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Buspirone Hydrochloride

Drug Approvals

(BANM, US Adopted Name, rINNM)

Synonyms: Buspiron-hydrochlorid; Buspirona, hidrocloruro de; Buspironhydroklorid; Buspironi Hydrochloridum; Buspironihydrokloridi; MJ-9022-1
BAN: Buspirone Hydrochloride [BANM]
USAN: Buspirone Hydrochloride
INN: Buspirone Hydrochloride [rINNM (en)]
INN: Hidrocloruro de buspirona [rINNM (es)]
INN: Buspirone, Chlorhydrate de [rINNM (fr)]
INN: Buspironi Hydrochloridum [rINNM (la)]
INN: Буспирона Гидрохлорид [rINNM (ru)]
Chemical name: 8-[4-(4-Pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride
Molecular formula: C21H31N5O2,HCl =422.0
CAS: 36505-84-7 (buspirone); 33386-08-2 (buspirone hydrochloride)
ATC code: N05BE01
Read code: y01zJ

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Buspirone Hydrochloride). A white or almost white, crystalline powder. It exhibits polymorphism. Freely soluble in water and in methyl alcohol practically insoluble in acetone. Protect from light.

Buspirone Hydrochloride5mg

The United States Pharmacopeia 31, 2008 (Buspirone Hydrochlonde). A white crystalline powder. Very soluble in water sparingly soluble in alcohol and in ace-tonitrile freely soluble in dichloromethane and in methyl alcohol very slightly soluble in ethyl acetate practically insoluble in hexanes. Store in airtight containers at a temperature between 15° and 30°. Protect from light.

Dependence and Adverse Effects

Dizziness, nausea, headache, nervousness, light-head-edness, excitement, paraesthesias, sleep disturbances, chest pain, tinnitus, sore throat, and nasal congestion are amongst the most frequent adverse effects reported after the use of buspirone hydrochloride. Other adverse effects have included tachycardia, palpitations, drowsiness, confusion, seizures, dry mouth, fatigue, and sweating. A syndrome of restlessness appearing shortly after the start of treatment has been reported in a small number of patients given buspirone. Buspirone is reported to produce less sedation, and to have a lower potential for dependence, than the benzodiazepines.

Effects on the nervous system. Mild acute hypertension and panic were reported on two occasions after the addition of single 10-mg doses of buspirone to therapy with tricyclic antidepres-sants in a 40-year-old man with panic disorder. Adrenergic or serotonin dysfunction were postulated as possible mechanisms for the reaction. Psychotic reactions associated with buspirone treatment have also been reported in a few patients. There have also been isolated reports of mania, and seizures have been reported, primarily in overdosage.

EXTRAPYRAMIDAL DISORDERS. There have been isolated reports of exacerbation or precipitation of movement disorders associated with the use of buspirone. However, buspirone has also been reported to have been of benefit in some patients with tardive dyskinesia (see Extrapyramidal Disorders under Uses and Administration, below).

buspirone10mg

Precautions

Buspirone hydrochloride should be used with caution in patients with renal or hepatic impairment and is contra-indicated if the impairment is severe. It should not be used in patients with epilepsy or a history of such disorders. It does not exhibit cross-tolerance with ben-zodiazepines or other common sedatives or hypnotics and will not block symptoms of their withdrawal they should, therefore, be gradually withdrawn before starting treatment with buspirone. Buspirone may impair the patient’s ability to drive or operate machinery.

Diagnosis and testing. Buspirone may interfere with diagnostic assays of urinary catecholamines.

Hepatic impairment. Caution has been advised when using buspirone in patients with liver disease. The mean peak plasma-buspirone concentration after an oral dose was about 16 times higher in cirrhotic patients than in controls and the elimination half-life was prolonged about twofold. A secondary peak concentration was seen in some subjects, occurring between 4 and 24 hours after a dose in the cirrhotics and after between 2 and 8 hours in controls. Data from a multiple-dose study suggested that there was accumulation of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in hepatic impairment, but that plasma concentrations appeared to reach steady state after 3 days regardless of the state of liver function. The area under the curve and mean peak concentration for buspirone were both higher in patients with hepatic impairment than in healthy subj ects, but there were no significant differences for its metabolites. Specific dosing recommendations could not be made for patients with hepatic impairment because of the high intra- and inter-subject variations in plasma-buspirone concentrations.

Pregnancy and breast feeding. In some animal studies, large doses of buspirone during pregnancy had adverse effects on survival and on birth and weanling weight. Recommendations in licensed product information for use during pregnancy or breast feeding vary from avoid, if possible, to contra-indicated.

