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Mechanism of Action
US Drug Names
7.5 mg PO twice daily initially, then increase as needed by 5 mg/day every 2 to 3 days. Usual maintenance dose: 15 to 30 mg/day administered in 2 to 3 divided doses. Max: 60 mg/day PO.
5 mg PO twice daily initially, then increase as needed by 5 mg/day every 2 to 3 days. Usual maintenance dose: 15 to 30 mg/day administered in 2 to 3 divided doses. Max: 60 mg/day. According to the federal Omnibus Budget Reconciliation Act (OBRA), tapering attempts or documentation of medical necessity are required in residents of long-term care facilities receiving an anxiolytic. 
Effectiveness has not been established. The safety and effectiveness of buspirone in pediatric patients 6 to 17 years of age (n= 559) were evaluated in 2 placebo-controlled 6-week trials. There was no significant efficacy difference between buspirone and placebo. Long-term safety and efficacy data are lacking. Dosages studied: 2.5 mg to 5 mg PO twice daily, initially. Increase by 5 mg/day at intervals of 3 to 7 days as needed and tolerated. Max: 60 mg/day, given in 2 to 3 divided doses. In one study of pediatric patients with an anxiety disorder, doses of 5 to 7.5 mg PO twice a day were safe and well-tolerated in children (n = 13) and doses of 5 to 30 mg PO twice daily were found to be safe and tolerated in adolescents (n = 12). The study indicated that children 12 years of age and younger may have a decreased tolerability to high dosages. 
60 mg/day PO.
Safety and efficacy have not been established.
Buspirone is not recommended for use in patients with severe hepatic impairment.
CrCl less than 30 mL/minute: Buspirone is not recommended for use in patients with severe renal impairment or renal failure.
Buspirone is not recommended in patients with renal failure.
Buspirone is an oral anxiolytic that is structurally and pharmacologically distinct from all other anxiolytics. The clinical use of buspirone is limited to the treatment of generalized anxiety disorder (GAD) in adults. While used clinically off-label in pediatrics 6 years of age and older with anxiety, the efficacy of buspirone in pediatric patients with GAD has not been formally established. Results from clinical trials of buspirone for panic disorder in adults are generally unfavorable, and data on its use in social anxiety disorder and obsessive-compulsive disorder have produced mixed results. Evidence on the use of buspirone for post-traumatic stress disorder is too limited to be informative. Buspirone differs from other anxiolytics in that it does not possess anticonvulsant or muscle-relaxant properties, does not impair psychomotor function, and does not cause physical or psychological dependence. Unlike benzodiazepine anxiolytics, buspirone should not be used for the acute relief of anxiety because its onset of effect is delayed by 2 weeks or more.
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Centrally-mediated (CNS) adverse effects were the most frequently occurring reactions during buspirone clinical trials and were among the most common events resulting in discontinuation of therapy (3.4%). Common causes of treatment discontinuation included dizziness, insomnia, nervousness, drowsiness, and lightheadedness. During clinical trials of buspirone in the treatment of anxiety, the following CNS effects occurred in at least 1% of patients receiving buspirone and with a frequency greater than in placebo patients: dizziness (12%), drowsiness (10%), nervousness (5%), lightheadedness (3%), excitability (2%), anger/hostility (2%), confusion (2%), numbness (2%), paresthesias (1%), incoordination (1%), tremor (1%), and headache (6%). During other premarketing evaluations, dream disturbances (abnormal dreams) were reported in at least 1% of patients. CNS effects reported in 0.1% to 1% of patients included depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures. Rarely reported effects (less than 0.1%) included claustrophobia, cold intolerance, stupor, dysarthria, psychosis, and roaring sensation in the head. During postmarketing use, extrapyramidal symptoms (EPS) including pseudoparkinsonism (i.e., cogwheel rigidity, dyskinesia), dystonic reaction, akathisia, and tardive dyskinesia have been reported. Although causality has not been established, buspirone affects central dopamine receptors which may be a contributing factor in the development of extrapyramidal reactions. Other postmarketing events include dizziness/vertigo, ataxia, emotional lability, serotonin syndrome, transient difficulty with recall, restless legs syndrome (RLS), and restlessness. Because individual response and tolerability to CNS active drugs are unpredictable, patients should be advised to avoid driving or engaging in activities requiring mental alertness until they know how the drug affects their cognition. Unlike many other anxiolytics, buspirone does not appear to cause physical or psychological dependence.
