NDA 21-372
`Page 4
`
`
` AloxiTM (Palonosetron Hydrochloride) Injection
`
`Helsinn Healthcare S.A. NDA 21-372 Palonosetron: Proposed Labeling
`DESCRIPTION
`Aloxi1 (palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is a selective serotonin
`subtype 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor. Chemically,
`palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-
`oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C19H24N2O.HCl, with a
`molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the
`following structural formula:
`
`
`
`
`
`
`Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely 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. Each 5-ml vial of Aloxi injection contains 0.25 mg palonosetron base as
`hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous
`administration. The pH of the solution is 4.5 to 5.5.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics
`Palonosetron is a selective 5-HT3 receptor antagonist with a strong binding affinity for this receptor
`and little or no affinity for other receptors.
`
`Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly
`when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of
`the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is
`thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the
`enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3
`receptors located on vagal afferents to initiate the vomiting reflex.
`
`
`1 Pending trademark of Helsinn Healthcare SA
`Lugano, Switzerland
`All rights reserved
`COPYRIGHT Helsinn Healthcare SA, 2003
`
`

`

`NDA 21-372
`Page 5
`
`The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were
`comparable to ondansetron and dolasetron in clinical trials. In non-clinical studies palonosetron
`possesses the ability to block ion channels involved in ventricular de- and re-polarization and to
`prolong action potential duration. In clinical trials, the dose-response relationship to the QTc interval
`has not been fully evaluated.
`Pharmacokinetics
`
`After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in
`plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma
`concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-
`proportional over the dose range of 0.3–90 µg/kg in healthy subjects and in cancer patients. Following
`single IV dose of palonosetron at 3 µg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD)
`maximum plasma concentration was estimated to be 5.6 ± 5.5 ng/mL and mean AUC was 35.8 ± 20.9
`ng•hr/mL.
`
`Distribution
`
`Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of
`palonosetron is bound to plasma proteins.
`
`Metabolism
`Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two
`primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each
`have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism
`studies have suggested that CYP2D6 and to a lesser extent, CYP3A and CYP1A2 are involved in the
`metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly
`different between poor and extensive metabolizers of CYP2D6 substrates.
`
`Elimination
`
`After a single intravenous dose of 10 µg/kg [14C]-palonosetron, approximately 80% of the dose was
`recovered within 144 hours in the urine with palonosetron representing approximately 40% of the
`administered dose. In healthy subjects the total body clearance of palonosetron was 160 ± 35 mL/h/kg
`and renal clearance was 66.5± 18.2 mL/h/kg . Mean terminal elimination half-life is approximately 40
`hours.
`
`Special Populations
`Geriatrics
`Population PK analysis and clinical safety and efficacy data did not reveal any differences between
`cancer patients ≥ 65 years of age and younger patients (18 to 64 years). No dose adjustment is
`required for these patients.
`
`
`

`

`NDA 21-372
`Page 6
`
`Race
`
`Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects
`over the dose range of 3 – 90 µg/kg. Total body clearance was 25% higher in Japanese subjects
`compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron
`in Blacks has not been adequately characterized.
`
`Renal Impairment
`Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic
`parameters. Total systemic exposure increased by approximately 28% in severe renal impairment
`relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal
`impairment.
`
`Hepatic Impairment
`
`Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the
`healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic
`impairment.
`
`Drug-Drug Interactions
`
`
`Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with
`the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is
`not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CPY2D6, CYP2E1 and CYP3A4/5
`(CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5.
`Therefore the potential for clinically significant drug interactions with palonosetron appears to be low.
`
` A
`
` study in healthy volunteers involving single-dose IV palonosetron (0.75 mg) and steady state oral
`metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.
`
`In controlled clinical trials, Aloxi injection has been safely administered with corticosteroids,
`analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.
`
`
`Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin,
`cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.
`
`
`
`CLINICAL STUDIES
`Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting
`induced by both moderately and highly emetogenic chemotherapy was studied in three Phase 3 trials
`and one Phase 2 trial. In these double-blind studies, complete response rates (no emetic episodes and
`no rescue medication) and other efficacy parameters were assessed through at least 120 hours after
`
`

