The Efficacy of RS-25259, a Long-Acting Selective 5-HT 3
`Receptor Antagonist, for Preventing Postoperative Nausea
`and Vomiting After Hysterectomy Procedures
`Jun Tang, MD*, Robert D'Angelo, MD+, Paul F. White, PhD, MD, FANZCA*, and
`Phillip E. Scuderi, MD+
`*Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas,
`Dallas, Texas; and +Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem,
`North Carolina
`
`We evaluated the safety and efficacy of RS-25259, a po-
`tent and long-acting selective 5-HT3 receptor antago-
`nist, for the prevention of postoperative nausea and
`vomiting (PONV) in women undergoing hysterectomy
`procedures. In this randomized, double-blind, placebo
`controlled, dose-ranging study, 218 healthy, consent-
`ing women were assigned to one of the six treatment
`groups: placebo or RS-25259 0.1, 0.3, 1.0, 3.0, or 30
`1-tg/kg. All patients Uillderwent a standardized general
`anesthetic technique. The study medication was ad-
`ministered IV 20-30 min before the end of surgery.
`During the initial 24-h period after surgery, the inci-
`dence of vomiting, the need for rescue antiemetics, the
`time to the first episode of emesis, and administration
`of rescue antiemetic medication, as well as a nausea vi-
`sual analog scale andl verbal categorical scale scores
`were recorded. In addition, recovery times from the end
`of anesthesia and the incidences of perioperative side
`effects were noted. Only 30 1-tg/kg RS-25259 signifi-
`cantly decreased the incidence of vomiting and the
`
`requirement for rescue antiemetics. The largest dose of
`RS-25259 also delayed the time to the first emetic epi-
`sode and reduced the number of treatment failures.
`However, no differences were found in the severity of
`postoperative nausea (versus saline), and postopera-
`tive headaches were more common after the adminis-
`tration of RS-25259 0.3-30 1-tg/kg IV. In conclusion, RS-
`25259 30 p.g/kg IV was effective in reducing the
`incidence of PONV after major gynecologic surgery,
`but the occurrence of headaches with the larger doses of
`RS-25259 is a concern. Implications: RS-25259, a long-
`acting 5-HT3 antagonist, was effective in reducing post-
`operative vomiting only at the largest dose studied
`(30 1-tg/kg). However, RS-25259 had no antinausea ac-
`tivity, and the larger doses were associated with an in-
`creased incidence of headaches in the postoperative
`period.
`
`(Anesth Analg 1998;87:462-7)
`
`N ausea, retching, and vomiting are common com-
`
`plications after major gynecologic surgery (1-3).
`Dehydration, electrolyte imbalance, excessive
`tension on suture lines, venous hypertension, and in-
`creased hematoma formation are secondary problems
`related to persistent or intractable postoperative eme-
`sis (4). Several different classes of prophylactic anti-
`emetics have been administered in an attempt to de-
`crease the incidence of postoperative nausea and
`vomiting (PONV). However, many of the commonly
`
`This work was supported, ln part, by a grant from Syntex, Palo
`Alto, CA.
`Accepted for publication April 29, 1998.
`Address correspondence and reprint requests to Dr. Paul F.
`White, Department of Anesthesiology and Pain Management, Uni-
`versity of Texas Southwestern Medical Center at Dallas, 5161 Harry
`Hjnes Blvd., CS2.202, Dallas, TX 75235-9068. Address e-mail to
`pwhlte@mednet.swmed.edu.
`
`used antiemetics are associated with undesirable side
`effects (5,6).
`Ondansetron, the first 5-ill 3 receptor antagonist, pos-
`sesses antiemetic activity in women who develop intrac-
`table PONV after gynecologic surgery (7). Studies have
`confirmed the efficacy of ondansetron in both the treat-
`ment and prevention of PONV (8,9). However, a meta-
`analysis suggested that the use of orndansetron is asso-
`ciated with an increased incidence of headaches and
`transient elevations in liver enzymes (10).
`RS-25259 is a potent and highly selective 5-HT3
`receptor antagonist (11) that is more effective than
`ondansetron in preventing chemotherapy-induced
`emesis in animals (12). In this preliminary, double-
`blind, dose-ranging study, the efficacy and safety of
`RS-25259 were evaluated when administered prophy-
`lactically to women undergoing major gynecologic
`surgical procedures.
