BUSPIRONE HCL 5 MG TABLET

Uses Dosage and Administration Cautions Drug Interactions Pharmacokinetics

Uses

Anxiety Disorders

Buspirone is used for the management of anxiety disorders (anxiety and phobic neuroses) and for short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of buspirone for long-term use (i.e., longer than 3-4 weeks) as an anxiolytic has not been established by controlled studies, but the drug has been used in some patients for substantially longer periods (e.g., 6-12 months) without apparent loss of clinical effect. If the drug is used for extended periods, the need for continued therapy should be reassessed periodically.

Generalized Anxiety Disorder

Efficacy of buspirone has been established principally in outpatient settings for the management of generalized anxiety disorder in which anxiety was present for periods of 1 month up to 1 year (average symptom duration: 6 months) of continual duration. Generalized anxiety disorder is characterized principally by unrealistic or excessive anxiety and worry (apprehensive expectation) about 2 or more life circumstances (e.g., worry about possible misfortune to a child who is in no danger, worry about personal finances for no good reason, anxiety and worry about academic, athletic, and/or social performance). The disorder is manifested as symptoms of motor tension (e.g., trembling, twitching, shakiness, muscle tension, restlessness), autonomic hyperactivity (e.g., sweating, palpitation and/or tachycardia, dyspnea, dry mouth, dizziness, clammy hands, hot flushes [ flashes]), and vigilance and scanning (e.g., hyperattentativeness, feeling keyed up or on edge, difficulty concentrating, insomnia, irritability). Although patients with generalized anxiety disorder may have another underlying mental disorder (axis I disorder), the focus of the anxiety and worry is unrelated to the latter disorder. In addition, symptoms of generalized anxiety disorder should not occur only during the course of a mood or psychotic disorder, nor should the anxiety be initiated and maintained by an underlying organic factor (e.g., hyperthyroidism, caffeine intoxication).

Controlled studies in patients with generalized anxiety disorder have shown that buspirone at usual dosages is as effective as usual dosages of benzodiazepines (e.g., alprazolam, clorazepate, diazepam, lorazepam) and more effective than placebo in reducing symptoms associated with anxiety. Limited evidence suggests that buspirone may be more effective for cognitive and interpersonal problems, including anger and hostility, associated with anxiety, while benzodiazepines may be more effective for somatic symptoms of anxiety. The drug also has been shown to reduce symptoms of anxiety in patients with coexisting depressive symptoms. Buspirone therapy generally is associated with fewer and less severe adverse CNS effects (e.g., sedation, psychomotor impairment) compared with benzodiazepines and appears to have little, if any, dependence liability. Because of these differences, buspirone may be preferred as initial therapy in some patients with generalized anxiety disorder. The drug may be particularly useful in patients in whom potential adverse effects of benzodiazepines would be of concern (e.g., patients whose work or life-style requires mental acuity, geriatric patients who may be particularly sensitive to the adverse CNS effects of benzodiazepines) and/or those in whom the abuse potential, dependence liability, and/or potential withdrawal associated with benzodiazepines are of concern. In addition, buspirone may be safer than benzodiazepines in those patients with anxiety disorders who, despite all warnings, are considered likely to combine anxiolytic therapy with CNS depressants and/or alcohol.(See Drug Interactions: Alcohol and also Other CNS Depressants.)

Depressive Symptoms

In addition to symptoms of anxiety, buspirone has reduced depressive symptoms in patients with generalized anxiety disorder, as determined using the Hamilton (HAM-D) or Raskin depression rating scale. Buspirone generally has been as effective as benzodiazepines in relieving symptoms of depression in these patients, although the drug may be less effective than benzodiazepines in relieving sleep disturbances. It has been suggested that improvement in depressive symptoms observed in these patients actually may reflect improvement in anxiety symptoms that are included in the depression rating scales rather than an antidepressant effect per se, and additional study is needed to determine whether the drug has clinically important antidepressant activity. Buspirone also has been used in combination with antidepressants in a limited number of patients with symptoms of both anxiety and depression.

Symptoms of Sexual Dysfunction

The efficacy of buspirone for the management of sexual dysfunction in patients with generalized anxiety disorder has not been established, but limited data suggest that the drug may improve sexual function in these patients. Although the improvement in sexual function paralleled improvement in anxiety in one study, other mechanisms may have been involved. Further study is needed to more fully elucidate the value of buspirone in these patients.

Other Anxiety Disorders

Because buspirone may diminish anger and hostility and appears to be less likely than benzodiazepines to cause disinhibition, some clinicians suggest that buspirone may be preferred in patients with a history of aggression or in whom disinhibition has occurred during benzodiazepine therapy. Benzodiazepines may be preferred as initial therapy in patients with anxiety symptoms (e.g., insomnia, muscle tension) that might benefit from the sedative and/or muscle relaxant effects of these drugs. If buspirone is used in patients whose anxiety includes insomnia as a component, concomitant use of a sedative/hypnotic at bedtime may be necessary. Because buspirone may have a slower onset of action than some anxiolytics (e.g., diazepam) (see Dosage and Administration: Dosage), patients may become discouraged during initial therapy with the drug, particularly when buspirone is used for the short-term management of anxiety associated with severe stress.

The influence of previous, long-term benzodiazepine therapy on the anxiolytic response to buspirone remains to be fully elucidated, but response may be discouraging in some patients, possibly because buspirone has a slower onset of action and does not attenuate manifestations of benzodiazepine withdrawal. In addition, the anxiolytic expectations of some patients who previously have received long-term benzodiazepine therapy may differ considerably from the actual effects of buspirone therapy, which also could contribute to a discouraging response to buspirone in such patients. Because of the sometimes discouraging response to buspirone in such patients, some clinicians suggest that newly diagnosed patients and those with no previous benzodiazepine use may be optimal candidates for buspirone therapy.

