palonosetron 0.25 MG in 5 ML Injection
DRUG INTERACTIONS
7 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.
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [ see Warnings and Precautions (5.2) ].
Coadministration of 0.25 mg I.V.
palonosetron and 20 mg I.V.
dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.
In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V.
bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C max : 15% increase).
A study in healthy volunteers involving single-dose I.V.
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.
The potential for clinically significant drug interactions with palonosetron appears to be low ( 7 )
OVERDOSAGE
10 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 mcg/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.
DESCRIPTION
11 ALOXI (palonosetron hydrochloride) is an antiemetic and antinauseant agent.
It is a serotonin-3 (5-HT 3 ) receptor antagonist with a strong binding affinity for this receptor.
Chemically, palonosetron hydrochloride is: (3a S) -2-[( S )-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1 H benz[ de ]isoquinoline hydrochloride.
The empirical formula is C 19 H 24 N 2 O.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, nonpyrogenic, isotonic, buffered solution for intravenous administration.
ALOXI injection is available as 5 mL single use vial or 1.5 mL single use vial.
Each 5 mL vial contains 0.25 mg palonosetron base as 0.28 mg palonosetron hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.
Each 1.5 mL vial contains 0.075 mg palonosetron base as 0.084 mg palonosetron hydrochloride, 62.25 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.
The pH of the solution in the 5 mL and 1.5 mL vials is 4.5 to 5.5.
The structural formula for serotonin-3 (5-HT3) is a 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.
CLINICAL STUDIES
14 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 14.1 Chemotherapy-Induced Nausea and Vomiting in Adults 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 assessed.
Moderately Emetogenic Chemotherapy Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V.
ALOXI with either single-dose I.V.
ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide 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 I.V.
palonosetron from 0.3 to 90 mcg/kg (equivalent to 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 I.V.
ALOXI with single-dose I.V.
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 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.
Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 81 0.009 Ondansetron 32 mg I.V.
185 69 2 ALOXI 0.25 mg 189 63 NS Dolasetron 100 mg I.V.
191 53 Highly Emetogenic 3 ALOXI 0.25 mg 223 59 NS Difference in Complete Response Rates Ondansetron 32 mg I.V.
221 57 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-HT 3 receptor antagonists has not been adequately demonstrated in the acute phase.
Table 5: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 74 <0.001 Ondansetron 32 mg I.V.
185 55 2 ALOXI 0.25 mg 189 54 0.004 Dolasetron 100 mg I.V.
191 39 Difference in Complete Response Rates 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 6: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 69 <0.001 Ondansetron 32 mg I.V.
185 50 2 ALOXI 0.25 mg 189 46 0.021 Dolasetron 100 mg I.V.
191 34 Difference in Complete Response Rates 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.
14.2 Chemotherapy-Induced Nausea and Vomiting in Pediatrics One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients.
The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white.
Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg).
Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m 2 ), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin.
Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.
Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy.
Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron.
Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%.
The non-inferiority margin was 15%.
Efficacy Results As shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.
Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates I.V.
ALOXI 20 mcg/kg (N=165) I.V.
Ondansetron 0.15 mg/kg x 3 (N=162) Difference [97.5% Confidence Interval]*: I.V.
ALOXI minus I.V.
Ondansetron Comparator 59.4% 58.6% 0.36% [-11.7%, 12.4%] * To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.
In patients that received ALOXI at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.
14.3 Postoperative Nausea and Vomiting In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (Study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery.
All patients received general anesthesia.
Study 1 was a pivotal study conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of post operative nausea and vomiting and/or motion sickness.
In Study 1 patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia.
The antiemetic activity of palonosetron was evaluated during the 0 to 72 hour time period after surgery.
Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers.
As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian.
The age of patients ranged from 21 to 74 years, with a mean age of 37.9 years.
Three patients were greater than 65 years of age.
Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72 hours postoperatively.
Secondary efficacy endpoints included: Complete Response (CR) 0-48 and 0-72 hours Complete Control (CC) defined as CR and no more than mild nausea Severity of nausea (none, mild, moderate, severe) The primary hypothesis in Study 1 was that at least one of the three palonosetron doses were superior to placebo.
Results for Complete Response in Study 1 for 0.075 mg palonosetron versus placebo are described in the following table.
Table 8: Prevention of Postoperative Nausea and Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo Treatment n/N (%) Palonosetron Vs Placebo Δ p-value* Co-primary Endpoints CR 0-24 hours Palonosetron 59/138 (42.8%) 16.8% 0.004 Placebo 35/135 (25.9%) CR 24-72 hours Palonosetron 67/138 (48.6%) 7.8% 0.188 Placebo 55/135 (40.7%) * To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017.
Δ Difference (%): palonosetron 0.075 mg minus placebo Palonosetron 0.075 mg reduced the severity of nausea compared to placebo.
Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.
A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate I.V.
palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy.
Five I.V.
palonosetron doses (0.1, 0.3, 1.0, 3.0, and 30 µg/kg) were evaluated in a total of 381 intent-to-treat patients.
The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery.
The lowest effective dose was palonosetron 1 µg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004.
