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Sections 2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 6.1, 10 - update to side effects.
Update to Sections: 4.2, 4.4, 4.5, 4.6, 4.8, 5.1
PSUR updates
4.8 Undesirable effects
The safety profile of aprepitant was evaluated in approximately 4,900
5,300 individuals. Adverse reactions considered as drug-related by the investigator were reported in approximately 17 % of patients treated with the aprepitant regimen compared with approximately 13 % of patients treated with standard therapy in patients receiving highly emetogenic chemotherapy
Adverse reactions considered as drug-related by the investigator were reported in approximately 17 % of patients treated with the aprepitant regimen compared with approximately 13 % of patients treated with standard therapy in patients receiving highly emetogenic chemotherapy
(HEC). Aprepitant 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. In a combined analysis of 2 clinical studyies of patients receiving moderately emetogenic chemotherapy (MEC), clinical adverse reactions were reported in approximately 2114 % of patients treated with the aprepitant regimen compared with approximately 2015 % of patients treated with standard therapy. Aprepitant was discontinued due to adverse reactions in 1.10.7 % of patients treated with the aprepitant regimen compared with 0.50.2 % of patients treated with standard therapy. The most common adverse reactions reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving highly emetogenic chemotherapy were: hiccups (4.6 % versus 2.9 %), asthenia/fatigue (2.9 % versus 1.6 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.5 %), constipation (2.2 % versus 2.0 %), headache (2.2 % versus 1.8 %), and anorexia (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving moderately emetogenic chemotherapy was fatigue (2.5
The most common adverse reactions reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving highly emetogenic chemotherapy were: hiccups (4.6 % versus 2.9 %), asthenia/fatigue (2.9 % versus 1.6 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.5 %), constipation (2.2 % versus 2.0 %), headache (2.2 % versus 1.8 %), and anorexia (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving moderately emetogenic chemotherapy was fatigue (2.5
1.4 % versus 1.60.9 %). The following adverse reactions were observed
The following adverse reactions were observed
in either HEC or MEC studies in patients treated with the aprepitant regimen and at a greater incidence than with standard therapy: Frequencies are defined as: very common (
Frequencies are defined as: very common (
≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data). System Organ Class Adverse reaction Frequency Investigations ALT increased, AST increased alkaline phosphatase increased, hyperglycaemia, microscopic haematuria, hyponatraemia, weight decreased , neutrophil count decreased common uncommon Cardiac disorders b Bradycardia, palpitations, cardiovascular disorder uncommon Blood and lymphatic system disorders febrile neutropenia, anaemia uncommon Nervous system disorders headache, dizziness dream abnormality, cognitive disorder , lethargy, somnolence common uncommon Eye disorders conjunctivitis uncommon Ear and labyrinth disorders tinnitus uncommon Respiratory, thoracic and mediastinal disorders hiccups pharyngitis, sneezing, cough, postnasal drip, throat irritation common uncommon Gastrointestinal disorders constipation, diarrhoea, dyspepsia, eructation perforating duodenal ulcer, nausea*, vomiting*, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, abdominal pain, dry mouth, enterocolitis, flatulence, stomatitis , abdominal distension, faeces hard, neutropenic colitis common uncommon Renal and urinary disorders polyuria, dysuria, pollakiuria uncommon Skin and subcutaneous tissue disorders rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion , rash pruritic uncommon Musculoskeletal and connective tissue disorders muscle cramp, myalgia , muscular weakness uncommon Metabolism and nutrition disorders anorexia weight gain, polydipsia common uncommon Infection and infestations candidiasis, staphylococcal infection uncommon Vascular disorders flushing/hot flush uncommon General disorders and administration site conditions asthaenia/fatigue oedema, chest discomfort, lethargy, malaise, thirst, chills, gait disturbance common uncommon Psychiatric disorders disorientation, euphoria, anxiety uncommon *Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter. The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies for up to 56 additional cycles of chemotherapy were generally similar to those observed in Cycle 1 5.1 Pharmacodynamic properties The estimated time to first emesis in the study is depicted by the Kaplan-Meier plot in Figure 2. Figure 2 Percent of Patients Receiving Moderately Emetogenic Chemotherapy Who Remain Emesis Free Over Time – Cycle 1