Efficacy of buspirone in the management of panic attacks or disorder has not been established.

Other Uses

Results of an uncontrolled study suggest that relatively high dosages of buspirone hydrochloride (i.e., usually 40-60 but up to 90 mg daily) may provide some reduction in depressive symptoms in patients with major depression (nonmelancholic type), but not in patients whose major depression is of the melancholic type. Well-controlled studies, particularly those comparing buspirone with antidepressants, are necessary to determine whether buspirone has clinically important antidepressant activity.

Although buspirone exhibited some evidence of neuroleptic potential in several animal models and reportedly has produced transient antipsychotic effects when administered in large doses to patients with schizophrenia, the drug has no established antipsychotic activity in humans at usual dosages and should not be used in place of appropriate antipsychotic therapy when such therapy is indicated.

Because of buspirone's effects on dopamine receptors, the drug has been studied for potential therapeutic effects in patients with parkinsonian syndrome. At dosages of 10-70 mg daily, buspirone provided no clinically important improvement or deterioration in a limited number of patients with parkinsonian syndrome who were receiving antiparkinsonian therapy (e.g., levodopa/carbidopa, bromocriptine) concomitantly. At higher dosages, however, some deterioration in parkinsonian manifestations (e.g., functional disability) was observed. Therefore, current evidence indicates that buspirone is not useful in the management of parkinsonian syndrome and may exacerbate the syndrome at relatively high dosages. The drug may be useful, however, as an anxiolytic in parkinsonian patients, provided high dosages are avoided.

Dosage and Administration

Administration

Buspirone hydrochloride is administered orally. Concomitant administration of the drug with food can increase oral bioavailability of buspirone. Therefore, the manufacturer states that the drug should be given in a consistent manner relative to food intake.(See Drug Interactions: Food.)

The 15- and 30- mg tablets are provided as Dividose tablets and are scored to be broken in 2 halves (each providing a dose of 7.5 and 15 mg, respectively, or in 3 thirds) (each providing a dose of 5 and 10 mg, respectively).

Dosage

For the management of anxiety disorders, the usual initial adult dosage of buspirone hydrochloride is 10-15 mg daily, usually in 2 or 3 divided doses. Dosage is increased as necessary in increments of 5 mg daily every 2-4 days, according to the patient's response and tolerance. In clinical studies, most patients responded to maintenance dosages of 15-30 mg daily in 2 or 3 divided doses. Modification of the usual adult dosage does not appear necessary for geriatric patients. The manufacturer recommends that adult dosage not exceed 60 mg daily.

The manufacturer states that when buspirone is administered concomitantly with a potent CYP3A4 inhibitor, it should be administered at a low dosage (i.e., 2.5 mg once or twice daily) and that subsequent dosage adjustment of either drug should be based on clinical assessment. (See Drug Interactions: Drugs Affecting Microsomal Enzymes and see Dosage and Administration: Administration.)

Buspirone may have a slower onset of action than some anxiolytics (e.g., diazepam), and some patients may require motivation and education about the drug's effects during initial therapy to assure compliance. Symptomatic relief may occur during the first 2 weeks of buspirone therapy in some patients, but optimum anxiolytic effect usually requires at least 3-4 weeks of therapy; occasionally, 4-6 weeks may be required for optimum effect.

The efficacy of continued buspirone therapy for longer than 3-4 weeks has not been established by controlled studies. However, the drug has been used for longer periods (e.g., several months to a year) without unusual adverse effect or decreased efficacy in some patients. If buspirone is administered for longer than 3-4 weeks, the need for continued therapy should be reassessed periodically. Dosage during prolonged maintenance therapy should be kept at the lowest effective level; once an adequate response has been achieved, dosage should be reduced gradually and subsequently adjusted according to the patient's response and tolerance.

Discontinuance of benzodiazepines and some other anxiolytic agents has been associated with symptoms of withdrawal, and buspirone will not prevent the development of these symptoms. Therefore, it is important that therapy with such agents be withdrawn gradually in patients being switched to buspirone, particularly when therapy with one of these agents has been prolonged and/or when relatively high dosages were used.

Dosage in Renal and Hepatic Impairment

The need for modification of buspirone hydrochloride dosage in patients with renal impairment has not been fully elucidated, and the drug should be used with caution in such patients. There is some evidence that the pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinylpiperazine (1-PP), are not affected substantially in patients with mild to moderate renal impairment.(See Pharmacokinetics: Elimination) In anuric patients, however, accumulation of 1-PP may occur, and adjustment in buspirone hydrochloride dosage may be necessary. Some clinicians suggest that dosage of the drug be reduced by 25-50% in anuric patients. However, other clinicians state that because of the high interindividual and intraindividual variability in plasma concentrations of buspirone and 1-PP, it is difficult to make dosage adjustment recommendations for patients with renal impairment. Based on results from other studies, several clinicians state that because of the high interindividual and intraindividual variability in plasma buspirone concentrations, dosing recommendations for patients with renal impairment receiving buspirone cannot be made at this time. In addition, the manufacturer states that the drug is not recommended for use in patients with severe renal impairment. The need for supplemental doses during hemodialysis has not been determined, but such doses do not appear necessary since the drug does not appear to be removed substantially by hemodialysis.

