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Drug: Dolasetron - Anzemet®

Usual Diluents

NS, D5W, D5.45NS, D5LR, LR, 10% mannitol

Dilution Data

WARNINGS
FDA MedWatch:
Anzemet (dolasetron mesylate): Drug Safety Communication - Reports of Abnormal Heart Rhythms

[Posted 12/17/2010]

AUDIENCE: Oncology, Cardiology

ISSUE: FDA notified healthcare professionals that a contraindication is being added to the prescribing information advising that the injection form of Anzemet (dolasetron mesylate) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in pediatric and adult patients. New data demonstrate that Anzemet injection can increase the risk of developing torsade de pointes, an abnormal heart rhythm, which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Anzemet causes a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram.

BACKGROUND: FDA previously noted cardiovascular safety concerns which suggested Anzemet could cause QT prolongation. However, limitations of the previous data did not clearly establish the degree to which Anzemet may cause QT prolongation. FDA recommended that the drug sponsor conduct a thorough QT study in adults in order to determine the degree of the prolongation. A pediatric study was not recommended due to the wide variability in heart rate and, thus, QTc interval in the pediatric population. See the Data Summary section of the Drug Safety Communication (DSC) for information that supports this change in the prescribing information.

RECOMMENDATION: Anzemet should not be used in patients with congenital long-QT syndrome. Hypokalemia and hypomagnesemia should be corrected before administering Anzemet. These electrolytes should be monitored after administration as clinically indicated. Use electrocardiogram monitoring in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking Anzemet. Anzemet injection may still be used for the prevention and treatment of postoperative nausea and vomiting because the lower doses used are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms.

Anzemet tablets may still be used to prevent CINV because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form. However, a stronger warning about this potential risk is being added to the Warnings and Precautions sections of the Anzemet tablet label.

See the DSC for additional recommendations for healthcare professionals and for patients.

[12/17/2010 - Drug Safety Communication - FDA]

[Prescribed dose] [ 50 ml ] [ 5 - 15 minutes]

ADMINISTRATION
ANZEMET Injection can be safely infused intravenously as rapidly as 100 mg/30 seconds or diluted in a compatible intravenous solution (see below) to 50 mL and infused over a period of up to 15 minutes. ANZEMET Injection should not be mixed with other drugs. Flush the infusion line before and after administration of ANZEMET Injection.

STABILITY
After dilution, ANZEMET Injection is stable under normal lighting conditions at room temperature for 24 hours or under refrigeration for 48 hours with the following compatible intravenous fluids: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, 5% dextrose and Lactated Ringer's injection, Lactated Ringer's injection, and 10% mannitol injection. Although ANZEMET Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative. After dilution, do not use beyond 24 hours, or 48 hours if refrigerated.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Stability / Miscellaneous

WARNINGS	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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DESCRIPTION
ANZEMET (dolasetron mesylate) is an antinauseant and antiemetic agent. Chemically, dolasetron mesylate is (2

,9a

)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-carboxylate monomethanesulfonate, monohydrate. It is a highly specific and selective serotonin subtype 3 (5-HT3) receptor antagonist both in vitro and in vivo.

The empirical formula is C19H20N2O3 • CH3SO3H • H2O, 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.

ANZEMET Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous administration. Each milliliter of ANZEMET Injection contains 20 mg of dolasetron mesylate and 38.2 mg mannitol, USP, with an acetate buffer in water for injection. The pH of the resulting solution is 3.2 to 3.8.

ANZEMET Injection multidose vials contain a clear, colorless, nonpyrogenic, sterile solution for intravenous administration. Each ANZEMET multidose vial contains 25 mL (500 mg) dolasetron mesylate. Each milliliter contains 20 mg dolasetron mesylate, 29 mg mannitol, USP, and 5 mg phenol, USP, with an acetate buffer in water for injection. The pH of the resulting solution is 3.2 to 3.7.

CLINICAL PHARMACOLOGY
Dolasetron mesylate and its active metabolite, hydrodolasetron (MDL 74,156), are selective serotonin 5-HT3 receptor antagonists not shown 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 the released serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the vomiting reflex.

Acute, usually reversible, ECG changes (PR and QTc prolongation; QRS widening), caused by dolasetron mesylate, have been observed in healthy volunteers and in controlled clinical trials. The active metabolites of dolasetron may block sodium channels, a property unrelated to its ability to block 5-HT3 receptors. QTc prolongation is primarily due to QRS widening. Dolasetron appears to prolong both depolarization and, to a lesser extent, repolarization time. The magnitude and frequency of the ECG changes increased with dose (related to peak plasma concentrations of hydrodolasetron but not the parent compound). These ECG interval prolongations usually returned to baseline within 6 to 8 hours, but in some patients were present at 24 hour follow up. Dolasetron mesylate administration has little or no effect on blood pressure.

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 mesylate has no effect on plasma prolactin concentrations.

INDICATIONS AND USAGE
ANZEMET Injection is indicated for the following:

(1) the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high dose cisplatin;

(2) the prevention of postoperative nausea and vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ANZEMET Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low;

(3) the treatment of postoperative nausea and/or vomiting.

CONTRAINDICATIONS
ANZEMET Injection is contraindicated in patients known to have hypersensitivity to the drug.

