Anzemet Information
Anzemet (Dolasetron) Description
Anzemet (Dolasetron) (dolasetron mesylate) is an antinauseant and antiemetic agent. Chemically, dolasetron mesylate is (2α,6α,8α,9aβ)-octahydro-3-oxo-2,6-methano-2-quinolizin-8-yl-1-indole-3-carboxylate monomethanesulfonate, monohydrate. It is a highly specific and selective serotonin subtype 3 (5-HT) receptor antagonist both in vitro and in vivo. Dolasetron mesylate has the following structural formula:
The empirical formula is CHNO • CHSOH • HO, with a molecular weight of 438.50. Approximately 74% of dolasetron mesylate monohydrate is dolasetron base.
Dolasetron mesylate monohydrate is a white to off-white powder that is freely soluble in water and propylene glycol, slightly soluble in ethanol, and slightly soluble in normal saline.
Each Anzemet (Dolasetron) Tablet for oral administration contains dolasetron mesylate (as the monohydrate) and also contains the inactive ingredients: carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, synthetic red iron oxide, titanium dioxide, and white wax. The tablets are printed with black ink, which contains lecithin, pharmaceutical glaze, propylene glycol, and synthetic black iron oxide.
Anzemet (Dolasetron) Clinical Pharmacology
Dolasetron mesylate and its active metabolite, hydrodolasetron (MDL 74,156), are selective serotonin 5-HT receptor antagonists not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. The serotonin 5-HT 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 thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that the released serotonin then activates 5-HT receptors located on vagal efferents to initiate the vomiting reflex.
In healthy volunteers (N=64), dolasetron mesylate in single intravenous doses up to 5 mg/kg produced no effect on pupil size or meaningful changes in EEG tracings. Results from neuropsychiatric tests revealed that dolasetron mesylate did not alter mood or concentration. Multiple daily doses of dolasetron have had no effect on colonic transit in humans. Dolasetron has no effect on plasma prolactin concentrations.
Anzemet (Dolasetron) Indications And Usage
Anzemet (Dolasetron) Tablets are indicated for:
Anzemet (Dolasetron) Contraindications
Anzemet (Dolasetron) Tablets are contraindicated in patients known to have hypersensitivity to the drug.
Anzemet (Dolasetron) Precautions
Dolasetron should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QT. These include patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital QT syndrome, patients taking anti-arrhythmic drugs or other drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy.
Cross hypersensitivity reactions have been reported in patients who received other selective 5-HT receptor antagonists. These reactions have not been seen with dolasetron mesylate.
The potential for clinically significant drug-drug interactions posed by dolasetron and hydrodolasetron appears to be low for drugs commonly used in chemotherapy or surgery, because hydrodolasetron is eliminated by multiple routes. Seefor information about potential interaction with other drugs that prolong the QT 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 Anzemet (Dolasetron) is coadministered with drugs, including those used in chemotherapy and surgery, that prolong ECG intervals and/or cause hypokalemia or hypomagnesemia. (see).
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. Anzemet (Dolasetron) did not influence anesthesia recovery time in patients. Dolasetron mesylate did not inhibit the antitumor activity of four chemotherapeutic agents (cisplatin, 5-fluorouracil, doxorubicin, cyclophosphamide) in four murine models.
In a 24-month carcinogenicity study, there was a statistically significant (P
In a 24-month rat (Sprague-Dawley) carcinogenicity study, oral dolasetron mesylate was not tumorigenic at doses up to 150 mg/kg/day (900 mg/m/day, 12 times the recommended human dose based on body surface area) in male rats and 300 mg/kg/day (1800 mg/m/day, 24 times the recommended human dose based on body surface area) in female rats.
Dolasetron mesylate was not genotoxic in the Ames test, the rat lymphocyte chromosomal aberration test, the Chinese hamster ovary (CHO) cell (HGPRT) forward mutation test, the rat hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test.