Buspirone hydrochloride should be used with caution in patients with impaired hepatic function, and the need for reduced dosage should be considered.(See Pharmacokinetics: Elimination.) The manufacturer states that the drug is not recommended for use in patients with severe hepatic impairment.

Cautions

Buspirone generally is well tolerated. A causal relationship between many adverse reactions and the drug has not been established but cannot be excluded. In controlled studies, the incidence of some adverse effects was similar in patients receiving buspirone or placebo.

Nervous system effects (e.g., dizziness, headache, drowsiness, light-headedness) are the most common adverse effects of buspirone, but those secondary to CNS depression (e.g., sedation, psychomotor dysfunction) generally occur less frequently than with other currently available anxiolytics (e.g., benzodiazepines). In clinical studies, adverse reactions requiring discontinuance of buspirone therapy occurred in about 10% of patients and included nervous system effects (e.g., dizziness, insomnia, nervousness, drowsiness, light-headedness, headache, fatigue) and GI effects (e.g., nausea). There is some evidence that tolerance of buspirone's adverse effects (e.g., dizziness) may be slightly less in geriatric patients than in younger adults.

The incidence and severity of adverse reactions to buspirone relative to dosage and duration of therapy have not been fully characterized; however, adverse effects appear to occur more frequently at increasing dosages but generally appear to diminish with time during continued therapy. Because buspirone can bind to central dopamine receptors, the possibility exists that chronic therapy could result in adverse effects secondary to changes in dopamine-mediated neurologic function.(See Cautions: Nervous System Effects.) Although clinical experience to date has failed to reveal substantial evidence of such long-term effects at usual dosages, the possibility of risk cannot be ruled out and additional experience is needed to determine buspirone's potential for long-term sequelae.

Nervous System Effects

The most frequent adverse effects associated with buspirone therapy are nervous system effects. In controlled studies, dizziness, drowsiness, and headache occurred in about 10% of patients; fatigue, nervousness, insomnia, and light-headedness occurred in about 5%; and excitement, depression, decreased concentration, nightmares/vivid dreams, anger/hostility, confusion, weakness, incoordination, paresthesia, numbness, and tremor occurred less frequently. In these studies, dizziness, headache, nervousness, light-headedness, paresthesia, and excitement occurred appreciably more frequently in patients receiving buspirone than in those receiving placebo. Insomnia and nervousness may become particularly evident at high dosages (e.g., 100 mg daily), and may be secondary to a dose-dependent stimulation of α-adrenergic (noradrenergic) cells of the locus ceruleus.

Buspirone is relatively nonsedating compared with other currently available anxiolytics (e.g., benzodiazepines), although sedative effects (e.g., drowsiness, lethargy, sedation) may become more prominent as dosage is increased (e.g., at dosages exceeding 20 mg daily). In addition, buspirone's sedative effects often are most apparent during initiation of therapy or upward titration of dosage and tend to decrease with time. However, the drug's CNS effects show interindividual variation and the potential for their development may not be predictable in a given patient. Adverse effects resulting from CNS and psychomotor depression (e.g., drowsiness, fatigue, mental depression, confusion, decreased concentration, incoordination, weakness) generally occur less frequently with buspirone than with benzodiazepines (e.g., clorazepate, diazepam, lorazepam), while dizziness, headache, nervousness, and paresthesia generally occur more frequently with buspirone.

Dream disturbances occur in at least 1% of patients receiving buspirone, but a causal relationship to the drug has not been established. Other adverse nervous system effects not directly attributed to the drug but occurring less frequently include depersonalization, dysphoria, noise intolerance, euphoria, fearfulness, loss of interest, dissociative reaction, hallucinations, suicidal ideation, and seizures. Claustrophobic feelings, cold intolerance, stupor, slurred speech, and psychosis occur rarely. Depression and increased appetite occasionally have emerged during chronic (i.e., 6 months or longer) therapy with the drug.

Buspirone's potential for causing acute and chronic changes in dopamine-mediated neurologic function (e.g., dystonia, parkinsonian-like manifestations, akathisia, tardive dyskinesia) has not been fully elucidated. Clinical experience to date suggests that the risk for such effects during buspirone therapy at usual anxiolytic dosages is minimal, and such experience has not revealed evidence of definitive extrapyramidal reactions directly attributable to the drug. However, akathisia, hypertonia, dystonia, tremor, involuntary movements, slowed reaction time, and rigid/stiff muscles reportedly have been associated with anxiolytic dosages of buspirone in a few patients. In addition, a syndrome of restlessness, appearing shortly after initiation of therapy with the drug, has been reported occasionally. This syndrome may have resulted from increased central α-adrenergic activity or from dopaminergic or other effects. In addition, extrapyramidal manifestations (e.g., akathisia, tremor, rigidity) also have occurred in at least one patient receiving a buspirone hydrochloride dosage substantially exceeding usual anxiolytic dosages. In a limited number of patients with parkinsonian syndrome, dosages of 10-70 mg daily caused no clinically important deterioration in manifestations of the syndrome, although some deterioration (e.g., in functional ability) was apparent at relatively high dosages (e.g., 90-100 mg daily).(See Uses: Other Uses.) Myoclonus, which may have been serotonergically mediated, also has been reported in at least one patient shortly after initiation of usual anxiolytic dosages of buspirone; the myoclonus resolved following discontinuance of the drug and administration of clonazepam.

