DailyMed Label: ANZEMET

DailyMed Label: ANZEMET

2023

DailyMed Prescription

ANZEMET

dolasetron mesylate

Validus Pharmaceuticals LLC

NDC: 30698-220

NDC: 30698-220

ANZEMET (dolasetron mesylate, USP) is an antinauseant and antiemetic agent. Chemically, dolasetron mesylate is (2α,6α,8α,9aß)-octahydro-3-oxo-2,6-methano-2 H -quinolizin-8-yl-1 H -indole-3-carboxylate monomethanesulfonate, monohydrate.  It is a highly specific and selective serotonin subtype 3 (5-HT 3 ) receptor antagonist both in vitro  and  in vivo .  Dolasetron mesylate has the following structural formula: The empirical formula is C 19 H 20 N 2 O 3 • CH 3 SO 3 H • H 2 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. Each ANZEMET Tablet for oral administration contains dolasetron mesylate (as the monohydrate) and also contains the inactive ingredients: croscarmellose sodium, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, synthetic red iron oxide, and titanium dioxide. See the source image

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.

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 100 mg 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 ).

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

Dolasetron should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QT c .   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 3 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 because hydrodolasetron is eliminated by multiple routes.   See PRECAUTIONS, General   for information about potential interaction with other drugs that prolong the QT c interval. When oral dolasetron (200 mg once daily) was co-administered 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 co-administered 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 co-administered 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. Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs). 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 2 /day).  For a 50 kg person of average height (1.46 m 2 body surface area), these doses represent 3, 6, and 12 times the recommended clinical dose (74 mg/m 2 ) 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 2 /day, 12 times the recommended human dose based on body surface area) in male rats and 300 mg/kg/day (1800 mg/m 2 /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 2 /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 2 /day, 32 times the recommended human dose based on body surface area) in male rats. 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. 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 ( s ee 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 ). 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 ). 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.

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

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 QT c interval. When oral dolasetron (200 mg once daily) was co-administered 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 co-administered 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 co-administered 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. Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs).

ANZEMET ®   Tablets (dolasetron mesylate , USP ) Strength Quantity NDC Number Description 50 mg 10 ct Bottle 30698-220-10 Light pink, film coated, round tablet debossed with “A” on one side and “50” on the other. Store at 68° to 77°F (20° to 25°C) [See USP Controlled Room Temperature].  Protect from light.

