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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.

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

The overall safety of fosaprepitant was evaluated in approximately 1100 individuals and the overall safety of aprepitant was evaluated in approximately 6500 individuals.

Oral Aprepitant

Highly Emetogenic Chemotherapy (HEC)

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

In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥ 1% and greater than standard therapy are listed in Table 5.

Table 5 : Adverse Reactions (incidence ≥ 1%) in patients receiving HEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

  Aprepitant Regimen
(N=544)
Standard Therapy
(N=550)
Respiratory System
hiccups 4.6 2.9
Body as a Whole/Site Unspecified
asthenia/fatigue 2.9 1.6
Investigations
ALT increased 2.8 1.5
AST increased 1.1 0.9
Digestive System
constipation 2.2 2.0
dyspepsia 1.5 0.7
diarrhea 1.1 0.9
Nervous System
headache 2.2 1.8
Metabolism and Nutrition
anorexia 2.0 0.5

A listing of adverse reactions in the aprepitant regimen (incidence < 1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection below.

In an additional active-controlled clinical study in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant.

Moderately Emetogenic Chemotherapy (MEC)

In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 868 patients were treated with the 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 (aprepitant regimen).

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 aprepitant regimen with an incidence ≥ 1% and greater than standard therapy are listed in Table 6.

Table 6 : Adverse Reactions (incidence ≥ 1%) in patients receiving MEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

  Aprepitant Regimen
(N=868)
Standard Therapy
(N=846)
Gastrointestinal disorders
eructation 1.0 0.1
General disorders and administration site conditions
fatigue 1.4 0.9

A listing of adverse reactions in the aprepitant regimen (incidence < 1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection below.

Less Common Adverse Reactions

Adverse reactions reported in either HEC or MEC studies in patients treated with the aprepitant regimen with an incidence < 1% and greater than standard therapy are listed in Table 7.

Table 7 : Adverse Reactions (incidence < 1%) in patients observed in either HEC or MEC Studies with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

Infection and infestations candidiasis, staphylococcal infection
Blood and the lymphatic system disorders anemia, febrile neutropenia
Metabolism and nutrition disorders weight gain, polydipsia
Psychiatric disorders disorientation, euphoria, anxiety
Nervous system disorders dizziness, dream abnormality, cognitive disorder, lethargy, somnolence
Eye disorders conjunctivitis
Ear and labyrinth disorders tinnitus
Cardiac disorders bradycardia, cardiovascular disorder, palpitations
Vascular disorders hot flush, flushing
Respiratory, thoracic and mediastinal disorders pharyngitis, sneezing, cough, postnasal drip, throat irritation
Gastrointestinal disorders nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, faeces hard, neutropenic colitis, flatulence, stomatitis
Skin and subcutaneous tissue disorders rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion
Musculoskeletal and connective tissue disorders muscle cramp, myalgia, muscular weakness
Renal and urinary disorders polyuria, dysuria, pollakiuria
General disorders and administration site condition edema, chest discomfort, malaise, thirst, chills, gait disturbance
Investigations alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased

In another chemotherapy induced nausea and vomiting (CINV) 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.

Fosaprepitant

In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND (aprepitant). The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the 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.

The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above.

Table 8 : Adverse Reactions (incidence > 0.1%) in patients receiving Fosaprepitant 150 mg and not reported above for the Oral Aprepitant Regimen

General disorders and administration site conditions infusion site erythema, infusion site pruritus, infusion site induration, infusion site pain
Investigations blood pressure increased
Skin and subcutaneous tissue disorders erythema
Vascular disorders thrombophlebitis (predominantly, infusion-site thrombophlebitis)

Other Studies with Postoperative Nausea and Vomiting

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

Adverse reactions were reported in approximately 4% of patients treated with 40-mg aprepitant compared with approximately 6% of patients treated with 4-mg ondansetron intravenously.

In patients treated with aprepitant, increased ALT (1.1%) was seen at a greater incidence than with ondansetron (1.0%). The following additional adverse reactions were observed in patients treated with aprepitant at an incidence < 1% and greater than with ondansetron.

Table 9 : Adverse Reactions (incidence < 1%) in patients receiving Aprepitant 40 mg with a greater incidence in the Aprepitant group relative to ondansetron

Psychiatric disorders insomnia
Nervous system disorders dysarthria, hypoesthesia, sensory disturbance
Eye disorders miosis, visual acuity reduced
Cardiac disorders bradycardia
Respiratory, thoracic and mediastinal disorders dyspnea, wheezing
Gastrointestinal disorders abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach discomfort

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

Other Studies

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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of fosaprepitant and 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, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

Nervous system disorders: Events of ifosfamide-induced neurotoxicity have been reported after aprepitant and ifosfamide coadministration.