Transcript Slide Set

Summary of Clinical Information:
Role of EMEND® in Managing
Chemotherapy-Induced Nausea
and Vomiting
A Slide/Lecture Presentation
Reg. No.'s: 80 mg - A38/5.7.2/0626; 125 mg - A38/5.7.2/0627; Combi Pack - A38/5.7.2/0625, EMEND S4
Each capsule contains 80 mg or 125 mg Aprepitant150
®Registered
Trademark of MERCK & CO., INC., Whitehouse Station, N.J., U.S.A..
Slide 1
Risk Factors for Chemotherapy-Induced
Nausea/Vomiting (CINV)
Patient-Specific
History of emesis
Younger age
Female gender
Heightened anxiety
Expectation of
adverse effects
Hospital roommate with
nausea and vomiting
Low motivation
Low performance status
Food intake
Inadequate sleep
Low alcohol intake
Therapy-Specific
Agents with increased
emetogenic potential
Combination regimens
Higher-dose chemotherapy
Faster infusion rates
Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins,
2001:2869-2880; Antiemetic Subcommittee Ann Oncol 1998;9:811-819.
Slide 2
Types of CINV
Type
Onset, Duration
Acute emesis
Within first 24 hours of chemotherapy
Delayed emesis
At least 24 hours after chemotherapy;
can last up to seven days
Anticipatory emesis
Before second or subsequent courses
of chemotherapy but may begin during
or after chemotherapy in any treatment cycle
Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins,
2001:2869-2880; Antiemetic Subcommittee Ann Oncol 1998;9:811-819.
Slide 3
Need for Improved CINV
Most Distressing Adverse Effects of Chemotherapy Before
and During 5-HT3 Antagonist Era
Rank
1983
(Pre–5-HT3 Antagonist Era)
1996
(During 5-HT3 Antagonist Era)
1
2
3
4
5
6
7
8
9
10
Being sick (vomiting)
Feeling sick (nausea)
Loss of hair
Thought of coming for treatment
Duration of treatment at the clinic
Need to get a needle
Shortness of breath
Constantly tired
Difficulty sleeping
Affects family or partner
Feeling sick (nausea)
Loss of hair
Being sick (vomiting)
Constantly tired
Need for an injection
Constipation
Thought of coming for treatment
Affects family or partner
Feeling low, miserable (depression)
Feeling anxious or tense
Adapted from de Boer-Dennert M et al Br J Cancer 1997;76(8):1055-1061; Coates A et al Eur J Cancer Clin Oncol 1983;19:203-208.
Slide 4
Unmet Need
• ANCHOR Study
– 298 cancer patients and 24 oncology practitioners
– Demonstrated an unmet need for better control of both
acute and delayed vomiting
– Reports of acute experiences were generally accurate
– Many more patients reported delayed nausea and vomiting
than was predicted
• EONS Study
– 248 cancer patients
– 13% of patients had acute emesis
– Up to 38% had delayed emesis
ANCHOR=Anti-Nausea CHemOtherapy Registry; EONS=European Oncology Nursing Society
Adapted from Grunberg SM et al Cancer 2004;100:2261-2268; Glaus A et al Support Care Cancer 2004;12:708-715
Slide 5
CINV Compromises Quality of Daily Life
Mean Changes in Functional-Domain Scores of Health-Related Quality
of Life After 8 Days of Chemotherapy
Group 1 (no nausea or vomiting)
Group 2 (vomiting, no nausea)
Group 3 (nausea, no vomiting)
Group 4 (nausea and vomiting)
Mean change in score
10
5.3 5.3 4.9
5
0.8
0
–5
–10
1.9b
0.6f
–0.6–0.5
d
–0.6–1.1c
–1.1
–2.6
–3.8a
Quality of Life
Diminished
–5.7
–8.7
–8.4
–8.8e
–10
–7.4g
–15
–20
Quality of Life
Improved
–14.2
Physical
Emotional
Cognitive
Social
Global
Functional domain
Group 1: n=166; Group 2: n=30; Group 3: n=157; Group 4: n=332
aGroup 1 vs. Group 4, p=0.007; bGroup 1 vs. Group 4, p=0.0001; cGroup 3 vs. Group 4, p=0.0002; dGroup 3 vs. Group 4, p=0.003;
eGroup 1 vs. Group 4, p=0.0001; fGroup 2 vs. Group 4, p=0.0005; gGroup 3 vs. Group 4, p=0.002
Adapted from Osoba D et al Support Care Cancer 1997;5:307-313.
