Drug Evaluation: Dolasetron

Drug Evaluation: Dolasetron

Dolasetron mesylate is (2a,6a,8a,9aß)-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 (www.drugs.com). Dolasetron mesylate has the following structural formula:

The empirical formula is C19H20N2O3 •CH3SO3H•H2O, with a molecular weight of 438.50. Approximately 74% of dolasetron mesylate monohydrate is dolasetron base (www.nlm.nih.gov). 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 (www.rxlist.com). The tablets are printed with black ink, which contains lecithin, pharmaceutical glaze, propylene glycol, and synthetic black iron oxide.

Chemotherapy Patients

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 1) (www.drugs.com).

Table 1. Adverse Events = 2% from Chemotherapy-Induced Nausea and Vomiting Studies

Event

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%)

Postoperative Patients

In controlled clinical trials, 936 adult female patients have received oral ANZEMET for the prevention of postoperative nausea and vomiting. Following is a listing of all adverse events reported in = 2% of patients receiving either placebo or ANZEMET for prevention of postoperative nausea and vomiting in controlled clinical trials (Table 2) (www.drugs.com).

Table 2. Adverse Events = 2% from Placebo-Controlled Postoperative Nausea and Vomiting Studies

Event

ANZEMET 100 mg (N=228)

Placebo (N=231)

Headache

16 (7.0%)

11 (4.8%)

Hypotension

12 (5.3%)

15 (6.5%)

Dizziness

10 (4.4%)

0 (0.0%)

Fever

8 (3.5%)

7 (3.0%)

Pruritus

7 (3.1%)

8 (3.5%)

Oliguria

6 (2.6%)

3 (1.3%)

Hypertension

5 (2.2%)

7 (3.0%)

Tachycardia

5 (2.2%)

2 (0.9%)

In clinical trials, the following infrequently reported adverse events, assessed by investigators as treatment-related or causality unknown, occurred following oral or intravenous administration of ANZEMET to adult patients receiving concomitant cancer chemotherapy or surgery:

Cardiovascular: Hypotension; rarely-edema, peripheral edema. The following events also occurred rarely 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 (www.rxlist.com).

Dermatologic: Rash, increased sweating.

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

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

Hematologic: Rarely-hematuria, epistaxis, prothrombin time prolonged, PTT increased, anemia, purpura/hematoma, ...