During clinical trials of buspirone in the treatment of anxiety, musculoskeletal pain or aches (myalgia) occurred in 1% of patients receiving buspirone and more frequently than in patients receiving placebo. During other premarketing evaluations, musculoskeletal effects reported in 0.1% to 1% of patients included muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgia. Myasthenia was reported rarely (less than 0.1%).
During clinical trials of buspirone in the treatment of anxiety, the following dermatologic effects occurred in at least 1% of patients receiving buspirone and more frequently than in patients receiving placebo: skin rash (1%) and hyperhidrosis or clamminess (1%). During other premarketing evaluations, adverse dermatologic effects reported in 0.1% to 1% of patients included edema, pruritus, flushing, easy bruising (hematoma), hair loss (alopecia), xerosis, facial edema, and blisters. Acne vulgaris and thinning of nails were reported rarely (less than 0.1%). During postmarketing use, allergic reactions (e.g., urticaria, angioedema) and ecchymosis have been reported. Because of the uncontrolled nature of these spontaneous postmarketing reports, a causal relationship to buspirone has not been determined.
During premarketing evaluation of buspirone, adverse hematologic effects including eosinophilia, leukopenia, bleeding disturbance (unspecified), and thrombocytopenia were reported in less than 0.1% of patients.
During clinical trials of buspirone in the treatment of anxiety, the following adverse gastrointestinal (GI) effects occurred in at least 1% of patients receiving buspirone and more frequently than in patients receiving placebo: nausea (8%) and diarrhea (2%). During other premarketing evaluations, adverse GI effects reported in 0.1% to 1% of patients included elevated hepatic enzymes, flatulence, anorexia, appetite stimulation, hypersalivation, irritable colon, weight gain, weight loss, and rectal GI bleeding. Burning of the tongue was reported rarely (less than 0.1%).
During premarketing evaluation of buspirone, the following adverse respiratory effects or infections were reported in at least 1% of patients: sore throat and nasal congestion. Adverse effects reported in 0.1% to 1% of patients included hyperventilation, dyspnea, chest congestion, and fever. Epistaxis and hiccups were reported rarely (less than 0.1%).
During premarketing evaluation of buspirone, chest pain (unspecified) was reported in at least 1% of patients. Adverse cardiovascular effects reported in 0.1% to 1% of patients included syncope, hypotension, and hypertension. Rarely reported cardiovascular or cerebrovascular effects (less than 0.1%) included stroke, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia.
During clinical trials of buspirone in the treatment of anxiety, blurred vision occurred in 2% of patients receiving buspirone and more frequently than in patients receiving placebo. During other premarketing evaluations, adverse effects related to the special senses reported in 0.1% to 1% of patients included tinnitus, redness of the eyes, ocular pruritus, dysgeusia, parosmia, and conjunctivitis. Inner ear abnormality, ocular pain, photophobia, pressure on the eyes, and loss of voice were reported rarely (less than 0.1%). Visual impairment (including tunnel vision) has been reported during postmarketing use. Because of the uncontrolled nature of spontaneous postmarketing reports, a causal relationship to buspirone treatment has not been determined.
During premarketing evaluation of buspirone, adverse endocrine effects including galactorrhea and thyroid abnormality (unspecified) were reported in less than 0.1% of patients.
During premarketing evaluation of buspirone, the following adverse genitourinary effects or changes in sexual functioning were reported in 0.1% to 1% of patients: increased urinary frequency, urinary hesitancy, menstrual irregularity and spotting, dysuria, libido decrease, and libido increase. Rarely reported effects (less than 0.1%) included amenorrhea, pelvic inflammatory disease, enuresis, nocturia, ejaculation dysfunction (delayed ejaculation), and impotence (erectile dysfunction). Urinary retention has been reported during postmarketing use. Because of the uncontrolled nature of spontaneous postmarketing reports, a causal relationship to buspirone treatment has not been determined.
During clinical trials of buspirone in the treatment of anxiety, weakness occurred in 2% of patients receiving buspirone and more frequently than in patients receiving placebo. During other premarketing evaluations, malaise was reported in 0.1% to 1% of patients. Alcohol abuse was reported rarely (less than 0.1%).
Buspirone is contraindicated in patients with a known hypersensitivity to buspirone.
Buspirone may interfere with the urinary metanephrine/catecholamine assay. It has been mistakenly read as metanephrine during routine assay testing for pheochromocytoma, resulting in a false positive laboratory result. Buspirone hydrochloride should therefore be discontinued for at least 48 hours prior to undergoing a urine collection for catecholamines.