System Organ Class
Adverse reaction
Frequency
Investigations
ALT increased, AST increased
alkaline phosphatase increased, hyperglycaemia, microscopic haematuria, hyponatraemia, weight decreased
, neutrophil count decreased
common
uncommon
Cardiac disorders
b
Bradycardia, palpitations, cardiovascular disorder
Blood and lymphatic system disorders
febrile neutropenia, anaemia
Nervous system disorders
headache, dizziness
dream abnormality, cognitive disorder
, lethargy, somnolence
Eye disorders
conjunctivitis
Ear and labyrinth disorders
tinnitus
Respiratory, thoracic and mediastinal disorders
hiccups
pharyngitis, sneezing, cough, postnasal drip, throat irritation
Gastrointestinal disorders
constipation, diarrhoea, dyspepsia, eructation
perforating duodenal ulcer, nausea*, vomiting*, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, abdominal pain, dry mouth, enterocolitis, flatulence, stomatitis
, abdominal distension, faeces hard, neutropenic colitis
Renal and urinary disorders
polyuria, dysuria, pollakiuria
Skin and subcutaneous tissue disorders
rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion
, rash pruritic
Musculoskeletal and connective tissue disorders
muscle cramp, myalgia
, muscular weakness
Metabolism and nutrition disorders
anorexia
weight gain, polydipsia
Infection and infestations
candidiasis, staphylococcal infection
Vascular disorders
flushing/hot flush
General disorders and administration site conditions
asthaenia/fatigue
oedema, chest discomfort, lethargy,
malaise, thirst, chills, gait disturbance
Psychiatric disorders
disorientation, euphoria, anxiety
*Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.
The adverse reactions profiles in the Multiple-Cycle extension
of HEC and MEC studies for up to 56 additional cycles of chemotherapy were generally similar to those observed in Cycle 1
5.1 Pharmacodynamic properties The estimated time to first emesis in the study is depicted by the Kaplan-Meier plot in Figure 2. Figure 2 Percent of Patients Receiving Moderately Emetogenic Chemotherapy Who Remain Emesis Free Over Time – Cycle 1
Figure 2
Percent of Patients Receiving Moderately Emetogenic Chemotherapy Who Remain Emesis Free Over Time – Cycle 1
In the same clinical study, 744 patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles.
In a second multicenter, randomized, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 patients (652 females, 196 males) receiving a chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m2); or cytarabine IV (>1 g/m2). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1). Efficacy was based on the evaluation of the following primary and key secondary endpoints: No Vomiting in the overall period (0 to 120 hours post-chemotherapy), E
Efficacy was based on the evaluation of the following primary and key secondary endpoints: No Vomiting in the overall period (0 to 120 hours post-chemotherapy), E
evaluation of safety and tolerability of the aprepitant regimen for CINV, and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, No Significant Nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis.
A summary of the key study results is shown in Table 3.
Table 3
Percent of Patients Responding by TreatmentGroup and Phase for Study 2 – Cycle 1 Moderately Emetogenic Chemotherapy
Aprepitant Regimen
(N=
425) † %
%
Standard Therapy
406) %
Differences*
% (95 % CI)
Complete Response (no emesis and no rescue therapy)
Overall (0-120 hours)
0-24 hours
25-120 hours
68.7
89.2
70.8
56.3
80.3
60.9
12.4
8.9
9.9
(5.9, 18.9)
(4.0, 13.8)
(3.5, 16.3)
No Emesis (no emetic episodes regardless of use of rescue therapy)
76.2
92.0
77.9
62.1
83.7
66.8
14.1
8.3
11.1
(7.9, 20.3)
(3.9, 12.7)
(5.1, 17.1)
No Significant Nausea (maximum VAS <25 mm on a scale of 0-100 mm)
73.6
90.9
74.9
66.4
86.3
69.5
7.2
4.6
5.4
(1.0, 13.4)
(0.2, 9.0)
(-0.7, 11.5)
*
The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models.
The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men.
The estimated time to first vomiting in this study is depicted by the Kaplan-Meier plot in Figure 3.
Figure 3:
0
12
24
36
48
60
72
84
96
108
120
Percent of Patients
20
40
80
100
Time(hours) Since the First Chemotherapy Administration
Aprepitant Regimen(N=425)
Standard Regimen(N=407)