ANZEMET dolasetron mesylate injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
dolasetron mesylate (UNII: U3C8E5BWKR) (dolasetron - UNII:82WI2L7Q6E)
Available from:
sanofi-aventis U.S. LLC
INN (International Name):
dolasetron mesylate
Composition:
dolasetron mesylate 12.5 mg in 0.625 mL
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application

ANZEMET- dolasetron mesylate injection

sanofi-aventis U.S. LLC

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ANZEMET

Injection

(dolasetron mesylate)

DESCRIPTION

ANZEMET (dolasetron mesylate) is an antinauseant and antiemetic agent. Chemically, dolasetron

mesylate is (2α,6α,8α,9aβ)-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-HT )

receptor antagonist both in vitro and in vivo. Dolasetron mesylate has the following structural formula:

The empirical formula is C

H N O CH SO H H O, 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-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.

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.

Effects on Electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily)

controlled crossover study in 80 healthy adults, with 14 measurements over 24 hours on Day 4. The

maximum mean (95% upper confidence bound) differences in QTcF from placebo after baseline-

correction were 14.1 (16.1) and 36.6 (38.6) ms for 100 mg and supratherapeutic 300 mg ANZEMET

administered intravenously, respectively. ANZEMET 300 mg once daily resulted in approximately 3-

fold higher mean C

values of dolasetron mesylate and its active metabolite hydrodolasetron on Day

4 compared to those observed with the therapeutic 100 mg ANZEMET dose.

Based on exposure-response analyses in healthy volunteers, QTc interval prolongation appears to be

associated with concentrations of hydrodolasetron. Using the established exposure-response

relationship, the mean predicted increase (95% upper prediction interval) in QTcF intervals were 22.5

(23.9) and 21.2 (22.6) ms in pediatric and adult cancer patients following a single intravenous dose of

1.8 mg/kg.

In the thorough QT study, exposure dependent prolongation of the PR and QRS interval was also noted

in healthy subjects receiving ANZEMET. The maximum mean (95% upper confidence bound)

difference in PR from placebo after baseline-correction was 9.8 (11.6) ms and 33.1 (34.9) ms for 100

mg and supratherapeutic 300 mg ANZEMET, respectively. The maximum mean (95% upper confidence

bound) difference in QRS from placebo after baseline-correction was 3.5 (4.5) ms and 13 (14.5) ms for

100 mg and supratherapeutic 300 mg ANZEMET, respectively. Over one-fourth of the subjects treated

with the 300 mg dose had an absolute PR over 200 ms and absolute QRS of over 110 ms post-treatment.

A change from baseline ≥ 25% was noted in several of these subjects. (see CONTRAINDICATIONS

and WARNINGS)

Pharmacokinetics in Humans

Intravenous dolasetron mesylate is rapidly eliminated (t

<10 min) and completely metabolized to the

most clinically relevant species, hydrodolasetron.

The reduction of dolasetron to hydrodolasetron is mediated by a ubiquitous enzyme, carbonyl

reductase. Cytochrome P-450 (CYP)2D6 is primarily responsible for the subsequent hydroxylation of

hydrodolasetron and both CYP3A and flavin monooxygenase are responsible for the N-oxidation of

hydrodolasetron.

Hydrodolasetron is excreted in the urine unchanged (53.0% of administered intravenous dose). Other

urinary metabolites include hydroxylated glucuronides and N-oxide.

Hydrodolasetron appeared rapidly in plasma, with a maximum concentration occurring approximately

0.6 hour after the end of intravenous treatment, and was eliminated with a mean half-life of 7.3 hours

(%CV=24) and an apparent clearance of 9.4 mL/min/kg (%CV=28) in 24 adults. Hydrodolasetron is

eliminated by multiple routes, including renal excretion and, after metabolism, mainly glucuronidation,

and hydroxylation. Hydrodolasetron exhibits linear pharmacokinetics over the intravenous dose range

of 50 to 200 mg and they are independent of infusion rate. Doses lower than 50 mg have not been

studied. 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) in adults.

Sixty-nine to 77% of hydrodolasetron is bound to plasma protein. In a study with

C labeled dolasetron,

the distribution of radioactivity to blood cells was not extensive. The binding of hydrodolasetron to α -

acid glycoprotein is approximately 50%. The pharmacokinetics of hydrodolasetron are linear and

similar in men and women.

