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Palonosetron hydrochloride
ALOXI (palonosetron hydrochloride)
DESCRIPTION
ALOXI (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.
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.
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 ±20.9ng•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 ³
65 years of age and younger patients (18 to 64 years). No dose adjustment
is required for these patients.
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, CYP2D6,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 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 ³
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 ³
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.
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Table 1:Prevention of Acute Nausea and Vomiting (0-24
hours):Complete Response Rates
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Chemotherapy
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Study
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Treatment Group
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Na
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% with Complete Response
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p-valueb
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Moderately Emetogenic
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1
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ALOXI 0.25 mg
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189
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81
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0.009
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Ondansetron32 mg IV
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185
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69
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2
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ALOXI0.25 mg
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189
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63
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NS
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Dolasetron100 mg IV
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191
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53
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Highly Emetogenic
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3
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ALOXI0.25 mg
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223
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59
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NS
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Ondansetron 32 mg IV
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221
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57
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a Intent-to-treat cohort
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b 2-sided Fisher’s exact test.Significance level at a=0.025.
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c These studies were designed to show non-inferiority.A lower
bound greater than –15% demonstrates non-inferiority between ALOXI and
comparator.
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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.
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Table 2:Prevention of Delayed Nausea and Vomiting (24-120
hours):Complete Response Rates
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Chemotherapy
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Study
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Treatment Group
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Na
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% with Complete Response
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p-valueb
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Moderately Emetogenic
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1
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ALOXI0.25 mg
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189
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74
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<0.001
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Ondansetron32 mg IV
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185
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55
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2
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ALOXI0.25 mg
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189
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54
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0.004
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Dolasetron100 mg IV
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191
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39
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a Intent-to-treat cohort
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b 2-sided Fisher’s exact test. Significance level at a=0.025.
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c These studies were designed to show non-inferiority. A lower
bound greater than –15% demonstrates non-inferiority between ALOXI and
comparator.
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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.
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Table 3:Prevention of Overall Nausea and Vomiting (0-120
hours):Complete Response Rates
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Chemotherapy
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Study
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Treatment Group
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Na
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% with Complete Response
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p-valueb
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Moderately Emetogenic
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1
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ALOXI0.25 mg
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189
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69
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<0.001
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Ondansetron32 mg IV
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185
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50
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2
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ALOXI0.25 mg
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189
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46
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0.021
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Dolasetron100 mg IV
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191
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34
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a Intent-to-treat cohort
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b 2-sided Fisher’s exact test. Significance
level at a=0.025.
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c These studies were designed to show non-inferiority.
A lower bound greater than –15% demonstrates non-inferiority between ALOXI
and comparator.
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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.
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.
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.
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 July 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, USA ALOXI™ is
a pending trademark of Helsinn Healthcare, SA,Lugano, Switzerland.
SIDE EFFECTS
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 ³ 2% of patients in these trials
(Table 4).
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Table 4:Adverse Reactions from Chemotherapy-Induced
Nausea and Vomiting Studies ³ 2% in
any Treatment Group
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Event
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ALOXI 0.25 mg (N=633)
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Ondansetron 32 mg IV (N=410)
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Dolasetron 100 mg IV (N=194)
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Headache
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60 (9%)
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34 (8%)
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32 (16%)
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Constipation
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29 (5%)
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8 (2%)
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12 (6%)
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Diarrhea
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8 (1%)
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7 (2%)
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4 (2%)
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Dizziness
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8 (1%)
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9 (2%)
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4 (2%)
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Fatigue
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3 (<1%)
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4 (1%)
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4 (2%)
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Abdominal Pain
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1 (<1%)
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2 (<1%)
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3 (2%)
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Insomnia
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1 (<1%)
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3 (1%)
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3 (2%)
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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.
Metabolic: 1%:hyperkalemia,< 1%:electrolyte fluctuations,
hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.
Musculoskeletal: < 1%:arthralgia.
Nervous System: 1%:dizziness,< 1%:somnolence,insomnia,hypersomnia,paresthesia.
Psychiatric: 1%:anxiety,< 1%:euphoric mood.
Urinary System: < 1%:urinary retention.
Vascular: < 1%:vein discoloration, vein distention.
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).
WARNINGS
No separate information available.
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.
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 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 ³ 65 years old, while 71 (5%) were ³
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.
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