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									Emerging Drug List                                                               CANADIAN COORDINATING
                                                                                      OFFICE FOR HEALTH
                                                                                 TECHNOLOGY ASSESSMENT
APREPITANT         FOR    NAUSEA FROM CHEMOTHERAPY

                                                                                     NO. 50     SEPTEMBER 2003
Generic (Trade Name):    Aprepitant (Emend®)

      Manufacturer:      Merck & Co., Inc.

          Indication:    In the US, aprepitant, when used with other antiemetic agents, is indicated for the treat-
                         ment of acute and delayed nausea due to highly emetogenic chemotherapy (including
                         cisplatin).1

 Current Regulatory      Aprepitant was approved by the US Food and Drug Administration (FDA) on March 26,
            Status:      2003 and was launched on April 14, 2003.2 Aprepitant is now under review by Health
                         Canada and a potential Canadian marketing date has not been established (Dr. Ernest
                         Pregent, Merck Frosst Canada Ltd., Kirkland, Quebec: personal communication, 2003
                         May 20).

         Description:    Aprepitant is a substance P or neurokinin 1 (NK1) antagonist. Substance P is one of four
                         tachykinins found in neurons that are involved in the induction of vomiting.1 Substance P
                         mediates its biological effects through the NK1-receptor. Aprepitant has little or no
                         affinity for other emetogenic receptors including serotonin (5-HT3), dopamine and
                         corticosteroid.1 Aprepitant has been evaluated for its antiemetic activity when used with
                         ondansetron (a 5-HT3 receptor antagonist) and dexamethasone (a corticosteroid).1

 Current Treatment:      Agents that are used for treating or preventing chemotherapy-induced nausea and vomiting
                         (CINV) include 5-HT3 antagonists (dolasetron, granisetron, ondansetron), corticosteroids
                         (dexamethasone, methylprednisolone), metoclopramide, neuroleptics (prochlorperazine,
                         droperidol, haloperidol), benzodiazepines (alprazolam, diazepam, lorazepam), cannabi-
                         noids (nabilone, dronabinol) and antihistaminics or anticholinergics (diphenhydramine,
                         scopolamine).3,4 The standard treatment for acute nausea and vomiting associated with
                         highly emetogenic chemotherapy combines a 5-HT3 antagonist with a corticosteroid.
                         Delayed nausea and vomiting due to highly emetogenic chemotherapy is managed with
                         one of the following combinations: dexamethasone with metoclopramide, a 5-HT3
                         antagonist or prochlorperazine; or dexamethasone alone.3,4

                Cost:    The cost of aprepitant in the US is US$250 for a standard three-day course of therapy
                         (125 mg on day 1 and 80 mg daily on days 2 and 3).2 There is no Canadian price for
                         aprepitant at this time.

           Evidence:     The American approval of aprepitant was based on two multicentre, randomized, double-
                         blind, parallel group, active controlled trials. The results of these trials have not been
                         published, but detailed information was presented in the new drug application, which was
                         accessed through the FDA's web site.5,6 Over 1,000 subjects were included in the analysis




               The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
  is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List                                                               CANADIAN COORDINATING
                                                                                      OFFICE FOR HEALTH
                                                                                 TECHNOLOGY ASSESSMENT
APREPITANT        FOR    NAUSEA FROM CHEMOTHERAPY


                        (n=530 in protocol 052 and n=569 in protocol 054). The studies evaluated the efficacy
                        of aprepitant in combination with dexamethasone and ondansetron for preventing CINV
                        in cisplatin-naive patients who received cisplatin (dosage >70 mg/m2). Other chemotherapy
                        was permitted. Emetogenic agents such as doxorubicin and cyclophosphamide had to be
                        administered with cisplatin on day 1 to ensure a consistent emetogenic stimulus. Primary
                        objectives for both studies included complete response (no emesis or rescue medications)
                        for the first 120 hours after the start of cisplatin chemotherapy and safety of the triple
                        therapy. The triple regimen consisted of aprepitant 125 mg PO on day 1 and 80 mg PO
                        daily on days 2 and 3; dexamethasone 12 mg PO on day 1 and 8 mg PO daily on days 2
                        to 4; and ondansetron 32 mg IV on day 1. The standard therapy included dexamethasone
                        20 mg PO on day 1, then 8 mg PO bid on days 2 to 4; and ondansetron 32 mg IV on
                        day 1. A complete response for 120 hours was observed in significantly more subjects in
                        the aprepitant group than in the control group (i.e., 72.7% versus 52.3% in protocol 052
                        and 62.7% versus 43.3% in protocol 054, p<0.001). Aprepitant was also significantly
                        better than control when data were separated for acute and delayed phases. There was
                        a trend towards improved nausea scores with aprepitant, but they did not reach statistical
                        significance in protocol 052 and only a few parameters reached statistical significance
                        in protocol 054.