Slide 6
Goals of Antiemetic Therapy
• Primary
– Prevent CINV as completely as possible
• Related
– Minimize impact of CINV on health-related quality of life
– Provide therapy that is maximally convenient for
patients and health care personnel
– Reduce hospitalization, overall use of health care
resources, and associated costs
– Eliminate potential adverse effects of therapy
Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins,
2001:2869-2880; Gralla RJ et al J Clin Oncol 1999;17(9):2971-2994.
Slide 7
Mechanisms of CINV
•
•
•
•
•
•
•
•
•
Stimulation of chemoreceptor trigger zone (CTZ)
Peripheral mechanisms
Damage of gastrointestinal mucosa
Stimulation of gastrointestinal neurotransmitter receptors
Cortical mechanisms
Direct cerebral activation
Indirect (psychogenic) mechanisms
Vestibular mechanisms
Alterations of taste
Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins,
2001:2869-2880.
Slide 8
Role of Substance P and Other Neurotransmitters
in CINV
• Neurotransmitters involved in emesis
•
– Dopamine
– Serotonin
– Histamine
– Norepinephrine
– Substance P
Substance P exerts an emetic effect by binding to neurokinin-1
(NK1) receptors in the CTZ
Adapted from Berger AM, Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins,
2001:2869-2880.
Slide 9
Antiemetic Therapies
• 5-HT3 antagonists (Zofran® [ondansetron hydrochloride],
granisetron)
• Dexamethasone
• Antidopaminergics (prochlorperazine, fluphenazine)
• Metoclopramide
• NK1 receptor antagonist—EMEND® (aprepitant)
Zofran (ondansetron hydrochloride) is a registered trademark of GlaxoSmithKline Group of Companies.
Adapted from Beers MH, Berkow R, eds. The Merck Manual. 19th ed. Rahway, NJ: Merck Research Laboratories, 1999; Berger AM,
Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880.
®Registered
Trademark of MERCK & CO., INC., Whitehouse Station, N.J., U.S.A.
Slide 10
EMEND® (aprepitant):
The First NK1 Receptor Antagonist
• Inhibits emesis by central action
• Possesses selectivity 3000-fold greater for the NK1 receptor
•
•
•
•
•
versus other sites
Crosses blood-brain barrier
Occupies brain NK1 receptors
Maintains long duration of central activity
Inhibits acute and delayed emesis associated with highly
emetogenic chemotherapy as part of a regimen
Augments activity of existing antiemetic therapy against
cisplatin-induced emesis
Slide 11
EMEND®: Pharmacokinetics*
Absorption
Tmax
Cmax
~4 hr
1.5 µg/ml (day 1)
AUC0-24h
19.65 µg•hr/ml (day 1)
Distribution
Vdss
Crosses blood-brain barrier
66 L
Yes
Metabolism
Pathway
Largely by oxidation
Elimination
Route
T½
Primarily by metabolism
9–13 hr
*Following a 125 mg oral dose on day 1 and 80 mg once-daily oral doses on days 2 and 3
Tmax=time to maximum plasma concentration; Cmax=maximum plasma concentration; AUC0-24h= area under the time–concentration curve from time
0 (preadministration) through 24 hours afterward; Vdss=mean volume of distribution at steady state; T½ =terminal plasma half-life
Slide 12
EMEND®
Efficacy in Clinical Trials: Study Design
Objective: Compare EMEND with control regimens vs. control
regimens alone in two identically designed trials (N=1099)
in the prevention of CINV
Regimen
EMEND with
Control Regimen
Control Regimen
Day 1
EMEND 125 mg PO
Zofran® a 32 mg IVb
Dexamethasone 12 mg POc
Zofran® 32 mg IV
Dexamethasone 20 mg PO
Days 2 and 3
Day 4
EMEND 80 mg PO
Dexamethasone 8 mg
PO once daily
Dexamethasone 8 mg
PO
Dexamethasone 16 mgd
PO
Dexamethasone 16 mgd
PO
aZofran®
(ondansetron hydrochloride) was administered at the maximum recommended dose of 32 mg IV on day 1 and was not followed by oral
5-HT3 therapy on days 2–5.