Palonosetron 1 µg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.
HOW SUPPLIED
16 /STORAGE AND HANDLING NDC # 62856-797-01, ALOXI Injection 0.25 mg/5 mL (free base) single-use vial individually packaged in a carton.
NDC # 62856-798-01, ALOXI Injection 0.075 mg/1.5 mL (free base) single-use vial packaged in a carton containing 5 vials.
Storage 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.
RECENT MAJOR CHANGES
Indication ( 1.2 ) Dosage and Administration, Pediatric Cancer Patients ( 2.1 ) Warnings and Precautions, Serotonin Syndrome ( 5.2 ) 05/2014 05/2014 09/2014
GERIATRIC USE
8.5 Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years).
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 adjustment or special monitoring are required for geriatric patients.
Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old.
No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded.
No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients.
However, ALOXI efficacy in geriatric patients has not been adequately evaluated.
DOSAGE FORMS AND STRENGTHS
3 ALOXI is supplied as a single-use sterile, clear, colorless solution in glass vials that provide: 0.25 mg (free base) per 5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.25 mg/5mL (free base) single-use vial ( 3 ) 0.075 mg/1.5mL (free base) single-use vial ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Palonosetron is a 5-HT 3 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-HT 3 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-HT 3 receptors located on vagal afferents to initiate the vomiting reflex.
Postoperative nausea and vomiting is influenced by multiple patient, surgical, and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract.
The 5-HT 3 receptor has been demonstrated to selectively participate in the emetic response.
INDICATIONS AND USAGE
1 ALOXI is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses ( 1.1 ) Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses ( 1.1 ) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.
Efficacy beyond 24 hours has not been demonstrated ( 1.3 ) ALOXI is indicated in pediatric patients aged 1 month to less than 17 years for: Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy ( 1.2 ) 1.1 Chemotherapy -Induced Nausea and Vomiting in Adults ALOXI is indicated for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 M onth to Less than 17 Years ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.
1.3 Postoperative Nausea and Vo miting in Adults ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.
Efficacy beyond 24 hours has not been demonstrated.
As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.
In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low.
PEDIATRIC USE
8.4 Pediatric Use Chemotherapy-Induced Nausea and Vomiting Safety and effectiveness of ALOXI have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.
Use is supported by a clinical trial where 165 pediatric patients aged 2 months to <17 years were randomized to receive a single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [ see Clinical Studies (14.2) ] .
While this study demonstrated that pediatric patients require a higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [ see Adverse Reactions (6.1) ] .
Safety and effectiveness of ALOXI in neonates (less than 1 month of age) have not been established.
Postoperative Nausea and Vomiting Studies Safety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting.
Two pediatric trials were performed.
Pediatric Study 1, a dose finding study, was conducted to compare two doses of palonosetron, 1 mcg/kg (max 0.075 mg) versus 3 mcg/kg (max 0.25 mg).
A total of 150 pediatric surgical patients participated, age range 1 month to <17 years.
No dose response was observed.
Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared I.V.
palonosetron (1 mcg/kg, max 0.075 mg) versus I.V.
ondansetron.
A total of 670 pediatric surgical patients participated, age 30 days to <17 years.
The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group.
Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated.
Adverse reactions to palonosetron were similar to those reported in adults (Table 2).
PREGNANCY
8.1 Pregnancy Pregnancy Category B Risk Summary Adequate and well controlled studies with ALOXI have not been conducted in pregnant women.
In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively.
Because animal reproduction studies are not always predictive of human response, ALOXI should be used during pregnancy only if clearly needed.
Animal Data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether ALOXI is present 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 [ see Nonclinical Toxicology (13.1) ] , 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT 3 receptor antagonists ( 5.1 ) Serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs ( 5.2 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT 3 receptor antagonists.
5.2 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists.
Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue).
Some of the reported cases were fatal.
Serotonin syndrome occurring with overdose of another 5-HT 3 receptor antagonist alone has also been reported.
The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.
Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ALOXI and other serotonergic drugs.
If symptoms of serotonin syndrome occur, discontinue ALOXI and initiate supportive treatment.
Patients should be informed of the increased risk of serotonin syndrome, especially if ALOXI is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labelling ( Patient Information ).
Instructions for Patients Patients should be advised to report to their physician all of their medical conditions, including any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6.3) ].
Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI and another serotonergic agent such as medications to treat depression and migraines.
Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [ see Warnings and Precautions (5.2) ].
Patients should be instructed to read the Patient Information.
DOSAGE AND ADMINISTRATION
2 Chemotherapy-Induced Nausea and Vomiting ( 2.1 ) Age Dose* Infusion Time Adults 0 .
2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.
30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.
30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting ( 2.1 ) Adult Dosage: a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.
2.1 Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Age Dose* Infusion Time Adults 0 .
2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.
30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.
30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting Dosage for Adults – a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.
2.2 Instructions for I ntravenous Administration ALOXI is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/ mL).
ALOXI should not be mixed with other drugs.
The infusion line should be flushed with normal saline before and after administration of ALOXI.
Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.