Palonosetron Drug Information
Generic name: PALONOSETRON HYDROCHLORIDE
Uses of Palonosetron
- Palonosetron hydrochloride injection is indicated in adults for prevention of:
- Acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
- Acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC).
- 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, palonosetron hydrochloride is recommended even where the incidence of postoperative nausea and/or vomiting is low. Palonosetron hydrochloride injection is indicated in pediatric patients 1 month to less than 17 years of age for prevention of:
- Acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Palonosetron hydrochloride is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in: Adults for prevention of:
- Postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated. Pediatric patients aged 1 month to less than 17 years for prevention of:
Dosage & Administration of Palonosetron
Recommended Dosage Prevention of Chemotherapy-Induced Nausea and Vomiting The recommended dosage of palonosetron hydrochloride injection for prevention of nausea and vomiting associated with HEC and MEC in adults and associated with emetogenic chemotherapy, including HEC in pediatric patients 1 month to less than 17 years of age is shown in Table 1. Table 1: Recommended Dosage of Palonosetron Hydrochloride Injection for the Prevention of Nausea and Vomiting Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years Postoperative Nausea and Vomiting The recommended dosage of palonosetron hydrochloride injection in adults for PONV is 0.075 mg administered as a single intravenous dose over 10 seconds immediately before the induction of anesthesia.
Instructions for Intravenous Administration •
Palonosetron hydrochloride injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/mL). • Do not mix palonosetron hydrochloride injection with other drugs. • Flush the infusion line with normal saline before and after administration of palonosetron hydrochloride injection. • Inspect palonosetron hydrochloride injection visually for particulate matter and discoloration before administration. • Discard unused portion.
| Age | Dose Note different dosing units in pediatrics | Infusion Time |
| Adults | 0.25 mg as a single dose | Infuse over 30 second s beginning approximately 30 minutes before the start of chemotherapy |
| Pediatrics (1 month to less than 17 years) | 20 micrograms per kilogram (maximum 1.5 mg) as a single dose | Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy |
| Age | Dose Note different dosing units in pediatrics | Infusion Time |
|---|---|---|
| Adults | 0.25 mg as a single dose | Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy |
| Pediatrics (1 month to less than 17 years) | 20 micrograms per kilogram (max 1.5 mg) as a single dose | Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy |
Side Effects of Palonosetron
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chemotherapy-Induced Nausea and Vomiting Adults In double-blind randomized clinical trials for the prevention of nausea and vomiting induced by MEC or HEC, 1374 adult patients received a single dose of palonosetron hydrochloride injection, ondansetron (Studies 1 and 3) or dolasetron (Study 2) administered 30 minutes prior to chemotherapy. Adverse reactions were similar in frequency and severity in all 3 treatment groups.
Common adverse reactions reported in at least 2% of patients in these trials are shown in Table 2. Table 2: Common Adverse Reactions Reported in at least 2% of patients in any treatment group in Adults with Receiving MEC (Studies 1 and 2) or HEC (Study 3) Less common adverse reactions, reported in 1% or less of patients, in Studies 1, 2 and 3 were: • Cardiovascular: non-sustained tachycardia, bradycardia, hypotension, hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation • Dermatological: allergic dermatitis, rash • Hearing and Vision: motion sickness, tinnitus, eye irritation and amblyopia • Gastrointestinal System: diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups and flatulence • General: weakness, fatigue, fever, hot flash, flu-like syndrome • Liver: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy • Metabolic: hyperkalemia, electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia • Musculoskeletal: arthralgia • Nervous System: dizziness, somnolence, insomnia, hypersomnia, paresthesia • Psychiatric: anxiety, euphoric mood • Urinary System: urinary retention • Vascular: vein discoloration, vein distention In other studies, 2 subjects experienced severe constipation following a single palonosetron hydrochloride injection dose of approximately 0.75 mg (three times the recommended dose).
Adverse reactions were evaluated in pediatric patients receiving palonosetron hydrochloride injection for up to 4 chemotherapy cycles. Rates of adverse reactions between palonosetron hydrochloride injection and placebo groups were similar. Some events are known to be associated with, or may be exacerbated by, concomitant perioperative and intraoperative medications administered in this surgical population.
