Page 1 of 15
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`Helsinn Healthcare Exhibit 2055
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`NDA 21-372
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`Page 2
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`FDA's Fediatric Rule [at 21 CFR 314.55/21 CFR 601.27} was challenged in court. On October 17,
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`2002, the court rated that FDA did not have the authority to issue the Pediatric Rule and has barred
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`FDA from enforcing it. Although the government decided not to pursue an appeal in the courts, it will
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`work with Congress in an effort to enact iegislation requiring pharmaceutical manufacturers to conduct
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`appropriate pediatric clinical trials. In addition, third party interveners have decided to appeal the
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`court's decision striking down the rule. Therefore, we encourage you to submit a pediatric plan that
`describes development of your product in the pediatric population where it may be used. Please be
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`aware‘ that whether or not this pediatric plan and subsequent submission of pediatric data will be
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`required depends upon passage of legislation or the success of the third party appeal. In any event, we
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`hope you wiil decide to submit a pediatric plan and conduct the appropriate pediatric studies to provide
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`important information on the safe and effective use of this drug in the relevant pediatric populations.
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`The pediatric exciusivity provisions of FDAMA as reauthorized by the Best Pharmaceuticals for
`Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of
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`section 505A of the Federal Food, Drug, and Cosmetic Act may result in additional marketing
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`exclusivity for certain products. You should refer to the Guidance for hidustry on Qualifying for
`Pediatric Exc1usivity(availabie on our web site at www.fda.govlcder/pediatric) for details. We
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`acknowledge your fume 26, 2003 “Proposed Pediatric Study Request" submitted under JND 39,797.
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`We are reviewing your submission and will respond to your proposal in a separate letter. FDA.
`generally does not consider studies submitted to an NDA before issuance of 21 Written Request as
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`responsive to the Written Request. Applicants should obtain a Written Request before submitting
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`pediatric studies to an NDA.
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`In addition, submit three copies ofthe introductory promotional materials that you propose to use for
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`this product. Submit all proposed materials in draft or mocleup form, not final print. Send one copy to
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`this division and two copies of both the promotional materiais and the package insert directly to:
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`Division of Drug Marketing, Advertising, and Communications, HFD—42
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`Food and Drug Administration
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`5600 Fishers Lane
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`Rockvillc. MD 20857
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`Please submit one market package of the drug product when it is available.
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`We have not completed validation of the reguiatory methods. However, we expect your continued
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`_ cooperation to resolve any problems that may be identified.
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
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`314.80 and 314.81). In addition, we request that you initiate a 15-day report [21 CFR. 3 i4.80(c)] for
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`each of the following:
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`- All spontaneous reports of constipation requiring hospitalization or emergency room visit
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`0 All spontaneous reports of possible compiications of constipation such as obstruction,
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`perforation, intestinal ulceration, toxic rnegacolon, ileus, or impaction resulting in
`hospitalization or emergency room visit
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`0 Ail spontaneous reports of any cardiovascular adverse event
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`The McdWatch—to—Manufactm-er Program provides nianufacturers with copies of serious adverse event
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`reports that are received directly by the FDA. New molecular entities and important new biologics
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`Page2 of 15
`HIGHLY CONFIDENTIAL — OUTSIDE COUNSEL EYES ONLY
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`HELSN0387520
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`Page 2 of 15
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`NDA 21-372
`Page 3
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`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
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`this product. To paxticipate in the program, please see the enrollment instructions and program
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`description details at www. fda.gov/medwatch/reportfmm};.l1t1n.
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`If you have any questions, call Brian Strongin, R.Ph., M.B.A., Regulatory Project Manager at (301)
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`827-7473.
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`S incerely,
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`{See appended electronic sfigmmture page}
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`Julie Beitz, MD.
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`Deputy Director
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`Office of Drug Evaluation HI
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`Center for Drug Evaluation and Research
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`Enclosure
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`Page 3 of 15
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`HELSN0387521
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`Page 3 of 15
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`NDA 21-372
`Page 4
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`Aloxlm (Palonosetron Hydrochloride) Injection
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`I-Ielslnn 1-lealthcare S.A. NDA 21-372 Palonosetron: Proposed Labeling
`DESCRIPTION
`Alexi‘ (palonosetron hydrochloride) is an antiemetlc and antirtauseant agent. It is a selective serotonin
`subtype 3 (5-l-I13) receptor antagonist with a strong binding sflinity for this receptor Chemically,
`pelonosotron hydrochloride is: (3a§)—2-[(_S_)-1-Azabicyclo [2.2.2]oct-3-yi.]-2,3,3a,4,S,6-hexa.hydro-1-
`oxo- lHbenz[de]isoquinoline hydrochloride. The empirical formula is C19H24N20 HC1, with a
`molecular weight of 332 87 Palonosetron hydrochloride exists as a single isomer and has the
`following structural formula:
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`4
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`N
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`N\\‘
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`H
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`'0 H
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`HCI.
