Oncology 1992;49:273-278
`
`G. W Brown 3
`DPaes3
`J Brysonb
`A.J. Freeman 3
`a Glaxo Group Research Ltd. Greenford,
`Middlesex, UK:
`b Glaxo Inc. Research Triangle Park. N.C.,
`USA
`
`The Effectiveness of a
`Single Intravenous Dose of
`Ondansetron
`
`KeyWords
`Single dose
`Ondansetron
`Emesis
`
`Abstract
`This paper reviews data from 3 randomised, double-blind, parallel-group
`studies carried out in patients receiving high-dose cisplatin chemotherapy
`(50-120 mg/m2). These comparative trials show that a single intravenous dose
`of ondansetron (8-32 mg) is as effective as the continuous infusion and inter-
`mittent dose regimens used in previous clinical trials (8 mg i.v. followed by a I
`mg/b infusion for 24 h and 0.15 mg/kg i.v. X 3). One of the studies, carried out
`in Europe, demonstrated that a single 8 mg i.v. dose was as effective as 32 mg
`given either as an 8 mg loading dose followed by an infusion or as a single
`intravenous dose of 32 mg before chemotherapy. A similar study conducted in
`the U nited States showed that a 32 mg i.v. single dose was significantly more
`effective than both the 8 mg i.v. dose and the intermittent dose schedule. This
`study used a prospective stratification based on the dose of cisplatin (50-70
`mg/m2 and > I 00 mg/m2). In both strata the 32 mg dose was superior. These
`results emphasise the importance of selecting the dose of ondansetron (8-
`32 mg) based on factors that predispose patients to emesis, e.g., female gender,
`patients with a history of chemotherapy or motion sickness and the dose of
`cisplatin. The ondansetron dosing regimen for patients receiving a bighly-
`emetogenic chemotherapy (8-32 mg i. v. followed by 8 mg orally twice daily) is
`both simple and flexible.
`
`Introduction
`
`Ondansetron is superior to high-dose metoclopramide
`in the control of acute emesis following high-dose cispla-
`tin [ 1-3]. Early studies used either an intermittent ondan-
`setron dosing regimen (0.1 5 mg/kg i. v. X 3 [I]) or a con-
`stant infusion (8 mg i.v. followed by a I mg/h infusion for
`24 h [2, 3]). The infusion regimen was designed as a result
`
`of pre-clinical findings that suggested a plasma level of
`30 nglml would be necessary to block 5-HT 3 receptors in
`man. This dosing regimen was therefore designed to
`maintain this plasma level for 24 h [4]. The early studies
`demonstrated that the maximum emetic challenge oc-
`curred during the first 12 h following cisplatin (fig. I) [2]
`indicating that simpler treatment schedules may be just as
`effective as repeated doses or infusions. In support of this
`
`A.J. Frttman
`Gla•o Group Researeh
`Greenford Road
`Greenrord M1dd• UB
`
`Dr. Reddy's laboratories, Ltd., et at.
`V.
`Helsinn Healthcare S.A., et aL
`U.S. Patent No. 8,729,094
`Reddy Ex hibit 1044
`
`

`
`Oncolog) 1992:49:273-278
`
`G. W. Brown 3
`D Paes8
`1 Br}'sonb
`A.J. Freeman3
`
`• Glaxo Group Research Ltd. Greenford.
`Middlcsc:... UK:
`b Glaxo Inc. Research Triangle Park . • . C ..
`USA
`
`The Effectiveness of a
`Single Intravenous Dose of
`Ondansetron
`
`KeyWords
`Single dose
`Ondansetron
`Emesis
`
`Abstract
`This paper reviews data from 3 randomised, double-blind. parallel-group
`studies carried out in patients receiving high-dose cisplatin chemotherapy
`(50-120 mg/m2). These comparative trials show that a single intravenous dose
`of ondansetron (8-32 mg) is as effective as the continuous infusion and inter-
`mittent dose regimens used in previous clinical trials (8 mg i. v. followed by a I
`mglh infusion for 24 hand 0.15 mglkg i.v. X 3). One of the studies, carried out
`in Europe, demonstrated that a single 8 mg i.v. dose was as effective as 32 mg
`given either as an 8 mg loading dose followed by an infusion or as a single
`intravenous dose of 32 mg before chemotherapy. A similar study conducted in
`the United States showed that a 32 mg i.v. single dose was significantly more
`effective than both the 8 mg i.v. dose and the intermittent dose schedule. This
`study used a prospective stratification based on the dose of cisplatin (50-70
`mg/m2 and ~ I 00 mg/m2). In both strata the 32 mg dose was superior. These
`results emphasise the importance of selecting the dose of ondansetron (8-
`32 mg) based on factors that predispose patients to emesis, e.g., female gender,
`patients with a history of chemotherapy or motion sickness and the dose of
`cisplatin. The ondansetron dosing regimen for patients receiving a highJy-
`emetogenic chemotherapy (8-32 mg i. v. followed by 8 mg orally twice daily) is
`both simple and flexible.