`
`462 Anestlh Analg 1998;87:462- 7
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v_
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1019
`
`

`
`The Efficacy of RS-25259, a Long-Acting Selective 5-HT 3
`Receptor Antagonist, for Preventing Postoperative Nausea
`and Vomiting After Hysterectomy Procedures
`Jun Tang, MD*, Robert D'Angelo, MDt, Paul F. White, PhD, MD, FANZCA", and
`Phillip E. Scuderi, MD+
`*Department of Anesthesiology and Pain Management, University of Texas Southwestem Medical Center at Dallas,
`Dalla~, Texas; and +Department of Anesthesiology, Wake Forest Univ-ersity School of Medicine, Winston-Salem,
`North Carolina
`
`We evaluated the safety and efficacy of RS-25259, a po-
`tent and long-acting selective 5-HT3 receptor antago-
`nist, for the prevention of postoperative nausea and
`vomiting (PONV) in women undergoing hysterectomy
`procedures. In this randomized, double-blind, placebo
`controlled, dose-rmging study, 218 healthy, consent-
`ing women were assigned to one of the six treatment
`groups: placebo or RS-25259 O.l, 0.3, 1.0, 3.0, or 30
`!Lg/kg. All patiP.nto; underwent a standardized general
`anesthetic technique. The study medication was ad-
`ministered IV 20-30 min before the end of surgery.
`During tltt: initial 24-h period after surgery, tl1e inci-
`dence of vomiting, the need for rescue antiemetics, the
`time to the first episode of emesis, and administration
`of rescue antiemetic medication, as well as a nausea vi-
`sual analog scale and verbal categorical scale scores
`were recorded. In addition, recovery times from the end
`of anesthesia and the incidences of perioperative side
`ef!fects were noted. Only 30 J.Lg/kg RS-25259 signifi-
`cantly decreased the incidence of vomiting and the
`
`requirement for rescue antiemetics. The largest dose of
`RS-25259 also delayed the time to the first emetic epi-
`sode and reduced the number of treatment failures.
`However, no differences were found in the severity of
`postoperative nausea (versus saline), and postopera-
`tive headaches were more common after the adminis-
`tration of RS-25259 0.3-30 J.Lg/ kg IV. In conclusion, RS-
`25259 30 !Lg/kg IV was effective in reducing the
`incidenrP. of PONV after major gynecologic surgery,
`but the occurrence of headaches with the larger doses of
`R5-25259 is a concern. Implications: R5-25259, a long-
`adi.ng 5-HT 3 i:lntagunist, wi:ls effective in rt:UU(;ing post-
`operative vomiting only at the largest dose studied
`(30 J.Lg/kg). However, RS-25259 had no antinausea ac-
`tivity, and the larger doses were associated! with an in-
`creased incidence of headaches in the postoperative
`period.
`
`(Anesth Analg 1998;87:462-7)
`
`N ausea, retching, and vomiting are common com-
`
`plications after major gynecologic surgery (1-3).
`Dehydration, electrolyte imbalance, excessive
`tension on suture lines, venous hypertension, and in-
`creased hematoma formation are secondary problems
`related to persistent or intractable postoperative eme-
`sis (4). Several differell!t classes of prophylactic anti-
`emetics have been administered in an attempt to de-
`crease the incidence of postoperative nausea and
`vomiting (PONV). However, many of the commonly
`
`Tilis work was supported, in part, by a grant Jrom Syntex, Palo
`Altu,CA.
`Accepted for publication April 29, 1998.
`Address correspondence and repri.nt requests to Dr. Paul F.
`White, Department of Anesthesiology a.nd Pain Management, Uni-
`versity of Texas Southwestern Medical Center at Dallas, 5161 Harry
`Hines tllvd., CS2.2U2, Uallas, TX 75235-9068. Address e-mail to
`pwhite@mednet.~wmed.edu.
`
`462 Anesth Anal,g 1998;87:462-7
`
`used antiemetics are associated with undesirable side
`effects (5,6).
