Prevention and Management of Chemotherapy-Induced Nausea and Vomiting, Part 2

Transcription

1 CONTINUING EDUCATION SERIES ONCOLOGY/IMMUNOLOGY Prevention and Management of Chemotherapy-Induced Nausea and Vomiting, Part 2 Shantel Mullin, PharmD* and M. Christina Beckwith, PharmD Outline Part 1 Introduction Historical Perspective Definitions Pathophysiology Epidemiology Risk Factors Part 2 Pharmacology and Clinical Efficacy of Agents used to Manage CINV Selective 5-HT 3 Receptor Antagonists Corticosteroids Metoclopramide (Substituted Benzamides) Phenothiazines and Butyrophenones Benzodiazepines Miscellaneous Agents Treatments in the Pipeline Nonpharmacologic Methods for Managing CINV Treatment Algorithms Approach to the Oncology Patient Formulary Management Guidelines The Role of the Pharmacist Conclusions Credit This lesson is good for 0.3 CE units, with a passing grade of 70%. Goal The goal of this program is to inform the participant about cost-effective ways to prevent, identify, and manage nausea and vomiting induced by antineoplastic agents. Objectives At the completion of this program the participant will be able to: 1. List antineoplastic agents associated with a high incidence of nausea and vomiting. 2. Identify patient-specific risk factors for developing chemotherapy-induced nausea and vomiting (CINV) and how these factors may influence treatment of this syndrome. 3. Compare the three major types of CINV, including the pathophysiologic mechanism, time of onset, and symptom duration of each type. 4. Explain the mechanism of action and appropriate place in therapy for each type of antiemetic agent. 5. Differentiate between pharmacologic regimens for the prevention and treatment of CINV in adults. 6. Identify drug-specific factors that must be considered when developing a formulary management strategy for the antiemetic agents. 7. Describe specific information that the pharmacist can share with patients to help them understand and manage CINV. Key Words adverse reaction, antiemetic agents, antineoplastic agents, chemotherapy, emesis, nausea, vomiting INTRODUCTION Part 1 of this series introduced the topic of chemotherapy-induced nausea and vomiting (CINV), discussed risk factors for CINV, and described the major pathophysiologic pathways involved in the disorder. This article discusses the pharmacologic management of CINV and the role of specific drug classes in its prevention and con- *Clinical Drug Information Specialist, University Hospitals and Clinics, Department of Pharmacy Services, 50 North Medical Drive A-050, Salt Lake City, UT 84132; Clinical Drug Information Specialist, University Hospitals and Clinics, Department of Pharmacy Services, 50 North Medical Drive A-050, Salt Lake City, UT The authors thank Donald P. Alexander, PharmD; Steve Kirkegaard, PharmD; and Lance Muncey, PharmD for their contributions to our institution s antiemetic treatment standards. We appreciate the comments from Linda S. Tyler, PharmD, on the content of the manuscript, which were invaluable to its development. We also wish to thank Diann Millikan, RPh; Erin R. Fox, PharmD; Michelle Wheeler, PharmD; and Tony Dalpiaz, PharmD for their assistance during the production of this manuscript. And we thank Ron Rawley, CPhT for secretarial support and technical support. 280 Volume 36, March 2001

2 TABLE 1 Emetogenic Potential of Antineoplastics Frequency Level Of Emesis AGENTS 1 < 10% Arsenic trioxide* Hydroxyurea Low potential Bexarotene (oral)* Interferon alfa Bleomycin Melphalan (oral) Busulfan (oral, < 4 mg/kg/day) Mercaptopurine Capecitabine (oral)* Methotrexate ( 50 mg/m 2 ) Chlorambucil (oral) Pentostatin* 150,151 Cladribine Thioguanine (oral) Daunorubicin, liposomal* Tretinoin Doxorubicin, liposomal* Trimetrexate* Estramustine* Vinblastine Floxuridine* 148,149 Vincristine Fludarabine Vinorelbine Gemtuzumab ozogamicin* 2 10% to 30% Asparaginase Mitomycin Moderate-to-Low Cytarabine (< 250 mg/m 2 ) Paclitaxel potential Docetaxel Pegaspargase* 152 Doxorubicin HCl (< 20 mg/m 2 ) Temozolomide* Etoposide Teniposide Fluorouracil (< 1000 mg/m 2 ) Thiotepa Gemcitabine Topotecan Methotrexate ( mg/m 2 ) 3 30% to 60% Aldesleukin Doxorubicin HCl (20 60 mg/m 2 ) Moderate Altretamine (oral) Epirubicin potential Cisplatin (< 25 mg/m 2 ) Fluorouracil ( 1000 mg/m 2 ) Cyclophosphamide ( 750 mg/m 2 )Idarubicin Cyclophosphamide (oral) Ifosfamide ( 3500 mg/m 2 ) Cytarabine ( mg/m 2 ) Methotrexate ( mg/m 2 ) Dactinomycin ( 1.5 mg/m 2 ) Mitomycin Daunorubicin ( 50 mg/m 2 ) Mitoxantrone (< 15 mg/m 2 ) 4 60% to 90% Carboplatin Ifosfamide (> 3500 mg/m 2 ) Moderate-to-High Carmustine ( 250 mg/m 2 ) Irinotecan potential Cisplatin (25 75 mg/m 2 ) Lomustine ( 60 mg/m 2 ) Cyclophosphamide ( mg/m 2 ) Melphalan (IV) Cytarabine ( 1000 mg/m 2 ) Methotrexate ( 1000 mg/m 2 ) Dactinomycin (> 1.5 mg/m 2 ) Mitoxantrone ( 15 mg/m 2 ) Daunorubicin (> 50 mg/m 2 ) Procarbazine Doxorubicin HCl (> 60 mg/m 2 ) 5 > 90% Carmustine (> 250 mg/m 2 ) Lomustine (> 60 mg/m 2 ) High potential Cisplatin ( 75 mg/m 2 ) Mechlorethamine Cyclophosphamide (> 1500 mg/m 2 ) Streptozocin Dacarbazine *Adapted from references indicated or from product labeling. Medications classified based on incidence of severe or Grade III/IV nausea and vomiting reported with the agent, in the absence of antiemetic prophylaxis. Based on research by and clinical observations of clinical pharmacy staff at University of Utah Hospital. Sources: Lindley CM 147 ; ASHP Commission on Therapeutics 1 ; Gralla RJ 63 ; Mosby s GenRx 7 ; Ettinger DS 64 ; Hesketh PJ et al 2 ; Gralla RJ et al 53 ; Merrifield KR, Chaffee BJ 69 Hospital Pharmacy 281