`
`Introduction
`
`Ondansetron is superior to high-dose metoclopramide
`in the control of acute emesis following high-dose cispla-
`tin [ 1-3]. Early studies used either an intermittent ondan-
`setron dosing regimen (0.15 mglkg i.v. X 3 [I]) or a con-
`stant infusion (8 mg i.v. followed by a I mglh infusion for
`24 h [2, 3]). The infusion regimen was designed as a result
`
`of pre-clinical findings that suggested a plasma level of
`30 nglml would be necessary to block 5-HT3 receptors in
`man. This dosing regimen was therefore designed to
`maintain this plasma level for 24 h [4]. The early studies
`demonstrated that the maximum emetic challenge oc-
`curred during the first 12 h following cisplatin (fig. I) [2]
`indicating that simpler treatment schedules may be just as
`effective as repeated doses or infusions. In support of this
`
`.\.J.f~rmn
`Gb\o (irwp R~ Lid
`Grtcnford Road
`Gnoenfortl, ~11dd,, UB6 Oltf Cl• Kl
`
`0 199! S ..._,I'JCT AG. Basel
`0030-2414•921049<1-0273
`$2.7510
`
`Exh. 1044
`
`

`
`MeiOCiopnmi<k infusion
`
`mciOCiopranlide 1m1
`ondansc.tron arm
`
`S 6 7 8 9 10 II 12 13 14 IS 16 17 18 19 20 21 22 23 24
`Time af<et Cisplatin O>cmOlherapy (hr)
`
`Fig. 1. Episodes of emesis during the 24 h after cisplatin adminis-
`tration [from 2].
`
`observation, a similar degree of emetic control was
`achieved when ondansetron was administered in doses of
`0.15- 0.1 8 mg/kg every 2, 4, 6 or 8 h for 3 doses [I, 8, 9).
`The urinary excretion of 5-hydroxyindolacetic acid (5-
`HIAA), the maio metabolite of 5-hydroxytryptamine (5-
`HT or serotonin), has also been shown to increase in the
`4- to 6-hour period following cisplatin, indicating the
`likely depletion of 5-HT from the enterochromaffin cells
`within a few hours after cisplatin administration, in paral-
`lel with the development of emesis [5]. Kinetic studies
`have also suggested a correlation between the plasma level
`of ondansetron 3-6 h following cisplatin and acute emesis
`control [6,7]. These data suggested that if the initiation of
`the vomiting reflex is blocked, acute cisplatin-induced
`emesis may be prevented. A single dose of ondansetron
`given before cisplatin chemotherapy could therefore be as
`effective as the regimens used previously in clinical trials.
`This review summarises 3 studies undertaken to deter-
`mine whether the recommended total daily dose of on-
`dansetron (32 mg), when given as a single intravenous
`dose prior to cisplatin, is as effective and as well tolerated
`as the established continuous infusion and intermittent
`dose regimens. Two of the studies also included an 8 mg
`single-dose arm, equivalent to giving only the loading
`dose of the 'standard' regimens.
`
`Patients and Methods
`
`Three multiccntre. randomiscd. double-blind. parallel-grou~
`studies were carried out in hospitalized patients. Study I was con-
`ducted in France, Study 2 in Europe and Study 3 in the United
`States. The dose regimens used in these studies are summarised in
`table I.
`
`Pall-e/1/s
`Male or female patientS, aged at least 18 years, and who were
`scheduled to receive their first course of chemotherapy with cisplatin
`(S0-120 mglm2) over a period of up to 4 h, either alone or in combi-
`nation with other cytotoxic drugs, were recruited into these studies.
`Patients were excluded from the studies if they experienced nausea
`or vomiting in the 24-hour period prior to the start of treatment or
`had received anti-emetic therapy over this time. In addition, patients
`were excluded if they had a severe concurrent illness other than neo-
`plasia. or metastases to the central nervous system.
