slide 1 summary of clinical information: role of emend ® in managing chemotherapy-induced nausea...

Summary of Clinical Information: Summary of Clinical Information: Role of EMENDRole of EMEND®® in Managing in Managing

Chemotherapy-Induced Nausea Chemotherapy-Induced Nausea and Vomitingand 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 S4Each capsule contains 80 mg or 125 mg Aprepitant150

®Registered Trademark of MERCK & CO., INC., Whitehouse Station, N.J., U.S.A..

Risk Factors for Chemotherapy-Induced Risk Factors for Chemotherapy-Induced Nausea/Vomiting (CINV)Nausea/Vomiting (CINV)

Patient-SpecificPatient-Specific

History of emesis Younger age Female gender

Heightened anxiety Expectation of Hospital roommate withadverse effects nausea and vomiting

Low motivation Low performance status Food intake

Inadequate sleep Low alcohol intake Therapy-SpecificTherapy-Specific

Agents with increased Combination regimens Higher-dose chemotherapyemetogenic potential

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.

Types of CINVTypes 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.

Need for Improved CINVNeed for Improved CINV

1983 1996Rank (Pre–5-HT3 Antagonist Era) (During 5-HT3 Antagonist Era)

1 Being sick (vomiting) Feeling sick (nausea)2 Feeling sick (nausea) Loss of hair3 Loss of hair Being sick (vomiting)4 Thought of coming for treatment Constantly tired5 Duration of treatment at the clinic Need for an injection6 Need to get a needle Constipation7 Shortness of breath Thought of coming for treatment8 Constantly tired Affects family or partner9 Difficulty sleeping Feeling low, miserable (depression)

10 Affects family or partner Feeling anxious or tense

Most Distressing Adverse Effects of Chemotherapy Before and During 5-HT3 Antagonist Era

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.

Unmet NeedUnmet 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

CINV Compromises Quality of Daily LifeCINV Compromises Quality of Daily Life

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.

Mean Changes in Functional-Domain Scores of Health-Related Quality of Life After 8 Days of Chemotherapy

Mea

n c

han

ge

in s

core

Mea

n c

han

ge

in s

core

Quality of Life Diminished

Quality of Life Improved

Group 1 (no nausea or vomiting)Group 2 (vomiting, no nausea)Group 3 (nausea, no vomiting)Group 4 (nausea and vomiting)

–20

–15

–10

–5

0

5

10

1.9b

–0.6–1.1c

–8.4

–2.6–0.6–0.5d

–8.8e

0.6f

–1.1

–7.4g

–14.2

–3.8a

–5.7

–8.7–10

5.35.3 4.9

0.8

Physical Emotional Cognitive Social Global

Functional domainFunctional domain

Goals of Antiemetic TherapyGoals 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.

Mechanisms of CINVMechanisms 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.

Role of Substance P and Other Neurotransmitters Role of Substance P and Other Neurotransmitters in CINVin 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.

Antiemetic TherapiesAntiemetic 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.

EMENDEMEND®® (aprepitant): (aprepitant): The First NKThe First NK1 1 Receptor AntagonistReceptor 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

EMENDEMEND®®: Pharmacokinetics* : Pharmacokinetics*

Absorption Tmax ~4 hr

Cmax 1.5 µg/ml (day 1)

AUC0-24h 19.65 µg•hr/ml (day 1)

Distribution Vdss 66 L

Crosses blood-brain barrier Yes

Metabolism Pathway Largely by oxidation

Elimination Route Primarily by metabolismT½ 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

EMENDEMEND®®

Efficacy in Clinical Trials: Study DesignEfficacy in Clinical Trials: Study Design

Regimen Day 1 Days 2 and 3 Day 4 EMEND with EMEND 125 mg PO EMEND 80 mg POControl Regimen Zofran® a 32 mg IVb

