Palonosetron (palonosetron HCl)
Antiemetic Intravenous Syringe (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Palonosetron hydrochloride, a selective, second-generation inhibitor of type 3 serotonergic (5-HT3) receptors, is an antiemetic.
Palonosetron hydrochloride, a selective inhibitor of type 3 serotonergic (5-HT3) receptors, is an antiemetic. The drug is pharmacologically related to other 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron), but the 5-HT3 receptor antagonists differ structurally. Palonosetron has high binding affinity for 5-HT3 receptors and little or no affinity for other receptors.
The antiemetic activity of palonosetron appears to be mediated both centrally and peripherally via inhibition of 5-HT3 receptors.
Current evidence suggests that chemotherapeutic agents produce acute nausea and vomiting by inducing degenerative changes in the GI tract (e.g., small intestine), thus increasing endogenous serotonin release from the enterochromaffin cells of the small intestine; serotonin then stimulates 5-HT3 receptors on vagal and splanchnic nerves that project to the medullary vomiting (emetic) center of the brain and also appears to stimulate 5-HT3 receptors in the area postrema. Thus, 5-HT3 receptor antagonists appear to prevent or ameliorate acute chemotherapy-induced emesis by inhibiting visceral (from the GI tract) afferent stimulation of the emetic center probably indirectly at the level of the area postrema and by directly inhibiting serotonin activity within the area postrema and chemoreceptor trigger zone (CTZ).
Alternative mechanisms appear to be principally responsible for delayed nausea and vomiting induced by emetogenic chemotherapy, since similar temporal relationships between serotonin and emesis beyond the first day after a dose have not been established, and 5-HT3 receptor antagonists generally have not appeared to be effective alone in preventing or ameliorating delayed effects. In addition, other antiemetic drugs (e.g., aprepitant) that have no activity at 5-HT3 receptors effectively augment the activity of dexamethasone and ondansetron to inhibit both acute and delayed nausea and vomiting induced by highly emetogenic chemotherapy. Effective prevention of acute nausea and vomiting may decrease the risk of delayed nausea and vomiting in the same chemotherapy cycle.
Postoperative nausea and vomiting is influenced by a number of patient-, surgical-, and anesthesia-related factors and is triggered by a release of serotonin in a cascade of neuronal events involving both the CNS and the GI tract.
Following IV administration, palonosetron plasma levels initially decline rapidly, followed by slow systemic elimination. Exposure (AUC) and mean peak plasma concentrations increase dose-proportionally across a 0.3-90 mcg/kg range. Pharmacokinetics in surgical patients were comparable to those in cancer patients.
Palonosetron has approximately 62% plasma protein binding.
Palonosetron is eliminated through multiple pathways, with around 80% of an IV dose recovered in urine over 144 hours and 40% as unchanged drug. The mean terminal elimination half-life is approximately 40 hours in adults. Metabolism is primarily via cytochrome P450 (CYP) 2D6, with minor contributions from CYP3A4 and CYP1A2, generating two major metabolites with minimal activity.
In pediatric patients, mean AUC of palonosetron appears to increase in a dose-proportional manner over the dose range of 10 and 20 mcg/kg. Peak plasma concentrations have been shown to be highly variable in pediatric patients and generally lower in children under 6 years of age compared with older children. The median half-life of palonosetron across all pediatric age groups is 30 hours, with a range of 20 to 30 hours following administration of a 20 mcg/kg dose.
In Japanese patients, total body clearance of palonosetron was 25% higher than in white patients, though this was not clinically meaningful. Pharmacokinetics of palonosetron are not substantially different between poor and extensive metabolizers of CYP2D6 substrates.
USES: This medication is used to prevent nausea and vomiting caused by cancer drug treatment (chemotherapy). It is also used to prevent nausea and vomiting after surgery. Palonosetron works by blocking one of the body's natural substances (serotonin) that causes vomiting.
Generic name: palonosetron HCl
Pronunciation: (PAL-oh-NOE-se-tron)
Drug class: Antiemetic
Therapeutic class: Gastrointestinal Therapy Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Palonosetron
Indications
The following indications are listed for Palonosetron:
- Prevention Of Cancer Chemotherapy-Induced Nausea And Vomiting
- Prevention Of Post-Operative Nausea And Vomiting
Also known as: Cancer Chemotherapy-Induced N & V Prophylaxis, Postop Nausea And Vomiting Prophylaxis, Postoperative Nausea And Vomiting Prophylaxis.