`Ond ansetron, the first 5-HT3 receptor antagonist, pos-
`sesses antiemetic activity in women who develop intrac-
`table PONV after gynecologic surgery (7). Studies have
`confirmed the efficacy of ondansetron in both the treat-
`ment and prevention of PONV (8,9). However, a meta-
`analysis suggested that the use of ondansetron is asso-
`ciated with an increased incidence of headaches and
`transient elevations in liver enzymes (10).
`RS-25259 is a potent and highly selective 5-HT3
`receptor antagonist (11) that is more effective than
`ondansetron in preventing chemotherapy-induced
`emesis in animals (12). In this preliminary, double-
`blind, dose-ranging st udy, the efficacy and safety of
`RS-25259 were evaluated when administered prophy-
`lactically to women undergoing major gynecologic
`surgical procedures.
`
`e t998 by the International Anesthesia Research Society
`0003-2999/98 I $5.00
`
`Exh. 1019
`
`

`
`ANESTH ANALG
`1998;87:462-7
`
`TANG ET AL.
`THE ANTlEMETIC EFFICACY OF RS-25259
`
`463
`
`Methods
`This randomized, double-blind, placebo-controlled
`study was performed at two medical centers (Univer-
`sity of Texas Southwestern Medical Center in Dallas,
`TX and Wake Forest University Baptist Medical Cen-
`ter in Winston-Salem, NC). After obtaining institu-
`tional review board approval at both medical centers,
`218 ASA physical status I or II consenting women
`undergoing an abdominal or vaginal hysterectomy
`with a standardized general anesthetic techruque were
`enrolled in the study. Exclusion criteria included preg-
`nancy, body weight > 100% of the calculated ideal
`body weight, hypersensitivity to 5-Hf3 antagonists,
`vomiting or retching within 24 h before the operation,
`administration of antiemetic or psychoactive medica-
`tion within 24 h before the operation, a recent history
`of narcotic or alcohol abuse, and preexisting abnor-
`malities involving the renal, hepatic, cardiovascular,
`metabolic, or endocrine systems. Patients were asked
`to provide a detailed medical history and demo-
`graphic information (including age, weight, height,
`alcohol or drug consumption, last menstrual period,
`any history of PONY or motion sickness).
`Because a history of POI\TV is associated with an
`increased risk of PONV after a subsequent operation
`(1), patients were assigned to one of two strata based
`on their history of PONV after general anesthesia.
`Within each strata, patients were randomized to one
`of six prophylactic treatment groups: placebo (saline)
`or 0.1, 0.3, 1.0, 3.0, or 30 ~-tg/kg RS-25259. Each dose of
`study medication was prepared by the hospital phar-
`macy in a total volume of 15 mL of isotonic sodium
`chloride solution and was administered IV over 30 s
`approximately 20-30 min before the end of surgery.
`In the preoperative holding area, patients com-
`pleted a baseline 100-mm visual analog scale (VAS) for
`nausea (0 = no nausea to 100 = maximal nausea) and
`a verbal categorical scale (VCS) (1 = no nausea, 2 =
`mild nausea, 3 = moderate nausea, or 4 -
`severe
`nausea). Midazolam 2 mg IV was used to premedicate
`all p atients. On arrival ii.n the operating room, routine
`monitoring devices consisting of a noninvasive blood
`pressure cuff, pulse oximeter probe, and electrocardio-
`gram were placed. General anesthesia was induced
`with thiopental and an opioid analgesic (either fenta-
`nyl or sulfentanil) and was maintained with isoflu-
`rane, nitrous oxide (N20) in oxygen, and a nondepo·
`larizing neuromuscular blocking drug. Residual
`neuromuscular block was antagonized with neostig-
`mine and glycopyrrolate. After tracheal extubation,
`the patients were transported to the postanesthesia
`care unit (P ACU) where morphine or meperidine was
`administered as needed for postoperative analgesia.
`The anesthetic time (from induction of anesthesia to
`discontinuation of N 20) and the operating time (from
`surgical incision to completion of the last suture) were
`
`recorded. The times at which patients were able to
`follow commands (e.g., squeeze the investigator's
`hand) and were discharged from the P ACU were also
`noted .. Episodes of PONV and admirustration of res-
`cue antiemetics were recorded during the first 24-h
`period after surgery. An emetic episode was defined
`as a single vomiting or retching event or any combi-
`nation of these events separated by less than 1 min.