3 trol. Formulary selection guidelines for antiemetics and pharmacoeconomic implications are also addressed, along with the pharmacist s role in managing this disease and providing patient education. This article also addresses institution-specific treatment algorithms and how to evaluate the available consensus guidelines for managing CINV. As discussed in Part 1, clinicians must first determine the emetogenic risk of the planned chemotherapy before choosing an antiemetic regimen. Table 1 lists the emetogenic potential of antineoplastic agents, based on the classification system proposed by Hesketh et al. The procedure for determining the emetogenicity for a combination of antineoplastic agents is shown in Figure 1. 1,2 This information is repeated in Part 2 of this series to help pharmacists understand the role of antiemetic treatment algorithms. PHARMACOLOGY AND CLINICAL EFFICACY OF AGENTS USED TO MANAGE CINV The first agents with proven efficacy in CINV were phenothiazines, cannabinoids, corticosteroids, and diazepam. 3 These agents produced some relief for patients receiving chemotherapy regimens with a lower potential for causing nausea, such as fluorouracil. 4 The development of cisplatin in the 1970s changed the way practitioners viewed CINV. 5 This highly emetogenic agent quickly showed that treatment failure could result if patients refused further treatment for fear of CINV symptoms. The dilemma of how to adequately treat severe, potentially dose-limiting CINV soon became a major issue in oncology. Published studies provide support for specific antiemetics used to treat CINV associated with certain antineoplastic regimens. However, the information is fragmented leaving practitioners wondering which antiemetic drugs and doses and which combinations of agents are best for treating chemotherapy patients. Appropriate prevention and treatment of CINV is crucial to the success and safety of highly emetogenic antineoplastic regimens. The use of agents with both antidopaminergic and antiserotonergic activities greatly reduces the risk of CINV with highly emetogenic chemotherapy. High-dose metoclopramide was studied extensively in the 1980s, both as a single agent and in combination with corticosteroids. However, many patients were unable to tolerate metoclopramide s side effects, including extrapyramidal reactions, drowsiness, restlessness, and diarrhea. 6 Selective serotonin type 3 (5-HT 3 ) receptor antagonists ondansetron, granisetron, and dolasetron were marketed in the past decade for the management of acute CINV. 7 These agents are more efficacious and less toxic than other antiemetics, but they do not provide complete control of CINV. Currently the best CINV management strategy is to administer antiemetic combinations with different mechanisms of action. 8 Table 2 compares the available antiemetic agents discussed in this section. Selective 5-HT 3 Receptor Antagonists Three selective serotonin antagonists (ondansetron, granisetron, dolasetron) are approved in the US The 5-HT 3 receptor antagonists block peripheral 5-HT 3 receptors located on vagal afferent nerves and enterochromaffin cell membranes in the GI tract. 12 This, in turn, prevents the release of serotonin from enterochromaffin cells and eliminates neural afferent stimulation of the chemoreceptor trigger zone (CTZ). All three 5-HT 3 receptor antagonists are well absorbed with oral (PO) administration. Ondansetron (Zofran) and granisetron (Kytril) are administered in active form and bind 5-HT 3 receptors in the GI tract within 30 minutes of administration. Dolasetron (Anzemet) is rapidly absorbed after PO administration, metabolizes to its active form in the liver, and then circulates back to the GI tract, where it acts on gut 5-HT 3 receptors. Because the primary mechanism of action is peripheral, the 5-HT 3 receptor antagonists should be effective for preventing CINV, regardless of the route of administration. And, in fact, clinical trials demonstrate that these agents are equally effective with PO or IV administration. 12 Ondansetron Ondansetron is effective as a single agent in controlling acute CINV. 13 In clinical trials, ondansetron significantly reduced the incidence of CINV induced by cyclophosphamide 14 or cisplatin. 15 Ondansetron was more effective in controlling CINV and caused fewer side effects than high-dose metoclopramide The efficacy of ondansetron for preventing acute CINV is indisputable. However, the best dose and schedule are not well-defined. Several initial dose-ranging studies suggested that ondansetron 0.15 mg/kg was effective when given in three doses at 2- to 4- hour intervals Because administration of a single dose would be simpler and less expensive, later trials evaluated this strategy, comparing single doses of ondansetron 8 mg IV and ondansetron 32 mg IV with multipledose schedules. An initial study of 699 patients showed that single-dose ondansetron 32 mg IV was superior to both the 8 mg IV single-dose and to 3 consecutive doses of 0.15 mg/kg IV. 22 However, other trials compared these ondansetron-dosing regimens and found no significant difference in antiemetic response between singledose regimens (eg, 8 to 32 mg given once) and multiple-dose regimens (eg, 0.15 mg/kg given every 4 hours for Volume 36, March 2001

4 Determine the emetogenic Level of each antineoplastic agent in the regimen. Identify the most highlyemetogenic agent in the combination. Use the emetogenic Level for this agent as the starting point for the regimen s emetogenicity. Adjust the emetogenic potential of the regimen. Make no adjustment for Level 1 agents. Example: Level 3 Level 1 Level 3 Increase by 1 level if one or more Level 2 agents are included. Examples: Level 2 Level 2 Level 2 Level 3 Level 3 Level 2 Level 4 Level 3 Level 2 Level 2 Level 4 Increase by 1 level for each Level 3 or Level 4 agent included: Examples: Level 3 Level 3 Level 4 Level 3 Level 3 Level 3 Level 5 Level 4 Level 3 Level 5 Emetogenic Level of Regimen FIGURE 1. Algorithm for calculating the emotegenic potential of combination chemotherapy regimens. Note: The calculated potential will never exceed Level 5, the maximum emetogenicity level. Source: Hesketh PJ et al. 2 Hospital Pharmacy 283