bIV=intravenously; cPO=by mouth; d8 mg twice daily
Slide 13
EMEND®
Efficacy: Complete Response* in Acute Phase
100
13% improvement
(p<0.001)
% of patients
86
80
73
60
40
20
0
Acute (Day 1)
Time after chemotherapy administration
Control Regimen (n=523) Zofran® 32 mg IV, dexamethasone 20 mg PO, and placebo
EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran® 32 mg IV,
and dexamethasone 12 mg PO
*No emesis and no rescue medication
Slide 14
EMEND®
Efficacy: Complete Response* in Delayed Phase
% of patients
100
21% improvement
(p<0.001)
80
72
60
51
40
20
0
Delayed (Days 2–5)
Time after chemotherapy administration
Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4
EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3,
and dexamethasone 8 mg PO Days 2–4
*No emesis and no rescue medication
Slide 15
EMEND®
Efficacy: Complete Protection* in Acute Phase
100
12% improvement
(p<0.001)
% of patients
82
80
70
60
40
20
0
Acute (Day 1)
Time after chemotherapy administration
Control Regimen (n=523) Zofran® 32 mg IV, dexamethasone 20 mg PO, and placebo
EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran® 32 mg IV,
and dexamethasone 12 mg PO
*No emesis, no rescue medication, and no significant nausea (VAS <25 mm when 0=no nausea and 100 mm=nausea as bad as it could be)
Slide 16
EMEND®
Efficacy: Complete Protection* in Delayed Phase
% of patients
100
16% improvement
(p<0.001)
80
64
60
48
40
20
0
Delayed (Days 2–5)
Time after chemotherapy administration
Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4
EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3,
and dexamethasone 8 mg PO Days 2–4
*No emesis, no rescue medication, and no significant nausea (VAS <25 mm when 0=no nausea and 100 mm=nausea as bad as it could be)
Slide 17
EMEND®
Efficacy: Impact of CINV on Daily Life in Cycle 1
• Functional Living Index–Emesis (FLIE) measured the
impact of chemotherapy-induced nausea and vomiting on
daily life activities
• Substantially fewer patients reported that nausea and
vomiting interfered with daily living when EMEND was
added to control regimens* vs. control regimens** alone
(p<0.001)
*EMEND with
— Day 1: EMEND 125 mg PO, Zofran® 32 mg IV, and dexamethasone 12 mg PO
Control Regimen
Day 2: EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4
**Control Regimen — Day 1: Zofran® 32 mg IV, dexamethasone 20 mg PO, and placebo;
Day 2: Dexamethasone 16 mg PO and placebo Days 2–4
Slide 18
EMEND®
Efficacy: Percentage of Patients with No
Emesis* in Acute Phase
13% improvement
(p<0.001)
% of patients
100
80
87
74
60
40
20
0
Acute (Day 1)
Time after chemotherapy administration
Control Regimen (n=523) Zofran® 32 mg IV, dexamethasone 20 mg PO, and placebo
EMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran® 32 mg IV,
and dexamethasone 12 mg PO
* No emetic episodes regardless of use of rescue medication
Slide 19
EMEND®
Efficacy: Percentage of Patients with No
Emesis* in Delayed Phase
% of patients
100
22% improvement
(p<0.001)
76
80
60
54
40
20
0
Delayed (Days 2–5)
Time after chemotherapy administration
Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4
EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3,