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`Palonosetron hydrochloride is a white to off-white crystalline powder. It is Ereely soluble in water,
`soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.
`Aloxi injection is a sterile, clear. colorless, non-pyrogenic, isotonic, buffered solution for intravenous
`administration. Bach 5-nil vial of Aloxi injection contains 0.25 mg palonosetron base as
`hydrochloride, 207.5 mg mannitol, disodium edetate and citrate bufier in water for intravenous
`administration. The pH of the solution is 4.5 to 5.5.
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`CLINICAL PHARMACOLOGY
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`flisnnmrlrnsndst
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`Palonosetron is a selective 5-HT; receptor antagonist with a strong binding affinity for this receptor
`and little or no afllmty for other receptors.
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`Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly
`when certain agents, such as cisplntin, are used. 5-HT; receptors are located on the nerve terminals of
`the vagus in the periphery and centrally in the chemorcceptor trigger zone of the area postrerna.
`It ls
`thought that chemotherapwuc agents produce nausea and vomiting by releasing serotonin from the
`ontcroclwomalfin cells of the small intestine and that the released serotomn then activates 5-HT;
`receptors located on vagal affercnts to initiate the vomiting reflex.
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`iadanork of Hetshn Heeltnceru sn
`1 Pencil
`Ilzorland
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`oowmomo Helslnn l-leallhcera SA. 2003
`All lmls reserved
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`Page 4 of 15
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`HELSN0387522
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`NDA 21.372
`Page 5
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`The effect ofpalonos etron on blood pressure, heart rate, and ECG parameters including QTc were
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`comparable to ondansctron and dolasetron in clinical trials. In non-clinical studies palonosetron
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`possesses the ability to block ion channels involved in ventricular de- and re-polarization and to
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`prolong action potential duration. In clinical trials, the dose-response relationship to the QTc interval
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`has not been fully evaluated.
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`Phaz-niaeoklnetics
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`Afler intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in
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`plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma
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`concentration (Cmu) and area under the concentration-time curve (AUG...) are generally dose-
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`proportional over the dose range of 03-90 uglicg in healthy subjects and in cancer patients. Following
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`single N dose of palonosetron at 3 pgllcg (or 0.21 mg/70 kg) to six cancer patients, mean (iSD)
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`maximum plasma concentration was estimated to be 5.6 i 5.5 ng/mL and mean AUC was 35.8 i 20.9
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`ngohf/IEL.
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`Distribution
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`Palonosetron has a volume of distribution of approximately 8.3 i 2.5 Llkg. Approximately 62% of
`palonosetron is bound to plasma proteins.
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`Metabolism
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`Palonosetron is eliminated by multiple routes with approxirnately 50% metabolized to form two
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`primary metabolites: N-oxide-palonosetton and 6~S-hydroxypalonosetron. These metabolites each
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`have less than 1% of the 5-HT; receptor antagonist activity ofpalonosetron. In vitro metabolism
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`studies have suggested that CYP2D6 and to a lesser extent, CYPEA and CYP1A2 are involved in the
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`metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly
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`different between poor and extensive metabolizers of CYPZD6 substrates.
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`Elimination
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`Afier a single intravenous dose of 10 figfkg [”C]—pa1onosetron, approximately 80% of the dose was
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`recovered within 144 hours in the urine with pal-onosetron representing approximately 40% of the
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`administered dose. In healthy subjects the total body clearance of palonosetron was l60 :|: 35 mLfh/kg
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`' and renal clearance was 66.51: [82 mLfhll<g . Mean terminal elimination half-life is approximately 40
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`hours.
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`ggecial Populations
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`Population PK analysis and clinical Safely and efficacy data did not reveal any differences between
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`cancer patients 2 65 years of age and younger patients (18 to 64 years). No dose adjustment is
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`required for these patients.
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`—I
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`HELSN0387523
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`Page 5 of 15
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`NDA 21-372
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`Intravenous paionosetron pharrnacokinetics was characterized in twenty-four healthy Japanese subjects
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`over the dose range of 3 — 90 trglkg. Total body clearance was 25% higher in Japanese subjects
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`compared to Whites, however, no dose adjustment is required. The pharrnacokinetics of palonosetron
`in Blacks has not been adequately characterized.