`Rescue antiemetic medication was administered af-
`ter a repeat emetic episode or at the request of the
`patient. In addition, the time interval to first experi-
`encing an emetic episode or to receiving a rescue
`antiemetic, as well as treatment failures (defined as a
`situation in which the patient experienced a single
`emetic episode or required rescue antiemetic medica-
`tion), were noted. On arrival in the PACU and 1, 2, 4,
`8, 12, 16, 20, and 24 h after the end of anesthesia,
`patients were asked to assess their degree of nausea
`using the VAS and VCS. At the end of the 24-h obser-
`vation period, a VCS was also used to evaluate the
`overall degree of nausea during the postoperative pe-
`riod . Overall patient satisfaction with the control of
`their PONV was assessed using a VCS (1 = very good,
`2 = good, 3 = fair, and 4 = poor}. Finally, all patients
`were contacted 24 h, 3 days, and 14 days after the
`operation and asked the nonspecific question, "Is any-
`thing bothering you?"
`The statistical analysis consisted of a one-way anal-
`ysis of variance (ANOV A) to compare the continuous
`variables among the six treatment groups. If a sigtUf-
`icant difference was noted, Scheffe's multiple compar-
`ison test was performed to determine intergroup dif-
`ferences. A two-way ANOVA was used to analyze the
`repeated measures. Categorical variables were ana-
`lyzed by using the ?- test or Fisher's exact test as
`appropriate. All tests were two-sided, and a P value
`<0.05 was considered statistically significant. Data
`are presented as mean values ±so, numbers, or
`percentages.
`
`ResuHs
`The demographic data for the six treatment groups are
`summarized in Table 1. The six groups were compa-
`rable with respect to age, weight, height, number of
`days since the start of their last menstrual cycle, per-
`centage of patients with a history of PONV and mo-
`tion sickness, and type of hysterectomy procedure
`(i.e., transabdominal versus vaginal). The dosages of
`anesthetic and analgesic drugs administered during
`the intraoperative and postoperative period, the dura-
`tion of anesthesia and surgery, and the time to follow-
`ing ve·rbal commands, and the duration of the PACU
`stay were also similar among all six groups.
`Within the first 2 h after surgery, the incidence of
`vomiting was significantly reduced in patients receiv-
`ing RS-25259 30 p,g/kg IV compared with the groups
`
`Exh. 1019
`
`

`
`464 TANG ET AL.
`THE ANTIEMETIC EFFICACY OF R5-25259
`
`AATESTH ANALG
`1998;87:462-7
`
`Table 1. Demographic Characteristics and Surgical and Recovery Times
`
`Saline
`36
`41 ± 8
`70 ::±: 14
`162 ± 10
`
`0.1
`
`27
`43 ± 9
`76 ::±: 18
`164 ± 7
`
`7
`4
`24
`1
`14
`5
`
`7
`5
`14
`1
`12
`4
`
`0.3
`41
`39 ::±: 7
`70 ± 16
`163 ± 7
`
`RS-25259 (JLg/kg)
`1.0
`35
`39 ::±: 9
`74 ::±: 17
`164 ± 9
`
`3.0
`40
`42 ::±: 8
`73 ± 14
`164 ± 7
`
`12
`6
`23
`0
`14
`3
`
`12
`5
`16
`2
`13
`6
`
`10
`8
`21
`1
`15
`5
`
`30
`
`39
`42 ::±:8
`71 ::±: 13
`162 ± 7
`
`11
`8
`20
`0
`12
`2
`
`n
`Age (yr)
`Weight (kg)
`Height (em)
`Last menstrual period
`0---8 d
`9-16 d
`> 16 d
`UnknO'I'.rn
`Previous PONV
`Previous motion
`sickness
`Intraoperative opioid
`analgesics (IJ.g)
`Fentanyl
`Sufentanil
`Postoperative opioid
`analgesics (mg)
`Morphine
`Meperidine
`Anesthetic time (min)
`Operative time (min)
`Respond to
`commands (min)
`Duration of PACU
`stay (min)
`Values are means =: SD or n.