5 Therapeutic Options in Managing CINV in Adults Drug Class Specific Agents Mechanism of Action Adverse Effects Typical Uses Common Adult Doses SEROTONIN (5-HT 3 ) Dolasetron (Anzemet) Blocks serotonin (5-HT 3 ) Headache, diarrhea, RECEPTOR Use: Acute CINV gut receptors to prevent constipation, hypertension, ANTAGONISTS Dose : 100 mg IV/PO or peripheral stimulation of the hypotension, dizziness, 1.8 mg/kg IV once prior to CTZ by afferent neurons rare electrocardiograph chemotherapy. Give undiluted changes drug IV over 30 seconds. If diluted, give IV over 15 minutes. Granisetron (Kytril) Use: Acute CINV Dose : 1 2 mg IV/PO; 0.01 mg/kg IV once prior to chemotherapy. Give undiluted drug IV over 30 seconds. If diluted, give IV over 5 minutes. Ondansetron (Zofran) Use: Acute CINV Dose : 8 32 mg IV or 0.15 mg/kg IV once before chemotherapy. Give IV doses > 4 mg over 15 minutes. CORTICOSTEROIDS Dexamethasone (Decadron) Unknown; may modify Insomnia, agitation, capillary permeability in the psychosis, GI irritation, Use: Acute* CINV CTZ, decrease gut inflam- hyperglycemia, Dose : 8 20 mg IV/PO prior to mation, reduced sensitivity hypokalemia, perineal chemotherapy of the 5-HT 3 receptor, or burning with rapid stabilize intracellular infusion, increased Use: Delayed* CINV membranes [lysosomes]). appetite Dose : 4 8 mg given q12h for up to 4 days after chemotherapy Methylprednisolone sodium succinate (Solu-Medrol) Use: Acute* CINV Dose : mg IV prior to chemotherapy SUBSTITUTED Metoclopramide (Reglan) Dopamine (D 2 ) receptor EPS, sedation, akathesia, BENZAMIDES antagonist and a 5-HT 3 recep- diarrhea, hypotension Use: Acute CINV tor antagonist at high doses. Dose : 1 3 mg/kg IV once prior Increases gastric emptying to chemotherapy Use: Delayed* CINV Dose : mg/kg OR 20 mg PO Q6H for 4 days following chemotherapy Use: Breakthrough* CINV Dose : mg IV/PO q6h PRN TABLE 2 Key: See page 286 (continued) 284 Volume 36, March 2001

6 Therapeutic Options in Managing CINV in Adults Drug Class Specific Agents Mechanism of Action Adverse Effects Typical Uses Common Adult Doses NEUROLEPTICS Dopamine (D 2 ) receptor EPS, sedation, akathisia, antagonist in CTZ. Blocks dizziness, postural hypo- Phenothiazines Prochlorperazine (Compazine) afferent signals to the vomiting tension, tachycardias, center. elevated LFTs, agranulo- Use: Breakthrough CINV cytosis, lowered seizure Dose : threshold IR: 5 10 mg PO q4 6h PRN SR: mg PO q10 12h PRN Injectable: 5 20 mg IV/IM q4h PRN Suppositories: 25 mg PR q4 6h PRN Use: Delayed*CINV Dose : SR: mg PO q12h for 4 days after chemotherapy TABLE 2 CONTINUED Butyrophenones Droperidol (Inapsine) Use: Breakthrough* CINV Dose : mg IV/IM q3 4h PRN Use: Acute* CINV Dose : mg IV/IM before chemotherapy Haloperidol (Haldol) Use: Breakthrough* CINV Dose : 1 3 mg PO/IV/IM q4h PRN Use: Acute* CINV Dose : 1 3 mg PO/IV/IM before chemotherapy BENZODIAZEPINES Alprazolam (Xanax) Unknown mechanism of Sedation, prolonged Use: Anticipatory* CINV antiemetic activity. Anxiolytic, amnesia, dizziness, Dose : mg PO prior to anamnesitic activity, and CNS disorientation, paradoxical chemotherapy depression may contribute CNS excitement to efficacy. Diazepam (Valium) Use: Anticipatory* CINV Dose : 2 5 mg PO/IV prior to chemotherapy and q4 6h PRN Lorazepam (Ativan) Use: Anticipatory* CINV Dose : mg PO/SL/IV prior to chemotherapy and q3 4h PRN Use: Breakthrough* CINV Dose : mg PO/SL/IV q3 4h PRN Key: See page 286 (continued) Hospital Pharmacy 285

7 TABLE 2 CONTINUED Therapeutic Options in Managing CINV in Adults Drug Class Specific Agents Mechanism of Action Adverse Effects Typical Uses Common Adult Doses CANNABINOIDS Dronabinol (Marinol) Unknown. May produce CNS Mood changes, drowsiness, depression, disrupt cortical disorientation, dysphoria, Use: Acute CINV input, or bind opiate receptors euphoria, paranoia, impaired Dose : mg PO q4 6h that indirectly block the memory, dry mouth, scheduled vomiting center increased appetite, allergic reaction in patients Use: Delayed* CINV allergic to sesame oil; Dose : mg PO q4 6h smoking marijuana damages scheduled lungs and is carcinogenic Use: Breakthrough* CINV Dose : mg PO q4 6h PRN ANTIHISTAMINE & Diphenhydramine (Benadryl) Unknown. May block anti- Sedation, dry mouth, ANTICHOLINERGIC Use: Motion sickness histamine-1 and muscarinic constipation, urinary AGENTS Dose : mg PO/IV/IM receptors in the vomiting retention, blurred vision, q3 4h PRN center. Causes CNS sedation palpitations, paradoxical and reduces vertigo. Previously excitation, hypotension; Scopolamine (Transderm Scop) used to treat EPS caused by local irritation with Use: Motion sickness D 2 -antagonists. scopolamine patch Dose : Apply new patch every 72 hours Key (Abbreviations) BID = twice daily; CNS = central nervous system; CTZ = chemoreceptor trigger zone; EPS = extrapyramidal syndromes; GI = gastrointestinal; IM = intramuscular; IR = immediate-release product; IV = intravenous; LFTs = liver function tests; PO = orally administered; PRN = as needed; q12h = every 12 hours; q3 4h = every 3 to 4 hours; q4h = every 4 hours; q4 6h = every 4 to 6 hours; q6h = every 6 hours; SL = sublingual; SR = sustained-release product; TID = 3 times daily Doses obtained from consensus guidelines and clinical trial reports. Recommended doses may not agree with the manufacturer s package insert. *Unlabeled use Sources: Hebel SK, Burnham T 6 ; Mosby s GenRx 7 ; Herrstedt J et al. 50 ; Tortorice PV, O Connell MB 100 ; Wickham R 125 ; Barton-Burke M, et al. 153 doses). 23 Another large trial showed no difference in efficacy between single IV doses of ondansetron 8 mg or 32 mg. 24 Oral ondansetron 24 mg or 32 mg also proved successful when given prior to chemotherapy. Both doses were significantly better than ondansetron 8 mg PO in preventing acute nausea. 25 These trials are helpful, since they define 32 mg as the upper limit of efficacy for ondansetron as a single daily IV or PO dose. However, investigators have not yet determined the usefulness of other ondansetron doses (8 mg, 24 mg, etc) for managing CINV with moderately and highly emetogenic antineoplastic regimens. One study suggested that a standard IV dose of dexamethasone plus IV ondansetron 8 mg, 24 mg, and 32 mg may be equally efficacious for moderately, moderately high, and highly emetogenic regimens, respectively. 26 The trials also help establish the efficacy of ondansetron by the PO route. In general, oral ondansetron produces complete response rates of 42% to 89% in patients receiving moderately to highly emetogenic chemotherapy. 12 As a single agent, ondansetron is of little benefit in preventing delayed CINV with cisplatin, 27,28 particularly more than 2 days after chemotherapy. 29 Combinations of ondansetron 8 mg every 8 hours with dexamethasone reduced the incidence of delayed nausea compared with ondansetron alone, 30 but the addition of ondansetron 8 mg twice daily to dexamethasone did not significantly improve the response to delayed CINV seen with dexamethasone alone in another trial. 31 Ondansetron should not be used as a single agent for delayed CINV, and it should be used in doses of 8 mg twice 286 Volume 36, March 2001