`
`Study Designs and Ondansetron Treatmem Schedules
`Patients randomised to the continuous infusion schedules in
`Studies I and 2 received 8 mg ondansetron (as ondansetron hydro-
`chloride dihydrate) as a IS-min infusion in I 00 ml of normal saline,
`followed by a continuous infusion of I mglh for 24 h. Patients ran-
`domised to the intermittent dosing schedule in Study 3 received 3
`doses ofO.I S mglkg in SO ml of normal saline given over 15 min. The
`second and third doses were given 4 and 8 h after the initial dose.
`Patients randomised to the 32 or 8 mg single dose treatments
`received these doses as I S-rnin infusions in normal saline. This was
`followed by a placebo infusion for 24 h in Studies I and 2 and by 2
`placebo injections of SO ml normal saline after 4 and 8 h in Study 3.
`Cisplatin was administered 30 min after the initial dose of ondanse-
`tron. Study 3 used a prospective stratification according to the dose
`of cisplatin: S0-70 and 2: I 00 mglm2.
`
`Assessment Criteria
`The timing and number of emetic episodes were recorded in h()s-
`pital for 24 h following cisplatin administration. An emetic episode
`was defined as any episode of vomiting or retching. Emetic episodes
`were counted as separate if no vomiting or retching occurred for at
`least 1 min between episodes. Responses were categorised as follows:
`complete (0 emetic episodes in 24 h), major (1-2 emetic episodes),
`minor (3-S emetic episodes) and failure (> 5 emetic episodes or
`administration of rescue anti-emetic treatment). In Studies 1 and 2,
`nausea was assessed by the patient before treatment and at8 and 24 h
`after cisplatin using a 4-point graded scale (none, mild. moderate or
`severe). In Study 3. nausea was assessed using a visual analogue scale
`(0-1 00 rom) before treatment and after 24 h (0- no nausea, I 00 mm
`- nausea as bad as it could be). For Studies I and 2. the primary
`responses for emesis and nausea were based on the percentages of
`patients in each treatment group with complete or major control of
`emesis (0-2 emetic episodes) and none or mildl nausea. For Study 3,
`the primary response variable was based on the number of emetic
`episodes.
`Routine haematological and biochemical assessments were car-
`ried out before the study, at the end of the 24-hour observation
`period and 1-4 weeks later. Adverse events were reported or
`observed during treatment. with a further assessment at I week post-
`treatment for any delayed effects. The protocols were reviewed by
`the medical ethics committees oft he investigational centres. Patients
`
`274
`
`Brown/Paes/Bryson/Freeman
`
`Efficacy of a Single Intravenous Dose of
`Ondansetron
`
`Exh. 1044
`
`

`
`Table 1. Ondansetron dose schedules
`
`Study
`No.
`
`Ann
`
`Dose prior to
`chemotherapy
`mgi.v.
`
`Subsequent
`doses
`
`Total dose
`mg(24 h)
`
`2
`
`3
`
`A
`B
`A
`B
`('
`
`A
`B
`('
`
`8
`32
`8
`8
`32
`0.151
`8
`32
`
`- -- -
`
`I mglh (24 h)
`placebo (24 h)
`I rng/h (24 h)
`placebo (24 h)
`placebo (24 h)
`0.15 mglkg X 2. 4 hourly
`placebo X 2. 4 hourly
`placebo X 2. 4 hourly
`
`32
`32
`32
`8
`32
`32
`8
`32
`
`mglkg i.v.
`
`gave either written informed consent, or oral informed consent in the
`presence of a witness.
`
`Statistical Analrsis
`All analyses were performed on the total population (intention·
`to-treat analysis) and the evaluable population (patients satisfactorily
`complying \\1th the study protocol). The results rc\ iewed here are
`those for the e'aluable populations only. as there were no differences
`in the conclusions from the 2 sets of analyses. Statistical comparisons
`of the percentage of patients with a complete or major response
`(Studies I and 2) and a complete response (Study 3) arc described
`below. All patients were included in the evaluations of safety.
`
`Results
`
`Swdy 1: Continuous Infusion versus
`32 mg Single Dose
`Of the 324 patients randomised in Study I (median
`cisplatin dose of 85 mg/m2, range 50-100 mg!m2), 305
`( 165 men and 140 women) satisfactorily complied with
`the protocol. The control of emesis and nausea is shown
`in ligures 2 and 3. respectively. There were no statistically
`significant differences between the 2 treatment schedules
`in the control of emesis (p = 0.51) or nausea (p - 0.48).
