Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

Evidence, Challenges and Evidence, Challenges and Solutions:Solutions: Preventing and Preventing and Managing Chemotherapy-Managing Chemotherapy-Induced Nausea and VomitingInduced Nausea and Vomiting

Scott Edwards, Pharm DScott Edwards, Pharm D

Clinical Oncology PharmacistClinical Oncology Pharmacist

Eastern Health, St. John’s, NLEastern Health, St. John’s, NL

NOPS 2008NOPS 2008

Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy

Rank 19831 19932 19953 19994

1. Vomiting Nausea Nausea Nausea

2. Nausea Constantly tired Loss of hair Loss of hair

3. Loss of hair Loss of hair Vomiting Constantly tired

4. Thought of coming for treatment

Effect on family Constantly tired Vomiting

5. Length of time

treatment takes

Vomiting Having to have an injection

Changes in the way things taste

Adapted from:1Coates A et al. Eur J Cancer Clin Oncol. 1983;19:203-8.2Griffin AM et al. Ann Oncol. 1996;7:189-95.3De Boer-Dennert M et al. Br J Cancer. 1997;76:1055-61.4 Lindley C et al. Cancer Pract 1999;7:59-65.

CINV - Definitions

Acute – within a few minutes to several hours after drug administration and commonly resolves within 24 hours.

Delayed – develops in patients more than 24 hours after chemotherapy administration. May last up to 6 days It commonly occurs with cisplatin, carboplatin,

cyclophosphamide and/or anthracyclines.

Anticipatory – nausea and/or vomiting before patients receive their chemotherapy, after a prior negative experience with chemotherapy

Breakthrough – occurs despite prophylactic treatment and/or requires rescue.

Refractory – nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles

Adapted from:1. ASHP Am J Health Syst Pharm 1999;56:729-7642. NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis

Rates of CINV

Adapted from:1. Hickok JT, et al. Cancer. 2003;97:2880-6.2.http://www.ashpadvantage.com/previous_meetings/mcm_2005/cemornings2005/CEM_CINV_handout.pdf

Chemotherapy-Induced Emesis Risk Factors

Patient-related risk factors include: Younger age Female gender No/minimal prior history of alcohol use Prior CINV Anxiety High pretreatment expectation of severe nausea

Adapted from:1.Gregory RE et al. Drugs. 1998.; 2. Hesketh PJ et al. J Clin Oncol. 1997.2.Roscoe JA, Bushunnow P, Morrow GR, et al. Patient experience is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 2004;101:2701-2708

Influence of Patient Expectations on CINV

Expectancy of nausea assessed before patients received their first doxorubicin-based chemotherapy treatment was found to be a strong predictor of subsequent nausea.

Adapted from Roscoe et al. Cancer. 2004 101(11):2701-8.

Chemotherapy-Induced Emesis Risk Factors

Treatment-related risk factors include: High drug dose High emetogenicity of chemotherapy drugs

Of all the known predictive factors, the emetogenicity of a given chemotherapeutic agent is the predominant factor.

Adapted from ASHP Am J Health Syst Pharm 1999;56:729-64.

Causes of CINV

In addition to emesis induced by chemotherapy, CINV can be caused by:

Partial or complete bowel obstructionVestibular DysfunctionBrain MetastasesElectrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia, uremiaConcomitant drugs, including opiatesGastroparesis induced by a tumor or chemotherapy (such as vincristine)Psychophysiologic factors, including anxiety as well as anticipatory nausea and vomiting

Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.

Consequence of Unresolved CINV

Discontinuation of therapy Serious metabolic derangements Nutritional depletion and anorexia Esophageal tears Wound dehiscence Deterioration of patients’ physical and mental status Degeneration of self-care and functional ability

Adverse sequelae of nausea and vomiting in the cancer patient.

Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.

Poll of the audienceAs Health care professionals we often :

A. Accurately recognize the incidence of acute and delayed CINV in our own practices.

B. Underestimate the incidence of acute and delayed CINV in our own practices.

Anti Nausea Chemotherapy Registry (ANCHOR) study

The authors determined the incidence of acute and delayed CINV after modern antiemetics.

