Palonosetron

Palonosetron is a Selective 5-HT₃ Receptor Antagonist belonging to Antiemetic agent.

Palonosetron is a serotonin antagonist used in the prophylaxis or management of vomiting that results from emetogenic chemotherapy, and for the management of postoperative nausea and vomiting.

It is Well absorbed after oral administration and its absolute bioavailability is 97%. Time taken to reach peak plasma concentration: 5.1 ± 5.9 hours (oral). Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins. Palonosetron metabolized in the liver (approximately 50%) mainly by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2 isoenzymes into N-oxide-palonosetron and 6-S-hydroxy-palonosetron (inactive metabolites), via IV route in urine (approximately 80% and approximately 40% as unchanged drug), via oral route in urine (85-93%; approximately 40% as unchanged drug); faeces (5-8%). Terminal elimination half-life is approximately 40 hours.

Palonosetron shows side effects like Headache, constipation, pain, redness, or swelling at the injection site.

Palonosetron is available in the form of Injectable solution.

Palonosetron is available in India, US, France, Italy, Russia, Spain, Canada, China, UK, Malaysia, and Australia.

Palonosetron belongs to the Antiemetic agent acts as a Selective 5-HT₃ Receptor Antagonist.

Palonosetron is a selective serotonin 5-HT₃ receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT₃ receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT₃ receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. Alternative mechanisms appear to be primarily 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. It has been hypothesized that palonosetron's potency and long plasma half-life may contribute to its observed efficacy in preventing delayed nausea and vomiting caused by moderately emetogenic cancer chemotherapy.

The Onset of action of Palonosetron is about 30minutes (via IV route) and 60 minutes (via Oral route).

The Tmax of Palonosetron is 5.1-5.9 hours.

Palonosetron is an antiemetic drug used to prevent nausea and vomiting associated with cancer chemotherapy. It works by blocking the action of a natural substance that causes nausea and vomiting. Palonosetron is usually given 30 to 60 minutes prior to the start of chemotherapy.

Palonosetron is approved for use in the following clinical indications

• Prophylaxis of chemotherapy-induced nausea and vomiting
• Prophylaxis of postoperative nausea and vomiting

• Prophylaxis of chemotherapy-induced nausea and vomiting

Adult Oral Dose: For cases associated with moderately emetogenic cancer chemotherapy: 500 mcg approx. 1 hour prior to the start of chemotherapy.

Adult IV Dose: For cases associated with moderately or highly emetogenic cancer chemotherapy: 250 mcg as a single dose via bolus injection over 30 seconds to be given approx. 30 minutes before chemotherapy.

Child IV Dose: ≥1 month to 17 years for cases associated with moderately or highly emetogenic cancer chemotherapy: 20 mcg/kg (Max: 1,500 mcg) as a single dose via infusion over 15 minutes to be given approx. 30 minutes before chemotherapy.

• Prophylaxis of postoperative nausea and vomiting

Adult Intravenous Dose: 75 mcg as a single dose administered over 10 seconds immediately prior to the induction of anesthesia.

Palonosetron is available in various strengths as 0.25 mg/2 mL; 0.25 mg/5 mL; 0.075 mg/1.5 mL.

Palonosetron is contraindicated in patients with

• Hypersensitivity.

• ECG effects

Selective 5-HT₃ receptor antagonists have been associated with dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT). At doses of 9 times the maximum recommended adult dose, palonosetron does not prolong the QT interval to any clinically relevant extent. A thorough QT/QTc study evaluating the effect of palonosetron on QT/QTc demonstrated a magnitude of effect less than the threshold for regulatory concern. Reduction in heart rate may occur with the 5-HT₃ antagonists, including palonosetron.

• Hypersensitivity

Hypersensitivity reactions (including anaphylaxis and anaphylactic shock) have been reported in patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists.

• Serotonin syndrome

Serotonin syndrome (SS) has been reported with 5-HT₃ receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of SS reports due to 5-HT₃ receptor antagonists have occurred in a post-anesthesia setting or in an infusion center. SS has also been reported following overdose of another 5-HT₃ receptor antagonist. Signs of SS include mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile BP, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures.

• Chemotherapy-associated emesis

Antiemetics are most effective when used prophylactically. If emesis occurs despite optimal antiemetic prophylaxis, reevaluate emetic risk, disease status, concurrent morbidities, and current medications to assure antiemetic regimen is optimized.