Increased anxiety, agitation, and restlessness accompanied by pressured speech and racing thoughts occurred in several patients with panic disorder or generalized anxiety disorder who were receiving buspirone with tricyclic antidepressants and/or alprazolam; these manifestations resolved within 1-5 days following discontinuance of buspirone therapy. Hypomania also has been reported in a patient with bipolar disorder and symptoms of anxiety concurrently receiving buspirone, lithium, tranylcypromine, and alprazolam; symptoms of hypomania resolved within 3 days following discontinuance of buspirone therapy in this patient. Although the mechanism is unclear, it has been suggested that these reactions may have been caused by a buspirone-induced increase in dopaminergic or α-adrenergic activity, effects of the drug on 5-HT₁ receptors, and/or a possible drug interaction between buspirone and alprazolam.

GI Effects

Nausea has been reported in 6-8% of patients receiving buspirone in controlled studies, occurring more frequently than with placebo. Adverse GI effects occurring in 1-5% of patients include dry mouth, abdominal/gastric distress, diarrhea, constipation, and vomiting. Flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleedingoccur less frequently, and burning of the tongue occurs rarely, but these effects have not been directly attributed to the drug.

Cardiovascular Effects

Tachycardia and/or palpitation have been reported in about 1-2% of patients receiving buspirone, and nonspecific chest pain has been reported in at least 1% of patients; however, these effects have occurred at a frequency not appreciably different from that occurring with placebo. Syncope, hypotension, and hypertension occur less frequently, and cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia occur rarely; a causal relationship to the drug also has not been established for these effects.

Dermatologic Effects

Adverse dermatologic effects occur occasionally in patients receiving buspirone and include rash, edema, pruritus, flushing, easy bruisability, hair loss, dry skin, facial edema, and blisters. Acne and thinning of the nails occur rarely. A causal relationship to the drug for most of these dermatologic effects has not been established.

Other Adverse Effects

Buspirone produces a dose-dependent stimulation of prolactin secretion (see Pharmacology: Neuroendocrine Effects); however, the clinical importance of the drug's effect on prolactin has not been fully determined. Menstrual irregularities (e.g., spotting, amenorrhea), galactorrhea, and thyroid abnormalities have occurred occasionally in patients receiving buspirone, but a causal relationship has not been established. Increased or decreased libido, delayed ejaculation, and impotence also have occurred occasionally in patients receiving the drug, but therapy with the drug also has improved sexual function in some patients with generalized anxiety disorder and associated sexual dysfunction.(See Uses: Anxiety Disorders.)

Blurred vision has been reported in 2% of the patients receiving buspirone in controlled studies. A causal relationship for most other adverse effects generally has not been established, although such effects have been reasonably associated with buspirone therapy. Tinnitus, sore throat, and nasal congestion occur occasionally in patients receiving the drug. Redness and itching of the eyes, conjunctivitis, and altered taste or smell also occur occasionally. Rarely, inner-ear abnormality, eye pain, photophobia, and pressure on the eyes have occurred.

Urinary frequency or hesitancy; dysuria; muscle aches/pain, cramps, spasm, and weakness; arthralgia; hyperventilation; dyspnea; and chest congestion occur occasionally in patients receiving buspirone. Fever, weight loss or gain, and increased serum aminotransferase (transaminase) concentrations (e.g., AST [SGOT], ALT [SGPT]) also have been reported occasionally. Rarely, pelvic inflammatory disease, enuresis, nocturia, epistaxis, alcohol abuse, bleeding disturbance, loss of voice, and hiccups have occurred in patients receiving the drug. Eosinophilia, leukopenia, and thrombocytopenia also have occurred rarely.

Precautions and Contraindications

Although buspirone generally is less sedating than other currently available anxiolytics and does not produce substantial impairment of cognitive or psychomotor function at usual dosages, the CNS effects of buspirone exhibit interindividual variation and may not be predictable. Therefore, patients should be cautioned that buspirone may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they experience how the drug affects them. While drug interaction studies indicate that buspirone does not increase substantially alcohol-induced impairment of motor and mental performance, patients should be advised that it would be prudent to avoid concomitant use.(See Drug Interactions: Alcohol.)

Buspirone does not exhibit cross-tolerance with benzodiazepines or other sedative/hypnotic drugs, and will not prevent symptoms of withdrawal that may occur following cessation of therapy with these drugs. Therefore, it is important that therapy with such drugs be withdrawn gradually in patients being switched to buspirone, particularly when therapy with one of these agents has been prolonged and/or when relatively high dosages were used. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of drug being discontinued and its elimination characteristics. Clinicians should be aware that the development of any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal or muscle cramps, vomiting, sweating, flu-like symptoms without fever, or even seizures following initiation of buspirone therapy in patients previously receiving other anxiolytics and/or sedative/hypnotics may be manifestations of withdrawal from these drugs.

Because the potential risk of buspirone-induced changes in dopamine-mediated neurologic function, particularly those associated with long-term therapy, currently has not been elucidated, the possibility that such changes could occur in patients receiving the drug should be considered.(See Cautions: Nervous System Effects.)

In patients currently receiving a monoamine oxidase inhibitor, buspirone therapy should not be initiated.(See Drug Interactions: Psychotherapeutic Agents.)

Buspirone should be used with caution in patients with impaired renal function, since the drug and its metabolites are excreted principally by the kidneys. Buspirone also should be used with caution in patients with hepatic dysfunction.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Buspirone has no established antipsychotic efficacy in humans at usual anxiolytic dosages, and the drug should not be used in place of appropriate antipsychotic therapy when such therapy is indicated.

Buspirone is contraindicated in patients who are hypersensitive to the drug.