Then they compared the actual incidences of CINV to the predictions made by physicians and nurses regarding these patients.

Adapted from Grunberg SM et al. Cancer 2004;100:2261-8.

Anchor Study Perception vs Reality Moderately Emetogenic Chemotherapy

Adapted from Grunberg et al. Cancer 2004;100:2261-8.

Toxicity Assessments

Grade common toxicity effects of adjuvant breast cancer patients.

Patients are assessed the day of chemotherapy and again 2-3 days post chemotherapy.

Patients also have a number to call back if they experience any toxicities.

Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland

Rates of CINV in

N=26

Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland

Rate of CINV

Adapted from Cancer 2004;100:2261-8.

N=231

at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland in comparison to the Grunberg data

Health Care Professionals Perception of CINV at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland

Adapted from Cancer 2004;100:2261-8.

CINV—Decreased Quality of Life

CINV adversely impact patients' quality of life.

Ovarian cancer patients in a recent study included complete to almost complete control from CINV among the most favorable health states, just below perfect health and clinical remission.

Adapted from Support Care Cancer 2005;13:219-27.


Adapted from Support Care Cancer 2005;13:219-27.

Adapted from Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472.


FLIE Questionnaire HEC-FLIE > MEC-FLIE P=0.0049 FLIE-nausea > FLIE-Vomiting P=0.0097 There is a greater negative impact on

QOL from nausea than there is from vomiting There is a greater negative impact on

QOL from HEC than there is from MEC

FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.

Summary of the Importance of Prevention and Treatment of CINV

There still is a high level of anguish for CINV experienced by our patients.

As health care professionals, we may not be accurately predicting the level of CINV experienced by our patients.

CINV has a enormous impact on our patients quality of life.

Mechanisms of CINV

Central mechanism: Chemotherapeutic agent activates the chemoreceptor

trigger zone (CTZ). Activated CTZ invokes release of various

neurotransmitters, which stimulate vomiting center.

Peripheral mechanism: Chemotherapeutic agent causes irritation and damage

to gastrointestinal (GI) mucosa, resulting in the release of neurotransmitters.

Activated receptors send signals to vomiting center via vagal afferents.

Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869–2880.

Adapted from N Engl J Med 2008;358:2482-94.

Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dose metoclopramide.

Development of 5-HT3 antagonists has had dramatic impact: Highly effective in acute vomiting, less effective for

delayed events. Optimal use is with dexamethasone.

Primary mechanism of action appears to be peripheral.

Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:2869-80. Gralla RJ et al J Clin Oncol 1999;17:2971-94. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811-19. Endo T et al Toxicology 2000;153:189-201. Hesketh PJ et al Eur J Cancer 2003;39:1074-80.

Substance P and Neurokinin 1 (NK1) Receptor Pathway

High density of substance P/NK1 receptors located in brain regions implicated in the emetic reflex.

Primary mechanism of NK1 receptor blockade action appears to be central.

Effective for both acute and delayed events. Augments antiemetic activity of a 5-HT3 receptor

antagonist and corticosteroid.

Adapted from: Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18-24. Saria A Eur J Pharmacol 1999;375:51-60. Hesketh PJ Support Care Cancer 2001;9:350-54.

Conceptual Model of Acute & Delayed CINV

Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds). Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147.

5-HT3-sensitive phase

Prokinetic-sensitive phase

Steroid-sensitive phase

Disrupted gut motility

Cell breakdown products

Inte

nsity

of

emes

is

Time (days)0 1 2 3 4 5

5HT

NK1-sensitive phase

Pharmacogenomics

Quest for individualized therapy.

Identification and characterization of a large number of genetic polymorphisms(biomarkers) in drug metabolizing enzymes and drug transporters may provide substantial knowledge about the mechanisms of inter-individual differences in drug response.

Pharmacogenomics

Pharmacogenomics - the study of the relationship between specific DNA sequence variations and the actual effect of a drug.

