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Anzemet Injection

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Anzemet Injection

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.

Pharmacokinetics in Humans

Intravenous dolasetron mesylate is rapidly eliminated (t½< 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)IID6 is primarily responsible for the subsequent hydroxylation of hydrodolasetron and both CYPIIIA 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 14C labeled dolasetron, the distribution of radioactivity to blood cells was not extensive. The binding of hydrodolasetron to α1-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 (dolasetron mesylate injection) , 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 of hydrodolasetron in pediatric and adolescent patients is 1.4 times to twofold higher than in adults. The apparent clearance of hydrodolasetron is not affected by age in adult cancer patients. 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 pediatric cancer patients (ages 3 to 11, N=25; ages 12 to 17, N=21) given a single 0.6, 1.2, 1.8, or 2.4 mg/kg dose of ANZEMET Injection intravenously, apparent clearance values were highest and half-lives were lowest in the youngest age group. For the 3 to 11 and the 12 to 17 year age groups, all receiving doses between 0.6 to 2.4 mg/kg, mean apparent clearances are 2 and 1.3 times greater, respectively, than for healthy adults receiving the same range of doses.

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 (dolasetron mesylate injection) diluted with either apple or apple-grape juice and administered orally. In this study, the mean apparent clearances 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.

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 (dolasetron mesylate 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 (dolasetron mesylate 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 (dolasetron mesylate injection) *


  Age
(years)
Dose CLapp
(mL/min/kg)
t½
(h)
Cmax
(ng/mL)
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%)
Cancer Patients  
  Adults (N=273) 19-87 0.6-3.0 mg/kg 10.2 (34%) 7.5 (43%) 505 (26%)
  Adolescents (N=21) 12-17 0.6-3.0 mg/kg 12.5 (37%) 5.5 (31%) 562 (45%)§
  Children (N=25) 3-11 0.6-2.4 mg/kg 19.2 (30%) 4.4 (24%) 505 (100%)ll
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%)
CLapp: apparent clearance t½: terminal elimination half-life ( ): coefficient of variation in %
*: mean values
†: results from population kinetic study
‡: results from adult cancer study (dose=1.8 mg/kg, N=8)
§: results from adolescents (dose=1.8 mg/kg, N=7)
||: results from children (dose=1.8 mg/kg, N=5)

Clinical Studies

Prevention of Cancer Chemotherapy-Induced Nausea and Vomiting

ANZEMET Injection (dolasetron mesylate injection) administered intravenously at a dose of 1.8 mg/kg gave similar results in preventing nausea and vomiting as the other selective serotonin 5-HT3 receptor antagonists studied as active comparators. It was more effective than metoclopramide. Efficacy was based on complete response rates (0 emetic episodes and no rescue medication).

Cisplatin Based Chemotherapy

A randomized, double-blind trial compared single intravenous doses of ANZEMET Injection with metoclopramide in 226 (160 men and 66 women) adult cancer patients receiving ≥ 80 mg/m2 cisplatin. ANZEMET Injection (dolasetron mesylate injection) at a dose of 1.8 mg/kg was significantly more effective than metoclopramide in

the prevention of chemotherapy-induced nausea and vomiting in this study (Table 2).

Table 2. Prevention of Chemotherapy-Induced Nausea and Emesis from Cisplatin Chemotherapy*


  ANZEMET Injection (dolasetron mesylate injection)
1.8 mg/kg
Metoclopramide p-value
Number of Patients 72 69  
Response Over 24 Hours  
  Complete Response§ 41 (57%) 24 (35%) 0.0009
  Nausea Scorell 4 30 0.0400
*: Dose ≥ 80 mg/m2
†: Administered intravenously
‡: 3 mg/kg intravenous bolus and 0.5 mg/kg/h intravenously over 8 h.
§: 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."

A second randomized, double-blind trial compared single intravenous doses of ANZEMET Injection (dolasetron mesylate injection) with intravenous ondansetron in 609 (377 men and 232 women) adult cancer patients receiving ≥ 70 mg/m2 cisplatin. A single intravenous 1.8 mg/kg dose of ANZEMET Injection (dolasetron mesylate injection) was shown to be equivalent to a single intravenous 32 mg dose of ondansetron (Table 3).

Table 3. Prevention of Chemotherapy-Induced Nausea and Emesis from Cisplatin Chemotherapy*


  ANZEMET Injection (dolasetron mesylate injection)
1.8 mg/kg
Ondansetron
32 mg
p-value
Number of Patients 198 206  
Response Over 24 Hours  
  Complete Response§ 88 (44%) 88 (43%) NS
  Nausea Scorell 10 16 NS
*: Dose ≥ 70 mg/m2
†: Administered intravenously
‡: Includes 12 patients who received 3 doses 0.15 mg/kg of ondansetron intravenously.
§: 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 randomized, double-blind trial compared single IV doses of ANZEMET with a single 3-mg IV dose of granisetron in 474 (315 men and 159 women) patients receiving ≥ 80 mg/m2 cisplatin chemotherapy.

A single intravenous 1.8-mg/kg dose of ANZEMET gave similar results as those from granisetron.

Cyclophosphamide Based Chemotherapy

In a study of ANZEMET Injection (dolasetron mesylate injection) in 309 patients (96 men and 213 women) receiving moderately emetogenic chemotherapy such as cyclophosphamide based regimens, a single intravenous 1.8 mg/kg dose of ANZEMET Injection (dolasetron mesylate injection) was equivalent to metoclopramide administered as a 2 mg/kg intravenous bolus followed by 3 mg/kg intravenously over 8 hours. Complete response rates were 63% and 52%, respectively, p=0.12.

Prevention of Postoperative Nausea and Vomiting

ANZEMET Injection (dolasetron mesylate 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 (dolasetron mesylate injection) doses of 12.5, 25, 50, and 100 mg with placebo in 635 women surgical patients undergoing laparoscopic procedures. ANZEMET Injection (dolasetron mesylate 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 (dolasetron mesylate 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 (dolasetron mesylate injection) doses of 12.5, 25, 50, and 100 mg with placebo in 124 male and 833 female patients who had undergone surgery 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.

Last reviewed on RxList: 10/27/2009
This monograph has been modified to include the generic and brand name in many instances.

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