Pediatric Precautions

Safety and efficacy of buspirone in children younger than 18 years of age have not been established. Although safety and efficacy of buspirone in children have not been fully evaluated, the drug has been used in pediatric patients without unusual adverse effects. In 2 controlled studies in 559 pediatric patients 6-17 years of age with generalized anxiety disorder (GAD), no unexpected adverse effects were associated with buspirone; however, there was no difference in symptoms of GAD between those receiving buspirone 7.5-30 mg twice daily or placebo for 6 weeks. Long-term safety and efficacy of the drug in children younger than 18 years of age have not been evaluated.

Geriatric Precautions

Results of a study in about 600 geriatric patients (mean age: 70.8 years) indicate that safety and efficacy of buspirone in geriatric patients appear to be similar to those of younger adults (mean age: 43.3 years); no age-related differences in the pharmacokinetics of buspirone were observed. Although postmarketing experience has not revealed differences in the incidence of adverse effects between geriatric patients and younger adults, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Mutagenicity and Carcinogenicity

No evidence of buspirone-induced mutagenesis was seen in the Ames microbial mutagen test, with or without metabolic activation, or in the mouse lymphoma L5178Y/TK cell test system, nor was DNA damage observed in Wi-38 human cells. No chromosomal aberrations or abnormalities were observed in bone marrow cells of mice given one or five daily doses of buspirone.

No evidence of carcinogenesis was observed after 24 months in rats receiving oral buspirone hydrochloride dosages up to 133 times the maximum recommended human dosage or after 18 months in mice receiving oral dosages up to 167 times the maximum recommended human dosage.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral buspirone hydrochloride dosages up to 30 times the maximum recommended human dosage have not revealed evidence of fetal abnormality or impaired fertility. There are no adequate and controlled studies to date using buspirone in pregnant women, and the drug should be used during pregnancy only when clearly needed.

The effect of buspirone on labor and delivery in women is not known, but no adverse effects were observed during reproduction studies in animals.

Lactation

Although the extent of distribution of buspirone and its metabolites into human milk is not known, the drug and its metabolites are distributed into milk in rats. Therefore, the manufacturer recommends that the use of buspirone in nursing women be avoided whenever clinically possible.

Drug Interactions

Psychotherapeutic Agents

Elevations in blood pressure have been observed in several patients receiving buspirone and a monoamine oxidase (MAO) inhibitor concomitantly; however, no adverse sequelae were associated with these elevations. In addition, buspirone may have been partially responsible for a case of serotonin syndrome that resulted in death of a patient receiving buspirone, fluoxetine, and an MAO inhibitor (tranylcypromine) concomitantly. Pending additional data, it currently is recommended that buspirone not be used concomitantly with an MAO inhibitor and that at least 10 days elapse following discontinuation of an MAO inhibitor and administration of buspirone.

In a patient with depression, generalized anxiety disorder, and panic attacks who was receiving concomitant buspirone and trazodone therapy, an increase in anxiety symptoms to a level comparable to that observed prior to buspirone therapy occurred when fluoxetine was added to the regimen. Although the mechanism of this possible interaction has not been established, it was suggested that fluoxetine may have either directly antagonized the therapeutic activity of buspirone or may have precipitated the anxiety symptoms through a separate mechanism. However, combined use of the drugs also has been reported to potentiate therapeutic efficacy in patients with obsessive compulsive disorder.

Concomitant administration of buspirone and trazodone has resulted in a threefold to sixfold elevation in serum ALT (SGPT) concentrations in a few patients. However, in a study designed to attempt to confirm these findings, concomitant administration of the drugs was not associated with an interactive effect on aminotransferases. The manufacturer states that current evidence suggests that buspirone and trazodone can be used concomitantly, provided that liver function is monitored.

Concomitant administration of buspirone and haloperidol has resulted in increased serum haloperidol concentrations. When oral buspirone hydrochloride 45 mg daily and oral haloperidol 5 mg daily were administered concomitantly in healthy adults, peak serum concentrations of haloperidol increased by about 30% and area under the serum concentration-time curve increased by 46%. Buspirone pharmacokinetics were not affected and the increase in haloperidol concentrations was not associated with a substantial increase in adverse haloperidol effects. It has been suggested that buspirone's effect on haloperidol concentrations may have resulted from competitive inhibition of oxidative dealkylation of haloperidol, since both drugs are metabolized principally via this pathway. The manufacturer states that the clinical importance of this interaction has not been established.

Concomitant administration of buspirone hydrochloride 45 mg daily and amitriptyline hydrochloride 75 mg daily in healthy adults did not result in substantial changes in steady-state amitriptyline or nortriptyline (an active metabolite) concentrations. In addition, no increase in amitriptyline-induced adverse effects was observed during concomitant use of the drugs.

Because the effects of concomitant use of buspirone and most other psychotherapeutic agents have not been studied to date, such use should be undertaken with caution.

Protein-bound Drugs

Because buspirone is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs. The manufacturer states that therapeutic concentrations of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of buspirone binding to plasma proteins. Although an in vitro study indicated that buspirone did not displace some highly protein bound drugs (e.g., phenytoin, propranolol, warfarin), it may displace less firmly bound drugs (e.g., digoxin). In an in vitro protein binding study, aspirin increased free plasma buspirone concentrations by 23%, while flurazepam decreased free plasma buspirone concentrations by 20%, but the in vivo effects of aspirin or flurazepam on free buspirone plasma concentrations, and their clinical importance, are unknown. Also, there has been 1 report of increased prothrombin time when buspirone was added to the drug regimen of a patient receiving warfarin, phenytoin, phenobarbital, digoxin, and levothyroxine (Synthroid). However, the manufacturer states that the clinical importance of these changes is unknown.