CYP2D6 is involved in the metabolism of all of the most commonly available serotonin antagonists, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. As this enzyme is polymorphic, several different alleles may be present in different individuals.

Nu

mb

er o

f S

ub

ject

s

Increasing Metabolic Capacity

EMPM URM

Pharmacogenomics Polymorphic Distribution

CYP2D6 mutations or deletions, poor metabolizer (PM), occur in 10% of the general population

(UM) Ultrarapid metabolizer phenotype is observed in 2% of the general population.

EM (extensive metabolizer), which is the normal or usual phenotype.

Pharmacogenomics in CINV

Kaiser studied the impact of patient genotype for 2D6 (CYP2D6) on efficacy of ondansetron and tropisetron for CINV.

The ultrarapid metabolizer patients experienced significantly more nausea and vomiting after chemotherapy.

The impact of genotype on vomiting incidence was observed during both early (hours 0 to 4) and late (hours 5 to 24) observation periods, although delayed nausea and vomiting was not evaluated in this study.

Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20: 2805-11, 2002.

Figure 2. Mean number of episodes of vomiting ({+/-} standard deviation) experienced 5-24 hours after chemotherapy as a function of the number of active cytochrome P450 CYP2D6 enzyme genes in patients

receiving tropisetron, 5 mg once a day (A), and ondansetron, 8 mg twice a day (B)

Pharmacogenomics in CINV

Adapted from: Kaiser R, Sezer O, Papies A, et al: Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20:2805-11, 2002.

ANTIEMETIC GUIDELINE CONSENSUS

- Official Process Subscribed to by 9 International Oncology Groups -

International: MASCC

North America:

- U.S. ASCO, NCCN

- Canada CCO

Europe: ESMO, EONS

Africa: SASMO

Australia: COSA

Adapted from MASCC Antiemetic March 2008 Guideline Update.

MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES

ANTIEMETIC TREATMENT GUIDELINES - The Four Emetic Risk Groups -

HIGHHIGH Risk in nearlyRisk in nearly all patients (> 90%)all patients (> 90%)

MODERATEMODERATE Risk in 30% to 90% of patientsRisk in 30% to 90% of patients

LOWLOW Risk in 10% to 30% of patientsRisk in 10% to 30% of patients

MINIMALMINIMAL Fewer than 10% at riskFewer than 10% at risk



- Emetic Risk Groups - Single IV Agents -

HIGH

CisplatinMechlorethamineStreptozocinCyclophosphamide > 1500 mg/m2

CarmustineDacarbazine

MODERATE

OxaliplatinCytarabine >1 gm/m2

CarboplatinIfosfamideCyclophosphamide <1500 mg/m2

DoxorubicinDaunorubicinEpirubicinIdarubicinIrinotecan



- Committee I (3/5): Emetic Risk Groups - Single IV Agents

LOW

PaclitaxelDocetaxelMitoxantroneTopotecanEtoposidePemetrexedMethotrexateDoxorubicin HCL liposome injection

MitomycinGemcitabineCytarabine <100 mg/m2

5-FluorouracilBortezomibCetuximabTrastuzumab



ANTIEMETIC TREATMENT GUIDELINES - Committee I (5/5): Emetic Risk Groups - Single Oral Agents -

HIGHHIGH HexamethylmelamineHexamethylmelamineProcarbazineProcarbazine

MODERATEMODERATECyclophosphamideCyclophosphamideEtoposideEtoposideTemozolomideTemozolomide

VinorelbineVinorelbineImatinibImatinib

LOWLOW CapecitabineCapecitabineTegafur uracilTegafur uracil

MINIMALMINIMALChlorambucilChlorambucilHydroxyureaHydroxyureaL-Phenylalanine mustardL-Phenylalanine mustard

6-Thioguanine6-ThioguanineMethotrexateMethotrexateGefitinibGefitinib


Principles of Care for Acute Highly andModerately Emetic Settings

UNANIMOUS CONSENSUS: CATEGORY 1 EVIDENCE

- Use the lowest tested fully effective dose.- No schedule is better than a single dose given before

chemotherapy.- The antiemetic efficacy and adverse effects of serotonin

antagonist agents are comparable in controlled trials.- Intravenous and oral formulations are equally effective

and safe.