`Complete or major control of emesis (0-2 emetic epi-
`sodes) was achie,ed in 72% and 76% of patients receiving
`the infusion and 32 mg single dose regimens. respectively.
`Nausea was graded none or mild by 74% of patients in
`both groups.
`
`Study 2: Continuous Infusion l'ersus
`32 mg Single Dose versus 8 mg Single Dose
`Study 2 enrolled 535 patients, 263 men and 272
`women (median cisplatin dose 72 mg/m2• range 50-120
`mg/m2): 493 were evaluable for efficacy. The results are
`shown in ligures 2 (emesis) and 3 (nausea). As for Study I.
`there were no statistically significant differences in anti-
`emetic efficacy between the different dose regimens.
`Complete or major control of emesis (0-2 emetic epi-
`sodes) was achieved in approximately 75% of patients
`and nausea was equally well controlled in each group. A
`retrospective stratification of the efficacy data based on
`patient age. gender. chronic alcohol use, doses of cisplatin
`and the emetogenic potential of concurrent cytotoxic
`drugs administered. indicated that there were no signifi.
`cant differences between the treatments when these rele·
`vant prognostic factors were considered separately.
`
`Swdy 3: 0. 15 mglkg- X 3 versus 3 2 mg Single Dose
`l'erstts 8 mg Single Dose
`Study 3 used a prospective stratification based on the
`dose of cisplatin; 50-70 and ~ I 00 mg/m2• A total of 359
`patients were entered in the high-dose stratum (255 men
`and I 04 women): 317 patients were evaluable for efficacy.
`340 patients were enrolled in the medium-dose stratum
`(21 0 men and 130 women): 30 I patients successfully
`complied with the study protocol and were evaluable for
`efficacy. In both strata~ the 8 mg single dose was as effec·
`tive as the 0.15 mglkg X 3 dose schedule for the control of
`emesis (fig. 4) and nausea (fig. 5). The 32 mg single dose
`was superior to the 8 mg single dose and the 0.15 mglkg
`X 3 dose regimens in the control of emesis in both the
`
`275
`
`Exh. 1044
`
`

`
`80
`
`60
`
`4()
`
`20
`
`0
`
`SIUC!y I
`
`14'-' 14'-'
`M M
`
`-57 'A 63i
`
`N N
`
`Sllldy 2
`~ 15'-' 1~
`
`M M M
`
`1--
`
`54. 1---51'-'
`
`48'-'
`N N N
`
`n=l48 149
`Study I
`
`n-168 172 149
`Sllldy 2
`
`B ConliniJOUS Infusion (Sma + lmg/11)
`0 Singledose(32mg)
`0 Single dose (8mg)
`N•No Nausea
`M • Mild Nausea
`
`154
`n=ISI
`Study I
`
`173
`n•168
`Study2
`
`152
`
`rn Coclunuous lnfus•on (8mg + lmg/11)
`0
`0
`
`S•ngle dose (3lmg)
`Single dose (8mg)
`M • MIJOf conb'OI or emesis
`C = CompleiC eonb'OI of emesis
`
`Fig. 2. Control of acute cisplatin-induced emesis with ondanse-
`tron as a continuous infusion, 32 mg single dose or 8 mg single dose.
`
`Fig. 3. Control of acu1c cisplatin-induccd nausea with ondanse-
`tron as a continuous infusion. 32 mg stngle dose or 8 mg single dose.
`
`high and medium-dose cisplatin groups (fig. 4). For com-
`plete control of emesis (0 emetic episodes), this reached
`statistical significance when compared with the 8 mg sin-
`gle dose (p - 0.048 and p < 0.001 for the high and
`medium-dose cisplatin groups, respectively). In addition,
`there were significantly fewer treatment failures in the
`32 mg single-dose groups of both strata compared with
`the 8 mg single dose and 0.15 mglkg X 3 dose groups (p <
`0.02). The 32 mg single dose was also superior to the other
`dose regimens in the control of nausea (fig. 5). This
`reached statistical sigojficance when compared with the
`0.15 mg!kg X 3 dose in the high-dose cisplatin stratum
`(p = 0.036) and the 8 mg single dose in the medium-dose
`cisplatin group (p = 0.008). The superiority of the 32 mg
`single dose was maintained when a retrospective stratifi-
`cation based on age, gender and prior alcohol consump-
`tion was carried out and the groups compared.