Drugs and Food Affecting Hepatic Microsomal Enzymes

In vitro, metabolism of buspirone has been shown to be mediated by the cytochrome P-450 (CYP) isoenzyme 3A4. Drugs (e.g., erythromycin, itraconazole, nefazodone) that inhibit this enzyme increase plasma concentrations of buspirone, and drugs (e.g., rifampin) that induce this enzyme decrease plasma concentrations of buspirone. Therefore, if buspirone is to be administered concomitantly with a drug that is a potent inhibitor of the CYP3A4 isoenzyme, a low buspirone dosage (e.g., 2.5 mg once or twice daily) is recommended, and subsequent dosage adjustment of either drug should be based on clinical assessment. Alternatively, when buspirone is used concomitantly with a drug that is a potent inducer of the CYP3A4 isoenzyme, dosage adjustment of buspirone may be necessary to maintain the anxiolytic effect.

Erythromycin

In a study in healthy individuals, concomitant use of buspirone (10 mg daily) and erythromycin (1.5 g daily) increased peak plasma buspirone concentrations and area under the plasma concentration-time curve (AUC) by fivefold and sixfold, respectively, and was accompanied by an increased incidence of adverse effects attributable to buspirone. Therefore, the manufacturer states that if buspirone is administered concomitantly with erythromycin, a low buspirone dosage (e.g., 2.5 mg twice daily) is recommended, and subsequent dosage adjustment of either drug should be based on clinical assessment.

Itraconazole

In a study in healthy individuals, concomitant administration of buspirone (10 mg daily) and itraconazole (200 mg daily) increased peak plasma buspirone concentrations and AUC 13- and 19-fold, respectively, and was accompanied by an increased incidence of adverse effects attributable to buspirone. Therefore, if buspirone is administered concomitantly with itraconazole, a low buspirone dosage (e.g., 2.5 mg once daily) is recommended by the manufacturer, and subsequent dosage adjustment of either drug should be based on clinical assessment.

Nefazodone

In a steady-state pharmacokinetics study in healthy individuals, concomitant administration of buspirone (2.5 or 5 mg twice daily) and nefazodone (250 mg twice daily) increased peak plasma buspirone concentrations and AUC 20- and 50-fold, respectively, and substantially decreased buspirone metabolite 1-pyrimidinylpiperazine (1-PP) plasma concentrations by about 50%. Also, AUCs of nefazodone, hydroxynefazodone, and meta-chlorophenylpiperazine were increased by 23, 17, and 9%, respectively, and peak plasma concentrations of nefazodone and hydroxynefazodone were increased by 8 and 11%, in individuals receiving buspirone 5 mg twice daily with nefazodone. In addition, lightheadedness, asthenia, dizziness, and somnolence have been reported in patients receiving buspirone (5 mg twice daily) and nefazodone (250 mg twice daily); these adverse effects also have been reported when either drug was administered alone. Therefore, if buspirone is used concomitantly with nefazodone, a low buspirone dosage (e.g., 2.5 mg once daily) is recommended by the manufacturer, and subsequent dosage adjustment of either drug should be based on clinical assessment.

Calcium-Channel Blocking Agents

In a small study in healthy individuals, concomitant administration of buspirone (10 mg as a single dose) with verapamil (80 mg 3 times daily) or diltiazem (60 mg 3 times daily) increased peak plasma concentrations of buspirone by 3.4 or 4-fold, respectively, and increased AUC of buspirone by 3.4- or 5.5-fold, respectively. Because of the increased potential for adverse effects during concomitant use of buspirone with verapamil or diltiazem, the manufacturer suggests that dosage adjustment may be necessary.

Rifampin

Administration of a single 30-mg dose of buspirone to healthy individuals receiving rifampin (600 mg daily for 5 days) decreased peak plasma concentrations and AUC of buspirone by 83.7 and 89.6%, respectively. Decreased pharmacodynamic effects also were reported. The manufacturer of buspirone recommends that if the drug used concomitantly with rifampin, dosage adjustment of buspirone may be necessary to maintain anxiolytic effect.

Grapefruit Juice

In healthy individuals, concomitant administration of buspirone (10 mg as a single dose) with double-strength grapefruit juice (200 mL administered 3 times daily for 2 days) increased the peak plasma concentration and AUC of the drug by 4.3- and 9.2-fold, respectively. Therefore, the manufacturer states that concomitant administration of buspirone with large quantities of grapefruit juice should be avoided.

Cimetidine

Current limited evidence suggests that concomitant use of usual dosages of buspirone and cimetidine would be unlikely to result in a clinically important interaction. In a study in healthy adults, there was some evidence of cimetidine-induced changes in buspirone pharmacokinetics (e.g., shortened elimination half-life of buspirone, increased peak serum concentrations of buspirone (about 40%) and 1-pyrimidinylpiperazine [1-PP, an active metabolite of buspirone] increased time to achieve peak serum concentrations of buspirone [about twofold]) and an increase in certain adverse buspirone effects (e.g., light-headedness) during combined use, but such changes were not considered clinically important. Because of considerable interindividual and intraindividual differences in some buspirone pharmacokinetic parameters observed in this study and problems in study design, however, some clinicians state that firm conclusions regarding the possibility of a clinically important interaction between buspirone and cimetidine currently cannot be made. The drugs also have been used concomitantly without evidence of a clinically important interaction in patients with anxiety, but additional study is necessary.