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`Renal Impairment
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`Mild to moderate renal impairment does notsignificantly affect palonosetron pharrnaookinetic
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`parameters. Total systemic exposure increased by approximateiy 28% in severe renal impairment
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`relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal
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`impairment.
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`Hepatic Impairment
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`Hepatic impairment does not significantly affect total body clearance of patorrosetron compared to the-
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`healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic
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`impairment.
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`Drug-Drug Interactions.
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`Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with
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`the latter mediated via multiple CYP enzymes. Further in virro studies indicated that palonosetron is
`not an inhibitor of CYP1A2, CYP2A6, CYPZB6, CYPZC9, CPYZD5. CYP2Ei and CYP3A4/5 ,
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`(CYP2C 19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5.
`Therefore the potential for ciinically significant drug interactions with pslonosetron appears to be low.
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`A study in healthy volunteers involving single-dose IV palonosctron (0.75 mg) and steady state oral
`rnetociopramide (10 mg four times daily) dernonstrated no significant pharmacokiuetic interaction.
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`In controlled clinical trials, Aloxi injection has been safely administered with corticosteroids;
`analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.
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`Palonosetzcon did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin,
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`cyclophospharnide, cytarabine, doxorubicin and mitornycin C) in murine tumor models.
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`CLINICAL STUDIES
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`Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting
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`induced by both moderately and highly emctogcnic chemotherapy was studied in three Phase 3 trials
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`and one Phase 2 trial. In these double-blind studies, complete response rates (no emetic episodes and
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`no rescue medication) and other efficacy parameters were assessed through at least 120 hours after
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`Page6 of 15
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`Page 6 of 15
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`NBA 21«372
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`Page 7
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`administration of chemotherapy. The safety and efficacy of palonoseiron in repeated courses of
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`chemotherapy was also studied.
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`Moderately Emetogenic Chemotherapy
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`Two Phase 3, double-blind trials involving 1132 patients compared single-dose IV Alexi with either
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`single-dose IV ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately
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`emetogenic chemotherapy including cerboplatin, cisplatin 5 50 mglm’, cyclophosphamide < 1500
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`mg/m’, doxorubicin > 25 mg/In‘, cpirubiciu, irinotecan, and methotrexate > 250 mgm‘. Concomitant
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`corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of
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`patients in study 2. The majority of patients in these studies were women (77%), White (65%) and
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`naive to previous chemotherapy (54%). The mean age was 55 years.
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`Highly Emetogenic Chemotheragy
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`A Phase 2, double-blind, dose-ranging study evaluated the efficacy bf single-dose IV palonosetron
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`fiom 0.3 to 90 pgflrg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 ehemotherapy—naive adult
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`cancer patients receiving highly-emetogenic chemotherapy (either cisplatin E: 70 mg/m’ or
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`cyclophosphamide > 1100 mg/m’). Concomitant corticosteroids were not administered
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`prophylactically. Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in
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`preventing acute naiisea and vomiting induced by highly emetogenic chemotherapy.
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`A Phase 3, double-blind trial involving 667 patients compared single-dose W Alexi with single—dose
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`IV ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including
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`cisplatin 2 60 mg/ml, cyclophosphamide > 1500 mglm‘, and dacarbazine. Corticosteroids were co-
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`administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were
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`women, 60% White, and 59% naive to previous chemotherapy. The mean age was 52 years.
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`Efficacy Results
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`The antiemetic activity of Aloxi was evaluated during the acute phase (0-24 hours) [Table 1], delayed
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`phase (24-I20 hours) {Table 2], and overall phase (0420 hours) [Table 3] posmhemotherapy in Phase
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`Page 7 of 15
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`NDA 21-372
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`Page 8
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`Table 1:
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`Prevention of Acute Nausea and Vomiting (0-24 hours):
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`Com Iete Res - onse Rates
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`“In with
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`[-1%, 32%]
`I—.——---—-4
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`J
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`-9%, 13% I
`:——|j-I---r----r---I--I---r—-r--1
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`-10-50 5101520251035
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`Dliferenec In Compute Respnnn Rate:
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`a lntent—ta-lreatcohort
`b 1-sicIud.l-‘ishc:-‘s exact test. SigniI'Icanca1avr:Iatu-=o,o25.
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`c These studies were designed to show norrinfctiorily. A lower hound gmstcr than -—lS% demonstxates non-inferiority between Alexi and oompamlor.