`
`Adverse El'ents
`Ondansetron was weU tolerated in these studies. In
`particular, there was no increase in the incidence of
`adverse events in patients given a 32 mg single intrave-
`nous dose of ondansetron. Headache was the most com-
`monly reported adverse event, in approximately 12 o/o of
`patients.
`
`Discussion
`
`The 3 studies reviewed here clearly demonstrate that a
`single intravenous dose of ondansetron is as effective as
`the continuous infusion (8 mg i.v. followed by I mg!h for
`24 h) and intermittent (0.15 mg!kg X 3) dose schedules
`for the control of acute cisplatin-induced emesis. The effi-
`cacy rates in the French (Study I) and European (Study 2)
`studies (72-77% of patients with a complete or major
`response) are similar to those previously reported using
`
`276
`
`Brown/Pacs/Bt)son/Freeman
`
`EfficaC} of a Stnglc lntra\enous Dose of
`Ondansetron
`
`Exh. 1044
`
`

`
`Snxly 3
`
`~ or patients
`100
`
`88 ..
`
`80
`
`ro
`
`40
`
`20
`
`69'4
`
`73 ..
`
`38
`
`~
`
`c
`
`c
`
`o ....... --. ......... _.L...L_..~.-__.:.-......__L...-....1....1,._-'--
`""tot
`n-93
`.. t07
`CiJplul:30-~2
`
`D
`D
`D
`
`lturmium dose (O. I'm~& x 3)
`Single dose (32tnJ)
`Sin&Je dose (8mJ)
`
`M • Major eonuol or emesis
`C • Complece eonli'OI or emesis
`
`D
`D
`D
`
`lntetmlllelll dose (0. Um~ x 3)
`S•n&fe dose (32tng)
`Smale dose (8mg)
`
`Fig. 4. Control of acute cisplatin-induccd emesis with ondanse-
`tron given intermiuentl). as a 32 mg single dose or 8 mg single dose.
`
`Fig. 5. Control of acute cisplatin-induccd nausea with ondanse-
`tron given intermittently. as a 32 mg single dose or 8 mg single dose.
`
`the infusion regimen in comparative studies (72 and 75%
`of patients with a complete or major response [2, 3]).
`Pharmacokinetic modelling had suggested that the
`consistent 30 ng/ml plasma level produced by the infu-
`sion schedule (4] would block S-HT3 receptors for 24 h.
`Kinetic studies then demonstrated a correlation between
`the plasma level of ondansetron 4-6 h following dosing,
`acute emesis control [6. 7] and the urinary excretion of
`5-HIAA. the main metabolite of 5-HT [5]. These findings
`suggest that it may be imponant to prevent the initiation
`of the emetic renex by blockade of 5-HT 3 receptors for the
`first few hours after cisplatin administration, as it now
`seems likely that the depletion of 5-HT stores in entero-
`chromaffin cells within a few hours of cisplatin treatment
`may persist for up to 24 h. These studies have funher
`shown that a single 8 mg single dose is as effective as the
`previously recommended dose regimens (8 mg i.v. fol-
`lowed by a I mg/hour infusion for 24 hours and 0.15
`mglkgX 3).
`
`It is interesting to note that no differences were found
`between the 8 and 32 mg single-dose schedules in the
`European study (Study 2) whilst in the United States the
`32 mg was shown to be superior to 8 mg (Study 3). In the
`European study no differences emerged when a retro-
`spective stratificatjon was carried out according to factors
`known to inOuence the degree of emesis: age. gender.
`emetogenic potential of concurrently administered cyto-
`toxic drugs and the dose of cisplatin. However, only 20%
`of patients received cisplatin doses ~ 100 mglm1 reduc-
`ing the statistical power of the the latter comparison.
`The United States study. which used a prospective
`stratification based on the dose of cisplatin (50-70 mg/m2
`and > I 00 mg/m2), found that the 32 mg single dose was
`superior at aJI doses of cisplatin. These data are consistent
`with an earlier dose-ranging study carried out in the
`United States. in patients who received cisplatin doses
`~ 100 mg/m2, which suggested that higher doses of on-
`dansetron may be more effective [I 0].
`
`277
`
`Exh. 1044
`
`

`
`These and other recent clinical trials have confirmed
`5-HT as the main mediator of acute emesis, but failure to
`completely protect all patients with 5-HT 3 receptor antag-
`onists indicates that other mechanism(s) may also be
`involved. The addition of dexamethasone to ondansetron
`has been shown to significantly improve anti-emetic con-
`trol [II , 12). This suggests that dexamethasone contrib-
`utes to efficacy by suppressing one or more of these addi-
`tional, as yet unknown, mechanisms.