Food

Food may delay GI absorption of buspirone, thereby decreasing the extent of presystemic clearance of the drug (e.g., via first-pass metabolism in the liver) and increasing the amount of unchanged drug reaching systemic circulation. Following oral administration of a single 20-mg dose of buspirone hydrochloride with food, the area under the plasma concentration-time curve (AUC) and peak plasma concentration of unchanged buspirone increased by 84 and 116%, respectively, compared with administration in the fasted state, but the total amount of drug (changed and unchanged) in plasma was not affected. To minimize the variability in systemic exposure to buspirone, the manufacturer recommends that the drug should be given consistently with or without food.

Alcohol

Buspirone does not appear to alter blood alcohol concentrations nor to potentiate substantially alcohol-induced impairment of psychomotor and cognitive performance, and actually may produce some improvement in such impairment. In addition, patients receiving buspirone and alcohol may be more aware of alcohol-induced impairment, when present, than those receiving benzodiazepines and alcohol. It should be recognized, however, that subjective adverse effects, including fatigue, drowsiness, and dizziness, have occurred in some patients during administration of buspirone alone, and that adverse CNS effects associated with buspirone in individual patients may be unpredictable. In a controlled study in healthy adults, buspirone did not enhance alcohol-induced psychomotor impairment (as determined by objective measures such as lateral-gaze nystagmus, body sway, and the Maddox wing test), and subjective effects associated with concomitant buspirone and alcohol use were similar to those with buspirone alone. In another study in patients with a history of moderate to low-heavy alcohol use, driving-related motor skill performance was better in those given a single dose of alcohol after receiving buspirone for 9 days than in those given alcohol after receiving placebo. Although results of drug interaction studies suggest that buspirone does not potentiate substantially alcohol-induced psychomotor and cognitive impairment, patients should be advised that it would be prudent to avoid concomitant use.

Other CNS Depressants

Buspirone appears to interact minimally, if at all, with benzodiazepines. In a multiple-dose study, the addition of buspirone in patients receiving diazepam for 11 days did not substantially alter plasma diazepam concentrations measured on day 22 (11 days after initiating buspirone therapy), but corresponding plasma nordiazepam concentrations increased by approximately 20%. It is not known whether the increase in nordiazepam concentrations resulted from the relatively long time required for the metabolite to achieve steady-state plasma concentrations or from concomitant buspirone administration. In patients concurrently receiving buspirone and diazepam, mild adverse effects, including headache, nausea, dizziness, and muscle twitches, occurred but usually subsided within several days; however, such effects, except muscle twitches, appeared qualitatively similar to those associated with buspirone alone. Buspirone has potentiated the effects of diazepam on several tests of psychomotor function (e.g., the Maddox wing and letter cancellation tests) and has subjectively potentiated diazepam-induced sedation, but the drug also has counteracted diazepam-induced impairment of divided attention and learning acquisition; the combined effect of these drugs on psychomotor function did not appear to be more harmful than diazepam alone. Buspirone did not substantially alter the hypnotic or psychomotor effects of either flurazepam or triazolam when the drugs were administered concurrently in a limited number of patients, although a minimal decrease in card-sorting ability occurred in some patients. Although drug interaction studies suggest that buspirone does not potentiate benzodiazepine-induced CNS depression to a clinically important degree, the effects of combined therapy have not been fully evaluated to date. Pending further accumulation of data, benzodiazepines should be used with caution in patients receiving buspirone.

Data obtained from clinical studies indicate that other CNS depressants, including analgesics, antihistamines, and sedative/hypnotics, generally have little or no effect on the frequency or severity of adverse effects associated with buspirone. It should be recognized, however, that subjective adverse effects, including fatigue, drowsiness, and dizziness, have been reported in some patients receiving buspirone alone, and that adverse CNS effects associated with buspirone in individual patients may be unpredictable. Because the effects of concurrent administration have not been fully evaluated to date, caution should be exercised when buspirone and CNS depressants are administered concomitantly.

Pharmacokinetics

The pharmacokinetics of buspirone hydrochloride have been studied in healthy adults, geriatric patients, and in patients with renal or hepatic impairment. Single- and multiple-dose studies of buspirone have not revealed gender- or age-related differences in the pharmacokinetics (e.g., area under the plasma-concentration time curve [AUC], peak plasma concentrations) of the drug. Pharmacokinetics of buspirone hydrochloride with respect to race have not been determined.

Absorption

Buspirone hydrochloride is rapidly and almost completely absorbed from the GI tract. However, the drug undergoes extensive first-pass metabolism, with only about 4% (range: 1.5-13%) of a dose reaching systemic circulation unchanged following oral administration. The relative oral bioavailability of buspirone hydrochloride tablets reportedly is about 90% that of a solution of the drug; a lower relative bioavailability (i.e., 65%) has been reported for another tablet formulation of the drug that is not commercially available. Food may delay GI absorption of buspirone hydrochloride, thereby decreasing the extent of presystemic clearance of the drug and increasing the amount of unchanged buspirone reaching systemic circulation.(See Drug Interactions: Food.) Following multiple-dose administration of buspirone in patients with renal impairment (creatinine clearance of 10-70 mL/minute per 1.73 m), the steady-state AUC was increased fourfold compared with healthy adults (creatinine clearance of 80 mL/minute per 1.73 m or more). Following multiple-dose administration in patients with hepatic impairment, steady-state AUC of buspirone was increased 13-fold compared with healthy adults. AUC and peak plasma concentration of unchanged buspirone are increased substantially in patients with liver cirrhosis, exceeding those achieved in healthy adults by about 16-fold in one study following a single, 20-mg oral dose.