Renal impairment. Caution has been advised when giving buspirone to patients with renal impairment. There is evidence of accumulation of buspirone and its metabolite after repeated doses but plasma concentrations appeared to reach steady state after 3 days regardless of the degree of renal function. At steady state both the area under the curve and maximum concentrations for buspirone and its metabolite were greater in patients with renal failure than in healthy subjects. The metabolite, but not the parent drug, was removed by haemodialysis. Specific dosing recommendations could not be made for patients with renal impairment because of the high intra- and inter-subject variations in buspirone plasma concentrations on repeated dosage.

buspirone-15mg

Interactions

The sedative effects of buspirone may be enhanced if taken with alcohol or other CNS depressants. Because of reports of increased blood pressure in patients receiving buspirone hydrochloride with an MAOI, licensed product information for buspirone recommends that it should not be given with an MAOI. The metabolism of buspirone is mediated by the cyto-chrome P450 isoenzyme CYP3A4 and therefore there is the potential for interactions between buspirone and other drugs that inhibit or act as a substrate for this isoenzyme. The dose of buspirone may need to be reduced if given at the same time as potent inhibitors of CYP3A4. Plasma concentrations of buspirone may be reduced by enzyme-inducing drugs such as rifampicin.

Antibacterials. Pretreatment with erythromycin in healthy subjects given buspirone resulted in mild to moderate adverse effects associated with increased plasma concentrations of buspirone.

Pretreatment with rifampicin greatly reduced plasma concentrations of buspirone in healthy subjects. A reduced anxiolytic effect could be expected if buspirone is used with rifampicin or other potent inducers of the cytochrome P450 isoenzyme CYP3A4.

Antidepressants. Use of buspirone with nefazodone can raise plasma concentrations of buspirone. US licensed product information for nefazodone recommends that the initial dose of buspirone be lowered (e.g. 2.5 mg daily) and subsequent dose adjustments of either drug should be based on clinical assessment. A possible serotonin syndrome has been reported in a patient using buspirone with fluoxetine.

Antifungals. Pretreatment with itraconazole inhealthy subjects given buspirone resulted in mild to moderate adverse effects associated with increased plasma concentrations of buspirone.

 

Antipsychotics. For the effect of buspirone on serum concentrations of haloperidol, see under Chlorpromazine. For a report of potentially fatal gastrointestinal bleeding and marked hyperglycaemia after use of buspirone with clozapine, see under Clozapine.

Antivirals. Parkinson-like symptoms developed in a 54-year-old man taking a drug regimen that included buspirone, indinavir, and ritonavir It was suspected that ritonavir inhibited the metabolism of buspirone, which is mediated by the cytochrome P450 isoenzyme C YP3A4, leading to increased plasma concentrations of the latter. The inhibitory effect of indinavir on CYP3A4 was considered to be less than that of ritonavir. Symptoms resolved after a change in antiviral regimen and reduction in the dose of buspirone.

Calcium-channel blockers. Increases in buspirone plasma concentrations have been seen in healthy subjects pretreated with diltiazem or verapamil.

 

Grapefruit juice. Grapefruit juice increased the plasma concentrations of buspirone in healthy subjects.

Pharmacokinetics

Buspirone hydrochloride is rapidly absorbed from the gastrointestinal tract reaching peak plasma concentrations within 40 to 90 minutes after an oral dose. Systemic bioavailability is low because of extensive first-pass metabolism, but may be increased if given with food as this delays absorption from the gastrointestinal tract and thereby reduces presystemic clearance. Buspirone is about 95% bound to plasma proteins. Metabolism in the liver is extensive via the cytochrome P450 isoenzyme CYP3A4 hydroxylation yields several inactive metabolites and oxidative dealkylation produces 1-(2-pyrimidinyl)-piperazine, which is reported to be about 25% as potent as the parent drug in one model of anxiolytic activity. The elimination half-life of buspirone is usually about 2 to 4 hours but half-lives of up to 11 hours have been reported. Buspirone is excreted mainly as metabolites in the urine, and also in the faeces.

Uses and Administration

Buspirone hydrochloride is an azaspirodecanedione (azapirone) anxiolytic. It is reported to be largely lacking in sedative, anticonvulsant, and muscle relaxant actions.

Buspirone hydrochloride is given, in initial oral doses of 5 mg two or three times daily, in the short-term management of anxiety disorders. The dose may be increased in increments of 5 mg at 2- to 3-day intervals if required. The recommended maximum daily dose, to be given in divided doses, is 45 mg in the UK and 60 mg in the USA.

Action. Buspirone has dopaminergic, noradrenergic, and serotonin-modulating properties and its anxiolytic effects appear to be related to its action on serotonin (5-hydroxytryptamine, 5-HT) neurotransmission. Buspirone, and the related drugs gepirone and ipsapirone, are partial agonists at 5-HT1A receptors. While such drugs may inhibit serotonin neurotransmission (most likely via 5-HT1A autoreceptor stimulation), they may also have postsynaptic 5-HT1A agonist activity and thus facilitate serotonin neurotransmission. To complicate matters further, 5-HT1A partial agonists have shown both anxiolytic and anxiogenic properties in animal models of anxiety. Clinical studies have, however, shown that buspirone is effective in the treatment of generalised anxiety.’