Dosing
Dosage of palonosetron hydrochloride is expressed in terms of palonosetron.
Palonosetron hydrochloride is administered IV.
The commercially available 0.05 mg/mL injection does not need to be diluted prior to administration. Do not mix palonosetron hydrochloride with other drugs. Flush the IV line with 0.9% sodium chloride injection before and after administration. Inspect the solution visually for particulate matter and discoloration before administration; discard if present.
Store palonosetron vials at 20-25degreesC (excursions permitted between 15-30degreesC). Protect from light, and do not freeze.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Palonosetron Hcl 0.25 Mg/5 Ml | Maintenance | Inject 5 milliliters (0.25 mg) over 30 second(s) by intravenous routeonce 30 minutes before chemotherapy. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Palonosetron Hcl 0.25 Mg/5 Ml | Maintenance | Inject 5 milliliters (0.25 mg) over 30 second(s) by intravenous routeonce 30 minutes before chemotherapy. |
Drug interactions
Palonosetron is metabolized principally by cytochrome P-450 (CYP) isoenzyme 2D6, and to a lesser extent by CYP3A4 and CYP1A2.
Palonosetron does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5; its effect on CYP2C19 activity is undetermined. Palonosetron does not induce CYP1A2, 2D6, or 3A4/5.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
Moderate Interaction: Assess the risk to the patient and take action as needed.
5-Ht3 Antagonists/Tramadol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The interaction may involve a reduction in the binding involving 5-HT3 receptors.(1)
CLINICAL EFFECTS: Concurrent use of 5-HT3 antagonists may decrease the effectiveness of tramadol, resulting in increased use of tramadol.(1-3) 5-HT3 antagonists may not be effective in reducing tramadol-induced nausea.(4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Consider the use of alternative anti-emetics in patients receiving tramadol, or the use of other opioids in patients receiving 5-HT3 antagonists.
DISCUSSION: In a randomized study in 59 post-surgical patients in recovery, compared to tramadol alone, patients receiving concurrent ondansetron required significantly larger doses of tramadol at four hours (223 mg versus 71 mg), at 8 hours (285 mg versus 128 mg), and at 12 hours (406 mg versus 190 mg). Vomiting rates at 4 hours and 8 hours were significantly higher with tramadol and concurrent ondansetron compared to tramadol alone.(1) In a randomized, double-blind study in 40 surgical patients undergoing lumbar laminectomy, compared to tramadol alone, cumulative tramadol consumption with concurrent ondansetron during the first 24 hours was significantly increased (between 26% and 35%) as well as thereafter (22% to 25%).(2) In another randomized study in 120 post-surgical patients, it was discovered that tramadol consumption was increased in those patients receiving concurrent ondansetron compared to tramadol alone.(3) In a prospective, randomized, double-blinded study in dental patients, patients received one of four treatments: fentanyl and metoclopramide, tramadol and metoclopramide, fentanyl and ondansetron, or tramadol and ondansetron. The patients who received tramadol and ondansetron had the highest nausea scores among the treatment groups. There were no significant differences in the incidences of pain or nausea in the 24 hours following the procedure.(4) In a randomized, controlled trial in 40 surgical patients undergoing hernioplasty or thyroidectomy, compared to tramadol alone, cumulative tramadol consumption was higher at the 2-hour time point with concurrent ondansetron (0.24 +/- 0.1 vs. 0.17 +/- 0.16; p = 0.01).(5) A systematic review and meta-analysis of randomized controlled trials in the postoperative setting comparing tramadol alone and in combination with ondansetron were included. At 4-hours, 8-hours, 12-hours, and 24-hours post-procedure, patients had increased tramadol requirements when administered with concurrent ondansetron compared to tramadol alone.(6) 5-HT3 antagonists linked to this monograph include: alosetron, azasetron, dolasetron, granisetron, ondansetron, palonosetron, ramosetron, and tropisetron.
Contraindications
*Known hypersensitivity to palonosetron or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
- Neuroleptic malignant syndrome
- Serotonin syndrome
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=5% of adults receiving palonosetron for prevention of chemotherapy-induced nausea and vomiting include headache and constipation.
Adverse effects reported in >=2% of adults receiving palonosetron for PONV include QT prolongation, bradycardia, headache, and constipation.
