Anzemet (Dolasetron)

ANZEMET™

Hoechst Marion Roussel

Dolasetron Mesylate

Antiemetic

Action And Clinical Pharmacology: Dolasetron and its active metabolite, hydrodolasetron (MDL 74156), are selective 5-HT3 receptor antagonists shown not to have activity at other known serotonin receptors and with low affinity for dopamine 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 thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that serotonin then activates the 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

Acute, reversible, ECG changes (PR and QTc; QRS widening), caused by dolasetron, have been observed in controlled clinical trials. Dolasetron appears to prolong both depolarization and, to a lesser extent, repolarization time. Although QTc prolongation is primarily due to QRS widening, JT prolongation has also been observed. The magnitude and frequency of the ECG changes increased with dose (related to the peak plasma concentration of hydrodolasetron but not the parent compound). These ECG changes usually returned to baseline within 6 to 8 hours, but in some patients have lasted 24 hours or longer. Dolasetron administration has little or no effect on blood pressure.

In healthy volunteers (N=4), dolasetron in single i.v. 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 does not alter mood or concentration. Multiple daily doses of dolasetron have no effect on colonic transit in humans. Dolasetron has no effect on plasma prolactin concentrations.

Sixty-nine to 77% of hydrodolasetron is bound to plasma proteins. In a study with 4-labeled dolasetron, the distribution of radioactivity to blood cells was not extensive. The binding of hydrodolasetron to a1-acid glycoprotein is approximately 51%. The pharmacokinetics are similar in men and women. The pharmacokinetics of hydrodolasetron, in special and targeted patient populations following i.v. administration of dolasetron, are summarized in Table I. The pharmacokinetics of hydrodolasetron are similar in adult healthy volunteers and adult cancer patients receiving chemotherapeutic agents. The apparent clearance of hydrodolasetron is not affected by age in adult cancer patients. Following i.v. administration, the apparent clearance of hydrodolasetron remains unchanged with severe hepatic impairment and decreases 47% with severe renal impairment.

Pharmacokinetics in Humans (Oral Administration): Oral dolasetron is well absorbed, although the parent drug is rarely detected in plasma due to rapid and complete metabolism to the most clinically relevant species, hydrodolasetron. Hydrodolasetron appears rapidly in plasma, with a maximum concentration occurring approximately 1 hour after dosing, and is eliminated with a mean half-life of 8.1 hours (CV=18%; n=30). The apparent absolute bioavailability of oral dolasetron, determined by the major active metabolite hydrodolasetron, is about 75%. Food does not affect the apparent bioavailability of dolasetron taken by mouth. Hydrodolasetron is eliminated by multiple routes, including renal excretion, after metabolism, mainly glucuronidation and hydroxylation. Two-thirds of the administered dose is recovered in the urine and one-third in the feces. Hydrodolasetron is widely distributed in the body with a mean apparent volume of distribution of 5.8 L/kg (CV=25%; n=24). Sixty-nine to 77% of hydrodolasetron is bound to plasma proteins. The binding of hydrodolasetron to a1-acid glycoprotein is approximately 51%. In a study with 4-labeled dolasetron, the distribution of radioactivity to blood cells was not extensive. The pharmacokinetics of hydrodolasetron are linear and similar in men and women.

The pharmacokinetics of hydrodolasetron following oral administration, in special and targeted patient populations, are summarized in Table II. The pharmacokinetics of hydrodolasetron are similar between adult healthy volunteers and cancer patients receiving chemotherapeutic agents. The apparent clearance of hydrodolasetron following oral administration of dolasetron is not affected by age in adult cancer patients. The apparent clearance of hydrodolasetron decreases 42% with severe hepatic impairment and 44% with severe renal impairment.