`

`NDA 21-372
`Page 7
`
`administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of
`chemotherapy was also studied.
`
`Moderately Emetogenic Chemotherapy
`Two Phase 3, double-blind trials involving 1132 patients compared single-dose IV Aloxi with either
`single-dose IV ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately
`emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide < 1500
`mg/m², doxorubicin > 25 mg/m², epirubicin, irinotecan, and methotrexate > 250 mg/m². Concomitant
`corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of
`patients in study 2. The majority of patients in these studies were women (77%), White (65%) and
`naïve to previous chemotherapy (54%). The mean age was 55 years.
`
`Highly Emetogenic Chemotherapy
`A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose IV palonosetron
`from 0.3 to 90 µg/kg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve adult
`cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ≥ 70 mg/m² or
`cyclophosphamide > 1100 mg/m²). Concomitant corticosteroids were not administered
`prophylactically. Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in
`preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.
`
` A
`
` Phase 3, double-blind trial involving 667 patients compared single-dose IV Aloxi with single-dose
`IV ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including
`cisplatin ≥ 60 mg/m², cyclophosphamide > 1500 mg/m², and dacarbazine. Corticosteroids were co-
`administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were
`women, 60% White, and 59% naïve to previous chemotherapy. The mean age was 52 years.
`
`Efficacy Results
`
`The antiemetic activity of Aloxi was evaluated during the acute phase (0-24 hours) [Table 1], delayed
`phase (24-120 hours) [Table 2], and overall phase (0-120 hours) [Table 3] post-chemotherapy in Phase
`3 trials.
`
`
`

`

`NDA 21-372
`Page 8
`
`Table 1:
`
`
`Chemo-
`therapy
`
`Moderate
`ly
`Emetoge
`nic
`
`Highly
`Emetoge
`nic
`
`1
`
`2
`
`3
`
`81
`
`69
`
`63
`
`53
`
`59
`
`57
`
`18
`9
`
`18
`5
`
`18
`9
`
`19
`1
`
`22
`3
`
`22
`1
`
`Prevention of Acute Nausea and Vomiting (0-24 hours):
`Complete Response Rates
`
`
`
`% with
`Complete
`N a
`Study
`Treatm
`Response
`ent
`Group
`Aloxi
`0.25
`mg
`Ondans
`etron
`32 mg
`IV
`Aloxi
`0.25
`mg
`Dolaset
`ron 100
`mg IV
`Aloxi
`0.25
`mg
`Ondans
`etron
`32 mg
`IV
`
`
`p-value
`b
`
`0.009
`
`
`97.5% Confidence Interval
`Aloxi minus Comparator c
`
`
`[ 2%, 23% ]
`
`[
`
`[ -2%, 22% ]
`
`[
`
`]
`
`]
`
`NS
`
`[
`
`[ -9%, 13% ]
`]
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`NS
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=0.025.
`c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between Aloxi and comparator.
`
`These studies show that Aloxi was effective in the prevention of acute nausea and vomiting associated
`with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. In study 3,
`efficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical
`superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute
`phase.
`
`
`

`

`NDA 21-372
`Page 9
`
`Table 2:
`
`
`Chemo-
`therapy
`
`Moderate
`ly
`Emetoge
`nic
`
`1
`
`2
`
`Prevention of Delayed Nausea and Vomiting (24-120 hours):
`Complete Response Rates
`% with
`
`
`
`N a
`Comple
`Study
`Treatm
`te
`ent
`Respons
`Group
`e
`74
`
`
`p-value
`b
`
`
`97.5% Confidence Interval
`Aloxi minus Comparator c
`
`<0.001
`
`[ 8%, 30% ]
`
`[
`
`]
`
`55
`
`54
`
`39
`
`[
`
`[ 3%, 27% ]
`
`]
`
`0.004
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`18
`9
`18
`5
`
`18
`9
`19
`1
`
`Aloxi
`0.25 mg
`Ondanse
`tron 32
`mg IV
`Aloxi
`0.25 mg
`Dolasetr
`on 100
`mg IV
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=0.025.
`c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between Aloxi and comparator.
`
`These studies show that Aloxi was effective in the prevention of delayed nausea and vomiting
`associated with initial and repeat courses of moderately emetogenic chemotherapy.
`
`Table 3:
`
`Prevention of Overall Nausea and Vomiting (0-120 hours):
`Complete Response Rates
`% with
`
`
`
`N a
`Comple
`Study
`Treatm
`te
`ent
`Respons
`Group
`e
`69
`
`
`Chemo-
`therapy
`
`Moderate
`ly
`Emetoge
`nic
`
`1
`
`2
`
`
`p-value
`b
`
`
`97.5% Confidence Interval
`Aloxi minus Comparator c
`
`<0.001
`
`[ 7%, 31% ]
`
`]
`
`[
`
`50
`
`46
`
`34
`
`[
`
`[ 0%, 24% ]
`
`]
`
`0.021
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`18
`9
`18
`5
`
`18
`9
`19
`1
`
`Aloxi
`0.25 mg
`Ondanse
`tron 32
`mg IV
`Aloxi
`0.25 mg
`Dolasetr
`on 100
`mg IV
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=0.025.
`c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between Aloxi and comparator.
`
`These studies show that Aloxi was effective in the prevention of nausea and vomiting throughout the
`120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer
`chemotherapy.
`
`
`