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`These studiesshow th'c1tA10xi was effective in the prevention of acute nausea and vomiting associated
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`with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. In study 3,
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`cfficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical
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`superiority over other 5—HT3 receptor antagonists has not been adequately demonstrated in the acute
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`HELSN0387526
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`C°“‘P1°*°
`Response
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`97.5% Confidence Interval
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`3
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`Alma mmus Comparator
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`CI1emo-
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`Study
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`Prevention of Delayed Nausea and Vomiting (24~l20 hours):
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`Comlete Resonse Rates
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`Moderate
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`1y
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`Emetoge
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`NDA 21-372
`Page 9
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`'-
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`Table 2:
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`p~vaIue
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`1'
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`43.001
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`74
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`55
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`97.5% Confidence Interval
`Aloxi minus Comparator ”
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`um, 30%;
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`1m,2w.;
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`—1u—so51n1s:uzssoas
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`Difference In Complete Response Rain
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`1 8
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`9
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`lg
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`5
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`II I.nienI—to-Ireatcohon.
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`1) Zvsided Fisher’: exact test. Significance level at a.=0.025.
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`e Thesestudies were designed to show non-infilriority. A lower bound greater than -I 5% demonstrates non—infcriori£ybetwetn Alexi and compszatnr.
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`These studies show that Aloxi was effective in the prevention of delayed nausea and vomiting
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`associated with initial and repeat courses of moderately emetogenic chemotherapy.
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`"Fable 3:
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`Ondanse
`tron 32
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`In IV
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`Alex;
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`(125 mg
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`18
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`: l
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`Prevention of Overall Nausea and Vomiting (0—120 hours):
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`Com lete Res onse Rates
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`% with
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`Compie
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`Respons
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`*3
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`p-value
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`"
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`97.5% Confidence Interval
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`Aloxi minus Comparator ”
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`['1'/a.3I.°fl:]
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`50
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`34
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`15 2o 25 30 as
`10
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`Dilferenculn Complele Response mm.
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`1
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`a lnlent-lo-trcateuhon
`b 2-sided Fisher's exact lest. Significance lave! nm=D.0a5.
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`e These studies was designed to show non-inferierily. A lower bound greater than ~15"/. demonstrates non-infitriority between Alexi and comparator.
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`These studies show that Alexi was effective in the prevention of nausea and vomiting throughout the
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`120 hours (5 days) following initial and repeat courses of moderately emetogenie cancer
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`chemotherapy.
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`Page 9 of 15
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`HELSN0387527
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`Page 9 of 15
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`NDA 21-372
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`Page 10
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`INDICATIONS AND USAGE
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`Aloxi is indicated for;
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`the prevention of acute nausea and vomiting associated with initial and repeat courses of
`moderately and highly ernetogenic cancer chemotherapy, and
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`the prevention of delayed nausea and vomiting associated with initia} and repeat courses of
`modcratcly crnetogenic cancer chemotherapy.
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`1)
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`2)
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`5
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`CONTRAINDICATIONS
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`-1
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`Aloxi is contraindicated in patients known to have hypersensitivity to the drug or any of its
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`components.
`PRECAUTIONS
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`General
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`Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective
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`S-HT; receptor antagonists.
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`Although palonosetron has been safely administered to 192 patients with preexisting cardiac
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`impairment in the Phase 3 studies, Alexi should be administered with caution 11‘! patients who have or
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`may develop prolongation of cardiac conduction intervals, particularly QTc. These include patients
`with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte
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`abnormalities, patients with congenital QT syndrome, patients taking anti~arrhytlunic drugs or other
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`drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy. In 3 pivotal
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`trials, ECGs were obtained at baseline and 24 hours after subjects received palonosetron or a
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`comparator drug. In a subset of patients ECGs were also obtained 15 minutes following dosing. The
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`percentage of patients (< 1%) with changes in QT and QTc intervals (either absolute values of > 500
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`msec or changes of > 60 msec from baseline) was similar to that seen with the comparator drugs.
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`Drug Interactions
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`Paionosetron is eliminated from the body through both renal excretion and metabolic pathways.
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`Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low
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`(See CLINICAL PHARMACOLOGY, Drug-Drug Interactions section).
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of
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`palonosctron at 10, 30 and 60 mg/kg/day. Treatment with paloncsctron was not tumorigcnic. The
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`highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289
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`times the human exposure (AUC= 29.8 ng-hlml) at the recommended intravenous dose of 0.25 mg. in
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`a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral
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`doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kgfday, respectively. The highest doses
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`produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human
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`Page 10 of 15
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`Page 11
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`exposure at the recommended dose. Treatment with palonosetron produced increased incidences of
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`adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased
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`incidences of pancreatic Islet cell adenorna and combined adenoma and carcinoma and pituitary
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`acienoma in maie rats. In female rate, it produced hepatocelluiar adenorna and carcinoma and increased
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`the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.