8 TABLE 3 Comparison of 5-HT3 Receptor Antagonists Agent Approval Date / Approved Half-life Dosage Forms AWP ($) Manufacturer Patent Expiration Uses Dolasetron October 1997/ CINV Prodrug: < 10 min 50 mg tablets (Anzemet) March 2007 PONV Hydrodolasetron (active 100 mg tablets Hoechst Marion metabolite): hours 12.5 mg injection, SDV Roussel 100 mg injection, SDV Granisetron December 1993/ CINV 5 9 hours 1 mg tablets (Kytril) December mg injection, SDV SmithKline Beecham 4 mg injection, MDV Ondansetron January 1991/ CINV hours 4 mg tablet or ODT* (Zofran) January 2005 RINV 8 mg tablet or ODT* GlaxoWellcome PONV 24 mg tablets mg/5 ml oral solution mg/2 ml injection, SDV mg injection, MDV mg/50 ml premixed injection Abbreviations AWP = average wholesale price per unit; CINV = chemotherapy-induced nausea and vomiting; MDV = multiple-dose vial; ODT = orally-disintegrating tablet; PONV = postoperative nausea and vomiting; RINV = radiation-induced nausea and vomiting; SDV = single-dose vial *Regular tablets and orally-disintegrating tablets are priced the same and carry identical indications and dosage recommendations. Sources: Mosby s GenRx 7 ; Kytril (granisetron hydrochloride) injection 9 ; Zofran (ondansetron hydrochloride) injection 10 ; Anzemet injection 11 daily (BID) to 3 times daily (TID). Ondansetron is used in increasing doses to match the increasing emetogenicity of the chemotherapy regimen used. No added benefit has been noted with a weight-based dosing schedule that is administered every 4 hours for three doses starting prior to chemotherapy, which typically requires more drug than standard single-dose regimens of 8, 24, or 32 mg prior to chemotherapy. Either a single IV or PO dose of ondansetron prior to chemotherapy is an appropriate route of administration for this product. The oral route is particularly beneficial for patients receiving chemotherapy in the ambulatory setting. For some patients, oral ondansetron given BID following cisplatin may help reduce symptoms of delayed nausea; however many practitioners prefer the use of metoclopramide for delayed CINV based on efficacy and cost. In all cases, practitioners should prescribe ondansetron in combination with dexamethasone to improve antiemetic efficacy in controlling acute or delayed CINV. Granisetron Granisetron, given as a single infusion prior to chemotherapy, is efficacious in preventing acute CINV. 9 Granisetron 0.01 to 0.04 mg/kg IV produces a complete response in 40% to 47% of patients receiving highly emetogenic chemotherapy. 32 Several studies of granisetron 0.04 to 0.16 mg/kg IV also reported complete responses in 57% to 81% of patients. 33 Compared with metoclopramide plus dexamethasone in several other trials, single-agent granisetron (IV or PO) produced similar response rates with fewer significant side effects Some evidence is available that granisetron 1 mg IV is comparable to 3 mg IV for acute CINV. 38 Granisetron 1 mg, or 0.01 mg/kg, is the typical IV dose given prior to chemotherapy. 9 However, because newer studies show granisetron is also effective with PO administration, patients may be treated with granisetron PO at a substantially lower cost than IV therapy. Oral management of CINV with granisetron 2 mg/day PO (1 mg twice daily or 2 mg once daily) produced complete responses in 70 % to 87% of patients in several trials. 12 A direct comparison of granisetron 1 mg PO twice daily or 2 mg PO as a single dose prior to chemotherapy showed no difference between the two regimens in patients receiving moderately emetogenic chemotherapy. 39 Granisetron is not typically used Hospital Pharmacy 287