`

`NDA 21-372
`Page 10
`
`INDICATIONS AND USAGE
`Aloxi is indicated for:
`1) the prevention of acute nausea and vomiting associated with initial and repeat courses of
`moderately and highly emetogenic cancer chemotherapy, and
`2) the prevention of delayed nausea and vomiting associated with initial and repeat courses of
`moderately emetogenic cancer chemotherapy.
`
`CONTRAINDICATIONS
`Aloxi is contraindicated in patients known to have hypersensitivity to the drug or any of its
`components.
`
`PRECAUTIONS
`General
`
`Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective
`5-HT3 receptor antagonists.
`
`Although palonosetron has been safely administered to 192 patients with pre-existing cardiac
`impairment in the Phase 3 studies, Aloxi should be administered with caution in patients who have or
`may develop prolongation of cardiac conduction intervals, particularly QTc. These include patients
`with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte
`abnormalities, patients with congenital QT syndrome, patients taking anti-arrhythmic drugs or other
`drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy. In 3 pivotal
`trials, ECGs were obtained at baseline and 24 hours after subjects received palonosetron or a
`comparator drug. In a subset of patients ECGs were also obtained 15 minutes following dosing. The
`percentage of patients (< 1%) with changes in QT and QTc intervals (either absolute values of > 500
`msec or changes of > 60 msec from baseline) was similar to that seen with the comparator drugs.
`
`
`
`Drug Interactions
`
`Palonosetron is eliminated from the body through both renal excretion and metabolic pathways.
`Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low
`(See CLINICAL PHARMACOLOGY, Drug-Drug Interactions section).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of
`palonosetron at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The
`highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289
`times the human exposure (AUC= 29.8 ng•h/ml) at the recommended intravenous dose of 0.25 mg. In
`a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral
`doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively. The highest doses
`produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human
`
`

`

`NDA 21-372
`Page 11
`
`exposure at the recommended dose. Treatment with palonosetron produced increased incidences of
`adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased
`incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary
`adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased
`the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.
`
`Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT)
`forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse
`micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian
`(CHO) cell chromosomal aberration test.
`Palonosetron at oral doses up to 60 mg/kg/day (about 1894 times the recommended human intravenous
`dose based on body surface area) was found to have no effect on fertility and reproductive performance
`of male and female rats.
`
`
`Pregnancy. Teratogenic Effects: Category B
`Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the
`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
`have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are,
`however, no adequate and well-controlled studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response, palonosetron should be used during pregnancy
`only if clearly needed.
`
`
`
`Labor and Delivery
`Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the
`mother or child are unknown.
`Nursing Mothers
`It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in
`human milk and because of the potential for serious adverse reactions in nursing infants and the
`potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should
`be made whether to discontinue nursing or to discontinue the drug, taking into account the importance
`of the drug to the mother.
`
`
`
`Pediatric Use
`Safety and effectiveness in patients below the age of 18 years have not been established.
`Geriatric Use
`Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old,
`while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed
`between these subjects and the younger subjects but greater sensitivity in some older individuals
`cannot be ruled out. No dose adjustments or special monitoring are required for geriatric patients.
`
`