- Always give dexamethasone with a 5-HT3 antagonist before chemotherapy.


To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen is recommended including single doses of:

5-HT3 antagonistDexamethasoneAprepitant (or fosaprepitant)

given before chemotherapy is recommended.

MASCC Level of confidence : HighMASCC Level of consensus: HighASCO Level of evidence: IASCO Grade of recommendation: A

Adapted from slide from MASCC Antiemetic March 2008 Guideline Update.

Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk:

Example - Women receiving a combination of anthracycline + cyclophosphamide represent a situation with a particularly great risk of vomiting and nausea. To prevent acute vomiting and nausea in these women, a three-drug regimen including single doses of:

5-HT3 antagonistDexamethasoneAprepitant (or fosaprepitant)


MASCC Level of confidence: ModerateMASCC Level of consensus: HighASCO Level of evidence: IIASCO Grade of recommendation: A


Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

In patients who receive MEC, not including a combination of anthracycline plus cyclophosphamide:

5-HT3 receptor antagonist +Dexamethasone

is recommended for prophylaxis of acute nausea and vomiting in the first course.

MASCC level of confidence: HighMASCC level of consensus: HighASCO level of evidence: IASCO grade of recommendation: A


Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

B.C. Cancer Agency Antiemetic regimens

Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

ONS Putting Evidence into Practice

Adapted from ONS PEP Nausea Retrieved July 21, 2008 from http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf

Adapted from ONS PEP Nausea Retrieved July 21, 2008 from http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf

ONS Putting Evidence into Practice – Cont’d

Cancer Care Ontario - Telephone Nursing Practice - and Symptom Management Guidelines

Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

Cancer Care Ontario - Telephone Nursing Practiceand Symptom Management Guidelines

Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

Common CINV Challenges

Challenges in multiple-day chemotherapy regimens

Breakthrough CINV

Anticipatory CINV

Delayed CINV

Multiple-Day Chemotherapy Regimens

Challenge – Patients receiving multi-day chemotherapy (chemotherapy administered over several days per cycle) are at risk for both acute and delayed nausea and vomiting.

It is difficult to recommend appropriate antiemetics for each day since acute and delayed may overlap after the initial day of chemotherapy.

The period of risk for delayed nausea and vomiting also depends on the emetogenic potential of the last chemotherapy agent administered in the regimen.

Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

Multi-Day Chemotherapy Regimens (continued)

A 5-HT3 receptor antagonist should be administered prior to each days 1st dose of moderately or highly-emetogenic chemotherapy.

Dexamethasone should be administered once daily either orally or IV for every day of chemotherapy and for 2-3 days post chemotherapy.

Aprepitant may be used for multi-day chemotherapy. Aprepitant 125 mg on day 1, then aprepitant 80 mg daily on days 2 and 3 along with dexamethasone. Based on Phase II data, aprepitant may be safely administered on days 4 and 5 after chemotherapy.


Breakthrough CINV

Breakthrough emesis refers to vomiting that occurs despite prophylactic treatment and/or requires rescue.

Refractory emesis refers to emesis that occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles.

Challenge - Breakthrough nausea and vomiting represents a difficult situation as ongoing refractory nausea is hard to reverse.


Breakthrough CINV (continued)

Management Strategies -Give around the clock administration versus prn.

Additional agents should be from a different drug class

than initial therapy. No one treatment is better than the other. Possibilities include: dopamine antagonists,

metoclopramide, haloperidol, cannabinoids, corticosteroids, or agents such as lorazepam

If patient has dyspepsia, consider antacid therapy (H2 blocker or Proton Pump Inhibitor).


Breakthrough CINV – Cont’d

Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

Adapted from: 1. Roscoe JA, et al. J Pain Symptom Manage 2000;20:113.

2. Morrow GR, et al. Support Care Cancer 1998;6:244.

Anticipatory CINV

Anticipatory nausea and/or vomiting is the occurrence of nausea and/or vomiting before patients receive their chemotherapy treatment. Because it is a conditioned response, it can only occur after a negative past experience with chemotherapy.