Dexamethasone 12 mg POc Dexamethasone 8 mg Dexamethasone 8 mgPO once daily PO

Control Regimen Zofran® 32 mg IVDexamethasone 20 mg PO Dexamethasone 16 mgd Dexamethasone 16 mgd

PO 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

Objective: Compare EMEND with control regimens vs. control regimens alone in two identically designed trials (N=1099)

in the prevention of CINV

*No emesis and no rescue medication

EMENDEMEND®®

Efficacy: Complete Response* in Acute PhaseEfficacy: Complete Response* in Acute Phase

Time after chemotherapy administrationTime after chemotherapy administration

86

73

Acute (Day 1)0

20

40

60

80

100

% o

f p

atie

nts

% o

f p

atie

nts

Control Regimen (n=523) Zofran® 32 mg IV, dexamethasone 20 mg PO, and placeboEMEND with Control Regimen (n=520) EMEND 125 mg PO, Zofran® 32 mg IV, and dexamethasone 12 mg PO

13% improvement13% improvement(p<0.001)(p<0.001)

EMENDEMEND®®

Efficacy: Complete Response* in Delayed PhaseEfficacy: Complete Response* in Delayed Phase


72

51

Delayed (Days 2–5) 0

20

40

60

80

100

% o

f p

atie

nts

% o

f p

atie

nts


*No emesis and no rescue medication

Control Regimen (n=523) Dexamethasone 16 mg PO and placebo Days 2–4EMEND with Control Regimen (n=520) EMEND 80 mg PO Days 2 and 3, and dexamethasone 8 mg PO Days 2–4

EMENDEMEND®® Efficacy: Complete Protection* in Acute PhaseEfficacy: Complete Protection* in Acute Phase


82

70

Acute (Day 1)0

20

40

60

80

100

% o

f p

atie

nts

% o

f p

atie

nts


*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)


EMENDEMEND®® Efficacy: Complete Protection* in Delayed PhaseEfficacy: Complete Protection* in Delayed Phase


64

48


20

40

60

80

100

% o

f p

atie

nts

% o

f p

atie

nts



*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)

EMENDEMEND®®Efficacy: Impact of CINV on Daily Life in Cycle 1Efficacy: 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

EMENDEMEND®® Efficacy: Percentage of Patients with No Efficacy: Percentage of Patients with No Emesis* in Acute PhaseEmesis* in Acute Phase

* No emetic episodes regardless of use of rescue medication


87

74

Acute (Day 1)0

20

40

60

80

100%

of

pat

ien

ts%

of

pat

ien

ts13% improvement13% improvement

(p<0.001)(p<0.001)


EMENDEMEND®® Efficacy: Percentage of Patients with No Efficacy: Percentage of Patients with No Emesis* in Delayed PhaseEmesis* in Delayed Phase

* No emetic episodes regardless of use of rescue medication


76

54


20

40

60

80

100%

of

pat

ien

ts%

of

pat

ien

ts22% improvement22% improvement

(p<0.001)(p<0.001)


EMENDEMEND®® Efficacy: Percentage of Patients Who Efficacy: Percentage of Patients Who Remained Free of Vomiting Over Time in Cycle 1Remained Free of Vomiting Over Time in Cycle 1

Days since initiation of cisplatin therapyDays since initiation of cisplatin therapy

Day 10

20

40

60

80

100

EMEND with control regimen (n=520)

% o

f p

atie

nts

% o

f p

atie

nts

Control regimen (n=523)

Day 2 Day 3 Day 5Dose 1 Dose 2 Dose 3

Acute(0–24 hours)

Delayed

P<0.001

Day 4

Control Regimen Zofran® (32 mg IV), dexamethasone 20 mg PO, and placebo Day 1EMEND with Control Regimen EMEND 125 mg PO, Zofran® 32 mg IV, and dexamethasone 12 mg PO Day 1

Day 1

Control Regimen Dexamethasone 16 mg PO and placebo Days 2–4EMEND with Control Regimen EMEND 80 mg PO Days 2 and 3; dexamethasone 8 mg PO Days 2–4

Days 2–4

EMENDEMEND®®

Efficacy in Clinical Trials: No Vomiting, Efficacy in Clinical Trials: No Vomiting, No Significant NauseaNo Significant Nauseaaa in Cycles 1–6 in Cycles 1–6

a Nausea did not interfere with normal activities. b 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.