Clinical Trials: I.V. Administration: One thousand nine hundred and seventeen patients receiving emetogenic chemotherapy (including high dose cisplatin ³70 mg/m were studied in 5 randomized, double blind trials in which 597 patients were treated with the recommended dose of 1.8 mg/kg dolasetron injection (see Table III). Efficacy was based on complete response rates (no emetic episodes and no rescue medication). Dolasetron administered i.v. at a dose of 1.8 mg/kg gave similar results in preventing nausea and vomiting as the other selective 5-HT3 receptor antagonists studied as active comparators. Dolasetron injection was more effective than metoclopramide.

Oral Administration: One thousand and twenty-six patients receiving emetogenic chemotherapy were studied in 3 randomized, double blind trials in which 227 patients were treated with 100 mg oral dolasetron. Efficacy was based on complete response rates (no emetic episodes and no rescue medication). Dolasetron administered at an oral dose of 100 mg gave similar results in preventing nausea and vomiting as the other selective 5-HT3 receptor antagonists studied as active comparators.

Indications And Clinical Uses: For the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high dose cisplatin.

Contra-Indications: In patients with known hypersensitivity to the drug or any components of its formulations (see Supplied).

Manufacturers’ Warnings In Clinical States: Dolasetron can cause ECG interval changes (PR and QTc prolongations and QRS widening) in healthy volunteers and patients. In patients receiving chemotherapy or undergoing surgery, JT prolongations have also been observed following dolasetron, active comparator or placebo. JT prolongations have not been observed in healthy volunteers receiving dolasetron. ECG interval changes are related in magnitude and frequency to blood levels of the active metabolite, hydrodolasetron. These changes are self-limiting with declining blood levels. Some patients have interval prolongations for 24 hours or longer. Interval prolongations could lead to cardiovascular consequences, including heart block or cardiac arrhythmias. These have been rarely reported in patients receiving dolasetron.

Complete heart block was observed interoperatively in a 61-year-old woman who received 200 mg dolasetron oral tablet for the prevention of postoperative nausea and vomiting. This patient was also taking verapamil. A 66-year-old man receiving chemotherapy was found dead 6 hours after receiving 1.8 mg/kg (119 mg) i.v. dolasetron injection and concomitant anthracycline therapy. Vital signs taken at 1 and 4.5 hours after dolasetron injection indicated an adequate blood pressure and increasing heart rate. This patient had other potential risk factors including substantial exposure to doxorubicin and concomitant cyclophosphamide.

Precautions: General: Dolasetron should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc. These include patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital QT syndrome, patients taking antiarrhythmic drugs or other drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy.

Because dolasetron affects cardiac conductivity, the recommended doses should not be exceeded.

Children: Due to insufficient safety and efficacy data, dolasetron is not recommended for use in pediatric patients at this time.

Renal Impairment: Dosage adjustment is not necessary in mild to moderate renal impairment. However, dolasetron is not recommended in patients with severe renal impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels.

Hepatic Impairment: Dosage adjustment is not necessary in mild to moderate hepatic impairment. The oral formulation of dolasetron is not recommended in patients with severe hepatic impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. This drug is not recommended for use during pregnancy.

Lactation: It is not known whether dolasetron is excreted in human milk. Dolasetron should not be administered to a nursing woman.

Geriatrics: Dosage adjustment is not needed in patients over 65.

Carcinogenicity: In a 24-month carcinogenicity study in CD-1 mice, there was a statistically significant (p=0.001) increase in the incidence of combined hepatocellular adenomas and carcinomas in male mice treated orally with 150 mg/kg/day dolasetron and above. No increase in liver tumors was observed at a dose of 75 mg/kg/day in male mice and at doses up to 300 mg/kg/day in female mice.

In a 24-month carcinogenicity study in Sprague-Dawley rats, oral dolasetron mesylate was not tumorigenic at doses up to 150 mg/kg/day in males and 300 mg/kg/day in females.