The pharmacokinetics of hydrodolasetron, in special and targeted patient populations following

intravenous administration of ANZEMET Injection, are summarized in Table 1. The pharmacokinetics of

hydrodolasetron are similar in adult (young and elderly) healthy volunteers. The apparent clearance of

hydrodolasetron in pediatric and adolescent patients is 1.4 times to twofold higher than in adults.

Following intravenous administration, the apparent clearance of hydrodolasetron remains unchanged

with severe hepatic impairment and decreases 47% with severe renal impairment. No dose adjustment is

necessary for elderly patients (see PRECAUTIONS, Geriatric Use) or for patients with hepatic or renal

impairment.

In a pharmacokinetic study in 18 pediatric patients (2 to 11 years of age) undergoing surgery with

general anesthesia and administered a single 1.2 mg/kg intravenous dose of ANZEMET Injection, mean

apparent clearance was greater (40%) and terminal half-life shorter (36%) for hydrodolasetron than in

healthy adults receiving the same dose.

For 12 pediatric patients, ages 2 to 12 years receiving 1.2 mg/kg ANZEMET Injection diluted in apple

or apple-grape juice and administered orally, the mean apparent clearance was 34% greater and half-life

was 21% shorter than in healthy adults receiving the same dose.

Table 1. Pharmacokinetic Values for Plasma Hydrodolasetron Following Intravenous

Administration of ANZEMET Injection

Age

(years )

Dos e

CL

(mL/min/kg)

t

(h)

C

(ng/mL)

: apparent clearance t

: terminal elimination half-life ( ): coefficient of variation in %

Young Healthy Volunteers (N=24)

19–40

100 mg

9.4 (28%)

7.3 (24%)

320 (25%)

Elderly Healthy Volunteers (N=15)

65–75

2.4 mg/kg

8.3 (30%)

6.9 (22%)

620 (31%)

Pediatric Surgery Patients (N=18)

2–11

1.2 mg/kg

13.1 (47%)

4.8 (23%)

255 (22%)

Patients with Severe Renal

Impairment (N=12)

(Creatinine clearance ≤10 mL/min)

28–74

200 mg

5.0 (33%)

10.9 (30%)

867 (31%)

Patients with Severe Hepatic

Impairment (N=3)

42–52

150 mg

9.6 (19%)

11.7 (22%)

396 (45%)

Clinical Studies

Prevention of Postoperative Nausea and Vomiting

ANZEMET Injection administered intravenously at a dose of 12.5 mg approximately 15 minutes before

the cessation of general balanced anesthesia (short-acting barbiturate, nitrous oxide, narcotic and

analgesic, and skeletal muscle relaxant) was significantly more effective than placebo in preventing

postoperative nausea and vomiting. No increased efficacy was seen with higher doses.

One trial compared single intravenous ANZEMET Injection doses of 12.5, 25, 50, and 100 mg with

placebo in 635 women surgical patients undergoing laparoscopic procedures. ANZEMET Injection at a

dose of 12.5 mg was statistically superior to placebo for complete response (no vomiting, no rescue

medication) (p=.0003). Complete response rates were 50% and 31%, respectively.

Another trial compared single intravenous ANZEMET Injection doses of 12.5, 25, 50, and 100 mg with

placebo in 1030 (722 women and 308 men) surgical patients. In women, the 12.5 mg dose was

statistically superior to placebo for complete response. The complete response rates were 50% and

40%, respectively. However, in men, there was no statistically significant difference in complete

response between any ANZEMET dose and placebo.

Treatment of Postoperative Nausea and/or Vomiting

Two randomized, double-blinded trials compared single intravenous ANZEMET Injection doses of

12.5, 25, 50, and 100 mg with placebo in 124 male and 833 female patients who had undergone surgery

*

app

1/2

max

: mean values

with general balanced anesthesia and presented with early postoperative nausea or vomiting requiring

antiemetic treatment.

In both studies, the 12.5 mg intravenous dose of ANZEMET was statistically superior to placebo for

complete response (no vomiting, no escape medication). No significant increased efficacy was seen

with higher doses.

INDICATIONS AND USAGE

ANZEMET Injection is indicated for the following:

(1)

(2)

CONTRAINDICATIONS

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

ANZEMET Injection solution administered intravenously is contraindicated in adult and pediatric

patients for the prevention of nausea and vomiting associated with initial and repeat courses of

emetogenic cancer chemotherapy due to dose dependent QT prolongation. Mean QTc effects over 20

ms are expected in this patient population (see CLINICAL PHARMACOLOGY and WARNINGS).