Challenge - Anticipatory nausea and/or vomiting occurs in 18% to 57% of chemotherapy patients.

Younger patients may be more susceptible as they generally receive more aggressive therapy and have poorer emesis control than older patients.

Anticipatory CINV (continued)

The most effective way to treat is to prevent CINV by using optimal antiemetics during every cycle of therapy.

Either: Alprazolam PO 0.25 to 0.5 mg t.i.d. beginning on the

night before treatment OR; Lorazepam 0.5-2 mg PO on the night before and the

morning of treatment.

Behavioral therapy

Systemic densensitization


Adapted from Grunberg et al. Cancer 2004;100:2261.

Delayed CINV

Challenge - Delayed emesis is 2.5 times more prevalent than acute emesis.

For moderately emetogenic chemotherapy: Delayed nausea exceeds acute nausea by 16%. Delayed emesis exceeds acute emesis by 15%.

For highly emetogenic chemotherapy: Delayed nausea exceeds acute nausea by 27%. Delayed emesis exceeds acute emesis by 38%.

Prognostic Factors for Delayed CINV

Strongest predictor of delayed nausea and vomiting was the occurrence of acute nausea and vomiting.

Patients aged 52 years or younger and women were more likely to have delayed nausea than were those older than 52 years and men.

A high expectation of nausea was a significant predictor of more severe nausea.

Adapted from The Lancet Oncology October 2005;Vol(6):Issue(10):765-72.

Case 1

Initial Presentation

Mary T. is a 56-year-old female who was completely asymptomatic when a routine mammogram showed two lesions. She underwent diagnostic testing and had a mastectomy and auxiliary lymph node dissection.

Diagnosis – T3 (more than 5 cm) N0(0/6 lymph nodes) M0. poorly differentiated invasive ductal carcinoma of right breast, ER/PR positive and HER-2/neu negative.


PAST MEDICAL HISTORY: Unremarkable.

SOCIAL HISTORY: School teacher, married, mother of two grown children living away, non smoker, occasional drink on the weekends.

MEDICATIONS: Ranitidine 150 mg b.i.d., Lorazepam 1 mg prn

SYSTEM INQUIRY: Unremarkable.

Allergies : NKA (drugs, food, environmental allergens)

First Cycle of Chemotherapy (FEC)

The patient is prescribed FEC (Fluorouracil, Epirubicin, Cyclophosphamide) – for 3 cycles followed by Taxotere for 3 cycles.

She was given Ondansetron 8 mg and Dexamethasone 8 mg prior to her first cycle of chemotherapy.

She was given a prescription for Ondansetron 8 mg and Dexamethasone 4 mg po b.i.d. x 2 days post chemotherapy as well as Metoclopramide 10 mg po q6hprn to be taken post chemotherapy.

Nausea post Cycle 1

When she returned for cycle two she informed the pharmacist that she had vomited on day 2 and that she had experienced nausea for days 2-5 post chemotherapy.

She rates this nausea as a 8/10 for days 2-4 and 6/10 for day 5.

Case 1: Question 1

What anti-emetics would you recommend to be given prior to chemotherapy for her second cycle of FEC?

A.Metoclopramide 10 mg

B.Ondansetron 8 mg, Dexamethasone 8 mg and

Aprepitant 125 mg

A.Ondansetron 8 mg and Dexamethasone 8 mg

Women receiving a combination of anthracycline + cyclophosphamide represent a situation with a particularly great risk of vomiting and nausea. To prevent acute vomiting and nausea in these women, a three-drug regimen including single doses of:

5-HT3 antagonist

Dexamethasone

Aprepitant (or fosaprepitant)



Answer Question 1 = BGuideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC):

Case 1: Question 2

What anti-emetics would be offered to this patient as an anti-nausea take home prescription for the FEC (cycle 2) regimen?