`In conclusion, these studies have demonstrated that a
`single intravenous dose o f ondansetron is as effective as
`
`the continuous infusion and intermittent dose regimens
`used previously, in the management of acute emesis. This
`has the advantages of convenience and ease of adminis-
`tration, benefiting both patients and nursing stafT. Single
`intravenous dosing (8-32 mg) before chemotherapy to-
`gether with the twice-daily oral dosing for up to 5 days
`[ 13) offer a flexible, convenient and well-tolerated dose
`regimen for treating acute and delayed emesis in hopital-
`ized patients and patients who receive chemotherapy on
`an outpatient basis.
`
`References
`
`HamS\\orth J. Harvey W. Pendergrass K. Ka-
`simis B, Obion D, MonasJlan G. Gandara D.
`Hesketh P, Khojastch A. Harker G. York M.
`Siddiqui T. Finn A: A single-blind comparison
`of intravenous ondansctron, a selective scro·
`tonin antagonist. with intravenous metoclo-
`pramide in the prevention of nausea and vom-
`iting associated w1th hisJl-dosc CJsplaun che-
`mothempy.J Oin0ncoll991;9:721-728.
`2 Many M. Pouillan P. SchollS. Droz JP. Azab
`M. Brion ~. PuJadc-1..3uraine E. Paule B. Paes
`D. Bons J: Compari.son of 5-H)·dro~ytrypta­
`minc 3 (serotonin) antagonist ondansetron
`(GR38032F) with hisJl-dose metocloprnmidc
`in the control of acute cisplacin-indueed eme-
`sis. N Engl J Med 1990;322:816-821.
`3 De Mulder PHM, Seynaeve C. Vermorkcn JB.
`van Liessum PA. Mols-Jevdevic S. lane All-
`man E. Beranct.. P. Vcrweij J: Ondnnsetron
`compared with hisJl-dose metoclopramide in
`prophylaxis of acute and delayed cisplatin-
`indueed nausea nnd vomiting. A mulucentrc,
`randomised double-blind crossover study. Ann
`Intern Med 1990;113:834-840.
`
`4 Blact..,.ell CP. Harchng SM: The eli meal phar-
`macolog) of ondansetron. Eur J Chn Oncol
`1989;25 (suppl I ):S21-S24.
`5 Cubeddu LX, Hoffmann IS. Fuenma)or NT,
`Finn AL: Efficacyorondansetron (GR38032F)
`and the role of serotonin in cisplatin-induccd
`nausea and vomiting. N Engl J Med 1990:322:
`810-816.
`6 Grunberg SM. Grosheo S. Rob• nson DC. Stev-
`enson LL. Sanderson PE: Correlation of anu-
`emetic efficaC) and plasma IC\icls of ondanse-
`tron. Eur J Cancer 1990;26:879-882.
`7 Pritchard JF. Welts CD: The n:lationsh1ps be-
`tween systemic e~posure and efficacy or ondan·
`setron. Clin Pharmacol Thcr 1990;47:206.
`8 Kris MG, Oralia RJ. Clark RA, Tyson LB:
`Phase Ill trials or the serotonin antagonist
`GR38032F for the control of vomiting caused
`bycisplaun. JNCI 1989;81:42-46.
`9 Hesketh PJ. Murph) WK. Lester EP, Gandara
`DR. Khojasteh A. Tapazoglou E. Saniano GP.
`White DR, Werner K. Chubb JM: GR38032F
`(GR-C507175): A novel compound effecuve in
`the prevention or acute cisplatin-induced eme-
`sis. J Clin Oncol 1989:7:700-705.
`
`10 lane M. Grunberg SM. Lester EP. Sridhar KS.
`Sanderson PE: A double-blind comparison or
`three dose levels of 1v ondansetron (OND) in
`the prevention or cisplatin (DDP}-induced
`nausea and vomiting {V) (abstract 1271 ). Proc
`Am Soc Clin Oncol1990;9:329.
`II Roila F. Tonato M, Cogneni F, Cortesi E. Fa-
`valli G. Marangolo M. Amadori D, Bella MA.
`Grama7io V, Donati D. Balla tori E. Del Fa' ern
`A: Prevenuon of mplatio-mduced emes1s: A
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