Dolasetron

325.38

324.37

601-402-4

DTXSID4048276

62.4

log Kow = 2.63 (est)

white powder

1.37 g/cm3

278 ºC

499.6°C at 760 mmHg

277.4ºC

1.76

H2O: soluble

Refrigerator

1.7X10-9 mm Hg at 25 °C (est)

Henry's Law constant = 1.34X10-14 atm-cu m/mol at 25 °C (est)

Crystalline solid, mp 278 °C /Methanesulfonate/|MW: 438.50. White to off-white powder that is freely soluble in water and propylene glycol, slightly soluble in ethanol, and slightly soluble in normal saline|Hydroxyl radical reaction rate constant = 2.26X10-14 cu cm/molec-sec at 25 °C (est)

3

R36/37/38:Irritating to eyes, respiratory system and skin .

S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice . S36:Wear suitable protective clothing .

Xi

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl dolasetron mesylate approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Dolasetron mesylate/

The 5-HT3 receptor antagonists have been linked to occasional instances of serum enzyme elevations during therapy, but these are generally mild and asymptomatic, resolving rapidly. Because they are used at the time of surgery and with chemotherapy, instances of liver injury arising after their use have been reported, but other drugs or factors may have played a role in the published cases. The rate of serum enzyme elevations with 5-HT3 receptor antagonist therapy has ranged from 1% to 8% and has generally been no greater than that observed with placebo therapy. While moderate serum enzyme elevations during 5-HT3 receptor antagonist therapy have been described, there have been have been only rare and isolated reports of clinically apparent acute liver injury with jaundice attributed to these agents. The onset of injury has been within 1 to 2 weeks of exposure and the pattern of injury hepatocellular and without immunoallergic or autoimmune features. Instances of recurrence after re-exposure have been published. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to the 5-HT3 receptor antagonists.

Concurrent use of cimetidine, which is a nonselective cytochrome P450 enzyme inhibitor, with dolasetron for 7 days has been found to result in a 24% increase in hydrodolasetron blood concentrations.|Concurrent use of intravenous dolasetron and atenolol has been found to result in a 27% decrease in clearance hydrodolasetron.

While data specific to dolasetron were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

It is not known whether dolasetron is distributed into human breast milk.

The serotonin type 3 (5-HT3) receptor antagonists are potent antiemetics used for prevention of postsurgical or chemotherapy induced nausea and vomiting and for some agents as therapy of diarrhea-predominant irritable bowel syndrome. The 5-HT3 receptor antagonists are associated with a low rate of transient serum enzyme elevations during therapy, but have been only rarely implicated in cases of clinically apparent liver injury.

Gastrointestinal Agents

Antiemetic|Dolasetron injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin. Dolasetron tablets are indicated for the prevention of nausea and vomiting associated with moderate-emetogenic cancer chemotherapy, including initial and repeat courses. /Included in US product label/|Dolasetron injection and tablets are indicated for the prevention of postoperative nausea and/or vomiting. Routine prophylaxis is not recommended when there is little risk of nausea and/or vomiting developing postoperatively, except in patients in whom nausea and/or vomiting must be avoided. /Included in US product label/|Dolasetron injection is indicated for the treatment of postoperative nausea and/or vomiting. /Included in US product label/

/Administration is contraindicated in patients with/ known hypersensitivity to dolasetron mesylate.|Acute, usually reversible ECG alterations and/or risk of altered cardiac conduction. Prolongation of PR, QTC, and JT intervals and widening of the QRS complex have been observed in patients receiving dolasetron therapy. These alterations, which are caused by prolongation of cardiac depolarization and repolarization, appear to be related to plasma concentrations of the active metabolite hydrodolasetron and generally are self-limiting as these concentrations decline. ECG interval prolongation rarely has resulted in heart block or cardiac arrhythmias. Sudden death has occurred in at least one patient 6 hours after receiving IV dolasetron (1.8 mg/kg), although the patient had other potential risk factors such as prior therapy with doxorubicin and concomitant cyclophosphamide.|Dolasetron should be used with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTC, including those with congenital QT syndrome, those with uncorrected hypokalemia or hypomagnesemia, patients receiving diuretics that may induce electrolyte abnormalities, patients receiving antiarrhythmic agents or other drugs that alter cardiac conduction (e.g., prolong QT interval), and those receiving cumulative high-dose anthracycline therapy.|Sensitivity reactions, including anaphylactic reaction, facial edema, and urticaria, have been reported rarely. Cross-sensitivity reactions have been reported in patients receiving other selective 5-HT3 receptor antagonists but have not been reported to date with dolasetron.|For more Drug Warnings (Complete) data for DOLASETRON (7 total), please visit the HSDB record page.

Drugs used to prevent NAUSEA or VOMITING. (See all compounds classified as Antiemetics.)|Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS. (See all compounds classified as Serotonin Antagonists.)