The use of monoamine oxidase inhibitor therapy (MAOI therapy) intended to treat depression with buspirone or within 14 days of stopping treatment with buspirone is contraindicated because of an increased risk of serotonin syndrome and/or elevated blood pressure. The use of buspirone within 14 days of stopping an MAOI intended to treat depression is also contraindicated. Starting buspirone in a patient who is being treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome. Use other serotonergic medications with caution in patients taking buspirone due to a potential increase in serotonin syndrome risk. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate treatment.
Buspirone has a slow onset of action; buspirone does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs. Buspirone will not block the withdrawal syndrome often seen with cessation of therapy in those with benzodiazepine dependence. Therefore, before starting therapy with buspirone, it is advisable to withdraw patients gradually from the benzodiazepine or other prior CNS depressant treatment. Patients who are being converted from a benzodiazepine to buspirone therapy may need to overlap buspirone initiation with the downward titration of the benzodiazepine or other treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug, and its effective half-life of elimination.
Because buspirone can bind to central dopamine receptors, a question has been raised about its potential to cause acute and chronic changes in dopamine-mediated neurological function (e.g., dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant antipsychotic-like activity; however, a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients. The syndrome may be explained in several ways. For example, buspirone may increase central noradrenergic activity; alternatively, the effect may be attributable to dopaminergic effects (i.e., represent akathisia).
Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired renal function demonstrated increased plasma levels and a prolonged half-life of buspirone. Therefore, the administration of buspirone to patients with severe renal impairment or with renal failure is not recommended.
Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of buspirone to patients with severe hepatic disease is not recommended.
Studies indicate that buspirone is less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its CNS effects in any individual patient may not be predictable. Therefore, patients should be cautioned about driving or operating machinery until they are reasonably certain that buspirone treatment does not affect them adversely. While formal studies of the interaction of the drug with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid ethanol ingestion while taking buspirone.
The safety and efficacy profiles of buspirone in geriatric patients are similar to those in younger adults; however, greater sensitivity of some older patients cannot be ruled out; a lower initial dosage is recommended in geriatric patients. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). When buspirone is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.
Well-controlled studies in pregnant women have not been performed with buspirone; therefore, buspirone should be used during pregnancy only when clearly needed. In a non-interventional observational cohort study, buspirone accounted for 16 of the 831 pregnancies in which women had taken a newly marketed drug during their first trimester. Overall, birth defects were noted in 14 of 557 newborns (2.5%). The 16 buspirone outcomes included 2 elective abortions, 1 intrauterine death, 12 normal term babies, and 1 newborn with cystic fibrosis. Teratogenic effects were not observed in animal studies when using approximately 30 times the maximum recommended human dose (MRHD); however, animal reproduction studies are not always predictive of human response. The effects of buspirone during labor and delivery are unknown. 
Buspirone should be avoided during breast-feeding if clinically possible; the extent of excretion of buspirone and its active metabolite into human milk is not known. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Buspirone and its metabolites are excreted in the milk of lactating rats. There is often a lack of information regarding anxiolytic use during breast-feeding. Due to individual variability in the response to anxiolytics, it may be prudent to continue the existing regimen with caution if ongoing treatment is deemed necessary during breast-feeding. A pooled analysis found that maternal use of paroxetine usually produced undetectable or low drug concentrations in infant serum; this agent may be an option when initiating therapy for generalized anxiety disorder (GAD) in a breast-feeding mother. For acute anxiety requiring a benzodiazepine, short-acting agents such as oxazepam or lorazepam are preferred. The infant should be monitored regularly, and if sedation, nausea, reduced suckling, or other signs of toxicity are observed, either breast-feeding or the benzodiazepine should be discontinued.   
Buspirone is not approved by the FDA for any indication in infants, children, or adolescents. Buspirone has been used clinically in children and adolescents 6 years of age and older for the treatment of anxiety. However, efficacy in pediatric patients is uncertain; two placebo-controlled 6-week trials for generalized anxiety disorder (GAD) in pediatric patients 6 to 17 years of age reported no significant differences in efficacy between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in pediatric patients.  