WARNINGS
ANZEMET can cause ECG interval changes (PR, QTc, JT prolongation and QRS widening). These changes are related in magnitude and frequency to blood levels of the active metabolite. These changes are self-limiting with declining blood levels. Some patients have interval prolongations for 24 hours or longer. Interval prolongation could lead to cardiovascular consequences, including heart block or cardiac arrhythmias. These have rarely been reported.

A cardiac conduction abnormality observed on an intra-operative cardiac rhythm monitor (interpreted as complete heart block) was reported in a 61-year-old woman who received 200 mg ANZEMET for the prevention of postoperative nausea and vomiting. This patient was also taking verapamil. A similar event also interpreted as complete heart block was reported in one patient receiving placebo.

A 66-year-old man with Stage IV non-Hodgkins lymphoma died suddenly 6 hours after receiving 1.8 mg/kg (119 mg) intravenous ANZEMET Injection. This patient had other potential risk factors including substantial exposure to doxorubicin and concomitant cyclophosphamide.

Pediatric Use
Dolasetron should be administered with caution in pediatric patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc. Rare cases of sustained supraventricular and ventricular arrhythmias, cardiac arrest leading to death, and myocardial infarction have been reported in children and adolescents (See PACKAGE INSERT FOR Precautions, General, and Adverse Reactions – Postmarketing Experience).

DOSAGE AND ADMINISTRATION
The recommended dose of ANZEMET Injection should not be exceeded.

Prevention of Cancer Chemotherapy-Induced Nausea and Vomiting
Adults
The recommended intravenous dosage of ANZEMET Injection from clinical trial results is 1.8 mg/kg given as a single dose approximately 30 minutes before chemotherapy (see Administration). Alternatively, for most patients, a fixed dose of 100 mg can be administered over 30 seconds.

Pediatric Patients
The recommended intravenous dosage in pediatric patients 2 to 16 years of age is 1.8 mg/kg given as a single dose approximately 30 minutes before chemotherapy, up to a maximum of 100 mg (see Administration). Safety and effectiveness in pediatric patients under 2 years of age have not been established.

ANZEMET Injection mixed in apple or apple-grape juice may be used for oral dosing of pediatric patients. When ANZEMET Injection is administered orally, the recommended dosage in pediatric patients 2 to 16 years of age is 1.8 mg/kg up to a maximum 100 mg dose given within 1 hour before chemotherapy.

The diluted product may be kept up to 2 hours at room temperature before use.

Use in the Elderly, in Renal Failure Patients, or in Hepatically Impaired Patients
No dosage adjustment is recommended.

Prevention or Treatment of Postoperative Nausea and/or Vomiting
Adults
The recommended intravenous dosage of ANZEMET Injection is 12.5 mg given as a single dose approximately 15 minutes before the cessation of anesthesia (prevention) or as soon as nausea or vomiting presents (treatment).

Pediatric Patients
The recommended intravenous dosage in pediatric patients 2 to 16 years of age is 0.35 mg/kg, with a maximum dose of 12.5 mg, given as a single dose approximately 15 minutes before the cessation of anesthesia or as soon as nausea or vomiting presents. Safety and effectiveness in pediatric patients under 2 years of age have not been established.

ANZEMET Injection mixed in apple or apple-grape juice may be used for oral dosing of pediatric patients. When ANZEMET Injection is administered orally, the recommended oral dosage in pediatric patients 2 to 16 years of age is 1.2 mg/kg up to a maximum 100-mg dose given within 2 hours before surgery. The diluted product may be kept up to 2 hours at room temperature before use.

Use in the Elderly, in Renal Failure Patients, or in Hepatically Impaired Patients
No dosage adjustment is recommended.

ADMINISTRATION
ANZEMET Injection can be safely infused intravenously as rapidly as 100 mg/30 seconds or diluted in a compatible intravenous solution (see below) to 50 mL and infused over a period of up to 15 minutes. ANZEMET Injection should not be mixed with other drugs. Flush the infusion line before and after administration of ANZEMET Injection.

STABILITY
After dilution, ANZEMET Injection is stable under normal lighting conditions at room temperature for 24 hours or under refrigeration for 48 hours with the following compatible intravenous fluids: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, 5% dextrose and Lactated Ringer's injection, Lactated Ringer's injection, and 10% mannitol injection. Although ANZEMET Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative. After dilution, do not use beyond 24 hours, or 48 hours if refrigerated.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

HOW SUPPLIED
ANZEMET Injection (dolasetron mesylate injection) is supplied as a clear, colorless solution in single and multidose vials, and Carpuject® sterile cartridges with Luer Lock.

ANZEMET® Injection (dolasetron mesylate injection) 20 mg/mL
Strength	Description	NDC Number
*sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Origin Italy †Mfd by Hospira, Inc. McPherson, KS 67460 USA
12.5 mg	0.625mL single use vial* (Box of 6)	0088-1208-06
12.5 mg	0.625mL fill in single-use 2mL Carpuject with Luer Lock† (Box of 10)	0088-1208-76
100 mg/5 mL	5mL single-use vial*	0088-1206-32
500 mg/25 mL	25 mL multidose vial*	0088-1209-26

Store at 20–25°C (68–77°F) with excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature]. Protect from light.

Reference(s)

PRIMARY:
1) [PACKAGE INSERT DATA] : ANZEMET (dolasetron mesylate) injection. [sanofi-aventis U.S. LLC] Bridgewater, NJ 08807. August 2008.

Drug: Dolasetron - Anzemet®

Usual Diluents

Dilution Data

Stability / Miscellaneous

Reference(s)

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