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`Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell {CHO/I-IGPRT)
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`forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse
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`micronucieus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian
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`(Ci-IO) cell chromosomal aberration test.
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`Palonosetron at oral doses up to 60 rnglkg/day (about 1894 times the recommended human intravenous
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`dose based on body surface area) was found to have no effect on fertility and reproductive performance
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`of male and female rats.
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`Pregnancy. Teratogenic Effects: Category B
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`Teratology studies have been performed in rats at oral doses up to 60 mglkg/day (1894 times the
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`recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60
`mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) and
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`have revealed no evidence of impaired ‘fertility or-harm to the fetus clue to 'palonosetr-on. There are,
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`however, no adequate and well-controlled studies in pregnant women. Because animal reproduction
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`studies are not always predictive of human response, palonosetron should be used during pregnancy
`only if clearly needed.
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`-'5;-g
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`Labor and Deliver);
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`Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the
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`mother or child are unknown.
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`Nursing Mothers
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`It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in
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`human milk and because of the potential for serious adverse reactions in nursing infants and the
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`otential for tumorigcnicity shown for palonosetron in the rat carcinogenicity study, a decision should
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`e made whether to discontinue nursing or to discontinue the drug, taking into account the importance
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`of the drug to the mother‘
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`Pediatric Use
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`Safety and effectiveness in patients below the age of 18 years have not been established.
`Geriatric Use
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`Of the 1374 adult cancer patients in clinical studies of palonosetrou, 316 (23%) were 2 65 years old,
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`while 71 (5%) were 2 75 years old. No overall differences in safety or effectiveness were observed
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`between these subjects and the younger subjects but greater sensitivity in some older individuals
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`cannot be ruled out. No dose adjustments or special monitoring are required for geriatric patients,
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`NDA 21 -3 72
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`ADVERSE REACTIONS
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`In clinical trials for the prevention of nausea and vomiting induced by moderately or highly
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`emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar
`in frequency and severity with Alexi and ondansetron or dolasetron. Following is a listing of all
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`adverse reactions reported by P. 2% of patients in these trials (Table 4).
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`Table 4: Adverse Reactions from Clzemotherapydnduced Nausea and
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`Vomiting Studies 2 2% in any Treahnent Group
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`Ondcnsetron
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`Alexi 0.25 mg
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`Doiasetrcn 100 mg
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`32 mg IV
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`(N=633)
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`(N-=41D)
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`ln other studies, 2 subjects experienced severe constipation following a single palonosetron dose of
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`approximately 0.75 neg, three times the recommended dose. One patient received a 10 1.!g/kg oral dose
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`in a post—operative nausea and vomiting study and one healthy suhj ect received a 0.75 mg IV dose in a
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`phannacokinetic study.
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`In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as
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`treatment-related or causality unknown, occurred following administration of Alexi to adult patients
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`receiving concomitant cancer chemotherapy:
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`Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension,
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`myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles
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`and QT prolongation . In many cases, the relationship to Aloxi was unclear.
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`Dermatological: < 1%: allergic dermatitis, rash.
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`Hearing and Vision: *1 1% motion sickness, tinnitus, eye irritation and amblyopia.
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`Gastrointestinal system: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, drymouth, hiccups and
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`flatulence.
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`General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.
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`Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes
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`occurred predominantly in patients receiving highly emetogenic chemotherapy.
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`Metaboiic: 1%:hyperI<alen1ia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis,
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`glycosuria, appetite decrease, anorexia.
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`Musculoskeletalz < 1%: arthralgia.
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`Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paraesthesia.
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`Psychiatric: 1%: anxiety, < 1%: euphoric mood.
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`Urinary System: < 1%: urinary retention.
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`Vascular: < 1%: vein discoloration, vein distention.
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`Overdosage
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`There is no known antidote to Alexi. Overdose should be managed with supportive care. Fifty adult
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`cancer patients were administered palonosetron at a dose of 90 ug/kg (equivalent to 6 mg fixed dose)
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`as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg.
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`This dose group had a similar incidence of adverse events compared to the other dose groups and no
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`large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose.
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`A single intravenous close of palonosetron at 30 mg/kg (947 and 474 times the human dose for rate and
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`mice, respectively, based on body surface area) was lethal to rats