Following oral administration of a single 20-mg dose in healthy individuals, peak plasma buspirone concentrations of 1-6 ng/mL occur within 40-90 minutes. Peak plasma concentrations of the drug averaged 0.9, 1.7, and 3.2 ng/mL following single oral doses of 10, 20, and 40 mg, respectively, in a study in healthy adults. Plasma concentrations of unchanged buspirone exhibit interindividual variation following oral administration of the drug but generally are low, averaging about 1% of the total plasma drug concentration in one study in fasting, healthy adults receiving single doses of the drug. Although it has been suggested that the drug exhibits nonlinear pharmacokinetics and that increasing and/or multiple doses may result in higher plasma concentrations than those predicted from single-dose studies, this interpretation of the drug's pharmacokinetics has been questioned. In addition, in a study in healthy adults, the relationship between plasma buspirone concentration and dose appeared to be linear at single oral doses ranging from 10-40 mg. Following oral administration of buspirone hydrochloride, the onset of anxiolytic activity may be apparent within the first 2 weeks of therapy, but optimum therapeutic effect usually requires at least 3-4 weeks; occasionally, 4-6 weeks may be required for optimum effect. The relationship, if any, between plasma buspirone and active metabolite concentrations and the therapeutic and/or toxic effects of the drug have not been established.

Distribution

Distribution of buspirone into human body tissues and fluids has not been well characterized. Following IV administration in rats, buspirone is extensively distributed, achieving highest concentrations in lung, kidney, and adipose tissue, and lower concentrations in skeletal muscle, heart, liver, brain, and plasma. The concentration-time curve profiles of buspirone and its active metabolite 1-pyrimidinylpiperazine (1-PP) in brain almost parallel those in plasma after oral or IV administration, although 1-PP concentrations generally are higher in brain than in plasma, particularly following oral administration of the drug. In animals, 1-PP accumulates in the brain and reaches concentrations that are approximately 4-5 times higher than those in plasma. The apparent volume of distribution of buspirone in healthy adults reportedly averages 5.3 L/kg following a single IV dose.

Buspirone is approximately 86-95% bound to plasma proteins in vitro, mainly to albumin and, to a lesser extent, α₁-acid glycoprotein (α₁-AGP).

Buspirone and its metabolites are distributed into milk in animals. It is not known whether the drug distributes into milk in humans.

Elimination

Following single oral doses of 10-40 mg in healthy adults, the elimination half-life of buspirone averages about 2-4 hours (range: 2-11 hours). The elimination half-life of the drug appears to be slightly longer in females than in males, although the clinical importance of this difference has not been established. The elimination half-life does not appear to be affected by increases in dose or by concomitant administration with food, but may be prolonged in patients with renal impairment, particularly those with anuria, and in patients with liver impairment, including those with cirrhosis. In a limited number of patients with mild to moderate renal impairment (creatinine clearances of 60 mL/minute or less per 1.73 m) or with anuria, the buspirone elimination half-life averaged 5.7 or 6.1 hours, respectively, while it averaged 4 hours in healthy individuals. Elimination half-life of the drug averaged 6.1 hours in a limited number of patients with liver cirrhosis following oral administration.

Buspirone is metabolized extensively in the liver, mainly via oxidation by the cytochrome P-450 (CYP) isoenzyme 3A4, to form several hydroxylated metabolites, including 5-hydroxybuspirone (5-HB) and 1-pyrimidinylpiperazine (1-PP). 5-Hydroxybuspirone is further oxidized to at least 2 additional hydroxy metabolites, which subsequently undergo conjugation. Following oral administration of a single 20-mg dose of buspirone hydrochloride in healthy adults, the elimination half-lives of 1-PP, 5-HB, and the glucuronide of 5-HB have been reported to average about 6.1, 4.8, and 3.2 hours, respectively.

The major pharmacologically active metabolite is 1-PP. In animals, 1-PP has about 20-25% of the anxiolytic activity of buspirone but is present in the brain in concentrations up to 15-to 30-fold greater than those of unchanged drug. In humans, however, blood concentrations of 1-PP remain relatively low even after chronic administration of buspirone, and the contribution of this metabolite to the pharmacologic and/or toxic effects of the drug has not been fully elucidated. In one study, blood 1-PP concentrations reportedly averaged 3 ng/mL during chronic oral administration and did not exceed 17 ng/mL, which is less than 0.5% of the 1-PP concentrations found in animals that were given large doses (50-200 mg/kg) of buspirone hydrochloride without exhibiting signs of toxicity. Unlike buspirone, 1-PP does not affect the dopaminergic system but does appear to possess some α₂-adrenergic blocking activity, which may contribute to buspirone's anxiolytic and/or antidepressant effects.

Buspirone and its metabolites are excreted principally in urine and, to a lesser extent, in feces. About 29-63% of a single oral dose of the drug is excreted in urine and about 18-38% in feces within 24 hours, mainly as metabolites. Buspirone appears to be excreted in urine almost completely as metabolites, with less than 0.1% of the total oral dose being excreted as unchanged drug. Fecal excretion of the drug appears to occur via biliary secretion.

Following IV administration in healthy adults, total body clearance of buspirone from plasma averaged approximately 28 mL/minute per kg. Limited data suggest that elimination of unchanged buspirone is not altered substantially in patients undergoing hemodialysis, although plasma concentrations and elimination half-life of 1-PP may be reduced. The reduced clearance of 1-PP observed in anuric patients with chronic renal failure appears to be only partly reversed by hemodialysis. It is not known whether buspirone and/or its metabolites are removed by peritoneal dialysis.

Customer Reviews