Orally-administered dolasetron is well absorbed, but the parent drug is rarely detected in plasma due to rapid and complete metabolism to hydrodolasetron.|Orally-administered dolasetron intravenous solution and tablets are bioequivalent.|The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of dolasetron taken by mouth.|Time to peak plasma concentration /for hydrodolasetron/ following oral administration /was/ approximately 1 hour and following intravenous injection /was/ 0.6 hours.|For more Absorption, Distribution and Excretion (Complete) data for DOLASETRON (15 total), please visit the HSDB record page.

Biotransformation /is/ hepatic and complete, mainly to the active metabolite hydrodolasetron (by means of the ubiquitous enzyme, carbonyl reductase). Further hydroxylation is mediated by cytochrome P450 CYP2D6 and further N-oxidation by both CYP3A and flavin monooxygenase.|The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr post-dose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.|The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

Following oral administration hydrodolasetron has a elimination half-life of 8.1 hours (mean). Following intravenous injection dolasetron /has a elimination half-life of/ less than 10 minutes. Hydrodolasetron /has a elimination half-life of/ 7.3 hours after intravenous injection of dolasetron.|Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg/kg, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 hr. Less than 1 percent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0.625 hr (median). Its median terminal disposition half-life was 7.56 hr ...

Dolasetron, and its active metabolite hydrodolasetron, are highly specific and selective antagonist of serotonin subtype 3 (5-HT3) receptors. 5-HT3 receptors are present peripherally on vagal nerve terminals and centrally in the area postrema of the brain. Chemotherapeutic medications appear to precipitate release of serotonin from the enterochromaffin cells of the small intestine, which activates 5-HT3 receptors on vagal efferents to initiate the vomiting reflex. Dolasetron has not been shown to have activity at other known serotonin receptors, and has low affinity for dopamine receptors.|Dolasetron causes dose-related acute, and usually reversible, electrocardiogram (ECG) changes including QRS widening and PR, QTc, and JT prolongation; QTc prolongation is caused primarily by QRS widening. Dolasetron seems to prolong both depolarization and,to a lesser extent, repolarization time, and its active metabolites may block sodium channels.|The active metabolite of dolasetron (i.e., hydrodolasetron) may block sodium channels and prolong cardiac depolarization and, to a lesser extent, repolarization time.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SIGNS AND SYMPTOMS/ A 59-year-old man with metastatic melanoma and no known pre-existing cardiac conditions developed severe hypotension and dizziness 40 minutes after receiving a 15-minute intravenous infusion of 1000 mg (13 mg/kg) of dolasetron mesylate.|/CASE REPORTS/ ... The case of a 21-year-old woman who presented after an intentional overdose of 10x200 mg dolasetron tablets resulting in prolongation of the QTc interval and severe hypotension is reported here. Management of hypotension included intravenous fluid resuscitation and norepinephrine infusion with invasive monitoring in a high dependency unit. Sodium cardiac channel block contributes to cardiotoxicity observed in dolasetron overdose. Sodium bicarbonate was used in an attempt to reduce cardiac sodium channel block, although we observed no apparent benefit. ...|/CASE REPORTS/ The 5-hydroxytryptamine antagonists are commonly used agents for the treatment of postoperative nausea and vomiting. However, these drugs can have significant cardiovascular adverse effects. ... A case of acute myocardial infarction after administration of dolasetron in a 17-year-old adolescent girl during strabismus corrective surgery /is reoprted/.

1H-indole-3-carboxylic acid, (6R,9AS)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester, rel-, methanesulfonate, hydrate (1:1:1)

Dolasetron mesylate; MDL-73147EF; Anzemet /Dolasetron methanesulfonate/|Approximately 74% of dolasetron mesylate monohydrate is dolasetron base

Analyte: dolasetron mesylate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /dolasetron mesylate/|Analyte: dolasetron mesylate; matrix: chemical purity; procedure: liquid chromatography with detection at 285 nm and comparison to standards /dolasetron mesylate/|Analyte: dolasetron mesylate; matrix: pharmaceutical preparation (injection solution; tablet); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /dolasetron mesylate/|Analyte: dolasetron mesylate; matrix: pharmaceutical preparation (injection solution; tablet); procedure: liquid chromatography with detection at 285 nm and comparison to standards (chemical purity) /dolasetron mesylate/|Analyte: dolasetron; matrix: pharmaceutical preparation (oral liquid suspension); procedure: high-performance liquid chromatography with ultraviolet detection at 265 nm

Analyte: dolasetron; matrix: blood (plasma), urine; procedure: high-performance liquid chromatography with fluorescence detection at 285 nm (excitation) and 345 nm (emission); limit of quantitation: 10 nM (plasma), 50 nM (urine)

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients