Dolasetron

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

Dolasetron is an antinauseant and antiemetic used in chemotherapy and postoperatively.

It is Rapid and completely absorbed after oral administration. Bioavailability is approximately 75%. Time to peak plasma concentration Hydrodolasetron is approximately 1 hour (oral); 0.6 hour (IV). It is Widely distributed in the body. The volume of distribution is 5-7.9 L/kg and plasma protein binding is about 69-77%. Dolasetron rapidly metabolized hepatically via reduction by carbonyl reductase to hydrodolasetron (active metabolite); further metabolized by CYP2D6, CYP3A, and flavin monooxygenase enzymes. Excreted mainly via urine (approximately 67%); faeces (approximately 33%). Elimination half-life: Dolasetron: ≤10 min (IV); hydrodolasetron: 8.1 hours (oral); 7.3 hours (IV).

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

Dolasetron is available in the form of Oral Tablet and Injectable solution.

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

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

Dolasetron is a selective serotonin 5-HT₃ receptor antagonist. In vivo, the drug is rapidly converted into its major active metabolite, hydrodolasetron, which seems to be largely responsible for the drug's pharmacological activity. 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.

The Data of Onset and duration of action of Dolasetron is clinically not established.

The Tmax of Dolasetron is via IV route is about 0.6 hour and via orally 1-1.5 hour.

Dolasetron 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. Dolasetron is a highly specific and selective serotonin 5-HT3 receptor antagonist.

Dolasetron is approved for use in the following clinical indications

• Nausea and vomiting associated with cancer chemotherapy
• Prophylaxis of postoperative nausea and Vomiting
• Treatment and prophylaxis of postoperative nausea and vomiting

• Nausea and vomiting associated with cancer chemotherapy

Adult Oral Dose: 100 or 200 mg once daily within 1 hour before chemotherapy. Duration of treatment: 4-7 consecutive days/chemotherapy cycle.

• Prophylaxis of postoperative nausea and Vomiting

Adult Oral Dose: 50 mg at the induction of anaesthesia, or 100 mg within 2 hours before surgery.

• Treatment and prophylaxis of postoperative nausea and vomiting

Adult IV Dose: 12.5 mg once daily as IV push over 30 seconds or via infusion over 15 min; given as soon as nausea or vomiting present (treatment) or approximately 15 min before cessation of anaesthesia (prophylaxis).

Dolasetron is available in various strengths as 20 mg/mL; 50 mg; 100 mg.

Dolasetron is available in the form of Oral Tablet and Injectable solution.

Dolasetron is contraindicated in patients with

• Dolasetron Tablets are contraindicated in patients known to have hypersensitivity to Dolasetron.

• QT Interval Prolongation

Dolasetron prolongs the QT interval in a dose dependent fashion. Torsade de Pointes has been reported during post-marketing experience. Avoid Dolasetron in patients with congenital long QT syndrome, hypomagnesemia, or hypokalemia. Hypokalemia and hypomagnesemia must be corrected prior to Dolasetron administration. Monitor these electrolytes after administration as clinically indicated. Use ECG monitoring in patients with congestive heart failure, bradycardia, renal impairment, and elderly patients.

• PR And QRS Interval Prolongation

Dolasetron has been shown to cause dose dependent prolongation of the PR and QRS interval and reports of second- or third-degree atrioventricular block, cardiac arrest and serious ventricular arrhythmias including fatalities in both adult and pediatric patients. At particular risk are patients with underlying structural heart disease and preexisting conduction system abnormalities, elderly, patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (such as verapamil) and QRS interval (e.g., flecainide or quinidine). Dolasetron should be used with caution and with ECG monitoring in these patients. Dolasetron should be avoided in patients with complete heart block or at risk for complete heart block unless they have an implanted pacemaker.

• Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin re-uptake inhibitors (SSRIs), serotonin and norepinephrine re-uptake 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-HT3 receptor antagonist alone has also been reported. Most reports of serotonin syndrome related to 5-HT3 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 Dolasetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Dolasetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Dolasetron is used concomitantly with other serotonergic drugs.

It is not known whether Dolasetron mesylate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dolasetron Tablets are administered to a nursing woman.

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Common

● PR, QRS, and QT prolongation, Dizziness, headache, drowsiness, fatigue, syncope, flushing, paraesthesia, tremor, ataxia, twitching, agitation, anxiety, sleep disorder, depersonalization, confusion, abnormal dreaming, Bradycardia, HTN, orthostatic hypotension, tachycardia, peripheral oedema and ischaemia, phlebitis, Diarrhea, dyspepsia, flatulence, taste disturbance, constipation, abdominal pain, anorexia, pancreatitis. Bronchospasm, dyspnea, epistaxis. Oliguria, dysuria, polyuria, acute renal failure, urinary retention, hematuria, Anemia, hematoma, thrombocytopenia, prolonged partial thromboplastin time (PTT) and prothrombin time, Myalgia, arthralgia, Abnormal vision, photophobia, Tinnitus, Pruritus, urticaria, increased sweating, rash. Chills, fever, pain, pain at injection site.

Serotonergic Drugs

The potential for clinically significant drug-drug interactions posed by dolasetron and hydrodolasetron appears to be low for drugs commonly used in chemotherapy because hydrodolasetron is eliminated by multiple routes. General for information about potential interaction with other drugs that prolong the QTc interval. When oral dolasetron (200 mg once daily) was coadministered with cimetidine (300 mg four times daily) for 7 days, the systemic exposure (i.e., AUC) of hydrodolasetron increased by 24% and the maximum plasma concentration of hydrodolasetron increased by 15%. When oral dolasetron (200 mg once daily) was coadministered with rifampin (600 mg once daily) for 7 days, the systemic exposure of hydrodolasetron decreased by 28% and the maximum plasma concentration of hydrodolasetron decreased by 17%. Caution should be exercised when Dolasetron is coadministered with drugs, including those used in chemotherapy, that prolong ECG intervals and/or cause hypokalemia or hypomagnesemia.

In patients taking furosemide, nifedipine, diltiazem, ACE inhibitors, verapamil, glyburide, propranolol, and various chemotherapy agents, no effect was shown on the clearance of hydrodolasetron. Clearance of hydrodolasetron decreased by about 27% when dolasetron mesylate was administered intravenously concomitantly with atenolol. Dolasetron mesylate did not inhibit the antitumor activity of four chemotherapeutic agents (cisplatin, 5-fluorouracil, doxorubicin, cyclophosphamide) in four murine models.

The common side effects of Dolasetron include the following

Common side effects

● Headache, tiredness, heartburn, chills, less frequent urination.

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 B

Teratology studies have not revealed evidence of impaired fertility or harm to the fetus due to Dolasetron mesylate. These studies have been performed in pregnant rats at oral doses up to 100 mg/kg/day (8 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 100 mg/kg/day (16 times the recommended human dose based on body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

It is not known whether Dolasetron mesylate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DOLASETRON Tablets are administered to a nursing woman.

• Pediatric Use

Safety and effectiveness in pediatric patients (2 years and older) is based on pharmacokinetic studies and efficacy data in adults. Safety and effectiveness in pediatric patients under 2 years of age have not been established. Dolasetron Tablets are expected to be as safe and effective as when Dolasetron Injection is given. Dolasetron Tablets are recommended for children old enough to swallow tablets.

• Geriatric Use

Elderly patients are at particular risk for prolongation of the PR, QRS, and QT interval; therefore, caution should be exercised, and ECG monitoring should be performed when using Dolasetron in this population.

In controlled clinical trials in the prevention of chemotherapy-induced nausea and vomiting, 301 (29%) of 1026 patients were 65 years of age or older. Of the 301 geriatric patients in the trial, 282 received oral Dolasetron Tablets. No overall differences in safety or effectiveness were observed between geriatric and younger patients, and other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

Dolasetron is a highly specific and selective serotonin 5-HT₃ receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. It is structurally and pharmacologically related to other 5-HT₃ receptor agonists. The serontonin 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 Rapid and completely absorbed via (oral). Bioavailability is approximately 75%. Time to peak plasma concentration Hydrodolasetron is approximately 1 hour (oral); 0.6 hour (IV).

• Distribution

It is Widely distributed in the body. The volume of distribution is 5-7.9 L/kg and plasma protein binding is about 69-77%.

• Metabolism and Excretion

Dolasetron rapidly metabolized hepatically via reduction by carbonyl reductase to hydrodolasetron (active metabolite); further metabolized by CYP2D6, CYP3A, and flavin monooxygenase enzymes. Excreted mainly via urine (approximately 67%); faeces (approximately 33%). Elimination half-life: Dolasetron: ≤10 min (IV); hydrodolasetron: 8.1 hours (oral); 7.3 hours (IV).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020623s010lbl.pdf,020624s023lbl.pdf
• https://www.drugs.com/mtm/dolasetron.html
• https://www.rxlist.com/Dolasetron -tablets-drug.htm#description
• https://www.mims.com/india/drug/info/Dolasetron?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00757
• https://reference.medscape.com/drug/Dolasetron -dolasetron-342046