There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Palonosetron HCl Injection and any potential adverse effects on the breastfed infant from palonosetron or from the underlying maternal condition.

Palonosetron is not recommended for use in pregnant women unless necessary. All the risks and benefits should be discussed with the doctor before taking Palonosetron.

Common

● Bradycardia, sinus bradycardia, tachycardia, Pruritus, Hyperkalemia Constipation, diarrhea, flatulence, Urinary retention, Increased serum alanine aminotransferase, increased serum aspartate aminotransferase, Anxiety dizziness, headache, Asthenia.

Rare

● Abdominal pain, allergic dermatitis, amblyopia, anaphylactic shock, anaphylaxis, anemia, anorexia, arthralgia, cardiac arrhythmia, chills, decreased appetite, decreased gastrointestinal motility, decreased platelet count, dermatological disease (infants, children, and adolescents), distended vein, drowsiness, dyskinesia (infants, children, and adolescents), dyspepsia, electrolyte disturbance, epistaxis, euphoria, extrasystoles, eye irritation, fatigue, fever, flattened T wave on ECG, flu-like symptoms, glycosuria, hiccups, hot flash, hyperglycemia, hypersensitivity reaction (including bronchospasm, dyspnea, edema, erythema of skin, swelling, urticaria), hypersomnia, hypertension, hypokalemia, hypoventilation, increased bilirubin (transient), increased liver enzymes, infusion site pain (infants, children, and adolescents), injection site reaction (includes burning sensation at injection site, discomfort at injection site, induration at injection site, pain at injection site), insomnia, ischemic heart disease, laryngospasm, limb pain, metabolic acidosis, motion sickness, paresthesia, serotonin syndrome, sialorrhea, sinoatrial nodal rhythm disorder, sinus tachycardia, skin rash, supraventricular extrasystole, tinnitus, vein discoloration, ventricular premature contractions, xerostomia.

Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 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 HCl Injection, and initiate supportive treatment.

The common side effects of Palonosetron include the following

Common side effects

● Headache, constipation, pain, redness, or swelling at the injection site.

Rare side effects

● Hives, rash, itching, difficulty breathing or swallowing, chest pain, swelling of the face, changes in heartbeat or heart rhythm, dizziness or light-headedness, fainting, fast, slow or irregular heartbeat, agitation, confusion, nausea, vomiting, and diarrhea, loss of coordination, stiff or twitching muscles, seizures, coma (loss of consciousness).

• Pregnancy

Pregnancy Category

There are no available data on palonosetron HCl 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 HCl to rats and rabbits 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

• Nursing Mothers

There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Palonosetron HCl Injection and any potential adverse effects on the breastfed infant from palonosetron or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established.

• Geriatric Use

Of the total number of adult cancer patients of oral palonosetron HCl, 181 were 65 years of age and over. The number of geriatric patients receiving the 0.5 mg recommended dose of Palonosetron capsules was insufficient to draw any efficacy or safety conclusions.

There is no known antidote to palonosetron HCl. 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 HCl overdose. A single intravenous dose of palonosetron HCl 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.

Pharmacodynamic

Palonosetron is an antinauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. Palonosetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist that is pharmacologically related to other 5-HT₃ receptor antagonists but differs structurally. Palonosetron has a high affinity for 5-HT₃ receptors but has little to no affinity for other receptors. The serotonin 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 suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.

Pharmacokinetics

• Absorption

It is Well absorbed after oral administration and its absolute bioavailability is 97%. Time taken to reach peak plasma concentration: 5.1 ± 5.9 hours (oral).

• 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 and Excretion

Palonosetron metabolized in the liver (approximately 50%) mainly by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2 isoenzymes into N-oxide-palonosetron and 6-S-hydroxy-palonosetron (inactive metabolites), via IV route in urine (approximately 80% and approximately 40% as unchanged drug), via oral route in urine (85-93%; approximately 40% as unchanged drug); faeces (5-8%). Terminal elimination half-life is approximately 40 hours.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208109s001lbl.pdf
• https://medlineplus.gov/druginfo/meds/a610002.html
• https://www.drugs.com/cdi/palonosetron.html
• https://www.rxlist.com/Palonosetron -drug.htm
• https://www.mims.com/india/drug/info/palonosetron?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00377
• https://www.practo.com/medicine-info/palonosetron-1169-api
• https://www.uptodate.com/contents/palonosetron-drug-information?search=palonosetron&source=panel_search_result&selectedTitle=1~17&usage_type=panel&kp_tab=drug_general&display_rank=1