`PONY "' postoperative nausea and vomiting, PACU ~ poslanesthesia care unit.
`
`271 ± 140
`89 ± 30
`
`304 ::±: 129
`88 ::±: 27
`
`305 ± 92
`86 ± 29
`
`47 ± 35
`283 ± 173
`132 ± 46
`108 ± 39
`10 ± 7
`
`102 ± 34
`
`56 ± 31
`273 ± 102
`147 ::±: 73
`121 :!: 61
`11 ± 6
`
`46 ± 21.
`243 ± 151
`148 ± 64
`122 ± 57
`11±11
`
`101 ::±: 30
`
`102 ± 33
`
`262 ± 94
`78 ±27
`
`242 ::±: 103
`92 ::±: 33
`
`277 ± 113
`86 ± 32
`
`59 ± 25
`221 ± 180
`146 ± 76
`122 ± 72
`12 ::±: 10
`
`60 ± 31
`217 ± 152
`138 ±57
`117 :!: 53
`11 ± 6
`
`56 ± 26
`334 ± 118
`148 ± 71
`120 ± 66
`9±6
`
`101 ± 40
`
`106 ± 33
`
`87 ± 38
`
`receiving saline or RS-25259 0.1 or 1 .0 J.Lg/kg IV
`(Table 2). Similarly, RS-25259 30 J.Lg/kg IV was signif-
`icantly more effective in preventing vomiting within
`the firsit 12 h after surgery than either the saline or
`RS-25259 0.1. f.tg/kg IV. RS-25259 30 ~J.g/kg JV also
`marginally decreased the number of emetic episodes
`within the first 24 h postoperatively compared with
`placebo treatment (P = 0.05). Although the need for
`rescue .antiemetics within the first 2 h was similar
`among all groups, RS-25259 1.0, 3.0, and 30 J.Lg/kg IV
`significantly decreased the antiemetic requirement
`compared with saline within the first 12 h after sur-
`gery. Within the first 24 h after surgery, only the
`30 J..Lg/kg IV dose of RS-25259 significantly reduced
`the antiemetic requirement compared with the saline
`group. In addition, the time to the first emetic episode
`was significantly shorter in patients receiving saline or
`RS-25259 0.1 J.Lg/kg IV compared with those receiving
`30 J.Lg/kg IV RS-25259. Similarly, the mean time to the
`first episode of vomiting was significantly shorter in
`the patients receiving RS-25259 0.1 ~-tg/kg IV than in
`those receiving RS-25259 0.3 J.Lg/kg IV. The percent-
`age of treatment failures was significantly higher in
`the saline group than in the RS-25259 30 J.Lg/kg IV
`group during the first 24 h after surgery (Table 2).
`Among patients with a history of PONV, there were
`no differences in the incidence of vomiting or in the
`
`need for rescue antiemetic medication among the six
`groups (Table 3). However, among patients with no
`history of PONV, RS-25259 30 M-glkg IV was signifi-
`cantly more effective in the prevention of emetic epi-
`sodes within the first 2, 12, and 24 h after surgery, and
`it decreased the need for rescue antiemetic therapy
`within 12 and 24 h after surgery compared with saline.
`RS-25259 1.0 J.Lg/kg IV was also effective in reducing
`the number of emetic episodes and the need for anti-
`emetic rescue medication within 12 h compared with
`saline (Table 4). Of interest, the VAS and VCS scores
`for nausea did not differ among the sh groups (data
`not shown). The overall satisfaction with the control of
`PONV in the first 24 h after surgery was also similar
`(data not presented).
`Finally, the overall incidences of adverse side effects
`were similar among all treabnent groups (Table 5).
`However, more postoperative headaches were noted
`in patients who received larger doses of RS-25259
`(0.3-30 J.Lg/kg) compared with those who received
`saline and the smallest dose of RS-25259 (0.1 J..Lg/kg)
`(P < 0.02).