9 Antiemetic Agents Currently Being Studied in the United States Class and Agents Sponsoring Company Status NK 1 -antagonists CP-122,721 Pfizer Phase II Ezlopitant (CJ-11974) Pfizer Phase II MK-869 Merck Phase IIb SR Sanofi-Synthelabo Phase I BIIF-1149 Boehringer Ingelheim Preclinicals 5-HT 3 receptor antagonists Palonosetron Helsinn Healthcare S.A. Phase III Itasetron (DAU-6214 CL, Boehringer Ingelheim U-98079A) Phase III r-ondansetron Sepracor with Glaxo Preclinicals Substituted benamides r-zacopride Sanofi-Synthelabo Phase IIb Metoclopramide (Emitasol) Questcor and Phase III Roberts Pharmaceutical Source: NDA Pipeline 89 for delayed CINV. One clinical trial (n = 532) compared granisetron 3 mg IM QD with granisetron 3 mg IM QD plus dexamethasone 8 mg IM BID, administering both regimens for 3 days after cisplatin. The addition of dexamethasone significantly increased the rate of complete antiemetic responses to 78.9% (vs 58% with granisetron alone). 40 A similar study showed no additional improvement in delayed CINV when granisetron 1 mg PO QD was added to dexamethasone for 7 days after cisplatin. 41 When single-agent granisetron was compared with methylprednisolone plus granisetron or methylprednisolone plus metoclopramide, the highest complete response rates occurred in the corticosteroid groups. Granisetron alone provided the least protection against delayed CINV. 42 This trial suggests that metoclopramide plus dexamethasone is a better choice than granisetron for preventing delayed CINV, based on efficacy and cost. Dolasetron Dolasetron is the newest 5-HT 3 TABLE 4 (NDA filing planned for 2001) receptor antagonist available in the US. Although there are fewer published studies with dolasetron than with the previously discussed agents, its efficacy has been demonstrated in numerous clinical trials. The recommended dose is 100 mg IV or PO, or 1.8 mg/kg by either route, prior to chemotherapy. 11 A pooled analysis of 14 clinical trials demonstrated that fixed doses produce an antiemetic response comparable to weight-based dosing and may be more convenient for health care systems. Administration of dolasetron 100 mg IV prior to chemotherapy produced the highest rate of complete responses (53%), compared with doses ranging from 50 mg to 200 mg. 43 Similar to other 5-HT 3 receptor antagonists, the addition of dexamethasone significantly increases antiemetic response. Patients receiving several days of fractionated cisplatin therapy were treated with either dolasetron 100 mg IV alone or in combination with dexamethasone 20 mg IV, given each day prior to chemotherapy administration. The complete response rate was 72.9% in the combination group and 40.8% with dolasetron alone. 44 Clinical trials have evaluated the effects of dolasetron PO in doses ranging from 25 mg to 200 mg. In patients receiving moderately to highly emetogenic chemotherapy, dolasetron efficacy plateaus at approximately 100 mg PO. Higher doses provide no additional benefit. 12 Class Summary The 5-HT 3 receptor antagonists are equally efficacious in preventing acute CINV when given in the recommended doses. In clinical trials, the agents produced similar antiemetic responses and adverse reactions. 38,45 48 Head-to-head comparisons have shown approved doses of granisetron, ondansetron, and tropisetron to be equivalent for both moderately and highly emetogenic chemotherapy regimens. In general, the addition of dexamethasone significantly increases the overall efficacy of ondansetron, granisetron, and dolasetron in clinical trials. 38 Compared with alternative agents, the selective 5-HT 3 receptor antagonists produce fewer serious adverse effects. Their primary adverse effect is headache, occurring in 14% to 24% of patients. 6 Other possible side effects include either diarrhea (1% to 12%) or constipation (3% to 4%). 11,13,33 These adverse effects are typically manageable and generally do not require discontinuation of therapy. Cardiac arrhythmias and electrocardiograph (ECG) changes are the major serious adverse effects of the 5- HT 3 receptor antagonists and have been reported rarely with all the available agents. 6,8 Sinus bradycardia and tachycardia have each been reported in less than 5% of patients treated with dolasetron. 11 Arrhythmias have been reported rarely with granisetron and ondansetron, although incidence has not been determined. 9,10 While the risk of cardiac effects is similar with all 288 Volume 36, March 2001

10 TABLE 5 Nonpharmacologic Therapy of CINV: Online Resources For Patients Website Address Site Sponsorship University of Minnesota Cancer Center National Cancer Institute National Cancer Institute Huntsman Cancer Institute University of Pennsylvania Oncology Center of Central Baltimore Royal Marsden Cancer Centre, United Kingdom three agents, these side effects have been evaluated more fully with dolasetron. Dolasetron has been associated with prolonged cardiac conduction intervals, but these changes are usually self-limiting and have not been associated with cardiovascular toxicity. The incidence of dolasetron-induced ECG changes is proportional to serum concentrations of active drug. The ECG typically returns to normal as drug levels decline. 49 Controversy with 5-HT 3 Receptor Antagonists Several controversies surround the clinical use of the 5-HT 3 receptor antagonists, making it difficult to select the most appropriate agent for institutional or individual use. Although the agents are comparable in efficacy, no trial has specifically addressed exact milligram to milligram equivalence. Preclinical trials provided information about the doses recommended in the product labeling. But these are not necessarily the same doses used in clinical practice, especially as new data become available from Phase IV clinical trials. For example, because lower standard doses have demonstrated efficacy, few centers now use the weight-based dosing described in the package labeling. The dosage regimens recommended for granisetron and ondansetron in the US differ from those used in Europe. In the US, higher ondansetron doses and lower granisetron doses are typically used. Many trials address the dose and schedule of the 5-HT 3 receptor antagonists for certain chemotherapy regimens, but the appropriate dosage regimens for thousands of other combination chemotherapy regimens has not been studied. Additionally, very few clinical trials have addressed whether dosage modifications are necessary based on individual patient characteristics. Cost is another controversial issue with the 5-HT 3 receptor antagonists (see Table 3 for a comparison of the agents costs). Pharmacoeconomic analyses are difficult to perform because average wholesale prices rarely match the institution-specific contract prices. Another institution may not realize the cost savings reported with preferential use of one agent at a different institution. In order to find the best method for minimizing costs with 5-HT 3 receptor antagonists, additional clinical trials are necessary to further define comparative efficacy and dosing. With this information, an institution will be able to select for its fomulary a single 5-HT 3 for the management of CINV based on relative efficacy and cost. Corticosteroids The antiemetic potential of corticosteroids was first recognized when researchers noticed a decreased incidence of CINV in patients receiving steroid-containing regimens compared with similar regimens without steroids (i.e., MOPP vs. MOP). 50 Their exact mechanism of antiemetic activity is not known. Several hypotheses have been proposed; these include decreased permeability of the CTZ, local anti-inflammatory effects in the GI tract, reduced concentrations of serotonin in neural tissues, and stabilization of intracellular lysozome membranes resulting in reduced serotonin release. 50,51 In addition, corticosteroids potentiate the efficacy of other antiemetic agents, perhaps by altering the drug-receptor interaction or sensitizing specific receptors. 51,52 Corticosteroids are generally used for the prevention of acute and delayed CINV. They are recommended in combination with a 5-HT 3 receptor antagonist for moderately to highly emetogenic chemotherapy. 1,53 55 The rationale for such combinations is that their efficacy is increased significantly compared with use of a 5-HT 3 receptor antagonist alone. In patients receiving highly emetogenic regimens, 40% to 60% of patients have complete control with only a 5-HT 3 receptor antagonist and 60% to 90% have complete control with the combination of a corticosteroid and a 5-HT 3 receptor antago- Hospital Pharmacy 289

