Dolasetron Mesilate

Drug Approvals

(British Approved Name Modified, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Dolasetron, Mesilate de; Dolasetron Mesylate (USAN); Dolasetroni Mesilas; MDL-73I47EF (dolasetron or dolasetron mesilate); Mesilato de dolasetron.

C₁₉H₂₀N₂O₃CH₄O₃S = 420.5.

CAS — 115956-12-2 (dolasetron); 115956-13-3 (dolasetron mesilate).

ATC — A04AA04.

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008(Dolasetron Mesylate). A white to off-white powder. Freely soluble in water and in propylene glycol slightly soluble in alcohol and in sodium chloride 0.9%. Protect from light.

Stability. A study ofthe stability of two extemporaneous oral suspensions of dolasetron mesilate 10 mg/mL prepared from commercially available tablets found them to be stable for at least 90 days when stored at 3 to 5° and at 23 to 25°.

Adverse Effects and Precautions

As for Ondansetron, p. 1757. Diarrhoea, anorexia, and abdominal pain may also occur. Various ECG changes have been noted with dolasetron. Dolasetron should be used with caution in patients who have, or may develop, prolongation of the QT interval or other alterations in cardiac conduction intervals, and in those with electrolyte imbalances. Other adverse effects include dyspepsia, flatulence, taste disturbances, fever, chills or shivering, sleep disorders, fatigue, and drowsiness. There have been rare reports of intestinal obstruction, pancreatitis, jaundice, seizures, bronchospasm, cardiac arrhythmias, and oedema. Local reactions may occur on intravenous use. No dosage reduction is considered necessary in renal or hepatic impairment, despite possible reductions in clearance.

Effects on the cardiovascular system

For a discussion of the effects of 5-HT₃ antagonists on the cardiovascular system, see under Ondansetron.

Phlebitis

Venous irritation has been reported after intravenous use of dolasetron diluting subsequent doses with sodium chloride 0.9% and infusing it more slowly markedly reduced the frequency of phlebitis.

Interactions

Plasma concentrations of hydrodolasetron, the active metabolite of dolasetron, are increased by cimetidine and atenolol and decreased by rifampicin. Dolasetron should be used with caution in patients taking drugs that prolong the QT interval, including those likely to cause electrolyte disturbances.

Pharmacokinetics

Dolasetron given orally or intravenously is rapidly converted to the active metabolite hydrodolasetron by carbonyl reductase, a ubiquitous enzyme. Peak plasma concentrations of hydrodolasetron occur 1 hour after oral, and 0.6 hours after intravenous, doses of dolasetron. The apparent oral bioavailability of dolasetron determined as hydrodolasetron is about 75%. It has a mean elimination half-life of about 7 to 8 hours. Hydrodolasetron is partially metabolised by the cytochrome P450 isoenzymes CYP2D6 and CYP3A and about 50 to 60% is eliminated unchanged in the urine.

Two thirds of a dose of dolasetron is recovered in the urine and one third in the faeces. Clearance of hydrodolasetron is increased in children, but is not altered in the elderly. Clearance is reduced in severe hepatic impairment (Child-Pugh category B or C) and in severe renal impairment (creatinine clearance less than 10 mL/min) after oral use. After intravenous use, clearance is reduced in severe renal impairment but apparently unchanged in severe hepatic impairment.

Uses and Administration

Dolasetron is a 5-HT₃ antagonist with antiemetic actions similar to those of ondansetron. It is used as the mesilate in the prevention of nausea and vomiting associated with chemotherapy, and in the prevention and treatment of postoperative nausea and vomiting.

For prevention of acute nausea and vomiting associated with chemotherapy dolasetron mesilate may be given orally in a dose of 100 mg (in the USA) or 200 mg (in most other countries including the UK) within 1 hour before treatment. Alternatively, it may be given in a dose of 1.8 mg/kg, or 100 mg, by intravenous injection at a rate of up to 100 mg over 30 seconds about 30 minutes before chemotherapy the same dose may be diluted to 50 niL with a suitable infusion solution and given intravenously over up to 15 minutes. To protect against delayed emesis, a further 200-mg dose may be given orally once daily in Europe and the UK dolasetron may not normally be given for more than 4 consecutive days per chemotherapy cycle although some countries permit use for up to 7 days.

When given for the prevention of postoperative nausea and vomiting the recommended dose is usually 50 mg of dolasetron mesilate orally before induction of anaesthesia or 12.5 mg intravenously at the end of anaesthesia. In the USA, it is given as a 100-mg oral dose within 2 hours before surgery or 12.5 mg intravenously about 15 minutes before the end of anaesthesia. The same intravenous dose may be given for the treatment of postoperative nausea and vomiting.

The use of dolasetron mesilate in children is licensed in some countries, including the USA. However, others have not licensed such use and in the UK it is contra-indicated in children and adolescents under 18 years of age because they may be at increased risk of acute changes in the QT interval, and there have been reports of cardiac conduction disorders, cardiac arrest, and myocardial infarction in children treated with dolasetron. In the USA, children over 2 years of age may be given dolasetron mesilate 1.8 mg/kg orally (within 1 hour before chemotherapy) or intravenously (about 30 minutes before chemotherapy), up to a maximum dose of 100 mg, to prevent acute chemotherapy-induced nausea and vomiting.

For prevention of postoperative nausea and vomiting, 1.2 mg/kg by mouth, up to a maximum of 100 mg, may be given within 2 hours before surgery or 350 micrograms/kg, up to a maximum of 12.5 mg, may be given intravenously 15 minutes before the end of anaesthesia. The same intravenous dose may be given to treat established postoperative nausea and vomiting.

Pruritus

Dolasetron and other 5-HT₃ antagonists have been investigated for the management of pruritus (see under Ondansetron).

Preparations

The United States Pharmacopeia 31, 2008: Dolasetron Mesylate Injection Dolasetron Mesylate Oral Solution Dolasetron Mesylate Oral Suspension Dolasetron Mesylate Tablets.

Proprietary Preparations

Argentina: Anzemet

Australia:: Anzemet

Austria: Anzemet

Brazil: Anzemet

Canada: Anzemet

Czech Republic: Anzemet

Finland: Anzemet

France: Anzemet

Germany: Anemet

Greece: Anzemet

Hungary: Anemet

Italy: Anzemet

Mexico: Anzemet

The Netherlands: Anzemet

South Africa: Zamanon

Switzerland: Anzemet

United Kingdom: Anzemet

USA: Anzemet

Venezuela: Anzemet