The mechanism of action of buspirone is not clearly understood since anxiety may be mediated by more than one neuropathway. In general, buspirone suppresses serotonergic activity while enhancing noradrenergic and dopaminergic cell firing. Buspirone does not inhibit monoamine oxidase. Buspirone does not have any significant activity at benzodiazepine receptors, nor does it affect GABA receptors, however buspirone has some inhibitory actions on GABAergic pathways.In vitro, buspirone exhibits highest affinity for serotonin (5-HT) type 1A receptors, moderate affinity for dopamine type 2 (DA2) receptors, and weak affinity for serotonin type 2 (5-HT2) receptors. Type 1A serotonin receptors are found in high quantities in the dorsal raphe and the hippocampus. Buspirone binding to type 1A serotonin receptors occurs on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus. Animal studies reveal that buspirone inhibits the firing rate of 5-HT-containing neurons in the dorsal raphe. The dominant action of buspirone is partial agonism or mixed agonism/antagonism at 5-HT type 1A receptors.
Buspirone also binds at dopamine type 2 (DA2) receptors, displaying properties of both a dopamine agonist and an antagonist. Buspirone blocks presynaptic dopamine receptors, however, effects on postsynaptic receptors are conflicting. Affinity for dopamine receptors differentiates buspirone from gepirone, a related investigational agent which does not interact with dopamine receptors.
Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. Benzodiazepines, in contrast, decrease firing in the locus ceruleus. This may explain why benzodiazepines cause drowsiness while buspirone does not.
The net result of buspirone actions at serotonin and dopamine receptors and related secondary messengers is inhibition of the synthesis and release of serotonin, however, since anxiety is thought to be mediated via multiple CNS pathways, the effects on serotonin do not totally explain the anxiolytic action of buspirone. Clinically, buspirone relieves the symptoms associated with generalized anxiety disorder such as motor tension (restlessness, twitching, and muscle tension); autonomic hyperactivity (sweating, palpitations, and tachycardia); and vigilance and scanning.
The immunosuppressive action of buspirone appears to be distinct from its anxiolytic action. Buspirone has no muscle relaxant activity, anticonvulsant activity, and does not lead to dependence after chronic administration.
Buspirone is administered orally. Buspirone undergoes extensive first-pass metabolism, leaving only 1% of unchanged drug in plasma. Approximately 86% of buspirone is bound to plasma proteins. Buspirone is oxidized in the liver primarily by CYP3A4. Animal models indicate that the major active metabolite, 1-PP, has one-fourth of the activity of buspirone. In addition, blood samples from humans chronically exposed to buspirone hydrochloride do not exhibit high levels of 1-PP. Other hydroxylated metabolites are inactive. The average elimination half-life of buspirone is about 2 to 3 hours in healthy adults. In a single-dose study, 29% to 63% of a buspirone dose was excreted in the urine within 24 hours, primarily as metabolites. Fecal excretion accounted for 18% to 38% of the dose.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
Buspirone is metabolized primarily by CYP3A4. When administered with a potent inhibitor of CYP3A4, a low dose of buspirone and caution are recommended. Low doses of buspirone, as well as subsequent dose adjustments, may be required during coadministration of moderate CYP3A4 inhibitors. When used in combination with a potent inducer of CYP3A4, an increased dose of buspirone may be needed to maintain the anxiolytic effect.
After oral administration, buspirone is rapidly absorbed. Extensive first-pass metabolism results in plasma concentrations of buspirone that are low and variable between individuals. Because buspirone exhibits non-linear pharmacokinetics, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged buspirone than would be predicted from results of single-dose studies. When given with food, the AUC and Cmax of buspirone increase by roughly 84% and 116%, respectively; however, the total amount of buspirone does not change. Therefore, food may decrease the pre-systemic clearance of buspirone. For this reason, buspirone should be taken in a consistent manner with regard to the timing of dosing; either always with or always without food.
A pharmacokinetic study in patients with impaired hepatic function demonstrated increased plasma levels and a prolonged half-life of buspirone. After multiple-dose administration to patients with hepatic impairment, steady-state AUC of buspirone increased 13-fold, compared with healthy adults. Therefore, the administration of buspirone to patients with severe hepatic impairment is not recommended.
A pharmacokinetic study in patients with impaired renal function demonstrated increased plasma levels and a prolonged half-life of buspirone. After multiple-dose administration to patients with renal impairment (i.e., CrCl 10 to 70 mL/minute), the steady-state AUC of buspirone increased 4-fold compared with healthy adults. Therefore, the administration of buspirone to patients with severe renal impairment is not recommended.
Pharmacokinetic studies have shown that, for identical doses (i.e., 7.5 to 30 mg twice daily), plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients (age 6 to 17 years) than adults. No unexpected safety findings were associated with buspirone in these trials.
After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger adult subjects.
After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between men and women.
The effects of race or ethnicity on the pharmacokinetics of buspirone have not been studied.
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