Drug Interactions: 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 (see Warnings for information about potential interaction with other drugs that prolong QTc intervals). Blood levels of hydrodolasetron increased 24% when dolasetron was coadministered with cimetidine (nonselective inhibitor of cytochrome P450) for 7 days, and decreased 28% with coadministration of rifampin (potent inducer of cytochrome P450) for 7 days. Dolasetron injection has been safely coadministered with drugs used in chemotherapy and surgery. 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 was administered concomitantly with atenolol. Dolasetron does not influence anesthesia recovery time in patients. Dolasetron did not inhibit the antitumor activity of 4 chemotherapeutic agents (cisplatin, 5-fluorouracil, doxorubicin, cyclophosphamide) in 4 murine models.

Adverse Reactions: The safety of dolasetron has been evaluated in over 7 000 patients in North American and European clinical trials. Dolasetron was well tolerated, with headache being the most frequently reported adverse event.

Injection: In controlled and uncontrolled clinical trials, 2 265 adult patients received dolasetron injection of which 731 patients were treated at the recommended therapeutic dose (1.8 mg/kg). Patients were receiving chemotherapy (primarily cisplatin) and i.v. fluids. Adverse events were recorded for at least 24 hours following dolasetron injection administration.

Oral Administration: In controlled clinical trials, 943 patients received oral dolasetron of which 227 patients were treated at the recommended therapeutic dose (100 mg). These patients were receiving concurrent chemotherapy, predominantly cyclophosphamide and doxorubicin regimens.

Less frequently occurring adverse events: Injection: In controlled and uncontrolled clinical trials the following adverse events occurred at a frequency of 0.3 to 2.0% in patients treated with dolasetron injection at the recommended dose (1.8 mg/kg): Autonomic Nervous System: dry mouth, flushing.

Body as a Whole: malaise.

Cardiovascular (general): chest pain, edema, edema peripheral, fluid overload, hypotension.

Central and Peripheral Nervous System: drowsiness, paresthesia, tremor, vertigo.

GastroIntestinal: abdominal distension, anorexia, appetite increased, constipation, dyspepsia, flatulence, hiccup, nausea, stomatitis.

Hearing, Taste, and Vision: taste perversion.

Heart Rate and Rhythm: atrial arrhythmia, sinus arrhythmia, atrial flutter/fibrillation, first degree AV block, bradycardia, cardiac arrest, ECG abnormal specific, QT/QTc prolonged, ST-T wave change, T wave change.

Hematologic: bone marrow aplasia, epistaxis.

Musculoskeletal: myalgia.

Psychiatric: agitation, anxiety, confusion, sleep disorder.

Resistance Mechanism: sepsis.

Respiratory System: abnormal breath sounds, bronchospasm, cough, dyspnea, pneumonia, pulmonary congestion, throat irritation, upper respiratory congestion.

Skin and Appendages: facial edema, increased sweating.

Urinary System: urinary retention.

Oral Administration: In controlled clinical trials the following adverse events occurred at a frequency of 0.9 to 2.0% in patients treated with oral dolasetron at the recommended dose (100 mg): Application Site: injection site pain.

Autonomic Nervous System: dry mouth, flushing.

Body as a Whole: fever.

Cardiovascular (general): dependent edema, hypotension.

Central and Peripheral Nervous System: drowsiness.

GastroIntestinal: abdominal pain, anorexia, increased appetite, constipation, eructation, flatulence, nausea.

Hearing, Taste, and Vision: taste perversion.

Heart Rate and Rhythm: atrial arrhythmia, sinus arrhythmia, extrasystoles.

Liver and Biliary System: AST increased.

Metabolic and Nutritional: dehydration.

Resistance Mechanism: influenza-like symptoms.

Respiratory System: dyspnea, nasal irritation, sneezing, throat irritation.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: A 59-year-old male with metastatic melanoma (otherwise healthy) developed severe hypotension and dizziness 40 minutes after receiving a 15-minute infusion of 1 000 mg (13 mg/kg) of dolasetron. Treatment for 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 QTc 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 orally before surgery. No symptoms occurred and no treatment was required.

It is not known if dolasetron is removed by hemodialysis or peritoneal dialysis.