and dexamethasone 8 mg PO Days 2–4
* No emetic episodes regardless of use of rescue medication
Slide 20
EMEND®
Efficacy: Percentage of Patients Who
Remained Free of Vomiting Over Time in Cycle 1
Day 1
Control Regimen Zofran® (32 mg IV), dexamethasone 20 mg PO, and placebo Day 1
EMEND with Control Regimen EMEND 125 mg PO, Zofran® 32 mg IV,
and dexamethasone 12 mg PO Day 1
100
% of patients
80
EMEND with control regimen (n=520)
60
40
P<0.001
Control regimen (n=523)
Acute
(0–24 hours)
Delayed
Days 2–4
Control Regimen Dexamethasone 16 mg PO and placebo Days 2–4
EMEND with Control Regimen EMEND 80 mg PO Days 2 and 3;
dexamethasone 8 mg PO Days 2–4
20
0
Day 1
Dose 1
Day 2
Dose 2
Day 3
Day 4
Day 5
Dose 3
Days since initiation of cisplatin therapy
Slide 21
EMEND®
% of patients
with favorable responses
Efficacy in Clinical Trials: No Vomiting,
No Significant Nauseaa in Cycles 1–6
EMEND with Control Regimens
100
90
Control Regimensb
80
c
70
c
c
c
c
c
4
5
6
60
50
40
30
20
1
2
3
Cycle
d
EMEND with
Control Regimen
n=
516
308
245
170
117
89
Control Regimen
n=
522
281
203
142
95
78
a
Nausea did not interfere with normal activities.
Control regimens consisted of Zofran® (ondansetron hydrochloride) plus dexamethasone on day 1; and dexamethasone alone on days 2-4.
c p<0.001
d After cycle 1 data were analyzed, some patients continued their treatment regimen for up to 6 cycles of chemotherapy.
Adapted from deWit R et al Eur J Cancer 2004;40:403–410.
b
Slide 22
EMEND®: Overall Adverse Experiences
• Most adverse experiences were mild to moderate in intensity
• Drug-related adverse experiences: Cycle 1
– Approximately 17% of patients treated with EMEND with control regimens*
reported clinical adverse experiences compared with approximately 13% of
patients treated with control regimens** alone
– Drug-related clinical adverse experiences led to discontinuation in 0.6% of
patients treated with EMEND with control regimens compared with 0.4%
of patients treated with control regimens alone
– The most common drug-related adverse experiences reported in patients
treated with EMEND with control regimens were hiccups (4.6%),
asthenia/fatigue (2.9%), constipation (2.2%), headache (2.2%), anorexia
(2.0%), and increased ALT (2.8%)
*EMEND 125 mg orally on day 1 plus Zofran® (ondansetron hydrochloride) 32 mg IV and dexamethasone 12 mg orally; EMEND 80 mg
orally once daily on days 2 and 3 plus dexamethasone 8 mg orally; dexamethasone 8 mg orally once daily on day 4
**Placebo plus Zofran® (ondansetron hydrochloride) 32 mg IV and dexamethasone 20 mg orally on day 1; dexamethasone 8 mg orally twice
daily on days 2 to 4
ALT=alanine aminotransferase
Slide 23
EMEND®: Indications
EMEND, in combination with other antiemetic agents,
is indicated for the prevention of acute and delayed
nausea and vomiting associated with initial and
repeat courses of highly emetogenic cancer
chemotherapy, including high-dose cisplatin.
Slide 24
EMEND®: Contraindications
• EMEND is contraindicated in patients who are
hypersensitive to any component of the product.
• EMEND must not be used concurrently with
pimozide, terfenadine, astemizole, or cisapride.