WARNINGS

QT Interval Prolongation

ANZEMET prolongs the QT interval in a dose dependent fashion. Torsade de Pointes has been

reported during post-marketing experience. Avoid ANZEMET in patients with congenital long QT

syndrome, hypokalemia or hypomagnesemia. Hypokalemia and hypomagnesemia must be corrected prior

to ANZEMET administration. Monitor these electrolytes after administration as clinically indicated. Use

ECG monitoring in patients with congestive heart failure and bradycardia (see CLINICAL

PHARMACOLOGY).

PR and QRS Interval Prolongation

ANZEMET 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). ANZEMET should be used with caution and with ECG

monitoring in these patients. ANZEMET should be avoided in patients with complete heart block or at

risk for complete heart block, unless they have an implanted pacemaker (see CLINICAL

PHARMACOLOGY).

the prevention of postoperative nausea and vomiting (PONV) in adults and children 2 years

and older. 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.

When prophylaxis has failed, a repeat dose should not be initiated as rescue therapy.

the treatment of postoperative nausea and/or vomiting in adults and children 2 years and

older.

c

Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT receptor antagonists. Most

reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin

reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake 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-HT receptor

antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-

HT 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 Anzemet and

other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Anzemet and initiate

supportive treatment. Patients should be informed of the increased risk of serotonin syndrome,

especially if Anzemet is used concomitantly with other serotonergic drugs (see DRUG

INTERACTIONS, Patient Counseling Information).

PRECAUTIONS

General

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.

Drug Interactions

The potential for clinically significant drug-drug interactions posed by dolasetron and hydrodolasetron

appears to be low for drugs commonly used in surgery, because hydrodolasetron is eliminated by

multiple routes. See PRECAUTIONS, General for 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 Injection is coadministered with drugs that prolong ECG

intervals and/or cause hypokalemia or hypomagnesemia (see WARNINGS).

In patients taking furosemide, nifedipine, diltiazem, ACE inhibitors, verapamil, glyburide, and

propranolol, 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 did not influence anesthesia recovery time in patients.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms)

has been described following the concomitant use of 5-HT receptor antagonists and other

c

has been described following the concomitant use of 5-HT receptor antagonists and other

serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and

noradrenaline reuptake inhibitors (SNRIs).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, there was a statistically significant (P<0.001) increase in the

incidence of combined hepatocellular adenomas and carcinomas in male mice treated with 150

mg/kg/day and above. In this study, mice (CD-1) were treated orally with dolasetron mesylate 75, 150 or

300 mg/kg/day (225, 450 or 900 mg/m /day). For a 50 kg person of average height (1.46 m body

surface area), these doses represent 3.4, 6.8 and 13.5 times the recommended clinical dose (66.6 mg/m ,

intravenous) on a body surface area basis. 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 rat (Sprague-Dawley) carcinogenicity study, oral dolasetron mesylate was not

tumorigenic at doses up to 150 mg/kg/day (900 mg/m /day, 13.5 times the recommended human dose

based on body surface area) in male rats and 300 mg/kg/day (1800 mg/m /day, 27 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, 9 times the recommended human dose based on body

surface area) in female rats and up to 400 mg/kg/day (2400 mg/m /day, 36 times the recommended human

dose based on body surface area) in male rats.

Pregnancy

Teratogenic Effects

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 intravenous doses up to 60

mg/kg/day (5.4 times the recommended human dose based on body surface area) and pregnant rabbits at

intravenous doses up to 20 mg/kg/day (3.2 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 ANZEMET Injection is administered to a nursing

woman.

Pediatric Use

Prevention of chemotherapy-induced nausea and vomiting (CINV)

Dolasetron is contraindicated in pediatric patients for the prevention of nausea and vomiting

associated with initial and repeat courses of emetogenic cancer chemotherapy. (see

CONTRAINDICATIONS).

Prevention and treatment of post-operative nausea and vomiting (PONV)

Safety and effectiveness in pediatric patients (2 years and older) for prevention and treatment of

postoperative nausea and vomiting 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.

Two open-label, noncomparative pharmacokinetic studies have been performed in a total of 30 pediatric

patients undergoing surgery with general anesthesia. These patients received ANZEMET Injection

either intravenously or orally in juice. Pediatric patients from 2 to 12 years of age participated in these

trials, which included an intravenous ANZEMET Injection dose of 1.2 mg/kg, and an oral dose of 1.2

mg/kg. There is no experience in pediatric patients under 2 years of age. Overall, ANZEMET Injection

was well tolerated in these pediatric patients. No efficacy information was collected in the pediatric

postoperative nausea and vomiting studies.