Dolasetron mesylate and its active metabolite, hydrodolasetron (MDL 74,156), are selective serotonin 5-HT 3 receptor antagonists not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors. The serotonin 5-HT 3 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 3 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. 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) ms 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 max 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 analysis in healthy volunteers, QTc interval prolongations appear 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 16.0 (17.1) ms and 17.9 (19.1) ms for renally impaired and elderly subjects following an oral dose of 100 mg. 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 WARNINGS ) . Oral dolasetron is well absorbed, although parent drug is rarely detected in plasma due to rapid and complete metabolism 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 (61.0% of administered oral dose). Other urinary metabolites include hydroxylated glucuronides and N-oxide. 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%) and an apparent clearance of 13.4 mL/min/kg (%CV=29%) in 30 adults. The apparent absolute bioavailability of oral dolasetron, determined by the major active metabolite hydrodolasetron, is approximately 75%.  Orally administered dolasetron intravenous solution and tablets are bioequivalent.  Food does not affect the bioavailability of dolasetron taken by mouth. Hydrodolasetron is eliminated by multiple routes, including renal excretion and, 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) in adults. Sixty-nine to 77% of hydrodolasetron is bound to plasma protein. In a study with 14 C labeled dolasetron, the distribution of radioactivity to blood cells was not extensive. Approximately 50% of hydrodolasetron is bound to α 1 -acid glycoprotein. The pharmacokinetics of hydrodolasetron are linear and similar in men and women. The pharmacokinetics of hydrodolasetron, in special and targeted patient populations following oral administration of dolasetron, are summarized in Table 1. The pharmacokinetics of hydrodolasetron are similar in adult (young and elderly) healthy volunteers and in adult cancer patients receiving chemotherapeutic agents. The apparent clearance following oral administration of hydrodolasetron is approximately 1.6- to 3.4-fold higher in children and adolescents than in adults.  The clearance following oral administration of hydrodolasetron is not affected by age in adult cancer patients.  The apparent oral clearance of hydrodolasetron decreases 42% with severe hepatic impairment and 44% with severe renal impairment.  No dose adjustment is necessary for renally impaired or elderly patients, however ECG monitoring is recommended  (see WARNINGS and PRECAUTIONS, Geriatric Use ). No dose adjustment is recommended for patients with hepatic impairment. The pharmacokinetics of ANZEMET Tablets have not been studied in the pediatric population. However, the following pharmacokinetic data are available on intravenous ANZEMET Injection administered orally to children. Thirty-two pediatric cancer patients ages 3 to 11 years (N=19) and 12 to 17 years (N=13), received 0.6, 1.2, or 1.8 mg/kg ANZEMET Injection diluted with either apple or apple-grape juice and administered orally. In this study, the mean apparent clearances of hydrodolasetron were 3 times greater in the younger pediatric group and 1.8 times greater in the older pediatric group than those observed in healthy adult volunteers.  Across this spectrum of pediatric patients, maximum plasma concentrations were 0.6 to 0.7 times those observed in healthy adults receiving similar doses. 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. The table below summarizes the pharmacokinetic data from multiple populations. Please note that the doses studied may have exceeded the maximum recommended dose.  Table 1.   Pharmacokinetic Values for Plasma Hydrodolasetron Following Oral Administration of ANZEMET* Age (years) Dose CL app (mL/min/kg) t 1/2 (h) C max (ng/mL) Young Healthy Volunteers (N=30) 19-45 200 mg 13.4 (29%) 8.1 (18%) 556 (28%) Elderly Healthy Volunteers (N=15) 65-75 2.4 mg/kg 9.5 (36%) 7.2 (32%) 662 (28%) Cancer Patients    Adults (N=61) †    Adolescents (N=13)    Children (N=19) 24-84 12-17 3-11 25-200 mg 0.6-1.8 mg/kg 0.6-1.8 mg/kg 12.9 (49%) 26.5 (67%) 44.2 (49%) 7.9 (43%) 6.4 (30%) 5.5 (39%) -- ‡ 374 § (32%) 217 || (67%) Patients with Severe Renal Impairment (N=12) (Creatinine clearance ≤10 mL/min) 28-74 200 mg 7.2 (48%) 10.7 (29%) 701 (21%) Patients with Severe Hepatic Impairment (N=3) 42-52 150 mg 8.8 (57%) 11.0 (36%) 410 (12%) CL app : apparent clearance   t 1/2 :    terminal elimination half-life  ( ):      coefficient of variation in % *:      mean values †:      analyzed by nonlinear mixed effect modeling with data pooled across dose strengths ‡:      sampling times did not allow calculation §:      results from adolescents (dose=1.8 mg/kg, N=3) the maximum dose exceeded 100 mg. When data from patients who received greater than 47 mg (N=9) are combined and normalized to the 1.8 mg/kg dose with a cap of 100 mg, the mean C max was 229 ng/mL (51%). | |:      results from children (dose=1.8 mg/kg, N=7) Oral ANZEMET at a dose of 100 mg prevents nausea and vomiting associated with moderately emetogenic cancer therapy as shown by 24 hour efficacy data from two double-blind studies. Efficacy was based on complete response (i.e., no vomiting, no rescue medication). The first randomized, double-blind trial compared single oral ANZEMET doses of 25, 50, 100 and 200 mg in 60 men and 259 women cancer patients receiving cyclophosphamide and/or doxorubicin.  There was no statistically significant difference in complete response between the 100 mg and 200 mg dose.  Results are summarized in Table 2.         Table 2.   Prevention of Chemotherapy-Induced Nausea and Vomiting from Moderately Emetogenic Chemotherapy ANZEMET Tablets Response Over 24 Hours 25 mg (N=78) 50 mg (N=83) 100 mg † (N=80) 200 mg (N=78) p -value for Linear Trend Complete Response ‡ 24 (31%) 34 (41%) 49 (61%) 46 (59%) P<.0001 Nausea Score § 49 10 11 7 P=.0006 † : The recommended dose ‡: No emetic episodes and no rescue medication. §: Median 24-h change from baseline nausea score using visual analog scale (VAS): Score range 0= “none” to  100= “nausea as bad as it could be.” Another trial also compared single oral ANZEMET doses of 25, 50, 100, and 200 mg in 307 patients receiving moderately emetogenic chemotherapy.  In this study, the 100 mg ANZEMET dose gave a 73% complete response rate.

Oral ANZEMET at a dose of 100 mg prevents nausea and vomiting associated with moderately emetogenic cancer therapy as shown by 24 hour efficacy data from two double-blind studies. Efficacy was based on complete response (i.e., no vomiting, no rescue medication). The first randomized, double-blind trial compared single oral ANZEMET doses of 25, 50, 100 and 200 mg in 60 men and 259 women cancer patients receiving cyclophosphamide and/or doxorubicin.  There was no statistically significant difference in complete response between the 100 mg and 200 mg dose.  Results are summarized in Table 2.         Table 2.   Prevention of Chemotherapy-Induced Nausea and Vomiting from Moderately Emetogenic Chemotherapy ANZEMET Tablets Response Over 24 Hours 25 mg (N=78) 50 mg (N=83) 100 mg † (N=80) 200 mg (N=78) p -value for Linear Trend Complete Response ‡ 24 (31%) 34 (41%) 49 (61%) 46 (59%) P<.0001 Nausea Score § 49 10 11 7 P=.0006 † : The recommended dose ‡: No emetic episodes and no rescue medication. §: Median 24-h change from baseline nausea score using visual analog scale (VAS): Score range 0= “none” to  100= “nausea as bad as it could be.” Another trial also compared single oral ANZEMET doses of 25, 50, 100, and 200 mg in 307 patients receiving moderately emetogenic chemotherapy.  In this study, the 100 mg ANZEMET dose gave a 73% complete response rate.

NDC 30698-220-10 Anzemet ®  Tablets (dolasetron mesylate, USP) 50 mg 10 Tablets Rx Only NDC 30698-220-10 Anzemet® Tablets (dolasetron mesylate, USP) 50 mg 10 Tablets Rx Only