`

`Event
`
`Aloxi 0.25 mg
`(N=633)
`
`60 (9%)
`29 (5%)
`8 (1%)
`8 (1%)
`3 (< 1%)
`1 (< 1%)
`1 (< 1%)
`
`Dolasetron 100 mg
`IV (N=194)
`
`32 (16%)
`12 (6%)
`4 (2%)
`4 (2%)
`4 (2%)
`3 (2%)
`3 (2%)
`
`NDA 21-372
`Page 12
`
`ADVERSE REACTIONS
`In clinical trials for the prevention of nausea and vomiting induced by moderately or highly
`emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar
`in frequency and severity with Aloxi and ondansetron or dolasetron. Following is a listing of all
`adverse reactions reported by ≥ 2% of patients in these trials (Table 4).
`
`Table 4: Adverse Reactions from Chemotherapy-Induced Nausea and
`Vomiting Studies ≥ 2% in any Treatment Group
`Ondansetron
`32 mg IV
`(N=410)
`34 (8%)
`8 (2%)
`7 (2%)
`9 (2%)
`4 (1%)
`2 (< 1%)
`3 (1%)
`
`Headache
`Constipation
`Diarrhea
`Dizziness
`Fatigue
`Abdominal Pain
`Insomnia
`
`In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of
`approximately 0.75 mg, three times the recommended dose. One patient received a 10 µg/kg oral dose
`in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg IV dose in a
`pharmacokinetic study.
`
`In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as
`treatment-related or causality unknown, occurred following administration of Aloxi to adult patients
`receiving concomitant cancer chemotherapy:
`
`Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension,
`myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles
`and QT prolongation . In many cases, the relationship to Aloxi was unclear.
`
`Dermatological: < 1%: allergic dermatitis, rash.
`
`Hearing and Vision: < 1% motion sickness, tinnitus, eye irritation and amblyopia.
`
`Gastrointestinal system: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and
`flatulence.
`
`General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.
`
`Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes
`occurred predominantly in patients receiving highly emetogenic chemotherapy.
`
`

`

`NDA 21-372
`Page 13
`
`
`Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis,
`glycosuria, appetite decrease, anorexia.
`
`Musculoskeletal: < 1%: arthralgia.
`
`Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paraesthesia.
`
`Psychiatric: 1%: anxiety, < 1%: euphoric mood.
`
`Urinary System: < 1%: urinary retention.
`
`Vascular: < 1%: vein discoloration, vein distention.
`
`
`Overdosage
`There is no known antidote to Aloxi. Overdose should be managed with supportive care. Fifty adult
`cancer patients were administered palonosetron at a dose of 90 µg/kg (equivalent to 6 mg fixed dose)
`as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg.
`This dose group had a similar incidence of adverse events compared to the other dose groups and no
`dose response effects were observed. Dialysis studies have not been performed, however, due to the
`large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose.
`A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and
`mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of
`toxicity were convulsions, gasping, pallor, cyanosis and collapse.
`
`
`DOSAGE AND ADMINISTRATION
`
`Dosage for Adults
`The recommended dosage of Aloxi is 0.25 mg administered as a single dose approximately 30 minutes
`before the start of chemotherapy. Repeated dosing of Aloxi™ within a seven day interval is not
`recommended because the safety and efficacy of frequent (consecutive or alternate day) dosing in
`patients has not been evaluated.
`
`Use in Geriatric Patients and in Patients with Impaired Renal or Hepatic Function
`No dosage adjustment is recommended.
`
`Dosage for Pediatric Patients
`A recommended intravenous dosage has not been established for pediatric patients.
`
`Administration
`Aloxi is to be infused intravenously over 30 seconds. Aloxi should not be mixed with other drugs.
`Flush the infusion line with normal saline before and after administration of Aloxi.
`
`

`

`NDA 21-372
`Page 14
`
`Stability
`Parenteral drug products should be inspected visually for particulate matter and discoloration before
`administration, whenever solution and container permit.
`
`HOW SUPPLIED
`Aloxi (palonosetron hydrochloride), 0.25 mg (free base) in 5 ml, is supplied as a single-use sterile,
`clear, colorless solution in glass vials ready for intravenous injection.
`Store at controlled temperature of 20–25°C (68°F–77°F). Excursions permitted to 15–30 °C (59-
`86°F). Protect from freezing. Protect from light.
`NDC Number 58063-797-25
`Prescribing information as of XXXX, 2003
`Mfd by Cardinal Health, Albuquerque, NM, USA and
`Helsinn Birex Pharmaceuticals, Dublin, Ireland
`Mfd for Helsinn Healthcare SA, Switzerland
`Distributed by MGI PHARMA, INC.; Bloomington, MN, U.S.A.
`
`
`
`
`
`
`
`
`