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Alosetron Hydrochloride

Drug Approvals

(BANM, US Adopted Name, rINNM)

Alosetron HydrochlorideSynonyms: Alosetrón, hidrocloruro de; GR-68755C
BAN: Alosetron Hydrochloride [BANM]
USAN: Alosetron Hydrochloride
INN: Alosetron Hydrochloride [rINNM (en)]
INN: Hidrocloruro de alosetrón [rINNM (es)]
INN: Alosétron, Chlorhydrate d’ [rINNM (fr)]
INN: Alosetroni Hydrochloridum [rINNM (la)]
INN: Алосетрона Гидрохлорид [rINNM (ru)]
Chemical name: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one hydrochloride
Molecular formula: C17H18N4O,HCl =330.8
CAS: 122852-42-0 (alosetron); 122852-69-1 (alosetron hydrochloride)
ATC code: A03AE01

Adverse Effects

Serious gastrointestinal adverse effects have occurred with alosetron, and as a result, it was withdrawn from the market in the USA and subsequently reintroduced with more restricted indications. These adverse effects include severe constipation leading to obstruction, ileus, perforation, impaction, toxic megacolon, and secondary ischaemia, as well as ischaemic colitis. Fatalities have been reported.

Other gastrointestinal effects reported include abdominal distension and pain, nausea, reflux, and haemorrhoids. Adverse effects reported rarely include cardiac arrhythmias, cholecystitis, altered bilirubin levels, tremor, headache, myalgia, malaise, fatigue, and CNS effects such as confusion, anxiety, depression, and sedation. Urticaria, skin reactions, nail disorders, and alopecia can occur. Hyperglycaemia, hypoglycaemia, and disorders of calcium and phosphate metabolism have been reported.

Incidence of adverse effects. The incidence of serious gastrointestinal adverse effects with alosetron has been reviewed. Pooled data from clinical studies suggested that the rate of ischaemic colitis in patients taking alosetron was about 0.15%, or 6.4 cases per 1000 patient-years. Results from postmarketing surveillance (before and after its temporary withdrawal from the US market) were estimated to represent a rate of 1 case per 1000 patient-years. Serious complications of constipation did not seem to be increased in the population of alosetron users.

Precautions

Alosetron should be stopped immediately in patients who develop constipation or symptoms of ischaemic colitis such as new or worsening abdominal pain or blood in the stool. Treatment with alosetron should not be resumed in patients who develop ischaemic colitis.

Alosetron should not be used in patients with a history of severe or chronic constipation, intestinal obstruction or stricture, toxic megacolon, or gastrointestinal perforation or adhesions. It is also contra-indicated in patients with a history of ischaemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagu-lable state, and those with current or previous inflammatory bowel disease or diverticulitis.

Alosetron should not be used in those with severe hepatic impairment or a history thereof it should be used with caution in patients with mild to moderate hepatic impairment. Elderly patients may be at increased risk of severe complications if constipation develops.

Interactions

Plasma concentrations of alosetron are markedly increased, and its half-life prolonged roughly threefold, when given with fluvoxamine such a combination should be avoided. Licensed product information recommends that use with other more moderate inhibitors of cytochrome P450 isoenzyme CYP1A2 (such as quinolone antibacterials and cimetidine) should be avoided unless clinically necessary, because of the risk of similar interactions. Ketoconazole also increases plasma alosetron concentrations care should be taken if alosetron is used with this or other potent inhibitors of the CYP3A4 isoenzyme (including clarithro-mycin, telithromycin, HIV-protease inhibitors, voriconazole, and itraconazole).

Alosetron HydrochloridePharmacokinetics

Alosetron is rapidly absorbed from the gastrointestinal tract peak plasma concentrations are reached about 1 hour after an oral dose. Plasma concentrations are 30 to 50% lower in men than in women given the same oral dose clearance is lower in women. Bioavailability is about 60% the extent and rate of absorption are slightly reduced by food. Plasma protein binding is about 82%. Alosetron is extensively metabolised via cytochrome P450 isoenzymes, particularly CYP1A2, although CYP2C9 and CYP3A4 also play a role. Numerous metabolites are excreted in the urine and faeces only 6% of a dose is recovered unchanged from the urine. The terminal elimination half-life of alosetron is reported to be about 1.5 hours.

Uses and Administration

Alosetron is a 5-HT3 antagonist used in the treatment of severe diarrhoea-predominant irritable bowel syndromein women who have not responded to conventional therapy effectiveness in men has not been established. It is given orally as the hydrochloride but doses are expressed in terms of the base alosetron hydrochloride 1.12 mg is equivalent to about 1 mg of alosetron.

The initial dose is the equivalent of alosetron 500 micrograms twice daily for 4 weeks if tolerated, the dose may then be increased if necessary to 1 mg twice daily. If symptoms are not adequately controlled after 4 weeks of treatment with the higher dose, alosetron should be stopped.

Proprietary Preparations

 

Argentina: Lotronex

Mexico: Liminos

USA: Lotronex

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