiac Disorders bradycardia Vascular Disorders hematoma Respiratory, Thoracic and Mediastinal Disorders dyspnea, hypoxia, respiratory depression Gastrointestinal Disorders abdominal pain, dry mouth, dyspepsia Skin and Subcutaneous Tissue Disorders urticaria General Disorders and Administration Site Conditions hypothermia Investigations blood albumin decreased, bilirubin increased, blood glucose increased, blood potassium decreased Injury, Poisoning and Procedural Complications operative hemorrhage, wound dehiscence * Reported in > 0.5% of patients treated with aprepitant and at a greater incidence than ondansetron 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). 6.2 Postmarketing Experience 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.

<table ID="_Reft5" width="99.02%"><caption>Table 3: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies^*</caption><col width="41%"/><col width="28%"/><col width="31%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Aprepitant, ondansetron, and dexamethasone^&#x2020;</content> <content styleCode="bold"> (N=1412)</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Ondansetron and dexamethasone^&#x2021;</content> <content styleCode="bold"> (N=1396)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>fatigue</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>asthenia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>dyspepsia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>hiccups</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>white blood cell count decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>dehydration</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>alanine aminotransferase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>

<table ID="_Reft6" width="97.22%"><caption>Table 4: Less Common Adverse Reactions in Aprepitant-Treated Patients from a Pooled Analysis of HEC and MEC Studies^*</caption><col width="51%"/><col width="49%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Infection and Infestations</content></paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>oral candidiasis, pharyngitis</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and the Lymphatic System Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>anemia, febrile neutropenia, neutropenia, thrombocytopenia</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>decreased appetite, hypokalemia</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>anxiety</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>dizziness, dysgeusia, peripheral neuropathy</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>palpitations</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>flushing, hot flush</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>cough, dyspnea, oropharyngeal pain</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>alopecia, hyperhidrosis, rash</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>musculoskeletal pain</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders and Administration Site Condition</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>edema peripheral, malaise</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased</paragraph></td></tr></tbody></table>

<table cellpadding="0pt" width="92.04%"><col width="38%"/><col width="33%"/><col width="29%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Aprepitant and ondansetron</content><linkHtml href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=696f9e80-9cae-403b-de9e-078343ce4713&amp;audience=consumer">&#x2020;</linkHtml></paragraph><paragraph><content styleCode="bold">(N=184)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Ondansetron</content><linkHtml href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=696f9e80-9cae-403b-de9e-078343ce4713&amp;audience=consumer">&#x2021;</linkHtml></paragraph><paragraph><content styleCode="bold">(N=168)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>cough</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>fatigue</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>hemoglobin decreased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>hiccups</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>