A thorough QT/QTc study demonstrated palonosetron hydrochloride injection does not prolong the QT interval to any clinically relevant extent. Table 3: Common Adverse Reactions Reported in at least 2% of patients in any treatment group in Trials of Adults with Postoperative Nausea and Vomiting Less common adverse reactions, reported in 1% of less of patients, in these PONV clinical trials were: • Cardiovascular: QTc prolongation, sinus bradycardia, tachycardia, blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema, ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo. • Dermatological: pruritus • Gastrointestinal System: flatulence, dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia • General: chills • Liver: increases in AST and/or ALT, hepatic enzyme increased • Metabolic: hypokalemia, anorexia • Nervous System: dizziness • Respiratory: hypoventilation, laryngospasm • Urinary System: urinary retention
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of palonosetron hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock • Injection site reactions: including burning, induration, discomfort and pain
| Adverse Reaction | Palonosetron Hydrochloride Injection 0.25 mg intravenously (N = 633) | Ondansetron 32 mg intravenously (N = 410) | Dolasetron 100 mg intravenously (N = 194) |
|---|---|---|---|
| Headache | 9% | 8% | 16% |
| Constipation | 5% | 2% | 6% |
| Diarrhea | 1% | 2% | 2% |
| Dizziness | 1% | 2% | 2% |
| Fatigue | < 1% | 1% | 2% |
| Abdominal Pain | < 1% | < 1% | 2% |
| Insomnia | < 1% | 1% | 2% |
| Adverse Reaction | Palonosetron Hydrochloride Injection 0.075 mg intravenously (N = 336) | Placebo (N = 369) |
|---|---|---|
| Electrocardiogram QT prolongation | 5% | 3% |
| Bradycardia | 4% | 4% |
| Headache | 3% | 4% |
| Constipation | 2% | 3% |
Warnings & Cautions for Palonosetron
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of palonosetron hydrochloride injection. These reactions occurred in patients with or without known hypersensitivity to other 5-HT 3 receptor antagonists. If hypersensitivity reactions occur, discontinue palonosetron hydrochloride injection and initiate appropriate medical treatment.
Do not reinitiate palonosetron hydrochloride injection in patients who have previously experienced symptoms of hypersensitivity.
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 palonosetron hydrochloride and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue palonosetron hydrochloride and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if palonosetron hydrochloride is used concomitantly with other serotonergic drugs.
Drug Interactions with Palonosetron
Serotonergic Drugs
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). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue palonosetron hydrochloride and initiate supportive treatment.
Pregnancy Safety for Palonosetron
Pregnancy Risk Summary There are no available data on palonosetron hydrochloride use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron hydrochloride during the period of organogenesis at doses up to 1,894 and 3,789 times the recommended human intravenous dose in rats and rabbits, respectively (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In animal reproduction studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron hydrochloride at doses up to 60 mg/kg/day (1,894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3,789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.
Pediatric Use of Palonosetron
Pediatric Use Chemotherapy-Induced Nausea and Vomiting Safety and effectiveness of palonosetron hydrochloride injection 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 HEC. 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. Safety and effectiveness of palonosetron hydrochloride in neonates (less than 1 month of age) have not been established.
Postoperative Nausea and Vomiting Studies Safety and effectiveness have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed. A total of 150 pediatric surgical patients participated, age range 1 month to less than 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 intravenous palonosetron hydrochloride (1 mcg/kg, maximum 0.075 mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to less than 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, therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults.
Contraindications for Palonosetron
Palonosetron hydrochloride is contraindicated in patients known to have hypersensitivity to palonosetron. Hypersensitivity to palonosetron or any of its components
Overdosage Information for Palonosetron
There is no known antidote to palonosetron. Overdose should be managed with supportive care. 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 hydrochloride 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.
Clinical Studies of Palonosetron
Prevention of Nausea and Vomiting Associated with MEC and HEC in Adults Efficacy of a single intravenous dose of palonosetron hydrochloride injection in preventing acute and delayed nausea and vomiting associated with MEC or HEC were studied in 4 trials. 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 hydrochloride injection in repeated courses of chemotherapy was also assessed.
The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%). The mean age was 55 years. 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 associated with HEC. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. The mean age was 52 years.
Clinical superiority over other 5-HT 3 receptor antagonists has not been adequately demonstrated in the acute phase. In Study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly. Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (< 1500 mg/m2), 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 hydrochloride injection 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 hydrochloride injection minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.
Prevention of Postoperative Nausea and Vomiting in Adults In a multicenter, randomized, stratified, double-blind, parallel-group, clinical trial, palonosetron hydrochloride injection was compared to placebo for PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. The trial was conducted predominantly in the U.S. 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 PONV and/or motion sickness.
Patients were randomized to receive a single dose of palonosetron hydrochloride injection 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia. Antiemetic activity of palonosetron hydrochloride injection was evaluated during the 0 to 72-hour time period after surgery. The age of patients ranged from 21 to 74 years, with a mean age of 38 years.
Three patients were greater than 65 years of age. Secondary efficacy endpoints included: • Complete Response (CR) 0 to 48 hours and 0 to 72 hours • Complete Control (CC) defined as CR and no more than mild nausea • Severity of nausea (none, mild, moderate, severe) The primary hypothesis was that at least one of the three palonosetron doses were superior to placebo. Complete Response Rates for palonosetron hydrochloride injection 0.075 mg and placebo in this trial are described in Table 9.
Table 9: Prevention of Postoperative Nausea and Vomiting in Adults: Complete Response Rates Palonosetron hydrochloride injection as a single dose of 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron hydrochloride injection 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated. A randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate palonosetron hydrochloride injection for PONV following abdominal or vaginal hysterectomy.
Five intravenous doses mcg/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.
| Chemotherapy | Study | Treatment Group | N Intent-to-treat cohort | % with Complete Response | p-value 2-sided Fisher’s exact test. Significance level at α = 0.025. | 97.5% Confidence Interval Palonosetron Hydrochloride Injection Minus Comparator These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride injection and comparator. |
|---|---|---|---|---|---|---|
| Moderately Emetogenic | 1 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 81 | 0.009 | |
| Ondansetron 32 mg intravenously | 185 | 69 | ||||
| 2 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 63 | NS | ||
| Dolasetron 100 mg intravenously | 191 | 53 | ||||
| Highly Emetogenic | 3 | Palonosetron hydrochloride injection 0.25 mg intravenously | 223 | 59 | NS | |
| Ondansetron 32 mg intravenously | 221 | 57 |
| Chemotherapy | Study | Treatment Group | N Intent-to-treat cohort | % with Complete Response | p-value 2-sided Fisher’s exact test. Significance level at α = 0.025. | 97.5% Confidence Interval Palonosetron Hydrochloride Injection Minus Comparator These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride injection and comparator. |
|---|---|---|---|---|---|---|
| Moderately Emetogenic | 1 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 74 | < 0.001 | |
| Ondansetron 32 mg intravenously Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose. | 185 | 55 | ||||
| 2 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 54 | 0.004 | ||
| Dolasetron 100 mg intravenously | 191 | 39 |
| Chemotherapy | Study | Treatment Group | N Intent-to-treat cohort | % with Complete Response | p-value 2-sided Fisher’s exact test. Significance level at α = 0.025. | 97.5% Confidence Interval Palonosetron Hydrochloride Injection Minus Comparator These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride injection and comparator. |
|---|---|---|---|---|---|---|
| Moderately Emetogenic | 1 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 69 | < 0.001 | |
| Ondansetron 32 mg intravenously Ondansetron 32 mg intravenously was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose. | 185 | 50 | ||||
| 2 | Palonosetron hydrochloride injection 0.25 mg intravenously | 189 | 46 | 0.021 | ||
| Dolasetron 100 mg intravenously | 191 | 34 |
| Palonosetron Hydrochloride Injection 20 mcg/kg intravenously (N = 165) | Ondansetron 0.15 mg/kg for 3 intravenous doses (N = 162) | Difference [97.5% Confidence Interval] 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.: Palonosetron Hydrochloride Injection Minus Intravenous Ondansetron Comparator |
|---|---|---|
| 59.4% | 58.6% | 0.36% [-11.7%, 12.4%] |
| Δ Difference (%): palonosetron 0.075 mg minus placebo | |||
| Treatment | n/N (%) | Palonosetron Hydrochloride Injection vs. Placebo | |
| Δ | p-value To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p < 0.017. | ||
| Co-primary Endpoints | |||
| Complete Response Rate (0 to 24 hours) | |||
| Palonosetron hydrochloride injection 0.075 mg intravenously | 59/138 (42.8%) | 16.8% | 0.004 |
| Placebo | 35/135 (25.9%) | ||
| Complete Response Rate (24 to 72 hours) | |||
| Palonosetron hydrochloride injection 0.075 mg intravenously | 67/138 (48.6%) | 7.8% | 0.188 |
| Placebo | 55/135 (40.7%) | ||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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