11 TABLE 6 Summary of Consensus Guidelines for the Treatment of Acute and Delayed CINV in Adults Recommendations Available in Available in Available in MASCC ASHP ASCO Guidelines? Guidelines? Guidelines? Acute High-dose cisplatin 5-HT 3 antagonist + corticosteroid Yes Yes Yes Acute Low-dose cisplatin in repeated daily doses 5-HT 3 antagonist + corticosteroid on each day of therapy Yes NR Yes Acute Non-cisplatin containing regimens with high emetogenic potential 5-HT 3 antagonist + corticosteroid Yes Yes Yes Acute Chemotherapy regimens with moderate emetogenic potential 5-HT 3 antagonist + corticosteroid NR Yes Yes Acute Chemotherapy regimens with low emetogenic potential No antiemetic prophylaxis recommended for low emesis risk NR NR Yes Corticosteroids may be used for prophylaxis if emetic risk NR Yes Yes is 10% to 30% Prochlorperazine may be used for prophylaxis NR Yes NR Delayed Cisplatin therapy Dexamethasone + either metoclopramide or 5-HT 3 Yes Yes Yes antagonist Delayed Non-cisplatin chemotherapy with potential for delayed CINV Single-agent dexamethasone Yes NR Yes Dexamethasone + 5-HT 3 antagonist Yes Yes Yes Dexamethasone + prochlorperazine NR Yes Yes Anticipatory CINV Benzodiazepines including alprazolam Yes NR NR Systematic desensitization and hypnosis Yes NR Yes Rescue antiemetic treatment for therapeutic failure All chemotherapy recipients should have PRN antiemetics NR Yes NR available Metoclopramide, neuroleptics, corticosteroids, lorazepam, or NR Yes NR droperidol for treating established CINV Vomiting despite optimal prophylaxis, consider adding an NR NR Yes antianxiety agent and possibly substituting or adding a dopamine receptor antagonist such as metoclopramide. Miscellaneous recommendations Patients should be counseled on the appropriate use of NR Yes NR antiemetics and expectations of therapy For multiple-day chemotherapy regimens, daily antiemetic NR NR Yes doses for single-day chemotherapy should also be used daily Abbreviations ASCO = American Society of Clinical Oncology s Recommendations for the Use of Antiemetics; ASHP = American Society of Health-System Pharmacy Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting, Commission on Therapeutics; MASCC = Multinational Association of Supportive Care in Cancer, Antiemetic Subcommittee Perugia Consensus Conference; NR = No recommendation made for the specified treatment in the guideline PRN = as needed Sources: ASHP Commission on Therapeutics 1 ; Gralla RJ, et al. 53 ; Osoba D et al. 54 ; Antiemetic Subcommittee Volume 36, March 2001

12 Checklist for Educating Patients About Chemotherapy-induced Nausea and Vomiting INFORMATION ABOUT SYMPTOMS Definitions of nausea Possible causes of nausea When to contact the prescriber and vomiting and vomiting! Nausea is a sick or uncomfortable! Some chemotherapy drugs! Whenever you are worried feeling in the stomach. symptoms may start right after a! If you have questions about! Vomiting is a strong contraction of treatment or be delayed for 8 to 24 this side effect the stomach muscles that forces the hours. These symptoms may last a! Call immediately if you experience stomach contents out through the few hours or up to 5 days. any of the following: mouth.! Anxiety or extreme worry can cause Nausea or vomiting for >1 day! Nausea can occur without vomiting nausea or vomiting before treatment and are unable to keep liquids and vomiting can occur without even begins down nausea! Other medications, including Symptoms of dehydration, diethylstilbestrol and pain medications such as decreased urination,! Radiation, especially to the abdomen dizziness or light-headedness, (belly) or pelvis dry mouth, or increased thirst! Cancer itself Bloody emesis or coffeegrounds-like emesis PHARMACOLOGIC STRATEGIES FOR SYMPTOM MANAGEMENT General information about antiemetics Specific information for individual antiemetics! Take medications for preventing nausea and vomiting before the symptoms! Proper medication dose appear and frequency! Take the dose of antiemetic medication that is prescribed.! Common medication side effects! Ask the prescriber or pharmacist before changing the dose if you think! Other medications to avoid you need more or less antiemetic medication.! Other precautions NONPHARMACOLOGIC STRATEGIES FOR SYMPTOM MANAGEMENT How to decrease or prevent symptoms What to do after vomiting Dietary changes: Other Ideas:! Avoid eating favorite foods while! Have friends or family members! Clean your mouth by rinsing with nauseated. Also avoid sweet, spicy, prepare meals whenever possible. water, brushing your teeth, or fatty, or greasy foods. If you must cook, prepare and gargling. Clean your throat by! Eat smaller meals more often so freeze meals in advance for days taking a sip or two of water. you don t feel too full. Eat slowly, when you are ill.! Do not eat or drink more than a chewing food completely so it! Breathe deeply and slowly few mouthfuls/sips while you are digests easily. If you do not have through your mouth when nauseated. vomiting and for several hours mouth sores or a dry mouth,! Open a window and let in fresh air. Avoid afterward. Drink small sips of clear and you are nauseated in the eating in a stuffy or very warm room. liquids when your stomach settles. morning, you can eat dry foods! Wear loose-fitting clothes when eating.! Drink liquids instead of eating (cereal, toast, crackers) before Rest in a chair after eating. solid food to let your stomach rest. getting up. Wait at least 2 hours before lying flat. Try apple juice, clear soups, gelatin! Drink liquids an hour before or! Sleep through periods of nausea if you can. water, ginger ale, grape juice, after mealtime instead of with meals.! Do something you enjoy to distract lemon-lime soda, popsicles, or tea. Drink cold or chilled liquids. you from your symptoms. Your stomach may tolerate flat! Suck on ice cubes, mints, or hard! Ask about relaxation techniques to sodas more easily than sugarless candies. Freeze liquids you prevent anticipatory nausea, such fizzy ones. like into cubes. as biofeedback, acupressure, hypnosis,! Drink more fluids than normal! Avoid eating or drinking for several imagery, and rhythmic breathing. to replace fluid lost when hours before emetogenic you vomit. chemotherapy.! Avoid sights or smells that make you nauseated. Eat foods cold or at room temperature so they do not smell as strong. Do not eat in rooms with strong cooking odors. Sources: Beckwith MC, Tyler LS 154 ; Chemotherapy and You 155 TABLE 7 Hospital Pharmacy 291