Dolasetron mesylate was found to have no effect on fertility and reproductive performance at oral doses up to 100 mg/kg/day (600 mg/m/day, 8 times the recommended human dose based on body surface area) in female rats and up to 400 mg/kg/day (2400 mg/m/day, 32 times the recommended human dose based on body surface area) in male rats.
(See)
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.
Anzemet (Dolasetron) Tablets are expected to be as safe and effective as when Anzemet (Dolasetron) Injection is given orally to pediatric patients. Anzemet (Dolasetron) Tablets are recommended for children old enough to swallow tablets (see).
Anzemet (Dolasetron) Adverse Reactions
In controlled clinical trials, 936 adult female patients have received oral Anzemet (Dolasetron) for the prevention of postoperative nausea and vomiting. Following is a listing of all adverse events reported in ≥ 2% of patients receiving either placebo or Anzemet (Dolasetron) for prevention of postoperative nausea and vomiting in controlled clinical trials (Table 5).
In clinical trials, the following reported adverse events, assessed by investigators as treatment-related or causality unknown, occurred following oral or intravenous administration of Anzemet (Dolasetron) in
Cardiovascular:
PRECAUTIONS
In addition, the following asymptomatic treatment-emergent ECG changes were seen at rates less than or equal to those for active or placebo controls: bradycardia, T wave change, ST-T wave change, sinus arrhythmia, extrasystole (APCs or VPCs), poor R-wave progression, bundle branch block (left and right), nodal arrhythmia, U wave change, atrial flutter/fibrillation.
Furthermore, severe hypotension, bradycardia and syncope have been reported immediately or closely following IV administration.
Dermatologic:
Gastrointestinal System:
Hearing, Taste and Vision:
Hematologic:
Hypersensitivity:
Liver and Biliary System:
Metabolic and Nutritional:
Musculoskeletal:
Nervous System:
Psychiatric:
Respiratory System:
Urinary System:
Vascular (Extracardiac):
Postmarketing Experience
Anzemet (Dolasetron) Overdosage
There is no known specific antidote for dolasetron mesylate, and patients with suspected overdose should be managed with supportive therapy. Individual doses as large as 5 mg/kg intravenously or 400 mg orally have been safely given to healthy volunteers or cancer patients.
Following a suspected overdose of Anzemet (Dolasetron) Injection, a patient found to have second-degree or higher AV conduction block with ECG should undergo cardiac telemetry monitoring.
It is not known if dolasetron mesylate is removed by hemodialysis or peritoneal dialysis.
Single intravenous doses of dolasetron mesylate at 160 mg/kg in male mice and 140 mg/kg in female mice and rats of both sexes (6.3 to 12.6 times the recommended human dose based on body surface area) were lethal. Symptoms of acute toxicity were tremors, depression and convulsions.
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. Treatment for the overdose consisted of infusion of 500 mL of a plasma expander, dopamine, and atropine. The patient had normal sinus rhythm and prolongation of PR, QRS and QT intervals on an ECG recorded 2 hours after the infusion. The patient's blood pressure was normal 3 hours after the event and the ECG intervals returned to baseline on follow-up. The patient was released from the hospital 6 hours after the event.
A 7-year-old boy received 6 mg/kg of dolasetron mesylate orally before surgery. No symptoms occurred and no treatment was required.
Anzemet (Dolasetron) Dosage And Administration
The recommended doses of Anzemet (Dolasetron) Tablets should not be exceeded.
Anzemet (Dolasetron) Patient Counseling Information
Patients should be informed that Anzemet (Dolasetron) may cause serious cardiac arrhythmias such as QT prolongation or heart block. Patients should be instructed to tell their health care provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.
Patients should be informed that the chances of developing serious cardiac arrhythmias such as QT prolongation and Torsade de Pointes or heart block are higher in the following people:
Anzemet (Dolasetron) should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.
Anzemet (Dolasetron)
Anzemet (Dolasetron) Principal Display Panel - Mg Tablet Carton
Anzemet (Dolasetron) Principal Display Panel - Mg Tablet Carton