Less Frequent
- Bradycardia
- Hypoventilation
Rare or Very Rare
- Anaphylaxis
- Dyskinesia
- Dyspnea
- Extrasystoles
- Gastrointestinal hypomotility
- Hyperglycemia
- Hyperkalemia
- Hypersensitivity drug reaction
- Hypertension
- Hypokalemia
- Hypotension
- Increased alanine transaminase
- Increased aspartate transaminase
- Laryngismus
- Metabolic acidosis
- Myocardial ischemia
- Serotonin syndrome
- Sinus node dysfunction
- Sinus tachycardia
- Supraventricular premature beats
- Tachycardia
More Frequent
- Constipation
- Headache disorder
Less Frequent
- Chills
- Diarrhea
- Dizziness
- General weakness
- Pruritus of skin
- Symptoms of anxiety
Rare or Very Rare
- Abnormal hepatic function tests
- Acute abdominal pain
- Allergic dermatitis
- Anorexia
- Arthralgia
- Drowsy
- Dyspepsia
- Euphoria
- Fatigue
- Fever
- Flatulence
- Flu-like symptoms
- Flushing
- Glycosuria
- Hiccups
- Hypersomnia
- Injection site sequelae
- Insomnia
- Motion sickness
- Ocular irritation
- Paresthesia
- Skin rash
- Tinnitus
- Toxic amblyopia
- Urinary retention
- Urticaria
- Xerostomia
Precautions
No enhanced messaging available.
The safety and effectiveness of palonosetron hydrochloride injection for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy have been established in pediatric patients 1 month to <17 years of age. This indication is supported by evidence from a randomized clinical trial in 165 pediatric patients 2 months to <17 years of age who received a single dose of palonosetron hydrochloride injection 20 mcg/kg (maximum 1.5 mg) 30 minutes before chemotherapy. The study demonstrated that pediatric patients require a higher dose than adults to achieve efficacy. Adverse reactions in pediatric patients were generally consistent with those observed in adults.
Safety and efficacy of palonosetron hydrochloride injection have not been established in neonates <1 month of age for the prevention of chemotherapy-induced nausea and vomiting.
The safety and efficacy of palonosetron hydrochloride injection have not been established for the prevention of postoperative nausea and vomiting (PONV) in pediatric patients. In a dose-finding trial with 150 pediatric surgical patients, no dose-response relationship was observed between palonosetron 1 mcg/kg and 3 mcg/kg. In a randomized, double-blind, active-controlled, noninferiority study of 670 pediatric patients, palonosetron (1 mcg/kg; maximum, 0.075 mg) was compared to ondansetron for the prevention of PONV; the primary endpoint, complete response within 24 hours postoperatively, was achieved by 78.2% of palonosetron-treated patients versus 82.7% of ondansetron-treated patients. The prespecified margin for noninferiority was not met. Adverse reactions in pediatric patients were similar to those observed in adults.
There are no available clinical data regarding the use of palonosetron in pregnant women to assess potential drug-related risks. In animal studies, no harmful effects on embryo-fetal development were observed when pregnant rats were administered oral doses of palonosetron hydrochloride up to 60 mg/kg/day (equivalent to 1894 times the recommended human IV dose, adjusted for body surface area), or when pregnant rabbits were given oral doses up to 60 mg/kg/day (3789 times the human IV dose), during the organogenesis phase.
It is not known whether palonosetron is distributed into human milk or whether the drug has any effects on milk production or on the breastfed infant. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for palonosetron and any potential adverse effects on the nursing infant from the drug or underlying maternal condition.
No dosage adjustment is required in geriatric patients.
Among 1374 adult cancer patients in clinical studies of palonosetron for chemotherapy-induced nausea and vomiting, 23% were 65 years of age or older and 5% were 75 years of age or older. No overall differences in safety and effectiveness were observed between geriatric patients and younger adults in these studies, but increased sensitivity in older patients cannot be ruled out.
Among 1520 adult cancer patients in clinical studies of palonosetron for PONV, 5% were 65 years of age or older. No overall differences in safety were observed between these older individuals and younger individuals in these studies; however, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.
A population pharmacokinetic analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients 65 years of age or older and younger cancer patients. The manufacturer states that no dosage adjustment is required for geriatric patients receiving palonosetron.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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