Slide 25
EMEND®: Dosage and Administration
Regimen used in clinical studies
EMEND*
Dexamethasone**
Zofran® (ondansetron hydrochloride) ***
Day 1
Days 2 and 3
Day 4
125 mg
80 mg
None
12 mg orally
8 mg orally
8 mg orally
32 mg IV
None
None
* Administered orally one hour prior to chemotherapy on day 1 and in the morning on days 2 and 3
** Administered 30 minutes prior to chemotherapy on day 1 and in the morning on days 2 through 4 (dose chosen to account for drug interactions)
*** Administered 30 minutes prior to chemotherapy on day 1
Slide 26
Drug Interactions: Effect of EMEND®
on the Pharmacokinetics of Other Agents
Characteristic of Aprepitant
Can increase plasma concentrations
of coadministered agents that are
metabolized through CYP3A4
Clinical Relevance
Reduce oral corticosteroid doses by 50% when
coadministered with EMEND and IV doses by 25%
Consider potential effects of increased plasma
concentrations of midazolam or other benzodiazepines
metabolized via CYP3A4 (e.g., alprazolam, triazolam)
when coadministered with EMEND
Do not use EMEND concurrently with pimozide,
terfenadine, astemizole, cisapride
Caution is advised when EMEND is administered with the
following chemotherapeutic agents: etoposide, vinorelbine,
docetaxel, and paclitaxel
Continued
Slide 27
Drug Interactions: Effect of EMEND®
on the Pharmacokinetics of Other Agents (cont’d)
Characteristic of Aprepitant
Can decrease plasma concentrations
of coadministered agents that are
metabolized through CYP2C9
Clinical Relevance
Closely monitor prothrombin time in patients receiving
warfarin to establish and maintain dose after completion of
3-day regimen of EMEND with each chemotherapy course
Consider potential effects of decreased plasma
concentrations of tolbutamide
Efficacy of oral contraceptives may be reduced during
administration of EMEND; therefore, alternative
or backup methods of contraception should be used
Slide 28
Drug Interactions: Effect of Other Agents on the
Pharmacokinetics of EMEND®
Characteristic of Other Agents
Agents that strongly inhibit or
induce CYP3A4 may increase or
decrease plasma concentrations of
aprepitant, respectively
Source A
(WPC),
p. 5, ¶1, L1-3
Clinical Relevance
Approach cautiously
Coadministration of EMEND with strong inhibitors
of CYP3A4 (e.g., ketoconazole)
Coadministration of EMEND with strong inducers
of CYP3A4 (e.g., rifampin)
¶2, L1-3
Slide 29
EMEND®: Overall Adverse Experiences
• Most adverse experiences were mild to moderate in intensity
• Drug-related adverse experiences: Cycle 1
– Approximately 17% of patients treated with EMEND* with control regimens
reported clinical adverse experiences compared with approximately 13% of
patients treated with control regimens** alone
– Drug-related clinical adverse experiences led to discontinuation in 0.6% of
patients treated with EMEND with control regimens compared with 0.4%
of patients treated with control regimens alone
– The most common drug-related adverse experiences reported in patients
treated with EMEND with control regimens were hiccups (4.6%),
asthenia/fatigue (2.9%), constipation (2.2%), headache (2.2%), anorexia
(2.0%), and increased ALT (2.8%)
*EMEND 125 mg orally on day 1 plus Zofran® (ondansetron hydrochloride) 32 mg IV on day 1 and dexamethasone 12 mg orally; EMEND 80 mg
orally once daily on days 2 and 3 plus dexamethasone 8 mg orally; dexamethasone 8 mg orally once daily on day 4
**Placebo plus Zofran® (ondansetron hydrochloride) 32 mg IV on day 1 and dexamethasone 20 mg orally on day 1; dexamethasone 8 mg orally twice
daily on days 2 to 4
ALT=alanine aminotransferase
Slide 30
Summary
• CINV: common and highly distressing
• Treatment goals: complete prevention of CINV and
reduction of its impact on patients’ health-related daily life
activities
• EMEND® (aprepitant)
– Unique, highly effective NK1 receptor antagonist
– Improved response to antiemetic therapy
and protection from CINV
– Generally well tolerated
Adapted from Gralla RJ et al J Clin Oncol 1997;17(9):2971-2994; de Boer-Dennert M et al Br J Cancer 1997;76(8):1055-1061; Berger AM,
Clark-Snow RA. In Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:2869-2880.
Slide 31
Bibliography
Please refer to notes page.
Slide 32
Summary of Clinical Information: Role of EMEND®
in Managing Chemotherapy-Induced Nausea and
Vomiting
Before prescribing any of the products mentioned
in this slide presentation, please consult
the full package insert.
MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, Halfway House 1685
Copyright © 2003–2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
4-05 EMD 2004-W-6141-EM
12-2006-EMD-05-ZA-40-SS
Slide 33