`
`Discussion
`This clinical study demonstrated that the IV adminis-
`tration of RS-25259 30 J..Lg/ kg 20-30 min before the
`
`Exh. 1019
`
`

`
`ANESTH ANALG
`1998;87:462-7
`
`TANG .liT AL
`THE M-.lTIEMETIC EFFICACY OF RS-25259
`
`465
`
`Table 2. Patients Experiencing Vomiting, Receiving Antiemetic (Rescue) Medication, and Reported as Treatment Failures
`in the First 24 Hours After Surgery
`
`Saline
`36
`].7
`39
`47
`
`0.1
`27
`15
`41
`44
`
`31
`72
`75
`339:!: 319
`234:!: 211
`78
`
`22
`63
`67
`213 = 189
`314 = 308
`70
`
`n
`Vomiting (%)
`0-2h
`0-12h
`0-24 h
`Rescue antiemetics (%)
`0-2h
`0-12h
`0-24h
`Time to first emesis (min)
`Time to rescue antiemetic (min)
`Treatment failures (%)
`Va1ue5 cue percentages or means .= so.
`• P < 0.05 versus saline.
`t P < 0.05 versus R$-25259 0.1 !Lg/kg.
`j P < 0.05 versus RS-25259 l .O 1<g/ kg.
`
`RS-25259 (p.g/kg)
`1.0
`35
`14
`23
`34
`23
`43*
`54
`428 = 507
`381 ± 447
`60
`
`0.3
`41
`10
`24
`32
`22
`56
`61
`637 = 530+
`326 = 264
`63
`
`3.0
`40
`
`13
`23
`30
`
`20
`43*
`53
`475 = 544
`430 ± 473
`58
`
`30
`39
`o•t:t:
`13*+
`26
`
`23
`46*
`49*
`795 = 416*+
`474 ± 330*
`51*
`
`Table 3. Patients with a History of PONY Who
`Experienced Vomiting or Reqtrired Rescue Antiemetic
`Therapy Within 24 Hours After Surgery
`RS-25259 (p.g/kg)
`Saline 0.1 0.3 1.0 3.0 30
`14
`12 14 13 15 12
`1!
`Vomiting(%)
`14
`25 14 31 20
`0
`2h
`36
`50 43 46 27 25
`12 h
`58 50 54 33 42
`43
`24 h
`Rescue antiemetics (%)
`33 29 46 20 33
`29
`2h
`75 79 62 47 67
`79
`12 h
`75 86 62 67 67
`79
`24 h
`PONV = postoperative nausea and vomiting.
`
`Table 4. Patients with No History of PONV Who
`Experienced Emesis or Required Rescue Antiemetics
`Within 21 Hours After Surgery
`
`RS-25259 (J.tg/kg)
`Saline 0.1 0.3 1.0 3.0 30
`22
`15 27 22 25 27
`II
`Vomiting (%)
`8 o•
`18
`5
`2h
`7
`7
`41
`33 15
`9* 20
`12 h
`7*
`50
`33 22 23 28 19*
`24h
`Rescue antiemetics (%)
`32
`6 20 19
`13 19
`2h
`53 44 32• 40 37*
`68
`12 h
`60 48 50 44 41*
`73
`24 h
`POI\'V = postoperative nausea and vomiting.
`' P < 0.05 versus saline.
`
`end of surgery was effective in decreasing emesis in
`women undergoing major gynecologic surgery. How-
`ever, analogous to the recent findings of Tramer et al.
`(10) with ondansetron, larger doses of RS-25250 were
`associated with more headaches. Although the length
`of stay in the P ACU was slightly shorter in the large-
`dose RS-25259 group, this difference was not statisti-
`cally significant. Moreover, the patients' overall satis-
`faction with the control of the PONY symptoms was
`not improved by the administration of RS-25259. Con-
`sidering the more meaningful outcome measures (e.g.,
`recovery times, patient satisfaction), RS-25259 seems
`to be of limited benefit in this high-risk patient
`population.