13 Determine risk factors for CINV: Assess patient and chemotherapeutic regimen before each chemotherapy cycle/dose Risk factors for or history of anticipatory CINV? No Yes Give lorazepam mg PO/SL/IV prior to chemotherapy and PRN Select regimen with best reported efficacy and lowest acquisition cost High Emetogenic Potential (Level 4 or Level 5) Give a 5-HT 3 receptor antagonist PLUS a corticosteroid 1 dose before each daily chemotherapy dose: Ondansetron 8 or 32 mg IV/PO OR Granisetron 1 mg IV/PO OR Dolasetron 100 mg IV/PO PLUS Dexamethasone mg IV/PO For cisplatin-based regimens, add a scheduled regimen for delayed CINV: Metoclopramide 20 mg PO/IV q6 hrs 4 days PLUS Dexamethasone 8 mg PO/IV BID 2 days, then 4 mg PO/IV BID 2 days Moderate Emetogenic Potential (Level 3) Give a 5-HT 3 receptor antagonist PLUS a corticosteroid 1 dose before each daily chemotherapy dose: Ondansetron 8 PO OR Granisetron 1 mg PO OR Dolasetron 100 mg PO PLUS Dexamethason 10 mg PO Low Emetogenic Potential (Level 1 or Level 2) No prophylactic antiemetic regimen required. Ensure patient has PRN antiemetics for breakthrough CINV, such as prochlorperazine or lorazepam Counsel patient on antiemetic use and self-care. Assess patient s response: 1. Number of vomits 2. Severity of nausea 3. Effect on quality of life 4. Need for rescue antiemetic therapy 5. Compliance with prophylactic antiemetics 6. Side effects of antiemetics Determine cause and timeframe of failure, if possible. Modify regimen as needed: 1. Increase dose of same antiemetics 2. Switch to alternate antiemetic agent 3. Add another antiemetic to regimen 4. Add regimen for delayed CINV 5. Correct other causes of nausea and vomiting other medications or diseases 6. Add regimen for anticipatory CINV Success or Failure? Treatment Failure Treatment Success Continue initial antiemetic regimen. FIGURE 2. Proposed treatment algorithm for management of CINV Sources: ASHP Commission on Therapeutics 1 ; Gralla RJ et al. 53 ; Osoba D et al. 54 ; Fauser AA et al. 61 ; Nolte MJ et al. 134 ; Berard CM, Mahoney CD Volume 36, March 2001

14 nist. 56 Dexamethasone (Decadron), betamethasone, and methylprednisolone (Solu-Medrol) have all been studied for CINV and appear to be equally effective. 52 However, dexamethasone is the most commonly used corticosteroid for this indication Clinical trials have found no significant differences in antiemetic efficacy between low- and high-dose corticosteroid regimens. Methylprednisolone 40 mg TID is as effective as 125 mg TID and dexamethasone 8 mg IV is as effective as 32 mg. For acute CINV, dexamethasone doses of 10 mg or 20 mg are typically used in clinical practice Scheduled regimens of dexamethasone are also effective for preventing delayed CINV after cisplatin therapy. Dexamethasone is effective when used alone or in combination with another antiemetic. A common regimen for delayed CINV is dexamethasone 8 mg PO BID for 2 days followed by 4 mg PO BID for 2 days, either alone or given with metoclopramide or a 5-HT 3 receptor antagonist. 40 The adverse effects of corticosteroids may prove intolerable for some patients. Patients who develop psychosis, severe hyperglycemia, or cataracts should not receive corticosteroids for future antineoplastic courses. Most chemotherapy regimens require only occasional corticosteroid use, which is not associated with the risks of chronic therapy (eg, bone fracture or immunosupression). 56 Most adverse effects of short courses of corticosteroids are tolerable, and dexamethasone has the added benefit of PO and parenteral routes, both available at a low cost. 7 Metoclopramide (Substituted Benzamides) Metoclopramide (Reglan) is the only substituted benzamide available in the US. 50 At doses used for increasing gastric motility in patients with gastroparesis, metoclopramide inhibits both central and peripheral dopamine receptors. The drug may also sensitize the GI tract to acetylcholine. 7 At higher doses, metoclopramide competes for peripheral 5-HT 3 receptors, which may account for the drug s efficacy in cisplatininduced CINV. 12 Initial studies in dogs established the antiemetic efficacy of metoclopramide 1 to 3 mg/kg IV given prior to cisplatin infusions. 57,58 Based on this information, Gralla et al. conducted two trials comparing the effects of metoclopramide 2 mg/kg IV with placebo and with prochlorperazine 10 mg IV. Metoclopramide significantly reduced the number of vomiting episodes compared with either alternative treatment. 57 Other studies established the efficacy of metoclopramide 1 to 3 mg/kg IV, given either as repeated bolus doses or as a continuous infusion, for managing cisplatin-induced CINV. When given as a single agent, the average complete response rate for metoclopramide ranges from 20% to 40%. 59 The combination of metoclopramide plus dexamethasone, with either agent given IV or PO, was considered the gold standard for cisplatininduced CINV by In one study, metoclopramide PO effectively reduced the symptoms of delayed CINV after cisplatin. Metoclopramide controlled delayed nausea significantly better than ondansetron PO, although both drugs caused similar reductions in vomiting. 60 The primary role of metoclopramide today is for the prevention of delayed CINV after cisplatin. The usual regimen is metoclopramide 20 mg PO four times daily for 4 days, 55 often in combination with dexamethasone. Another possible role for metoclopramide is in patients with CINV despite prophylaxis in previous chemotherapy cycles or in patients who cannot tolerate their initial prophylactic regimen. In these cases, high-dose metoclopramide (2 to 3 mg/kg) may be substituted in or added to the preventative regimen, whichever is most appropriate. 53,61 Advantages of metoclopramide include multiple effective routes of administration, extensive clinical efficacy data, and low acquisition cost. 7 Low-dose metoclopramide (0.5 mg/kg or 10 to 20 mg/dose) 53,54 rarely produces extrapyramidal symptoms (EPS) such as akathisia, trismus, oculogyric crisis, and dystonic reactions. 52,59 At higher doses used for preventing CINV with highly emetogenic regimens, EPS occurs in up to 30% of patients under 30 years old, but only in 5% to 10% of older patients. 59 Extrapyramidal symptoms can often be prevented or reversed with a diphenhydramine 25 to 50 mg IV or IM. 57,59,62 Diarrhea also occurs frequently (10% to 20%) with high-dose metoclopramide and may be bothersome to patients. 59 Phenothiazines and Butyrophenones Two chemical classes of antipsychotic agents have antiemetic properties, the phenothiazines and butyrophenones. Both classes block dopamine (D 2 ) receptors centrally and have a higher affinity than metoclopramide for these receptors. 50 The phenothiazines, chlorpromazine (Thorazine) and prochlorperazine (Compazine), are successful in preventing and treating CINV associated with chemotherapy agents with low to moderate emetogenic potential. The butyrophenones, droperidol (Inapsine) and haloperidol (Haldol), are also effective in the prevention and treatment of CINV from mildly emetogenic regimens. 1,63,64 In one study evaluating acute CINV, there was no efficacy difference between prochlorperazine, haloperidol, or droperidol given prophylactically before cisplatin. 65 Hospital Pharmacy 293