A. Dexamethasone 8 mg bid x 3 days and Metoclopramide 10 mg q6hprn.

B. Metoclopramide 10 mg q6hprn.

C. Aprepitant 80 mg on days 2 and 3, Ondansetron 8 mg and Dexamethasone 4 mg bid x 2 days and Metoclopramide 10 mg q6hprn.

Answer Question 2

Adapted from http://www.bccancer.bc.ca.

Case 1: Question 3

What other actions can the pharmacist take to help M.T. control her CINV?

Answer Question 3 Explore patient adherence with anti-emetics. Assess effectiveness/ineffectiveness of anti-emetic

plan. Follow up toxicity assessments (use CCO telephone

toxicity guidelines). CINV education. Communication with her other health care providers. Patient nausea diary (CANO patient education for

CINV). Promote patient involvement through patient resources:

► Chemotherapy and You: A Guide to Self-Help During Cancer Treatment, http://www.nci.nih.gov/cancerinfo/chemotherapy-and-you

► http://www.cancernausea.com

Case 1: Question 4

The pharmacist asks the patient what medications she is currently taking.

She informs the nurse she is taking Warfarin, Metoprolol and ASA.

Should she be concerned about a drug interaction with Warfarin and Aprepitant?

Case 1: Question 5

Which of the following may occur with the addition of aprepitant to M.T’s regimen?

A. INR may decline

B. INR may increase

C. Warfarin levels may rise

Answer Question 4 and 5Warfarin Aprepitant Interaction

Aprepitant is a CYP3A4 substrate, a 3A4 inhibitor and inducer, and a 2C9 inducer.

INR may decline.

Adapted from Aprepitant Monograph. Retrieved July 22, 2008 from http://www.cancercare.on.ca/pdfdrugs/aprepitant.pdf

Importance of Medication Reconciliation

Pilot Project of Medication Reconciliation in St. John’s, Newfoundland Cancer Center

Summer project

Pharmacy Students

Obtaining an accurate medication history for chemotherapy patients

Total Number of Medications vs. Total Number of Inaccuracies or Omissions

Cancer Care Program

Identification of the number of patients with inaccuracies or omissions as well as the number of drug related problems identified

Cancer Care Program

Identification of the number of patients with inaccuracies or omissions as well as the number of patients taking OTC/Herbals

Cancer Care Program

Starting Docetaxel after FEC

M.T. completed her three cycles of FEC as part of the FEC-D regimen. Since the addition of Aprepitant, her nausea control has been much better.

Since she is starting Docetaxel, she needs to take Dexamethasone 8 mg po b.i.d. for 3 days, starting 24 hours prior to chemotherapy.

The medical oncology team would like to keep M.T. on Aprepitant due to her improved response.

Case 1: Question 6

As the oncology pharmacist, you tell the team that they need to be concerned about Aprepitant drug interactions.Which of the following would be correct to tell the team about Aprepitant:

A. Aprepitant is a Substrate for CYP3A4,and Moderate Inhibitor of CYP3A4.B. Aprepitant is a Weak Inducer of CYP3A4 and CYP2C9.C. Both A and B are correct.

Answer Question 6 - Aprepitant and P450

Substrate for CYP3A4, CYP2C19 and CYP1A2

Weak Inducer of CYP3A4 and CYP2C9

Moderate Inhibitor of CYP3A4

Weak inhibitor of CYP2C9 and CYP2C19

Case 1: Question 7

The general recommendations for dosing dexamethasone when combined with Aprepitant is:

A. Reduce the dose of dexamethasone by 50%

B. Increase the dose of dexamethasone by 50%

C. Do not adjust the dose of dexamethasone

Answer Question 7

Aprepitant increases the AUC of dexamethasone when the two are administered concomitantly.

Reduce dexamethasone dose by 50%.

Case 1: Question 8

What would be your recommendations for dosing dexamethasone for Docetaxel premedication when combined with Aprepitant for M.T. :

A. Reduce the dose of dexamethasone by 50%

B. Increase the dose of dexamethasone by 50%

C. Do not adjust the dose of dexamethasone

Case 2

Jimmy T. is a A 27 year old with a history of T2N2M1a, Stage III non-seminoma testicular cancer. He had surgery for this and in follow up was found to have metastatic disease. He had at least two lung lesions as well as some mediastinal adenopathy and retroperitoneal adenopathy.