Geriatric Use

Prevention of chemotherapy-induced nausea and vomiting (CINV)

Dolasetron is contraindicated in geriatric patients for prevention of nausea and vomiting

associated with initial and repeat courses of emetogenic cancer chemotherapy (see

CONTRAINDICATIONS).

Prevention and treatment of post-operative nausea and vomiting (PONV)

Controlled clinical studies in the prevention and treatment of post-operative nausea and vomiting did not

include sufficient numbers of patients aged 65 years or older – only 57 (2%) geriatric patients (43

received intravenous ANZEMET Injection) out of 3289 total patients participated in the controlled

PONV trials – to determine whether they respond differently from younger patients. Other reported

clinical experiences have not identified differences in responses between geriatric and younger

patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low

end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac

function, and of concomitant disease or other drug therapy.

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 ANZEMET for

prevention of postoperative nausea and vomiting in this population (see WARNINGS).

The pharmacokinetics, including clearance of intravenous ANZEMET Injection, in elderly and younger

patients are similar (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Humans). Dosage

adjustment is not needed in patients over the age of 65.

ADVERSE REACTIONS

Postoperative Patients

In controlled clinical trials with 2550 adult patients, headache and dizziness were reported more

frequently with 12.5 mg ANZEMET Injection than with placebo. Rates of other adverse events were

similar. Following is a listing of all adverse events reported in ≥2% of patients receiving either

placebo or 12.5 mg ANZEMET Injection for the prevention or treatment of postoperative nausea and

vomiting in controlled clinical trials (Table 2).

Table 2. Adverse Events ≥2% from Placebo-Controlled Postoperative

Nausea and Vomiting Studies

Event

ANZEMET Injection

12.5 mg

(n=615)

Placebo

(n=739)

Headache

58 (9.4%)

51 (6.9%)

Dizziness

34 (5.5%)

23 (3.1%)

Drowsiness

15 (2.4%)

18 (2.4%)

Pain

15 (2.4%)

21 (2.8%)

Urinary Retention

12 (2.0%)

16 (2.2%)

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 in < 2% of

adult patients undergoing surgery:

Body as a Whole: Chills/shivering.

Cardiovascular: Sinus arrhythmia, hypotension, orthostatic hypotension. The following events also

occurred and with a similar frequency as placebo and/or active comparator: Mobitz I AV block, chest

pain, syncope, severe bradycardia, and palpitations. See PRECAUTIONS section for information on

potential effects on ECG.

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, tachycardia, T wave change, ST-T wave

change, extrasystole (APCs or VPCs), bundle branch block (left and right).

Furthermore, severe hypotension, bradycardia and syncope have been reported immediately or closely

following IV administration.

Dermatologic: Rash.

Gastrointestinal System: Constipation, dyspepsia, abdominal pain.

Hearing, Taste and Vision: Taste perversion, abnormal vision.

Hypersensitivity: Anaphylactic reaction, urticaria.

Liver and Biliary System: Transient increases in AST (SGOT) and/or ALT (SGPT). The increases did

not appear to be related to dose or duration of therapy and were not associated with symptomatic hepatic

disease. Similar increases were seen with patients receiving active comparator.

Musculoskeletal: Myalgia, arthralgia.

Nervous System: Vertigo; flushing, paraesthesia.

Psychiatric: Agitation, anxiety, abnormal dreaming.

Respiratory System: Bronchospasm.

Vascular (Extracardiac): Local pain or burning on IV administration.

Postmarketing Experience

There are reports of wide complex tachycardia or ventricular tachycardia and of ventricular fibrillation

cardiac arrest following intravenous administration.

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 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.

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 dolasetron mesylate orally before surgery. No symptoms occurred

and no treatment was required.

DOSAGE AND ADMINISTRATION

The recommended dose of ANZEMET Injection should not be exceeded.

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

Intravenous Administration

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.

Oral Administration of the Intravenous Product

ANZEMET Injection solution may be mixed into apple or apple-grape juice for oral dosing in pediatric

patients. When ANZEMET Injection solution 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; however, ECG monitoring is recommended for elderly and

renally impaired patients (see WARNINGS and CLINICAL PHARMACOLOGY, Pharmacokinetics in

Humans).

ADMINISTRATION

ANZEMET Injection can be safely infused intravenously as rapidly as 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.