Clinical studies with buspirone and gepirone suggest that 5-HT1A partial agonists may be useful in the treatment of depression, possibly by downregulation of either 5-HT1A or 5-HT2 receptors or both. There is some suggestion that buspirone has an anti-aggressive action in humans it is unclear whether this is mediated via dopaminergic or serotonergic mechanisms. Buspirone also has characteristics of both a dopamine agonist and antagonist this may result in stimulation of both growth hormone and prolactin secretion.

Administration in hepatic or renal impairment. For cautions on the use of buspirone in patients with impaired liver or kidney function see under Precautions, above.

Anxiety disorders. Buspirone has been shown to be as effective as the benzodiazepines in the short-term treatment of generalised anxiety disorder and to be less likely to cause sedation or psychomotor and cognitive impairment. It also appears to have a lower propensity for interaction with alcohol and a lower risk of abuse and dependence. However, its usefulness may be limited by a relatively slow response to treatment, which may take up to 2 to 4 weeks to appear. Its efficacy may be reduced in patients who have recently taken benzodiazepines. It appears to be ineffective in panic disorder and convincing evidence of efficacy in other anxiety disorders is lacking. References.

Bruxism. SSRI-induced bruxism has been successfully controlled by adjunctive therapy with buspirone.

Cerebellar ataxias. In general the management of cerebellar ataxias is mainly supportive buspirone improved some symptoms of ataxia in a small study of patients with cerebellar cortical activity.

Depression. Buspirone has been investigated for augmentation of therapy with antidepressants with serotonin reuptake inhibiting activity in patients with refractory depression, but results have been variable.

Disturbed behaviour. Buspirone has been tried in various disorders for the control of symptoms such as agitation, aggression, and disruptive behaviour (see Disturbed Behaviour) but evidence of efficacy is limited. Nonetheless, in the management of dementia, some consider that it might be worth trying in nonpsychotic patients with disturbed behaviour, especially those with mild symptoms or those intolerant or unresponsive to antipsychotics.

Extrapyramidal disorders. Although there have been reports’ that buspirone may improve symptoms of drug-induced dyskinesia, drugs with dopaminergic actions have mostly exacerbated symptoms and there are a few reports of extrapyramidal disorders with buspirone (see under Adverse Effects, above).

Substance dependence. ALCOHOL Despite an early study suggesting that buspirone could reduce alcohol craving in alcohol dependent patients, later studies” have overall failed to confirm that buspirone improves abstinence or reduces alcohol consumption. Although some studies’ have found that buspirone may improve certain psychopathological symptoms in these patients, others have found no such benefit a meta-analysis of 5 studies favoured the former interpretation.

The management of alcohol withdrawal and abstinence is discussed.

NICOTINE. Buspirone has produced conflicting results in the management of smoking cessation. Although some studies suggest that in the short-term buspirone can increase the numbers of patients who are able to cease smoking, it does not necessarily decrease withdrawal symptoms.

Preparations

The United States Pharmacopeia 31, 2008: Buspirone Hydrochloride Tablets.

Proprietary Preparations

Argentina: Ansial †

Australia: Buspar

Austria: Buspar

Belgium: Buspar

Brazil: Ansienon † Ansitec Buspanil Buspar

Canada: Buspar Buspirex †

Chile: Paxon

Czech Republic: Anxiron † Buspar

Denmark: Buspar Stesiron †

Finland: Buspar Stesiron †

France: Buspar

Germany: Anxut Bespar Busp

Greece: Anchocalm Antipsichos Bergamo I Bespar Boronex Epsilat Hiremon Hobatstress Komasin Lanamont Lebilon Ledion Loxapin Nadrifor Nervostal Nevrorestol Norbal Pendium Stressigal Svitalark Tendanf Tensispes Trafuril † Umolit

Hong Kong: Buspar Kalmiren

Hungary: Anxiron Spitomin

India: Buscalm

Indonesia: Tran-Q Xiety

Ireland: Buspar

Israel: Buspirol-P Sorbon

Italy: Axoren Buspar Buspimen †

Mexico: Buspar

Norway: Buspar Stesiron †

New Zealand: Biron Buspar

Poland: Mabuson Spamilan

Portugal: Ansiten Busansil Buscalma Buspar Buspium Establix † Itagil Psibeter

South Africa: Buspar Pasrin

Spain: Buspar Effiplen †

Sweden: Buspar

Switzerland: Buspar

Thailand: Anxiolan

Turkey: Buspon

UK: Buspar

USA: Buspar

Venezuela: Dalpas

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