PAST MEDICAL HISTORY: Unremarkable.

SOCIAL HISTORY: He lives with his common law girlfriend, Occasional drink on weekends, non smoker

MEDICATIONS: Acetaminophen prn

SYSTEM INQUIRY: Unremarkable.

Allergies : NKA (drugs, food, environmental allergens)a

First cycle of chemotherapy (BEP)

The patient is prescribed BEP (BLEOMYCIN-ETOPOSIDE-CISPLATIN) Chemotherapy for 4 cycles.

Case 2 : Question 1

What anti-emetics would you recommend to be given prior to chemotherapy for his first cycle of BEP?

A. Metoclopramide 10 mg pre chemotherapy for 5 daysB. Ondansetron 8 mg, Dexamethasone 8 mg and Aprepitant

125 mg on day 1 pre chemotherapy and Ondansetron 8 mg, Dexamethasone 4 mg and Aprepitant 80 mg on days 2-5 pre chemotherapy

C. Ondansetron 8 mg and Dexamethasone 8 mg pre chemotherapy on days 1-5

Answer Question 1Multiple Day Chemotherapy

A 5-HT3 receptor antagonist should be administered prior to each days 1st dose of moderately or highly-emetogenic chemotherapy.

Dexamethasone should be administered once daily either orally or iv for every day of chemotherapy and for 2-3 days post chemotherapy.

Aprepitant may be used for multi-day chemotherapy. Aprepitant 125 mg on day 1, then aprepitant 80 mg daily on days 2 and 3 along with dexamethasone. Based on Phase II data, aprepitant may be safely administered on days 4 and 5 after chemotherapy.


Case 2: Question 2

The oncology pharmacist performs a toxicity assessment on Jimmy T. 3 days (Monday afternoon) post chemotherapy. The patient complains of significant nausea that started on Sunday evening. He vomited x 1 on Monday morning. He rates the nausea as 8 out of 10.

He states he was given a prescription for Ondansetron 8 and Dexamethasone 4 mg po bid x 2 days as well as Metoclopramide 10 mg po q6hprn. The Dexamethasone and Ondansetron were completed on Sunday morning. He did not take the Metoclopramide as he wasn’t sure if he should.

What should the oncology pharmacist do for this patient?

Answer Question 2 - Breakthrough CINV

Management Strategies -Give around the clock administration versus prn .

Additional agents should be from a different drug class than initial therapy. No one treatment is better than the other. Possibilities include: metoclopramide, haloperidol,

prochlorperazine, cannabinoids, corticosteroids, or agents such as lorazepam.

If patient has dyspepsia, consider antacid therapy

(H2 blocker or Proton Pump Inhibitor).


Case 2: Question 3

Which of the following consequence of unresolved CINV do you consider the most important for this patient?

A.Nutritional depletion and anorexia

B.Discontinuation of therapy

C.Esophageal tears

Unresolved issues in CINV?

Role of risk factor assessment in tailoring antiemetics to the individual at the onset of chemotherapy.

Need to develop a better understanding of the pathophysiology of delayed CINV.

Increase awareness of CINV for oncology professionals.

Newer agents/ formulations Olanzapine New NK-1 antagonists New formulations of 5HT3 antagonists eg transdermal

patches, oral sprays, longer acting SC injections

Emend Coverage

NL Coverage

Conclusion

Chemotherapy-induced nausea/vomiting (CINV) is a common side effect despite antiemetic therapy.

Health care professionals need to ensure patients are being treated according to current antiemetic guidelines.

‘It is always better and easier to PREVENT than to treat nausea/vomiting associated with chemotherapy.’

Acknowledgements

Katrina Mulherin, Pharm D Student Barbara Wilson, RN, BN, MS, CON(C) Staff (nurses, physicians, pharmacists) at St. John’s

Cancer Center

Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

Documents

Transcript of Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008