Following a suspected overdose of dolasetron, a patient found to have second-degree or higher AV conduction block should undergo cardiac telemetry monitoring.

There is no known specific antidote for dolasetron, and patients with suspected overdose should be managed with supportive therapy. Individual doses as large as 5 mg/kg i.v. or 400 mg orally have been safely given to healthy volunteers or cancer patients.

Single i.v. doses of dolasetron at 160 mg/kg in male mice and 140 mg/kg in female mice and rats of both sexes were lethal. Symptoms of acute toxicity were tremors, depression and convulsions.

Dosage And Administration: The following recommended doses should not be exceeded due to the effects on cardiac conductivity (see Warnings and Precautions).

I.V. Administration: Adults: The recommended i.v. dosage is 1.8 mg/kg given as a single dose approximately 30 minutes before chemotherapy. Most patients can be adequately treated with 100 mg. For light patients (90 kg), 1.8 mg/kg should be used.

The injection can be infused as rapidly as 100 mg over 30 seconds, or it can be diluted in a compatible i.v. solution such as normal saline or 5% dextrose to 50 mL and infused over 15 minutes. Dolasetron should not be mixed with other drugs. Flush the infusion line before and after administration of dolasetron.

Oral Administration: Adults: The recommended oral dosage is one 100 mg tablet given within 1 hour prior to chemotherapy.

Geriatrics: It is not necessary to adjust the dose of dolasetron in elderly patients.

Children: Due to insufficient safety and efficacy data, dolasetron is not recommended for use in pediatric patients at this time.

Hepatic Impairment: No dosage adjustment is necessary in mild to moderate hepatic impairment. However, oral dolasetron is not recommended in patients with severe hepatic impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels.

Renal Impairment: No dosage adjustment is necessary in mild to moderate renal impairment. However, dolasetron is not recommended in patients with severe renal impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels.

Parenteral Products: Administration of I.V. Infusion Solutions: Compatibility with I.V. Solutions: Dolasetron injection should only be admixed with the following recommended infusion fluids: 0.9% w/v Sodium Chloride Injection, 5% w/v Glucose Injection, 10% w/v Mannitol Injection, 0.45% w/v Sodium Chloride and 5% w/v Glucose Injection, Lactated Ringer’s Injection, 5% w/v Glucose Injection and Lactated Ringer’s Injection.

Dolasetron is compatible with polypropylene syringes, i.v. bags, and associated tubing.

Compatibility with Other Drugs: Dolasetron should not be mixed with other drugs. Flush the infusion line before and after administration of dolasetron.

Note: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used.

Dilution: To prepare dolasetron injection for i.v. infusion, aseptically transfer the appropriate amount of dolasetron injection to the desired volume of infusion fluid.

Stability and Storage of Diluted Solutions: Dilutions of i.v. fluids should be used immediately after preparation or stored for no more than 24 hours at 2 to 8°C.

Availability And Storage: Injection: Each mL of clear, colorless, sterile, nonpyrogenic solution for i.v. injection contains: dolasetron mesylate monohydrate 20 mg. Nonmedicinal ingredients: glacial acetic acid, mannitol, sodium acetate trihydrate and water for injection. pH: 3.2 to 3.8. Clear glass vials of 5 mL.

Tablets: 50 mg: Each pale pink, round, film-coated tablet, printed with “ANZEMET” around “50” centered on one side and plain on the other, contains: dolasetron mesylate monohydrate 50 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, red iron oxide, titanium dioxide and white wax. Bottles of 15.

100 mg: Each pink, oval, film-coated tablet, printed with “ANZEMET” on one side and “100” on the other, contains: dolasetron mesylate monohydrate 100 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, red iron oxide, titanium dioxide and white wax. Bottles of 15.

Store at controlled temperature (15 to 30°C) and protect from light.

ANZEMET™ Hoechst Marion Roussel Dolasetron Mesylate Antiemetic

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Nausea and Vomiting

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