`The 5-HT3 receptor antagonists are effective in re-
`ducing emesis by acting on both the central and pe-
`ripheral nervous systems (13). Ondansetron has been
`successfully used for both prophylaxis and treatment
`of PONV with few clinically significant adverse effects
`
`(7-9). Although apparently free of activity at histantin-
`ergic, dopaminergic, or cholinergic receptors (14), side
`effects such as chest pain, headaches, and extrapyra-
`midal symptoms have been reported with ondanse-
`tron (15,16) and other 5-HT3 antagonists. Granisetron
`an.d tropisetron, two more recently introduced 5-HT 3
`receptor antagonists that have also been reported to
`decrease emesis after surgical procedures (17,18), pos-
`sess longer elimination haU-life values than ondaru;e-
`tron [9-11 h (19) and 6 - 7 h (20) versus 2.8 ± 0.6 h (21),
`respectively]. However, the long-lasting antiemetic ac-
`tivity associated with granisetron is allegedly due to
`its high affinity for the 5-HT3 receptor (22,23). Of
`interest, Naguib et a!. (24} reported that the prophy-
`lactic adntinistration of ondansetron was as effective
`as granisetron and tropisetron in reducing the inci-
`dence of PONV during the first 24 h after laparoscopic
`cholecystectomy. Unfortunately, none of the currently
`
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`

`
`466
`
`TANG ET AL
`THE ANTIEMETIC EFFICACY OF RS-25259
`
`ANHSTH A.NALG
`1998;87:462-7
`
`Table 5. Perioperative Side Effects
`RS-25259 (p.g/ kg)
`0.3
`1.0
`3.0
`41
`40
`35
`
`Saline 0.1
`36
`27
`
`30
`39
`
`11
`Side effects (%)
`15
`7
`14
`Pain
`Anxiety
`5
`4
`0
`32
`37
`39
`Constipation
`4
`5
`0
`Dizziness
`5
`Drowsiness
`4
`3
`Headache
`7
`6
`17*
`Tnsomnia
`19
`11
`7
`17
`8
`22
`Itching
`5
`7
`6
`Rash
`• P < 0.05 versus saline and R$-25259 0.1 J.Lg/kg.
`
`9
`0
`31
`3
`3
`23 ..
`14
`14
`6
`
`13
`10
`5
`5
`23
`33
`8
`5
`0
`0
`15~ 21*
`18
`8
`15
`8
`3
`0
`
`available 5-HT3 receptor antagonists are completely
`effective in preventing PONV.
`RS-25259 is a highly potent and selective 5-HT3
`receptor antagonist (11) that decreases chemotherapy-
`induced emesis (12). The dose range chosen for this
`preliminary study was based on the single-dose safety
`and tolerability studies performed in healthy male
`volunteers (Robert Smith, PhD, personal communica-
`tion, 1993). After IV doses of 0.3-90 p..g/kg, RS-
`25259 has an elimination half-life of 30-40 h in hu-
`mans (data on file at Syntex/Roche, Palo Alto, CA).
`For this preliminary dose-ranging study, a female sur-
`gical population undergoing major gynecologic pro-
`cedures was chosen because it is at high-risk of devel-
`oping PONV. These resllits suggest that smaller doses
`of RS-25259 are ineffective in preventing of PONY.
`Only the largest dose of RS-25259, 30 j.tg/ kg rv, was
`effective in decreasing vomiting and the need for res-
`cue antiemetic drugs during the first 24 h after major
`gynecologic surgical procedures. Unfortunately, even
`the largest dose of RS-25259 did not reduce the sever-
`ity of nausea during the early postoperative period.
`Like other 5-HT3 receptor antagonists (17,25), R$-
`25259 also seems to increase postoperative headaches.
`Although oral RS-25259 1 JLg/kg is effective in pre-
`venting PONY in outpatients undergoing laparo-
`scopic surgery (26), it was less effective in this inpa-
`tient population undergoing major gynecologic
`procedures.
`When patients were stratified according to their
`history of PONY, RS-25259 was ineffective in the pre-
`vention of PONY in the high-risk subpopulation. It is
`possible that the failure to demonstrate a beneficial
`effect in patients with a history of PONY was related
`to the small number of subjects in these subgroups.
`The lack of an active comparative drug also limits the
`clinical implications of this study. However, before
`initiating comparative clinical trials with a new anti-
`emetic drug, it is necessary to determine the effective
`
`dose range and the side effect profile using a placebo-
`controlled, dose-ranging study design.
`In conclusion, RS-25259 30 p..g/kg IV was effective
`in preventing PONY in women undergoing major
`gynecologic surgery. However, it did not decrease
`postoperative nausea or .improve patient satisfaction.
`Of concern, postoperative headaches were increased
`in patients who received larger doses of RS-25259.
`
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