1 INDICATIONS AND USAGE Aprepitant is a substance P/neurokinin 1 (NK 1 ) receptor antagonist.

Aprepitant capsules is indicated • in combination with other antiemetic agents, in patients 12 years of age and older for prevention of: • acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin ( 1.1 ) • nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) ( 1.1 ) • for prevention of postoperative nausea and vomiting (PONV) in adults ( 1.2 ) Limitations of Use ( 1.3 ) • Aprepitant capsules have not been studied for treatment of established nausea and vomiting.

• Chronic continuous administration of aprepitant capsules are not recommended.

1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Aprepitant capsules, in combination with other antiemetic agents, are indicated in patients 12 years of age and older for the prevention of: • acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.

• nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

1.2 Prevention of Postoperative Nausea and Vomiting (PONV) Aprepitant capsules are indicated in adults for the prevention of postoperative nausea and vomiting.

1.3 Limitations of Use • Aprepitant capsules have not been studied for the treatment of established nausea and vomiting.

• Chronic continuous administration of aprepitant capsules is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.

6 ADVERSE REACTIONS Most common adverse reactions (≥3%) are ( 6.1 ): Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) • Adults: fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased • Pediatrics: neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness and hiccups PONV • Adults: constipation and hypotension To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 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 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 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 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies Reported in ≥3% of patients treated with the aprepitant regimen and at a greater incidence than standard therapy.

Aprepitant, ondansetron and dexamethasone Aprepitant regimen (N=1412) Ondansetron and dexamethasone Standard therapy (N=1396) fatigue 13% 12% diarrhea 9% 8% asthenia 7% 6% dyspepsia 7% 5% abdominal pain 6% 5% hiccups 5% 3% white blood cell count decreased 4% 3% dehydration 3% 2% alanine aminotransferase increased 3% 2% In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the aprepitant regimen are listed in Table 6 .

Table 6: Less Common Adverse Reactions in Aprepitant-Treated Patients from a Pooled Analysis of HEC and MEC Studies 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 .

Infection and Infestations oral candidiasis, pharyngitis Blood and the Lymphatic System Disorders anemia, febrile neutropenia, neutropenia, thrombocytopenia Metabolism and Nutrition Disorders decreased appetite, hypokalemia Psychiatric Disorders anxiety Nervous System Disorders dizziness, dysgeusia, peripheral neuropathy Cardiac Disorders palpitations Vascular Disorders flushing, hot flush Respiratory, Thoracic and Mediastinal Disorders cough, dyspnea, oropharyngeal pain Gastrointestinal Disorders dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting Skin and Subcutaneous Tissue Disorders alopecia, hyperhidrosis, rash Musculoskeletal and Connective Tissue Disorders musculoskeletal pain General Disorders and Administration Site Condition edema peripheral, malaise Investigations aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased In an additional active-controlled clinical study in 1169 patients receiving 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 Reported in ≥3% of patients treated with the aprepitant regimen and at a greater incidence than control regimen.

Aprepitant and Ondansetron Aprepitant regimen (N=184) Ondansetron Control regimen (N=168) neutropenia 13% 11% headache 9% 5% diarrhea 6% 5% decreased appetite 5% 4% cough 5% 3% fatigue 5% 2% hemoglobin decreased 5% 4% dizziness 5% 1% hiccups 4% 1% Forty-nine patients were treated with ifosfamide chemotherapy in each arm.

Two of the patients treated with ifosfamide in the 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 ), 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 8: Most Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies Reported in ≥3% of patients treated with the Aprepitant 40 mg and at a greater incidence than ondansetron.

Aprepitant 40 mg (N = 564) Ondansetron (N = 538) constipation 9% 8% hypotension 6% 5% In a pooled analysis of PONV studies, less common adverse reactions reported in patients treated with aprepitant are listed in Table 9 .

Table 9: Less Common Adverse Reactions in Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies Reported in >0.5% of patients treated with aprepitant and at a greater incidence than ondansetron.

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 1.

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: i fosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.