40

50

60

70

80

90

100

% o

f p

atie

nts

% o

f p

atie

nts

wit

h f

avo

rab

le r

esp

on

ses

wit

h f

avo

rab

le r

esp

on

ses

1CycleCycledd

30

2062 3 4 5

EMEND with Control Regimens

Control Regimensbb

EMEND withControl Regimen n= 516 308 245 170 117 89

Control Regimen n= 522 281 203 142 95 78

cc c

c c c

EMENDEMEND®®: Overall Adverse Experiences: Overall Adverse Experiences

*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 4ALT=alanine aminotransferase

• 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%)

EMENDEMEND®®: Indications: Indications

EMEND, in combination with other antiemetic agents, EMEND, in combination with other antiemetic agents,

is indicated for the prevention of acute and delayed is indicated for the prevention of acute and delayed

nausea and vomiting associated with initial and nausea and vomiting associated with initial and

repeat courses of highly emetogenic cancer repeat courses of highly emetogenic cancer

chemotherapy, including high-dose cisplatin.chemotherapy, including high-dose cisplatin.

EMENDEMEND®®: Contraindications : 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.

EMENDEMEND®®: Dosage and Administration: Dosage and Administration

Day 1 Days 2 and 3 Day 4

EMEND* 125 mg 80 mg None

Dexamethasone** 12 mg orally 8 mg orally 8 mg orally

Zofran® (ondansetron hydrochloride) *** 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

Regimen used in clinical studies

Drug Interactions: Effect of EMENDDrug Interactions: Effect of EMEND®® on the Pharmacokinetics of Other Agentson the Pharmacokinetics of Other Agents

Characteristic of Aprepitant Clinical Relevance Can increase plasma concentrations Reduce oral corticosteroid doses by 50% whenof coadministered agents that are coadministered with EMEND and IV doses by 25%metabolized through CYP3A4

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

ContinuedContinued

Drug Interactions: Effect of EMENDDrug Interactions: Effect of EMEND®®

on the Pharmacokinetics of Other Agents (cont’d)on the Pharmacokinetics of Other Agents (cont’d)

Characteristic of Aprepitant Clinical Relevance Can decrease plasma concentrations Closely monitor prothrombin time in patients receiving of coadministered agents that are warfarin to establish and maintain dose after completion ofmetabolized through CYP2C9 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 duringadministration of EMEND; therefore, alternativeor backup methods of contraception should be used

Characteristic of Other Agents Clinical Relevance Agents that strongly inhibit or Approach cautiously induce CYP3A4 may increase or decrease plasma concentrations of Coadministration of EMEND with strong inhibitorsaprepitant, respectively of CYP3A4 (e.g., ketoconazole)

Coadministration of EMEND with strong inducers of CYP3A4 (e.g., rifampin)

Drug Interactions: Effect of Other Agents on the Drug Interactions: Effect of Other Agents on the Pharmacokinetics of EMENDPharmacokinetics of EMEND®®

Source A(WPC), p. 5, ¶1, L1-3

¶2, L1-3

EMENDEMEND®®: Overall Adverse Experiences: Overall Adverse Experiences

*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 4ALT=alanine aminotransferase

• 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%)

Summary 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.

BibliographyBibliography

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Copyright © 2003–2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.

All rights reserved.

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Summary of Clinical Information: Role of EMENDSummary of Clinical Information: Role of EMEND® ®

in Managing Chemotherapy-Induced Nausea and in Managing Chemotherapy-Induced Nausea and VomitingVomiting

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