15 Although few clinical trials have studied prochlorperazine plus dexamethasone for the prevention of delayed CINV, the combination appears to be effective. 66 Complete responses have been reported in 70% to 100% of patients. 66,67 One clinical trial reported that the combination of prochlorperazine for 2 to 3 days plus dexamethasone for 5 days was more effective than granisetron alone, given as a single dose before chemotherapy, for cisplatin-induced delayed CINV. 68 The primary role of these drugs is in the treatment of breakthrough CINV, either alone or in combination with other antiemetics. 1,54 Most chemotherapy patients should receive a supply to use on an as-needed ( PRN ) basis. The phenothiazines and butyrophenones may also be used to prevent CINV due to low emetogenicity antineoplastics. 1 In adults who cannot tolerate corticosteroids, prochlorperazine is an alternative prophylactic agent prior to mildly or moderately emetogenic chemotherapy. Prochlorperazine may be substituted for metoclopramide and used in combination with dexamethasone in prophylactic regimens for delayed CINV, although this use is typically reserved for patients with metoclopramide-intolerance. 1 These drugs may also be useful add-on options in patients whose initial antiemetic therapy fails. These agents are marketed in multiple dosage forms, are available generically, and have low acquisition costs. 7 Adverse effects limit the use of these agents. Both the phenothiazines and the butyrophenones can cause EPS, agitation, and significant sedation Again, EPS are usually more common in younger adults and generally respond to treatment or prophylaxis with diphenhydramine. 3 Orthostatic hypotension has also been reported with these agents, particularly with IV prochlorperazine administration. 69,71 Benzodiazepines Benzodiazepines were initially used to reduce the adverse effects of high-dose metoclopramide. 50 The exact mechanism of antiemetic action is unknown, but it may be related to their anxiolytic, amnestic, and sedative effects. 72 Benzodiazepines may also have weak, direct antiemetic effects on the limbic system and the cerebral cortex. 1,73 Both lorazepam (Ativan) and diazepam (Valium) have been studied for the management of CINV, given in combination with prochlorperazine. 74,75 Alprazolam (Xanax) is also effective in reducing CINV and has been studied both alone 76 and in combination with other antiemetics. 61 Most studies have evaluated the benzodiazepines for preventing anticipatory CINV. In this setting, efficacy has been proven for all three agents. 1,55 Lorazepam is generally considered the preferred agent, both because there is a larger body of published clinical data and because it has no active metabolites. 1,6,53 In one study of 32 cisplatin-treated patients, lorazepam to 0.5 mg/kg IV prevented anticipatory CINV in all patients. Thirteen patients could not even recall receiving the cisplatin infusion. 77 Similarly, anticipatory and acute CINV were significantly reduced in patients with lorazepam compared with placebo, when both treatments were given in combination with metoclopramide and dexamethasone. 78 Compared with chemotherapy courses without lorazepam premedication, patients reported significantly less anxiety with these courses and preferred lorazepam slightly more than placebo. 74 The primary role of benzodiazepines is for anticipatory CINV, since they may prevent development of the conditioned response. 1 These agents can significantly reduce the symptoms of anticipatory CINV when given before chemotherapy, especially in patients with an increased risk of nausea. They may also be helpful to patients who have nausea associated with anxiety. In addition, lorazepam is recommended for adjunctive use in patients with breakthrough CINV. 1,53 Lorazepam is available generically, is relatively inexpensive, and may be administered by several routes, including PO, IV, IM, and sublingual (SL). 7 No special dosage form is available for SL administration; the PO tablet is simply placed under the tongue and allowed to dissolve. 7,79 Adverse effects of the benzodiazepines include sedation and shortterm retrograde amnesia. 6,7 While these effects are beneficial in preventing anticipatory CINV, they may adversely impact the patient s functioning immediately after the chemotherapy visit. Patients may not be good candidates for benzodiazepine therapy if they must drive home from the chemotherapy visit or operate heavy machinery later that day. 7 Miscellaneous Agents Cannabinoids Dronabinol (delta-9-tetrahydrocannabinol, Marinol) is the only prescription cannabinoid available in the US. It is structurally and pharmacologically similar to the active component of marijuana. Dronabinol acts by suppressing higher brain centers that stimulate nausea and vomiting. The cannabinoids, dronabinol and nabilone, are helpful for preventing CINV from mildly emetogenic chemotherapy, but are of little use for moderately to highly emetogenic regimens. 80,81 In clinical trials, dronabinol was more effective than placebo. Dronabinol efficacy was equivalent or superior to both prochlorperazine and low-dose metoclopramide. 82,83 No data shows that marijuana has improved efficacy or safety over dronabinol. The cannabinoids may be used for acute CINV in patients who are intolerant or refractory to 5-HT 3 receptor antagonists and corticosteroids. 53 They 294 Volume 36, March 2001