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) is supplied as a clear, colorless solution in single and

multidose vials.

ANZEMET Injection

(dolasetron mesylate)

20 mg/mL

Strength

Des cription

NDC Number

12.5 mg

0.625mL single use vial (Box of 6)

0088-1208-06

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.

PATIENT COUNSELING INFORMATION

Patients should be informed that ANZEMET 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:

Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT

syndrome

Patients with a personal history of sick sinus syndrome, atrial fibrillation with slow ventricular

response or myocardial ischemia

Patients who take medications that may prolong the PR interval, such as certain antihypertensives or

medications that may prolong the QRS interval, such as antiarrythmic medications

Patients who take medications, such as diuretics, which may cause electrolyte abnormalities

Patients with hypokalemia or hypomagnesemia

Elderly patients

ANZEMET should be avoided in these patients, since they may be more at risk for cardiac arrhythmias

such as QT prolongation and Torsade de Pointes.

Advise patients of the possibility of serotonin syndrome with concomitant use of Anzemet and another

serotonergic agent such as medications to treat depression and migraines. Advise patients to seek

immediate medical attention if the following symptoms occur: changes in mental status, autonomic

instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Prescribing information as of October 2014

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

®

A SANOFI COMPANY

©2014 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL - 12.5mg Vial Label

NDC 0088-1208-06

Anzemet

Injection

dolasetron mesylate

injection

12.5mg/0.625mL

PRINCIPAL DISPLAY PANEL - 100mg Vial Label

NDC 0088-1206-32

Anzemet

Injection

dolasetron mesylate

injection

100mg/5mL (20mg/mL)

Rx ONLY

1 Sterile 5mL Vial

®

®

PRINCIPAL DISPLAY PANEL - 500mg Vial Label

NDC 0088-1209-26

Anzemet

Injection

dolasetron mesylate

injection

500mg/25mL (20mg/mL)

FOR DIRECT INTRAVENOUS

INJECTION OR INFUSION

1 Sterile 25mL Multidose Vial

®

ANZEMET

dolasetron mesylate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 8 8 -120 8

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

do la setro n mesyla te (UNII: U3C8 E5BWKR) (do lasetro n - UNII:8 2WI2L7Q6 E)

do lasetro n mesylate

12.5 mg in 0 .6 25 mL

Inactive Ingredients

Ingredient Name

Stre ng th

Ma nnito l (UNII: 3OWL53L36 A)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 0 8 8 -120 8 -

6 in 1 BOX

1

0 .6 25 mL in 1 VIAL, SINGLE-USE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 6 24

0 9 /11/19 9 7

ANZEMET

dolasetron mesylate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 8 8 -120 6

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

do la setro n mesyla te (UNII: U3C8 E5BWKR) (do lasetro n - UNII:8 2WI2L7Q6 E)

do lasetro n mesylate

10 0 mg in 5 mL

Inactive Ingredients

Ingredient Name

Stre ng th

Ma nnito l (UNII: 3OWL53L36 A)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 0 8 8 -120 6 -

5 mL in 1 VIAL, SINGLE-USE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 6 24

0 9 /11/19 9 7

ANZEMET

dolasetron mesylate injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 8 8 -120 9

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

do la setro n mesyla te (UNII: U3C8 E5BWKR) (do lasetro n - UNII:8 2WI2L7Q6 E)

do lasetro n mesylate

50 0 mg in 25 mL

Inactive Ingredients

Ingredient Name

Stre ng th

Ma nnito l (UNII: 3OWL53L36 A)

Pheno l (UNII: 339 NCG44TV)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 0 8 8 -120 9 -

25 mL in 1 VIAL, MULTI-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 6 24

0 9 /11/19 9 7

sanofi-aventis U.S. LLC

Labeler -

sanofi-aventis U.S. LLC (783243835)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

sa no fi-

a ve ntis

S.p.A

338 454274

MANUFACTURE(0 0 8 8 -120 8 , 0 0 8 8 -120 6 , 0 0 8 8 -120 9 ) , ANALYSIS(0 0 8 8 -120 8 , 0 0 8 8 -120 6 , 0 0 8 8 -

120 9 ) , LABEL(0 0 8 8 -120 8 , 0 0 8 8 -120 6 , 0 0 8 8 -120 9 ) , PACK(0 0 8 8 -120 8 , 0 0 8 8 -120 6 , 0 0 8 8 -120 9 )

Revised: 10/2014

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