                        Data on aprepitant for CINV from two other controlled trials have been published. The
                        dosages of aprepitant used in these trials, however, differ from those approved by the
                        FDA, so details from these studies will not be disclosed in this review. In one study, the
                        dosage of aprepitant was 400 mg PO daily for six days.7 In the other study, aprepitant's
                        pro-drug (L-758,298) was given as an intravenous injection on day 1 followed by oral
                        aprepitant 300 mg daily for four more days.8

   Adverse Effects:     Determining the true incidence of adverse effects due to aprepitant is difficult since it
                        was used with ondansetron and dexamethasone in the large clinical trials. Adverse effects
                        that were reported more often with the aprepitant-ondansetron-dexamethasone combina-
                        tion over the ondansetron-dexamethasone combination include abdominal pain, diarrhea,
                        epigastric discomfort, dehydration, dizziness, gastritis, heartburn, anorexia and hiccups.1,5,6
                        Adverse effects were described as mild to moderate in intensity. Drugs that are metabo-
                        lized by CYP450 3A4 or 2C9 should be used with caution by patients taking aprepitant.

     Commentary:        Aprepitant seems to offer a significant advantage for treating vomiting when used with
                        standard therapy (i.e., dexamethasone and a 5-HT3 antagonist). The larger clinical trials,
                        however, failed to show a statistically significant improvement with aprepitant when only
                        nausea was evaluated. The FDA reviewer raised concern about the definition of highly
                        emetogenic doses of cisplatin being equal to or greater than 70 mg/m2. In the ondansetron
                        submission, the highly emetogenic dose of cisplatin was between 100 and 120 mg/m2.




              The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
 is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)
Emerging Drug List                                                                     CANADIAN COORDINATING
                                                                                            OFFICE FOR HEALTH
                                                                                       TECHNOLOGY ASSESSMENT
APREPITANT        FOR    NAUSEA FROM CHEMOTHERAPY


                        Whether the significant reduction in vomiting observed with aprepitant in these studies
                        would be maintained at higher doses of cisplatin is yet to be proven. More research with
                        higher cisplatin doses would be useful in determining aprepitant's place
                        following highly emetogenic chemotherapy.

        References:     1. EMEND® (aprepitant): capsules [product monograph]. Whitehorse Station (NJ): Merck & Co., Inc.;
                           2003. Available: http://www.emend.com/emend/shared/documents/pi.pdf (accessed 2003 May 13).

                        2. FDA approves EMEND® (aprepitant), Merck's new medicine to prevent nausea and vomiting in
                           chemotherapy patients [press release]. Whitehouse Station (NJ): Merck & Co., Inc.; 2003 Mar 26.
                           Available: http://www.merck.com/newsroom/press_releases/product/2003_0326.html (accessed 2003
                           May 13).

                        3. Beckwith MC, Mullin S. Prevention and management of chemotherapy-induced nausea and vomiting:
                           part one. Hosp Pharm 2001;36(1):67-82.

                        4. Beckwith MC, Mullin S. Prevention and management of chemotherapy-induced nausea and vomiting:
                           part two. Hosp Pharm 2001;36(3):280-305.

                        5. Background information regarding EMEND™ (Aprepitant) capsules: Gastrointestinal Drugs
                           Advisory Committee: March 6, 2003 [FDA Advisory Committee briefing information]. Rahway (NJ):
                           Merck Research Labs; 2003. Available:
                           http://www.fda.gov/ohrms/dockets/ac/03/briefing/3928B1_01_Merck%20Backgrounder.pdf (accessed
                           2003 May 13).

                        6. Background information regarding EMEND™ (Aprepitant) capsules: Gastrointestinal Drugs
                           Advisory Committee: March 6, 2003 [FDA memorandum]. Rockville (MD): U.S. Food and Drug
                           Administration; 2003. Available: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3928B1_02_FDA-
                           Emend%20Briefing%20Pkg.pdf (accessed 2003 May 13).

                        7. Campos D, Pereira JR, Reinhardt RR, Carracedo C, Poli S, Vogel C, et al. Prevention of cisplatin-
                           induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dex-
                           amethasone or with dexamethasone alone. J Clin Oncol 2001;19(6):1759-67.

                        8. Van Belle S, Lichinitser MR, Navari RM, Garin AM, Decramer ML, Riviere A, et al. Prevention of cis-
                           platin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-
                           869. Cancer 2002;94(11):3032-41.




                          This series highlights medical technologies that are not yet in widespread use in Canada and that
                           may have a significant impact on health care. The contents are based on information from early
                           experience with the technology; however, further evidence may become available in the future.
                          These summaries are not intended to replace professional medical advice. They are compiled as
                              an information service for those involved in planning and providing health care in Canada.
                                             These summaries have not been externally peer reviewed.

                                                             ISSN 1496-8398 (online only)



              The Canadian Coordinating Office for Health Technology Assessment (CCOHTA)
 is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)

								
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