Anzemet Tablets

Anzemet Tablets information, interactions and side effects, 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-1Hindole-3-carboxylate monomethanesulfonate, monohydrate. It is a highly specific and selective serotonin subtype 3 (5-HT3) receptor antagonist both in vitro and in vivo. Dolasetron mesylate has the following structural formula:

anzemet

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.

Each ANZEMET 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.

INDICATIONS

ANZEMET Tablets are indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses in adults and children 2 years and older.

DOSAGE AND ADMINISTRATION

The recommended doses of ANZEMET Tablets should not be exceeded.

Adults

The recommended oral dosage of ANZEMET (dolasetron mesylate) is 100 mg given within one hour before chemotherapy.

Pediatric Patients

The recommended oral dosage in pediatric patients 2 to 16 years of age is 1.8 mg/kg given within one hour before chemotherapy, up to a maximum of 100 mg. Safety and effectiveness in pediatric patients under 2 years of age have not been established.

In children for whom the 100 mg tablet is not appropriate based on their weight or ability to swallow tablets, the ANZEMET Injection solution may be mixed into apple or apple-grape juice for oral dosing in pediatric patients. The diluted product may be kept up to 2 hours at room temperature before use. However, ANZEMET Injection solution when 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.

Use in the Elderly, Renal Failure Patients, or 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).

HOW SUPPLIED

ANZEMET® Tablets (dolasetron mesylate)

 

Strength Quantity NDC Number Description
50 mg 5 ct Bottle 0088-1202-05 Light pink, film coated, round tablet imprinted with “A” on one side and “50”on the other.
10 ct Unit Dose Pack 0088-1202-43
100 mg 5 ct Bottle 0088-1203-05 Pink, film coated, elongated oval tablet imprinted with “100” on one side and “ANZEMET” on the other.
10 ct Unit Dose 0088-1203-43
5 ct Blister Pack 0088-1203-29

Store at controlled room temperature 20-25°C (68-77°F). Protect from light.

SIDE EFFECTS

In controlled clinical trials, 943 adult cancer patients received ANZEMET Tablets. These patients were receiving concurrent chemotherapy, predominantly cyclophosphamide and doxorubicin regimens. The following adverse events were reported in ≥ 2% of patients receiving either ANZEMET 25 mg or ANZEMET 100 mg tablets for prevention of cancer chemotherapy induced nausea and vomiting in controlled clinical trials (Table 3).

Table 3: Adverse Events ≥ 2% from Chemotherapy-Induced Nausea and Vomiting Studies

 

ANZEMET
25 mg
(N=235)
100 mg
(N=227)
Headache 42 (17.9%) 52 (22.9%)
Fatigue 6 (2.6%) 13 (5.7%)
Diarrhea 5 (2.1%) 12 (5.3%)
Bradycardia 12 (5.1%) 9 (4.0%)
Dizziness 3 (1.3%) 7 (3.1%)
Pain 0 7 (3.1%)
Tachycardia 7 (3.0%) 6 (2.6%)
Dyspepsia 7 (3.0%) 5 (2.2%)
Chills/Shivering 3 (1.3%) 5 (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 receiving concomitant cancer chemotherapy:

Cardiovascular: Hypotension; edema, peripheral edema. The following events also occurred and with a similar frequency as placebo and/or active comparator: Mobitz I AV block, chest pain, orthostatic hypotension, myocardial ischemia, 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, 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: Rash, increased sweating.

Gastrointestinal System: Constipation, dyspepsia, abdominal pain, anorexia; pancreatitis.

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

Hematologic: Hematuria, epistaxis, prothrombin time prolonged, PTT increased, anemia, purpura/hematoma, thrombocytopenia.

Hypersensitivity: Anaphylactic reaction, facial edema, urticaria.

Liver and Biliary System: Transient increases in AST (SGOT) and/or ALT (SGPT) values have been reported as adverse events in less than 1% of adult patients receiving ANZEMET in clinical trials. 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. Hyperbilirubinemia, increased GGT.

Metabolic and Nutritional: Alkaline phosphatase increased.

Musculoskeletal: Myalgia, arthralgia.

Nervous System: Flushing, vertigo, paresthesia, tremor; ataxia, twitching.

Psychiatric: Agitation, sleep disorder, depersonalization; confusion, anxiety, abnormal dreaming.

Respiratory System: Dyspnea, bronchospasm.

Urinary System: Dysuria, polyuria, acute renal failure.

Vascular (Extracardiac): Local pain or burning on IV administration; peripheral ischemia, thrombophlebitis/phlebitis.

Postmarketing Experience

There are reports of wide complex tachycardia or ventricular tachycardia and of ventricular fibrillation cardiac arrest following intravenous administration.

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 because hydrodolasetron is eliminated by multiple routes. See PRECAUTIONS, General for information about potential interaction with other drugs that prolong the QTc 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 is coadministered with drugs, including those used in chemotherapy, that prolong ECG intervals and/or cause hypokalemia or hypomagnesemia. (see WARNINGS).

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. Dolasetron mesylate did not inhibit the antitumor activity of four chemotherapeutic agents (cisplatin, 5-fluorouracil, doxorubicin, cyclophosphamide) in four murine models.

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, hypomagnesemia, or hypokalemia. 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, bradycardia, renal impairment, and elderly patients (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).

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.

Cross hypersensitivity reactions have been reported in patients who received other selective 5HT3 receptor antagonists. These reactions have not been seen with dolasetron mesylate.

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/m²/day). For a 50 kg person of average height (1.46 m² body surface area), these doses represent 3, 6, and 12 times the recommended clinical dose (74 mg/m²) 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/m²/day, 12 times the recommended human dose based on body surface area) in male rats and 300 mg/kg/day (1800 mg/m²/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/m²/day, 8 times the recommended human dose based on body surface area) in female rats and up to 400 mg/kg/day (2400 mg/m²/day, 32 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 oral doses up to 100 mg/kg/day (8 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 100 mg/kg/day (16 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 Tablets are administered to a nursing woman.

Pediatric Use

(See PRECAUTIONS, General)

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 Tablets are expected to be as safe and effective as when ANZEMET Injection is given orally to pediatric patients. ANZEMET Tablets are recommended for children old enough to swallow tablets (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Humans).

Geriatric Use

  1. 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 in this population (see WARNINGS).
  2. In controlled clinical trials in the prevention of chemotherapy-induced nausea and vomiting, 301 (29%) of 1026 patients were 65 years of age or older. Of the 301 geriatric patients in the trial, 282 received oral ANZEMET Tablets. No overall differences in safety or effectiveness were observed between geriatric and younger patients, and other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics, including clearance of oral ANZEMET Tablets, 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.

OVERDOSE

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.

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 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.

CONTRAINDICATIONS

ANZEMET Tablets are contraindicated in patients known to have hypersensitivity to the drug.

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