What Is Bucapsol Capsule Used For?

Commonly Observed

The more commonly observed untoward events associated with the use of buspirone hydrochloride not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Associated with Discontinuation of Treatment

One guide to the relative clinical importance of adverse events associated with buspirone hydrochloride is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the buspirone hydrochloride premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue.

In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. Incidence in Controlled Clinical Trials

The table that follows enumerates adverse events that occurred at a frequency of 1% or more among buspirone hydrochloride patients who participated in 4-week, controlled trials comparing buspirone hydrochloride with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.

TREATMENT-EMERGENT ADVERSE EXPERIENCE

INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS*

(Percent of Patients Reporting)

Adverse Experience

Buspirone Hydrochloride (n=477)

Placebo

(n=464)

Cardiovascular

• Tachycardia/Palpitations

1

1

CNS

• Dizziness

12

3

• Drowsiness

10

9

• Nervousness

5

1

• Insomnia

3

3

• Lightheadedness

3

-

• Decreased Concentration

2

2

• Excitement

2

-

• Anger/Hostility

2

-

• Confusion

2

-

• Depression

2

2

EENT

• Blurred Vision

2

-

Gastrointestinal

• Nausea

8

5

• Dry Mouth

3

4

• Abdominal/Gastric Distress

2

2

• Diarrhea

2

-

• Constipation

1

2

• Vomiting

1

2

Musculoskeletal

• Musculoskeletal Aches/Pains

1

-

Neurological

• Numbness

2

-

• Paresthesia

1

-

• Incoordination

1

-

• Tremor

1

-

Skin

• Skin Rash

1

-

Miscellaneous

• Headache

6

3

• Fatigue

4

• Weakness

2

-

• Sweating/Clamminess

1

-

*Events reported by at least 1% of buspirone hydrochloride patients are included.

-Incidence less than 1% Other Events Observed During the Entire Premarketing Evaluation of Bucapsol

TMCapsules

During its premarketing assessment, buspirone hydrochloride was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of buspirone hydrochloride in the dose range for which buspirone hydrochloride is being recommended (ie, the modal daily dose of buspirone hydrochloride fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to buspirone hydrochloride varied greatly, involving well- controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to buspirone hydrochloride treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug.

The following enumeration by organ system describes events in terms of their relative frequency of reporting in this database. Events of major clinical importance are also described in the

PRECAUTIONS

section.

The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients.

Cardiovascular

Frequent was nonspecific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia.

Central Nervous System

Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis.

EENT

Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes.

Endocrine

Rare were galactorrhea and thyroid abnormality.

Gastrointestinal

Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue.

Genitourinary

Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia.

Musculoskeletal

Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness.

Respiratory

Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis.

Sexual Function

Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence.

Skin

Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails.

Clinical Laboratory

Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia.

Miscellaneous

Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. Postmarketing Experience

Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes (including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone hydrochloride treatment has not been determined.

To report SUSPECTED ADVERSE REACTIONS, contact Pangea Pharmaceuticals, LLC at 1-855-892-8224 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The administration of Bucapsol ^TMcapsules to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when buspirone hydrochloride has been added to a regimen including an MAOI. Therefore, it is recommended that Bucapsol ^TMcapsules not be used concomitantly with an MAOI.

General Interference with Cognitive and Motor Performance Studies indicate that buspirone hydrochloride 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 operating an automobile or using complex machinery until they are reasonably certain that buspirone treatment does not affect them adversely. While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use of alcohol and buspirone. Potential for Withdrawal Reactions in Sedative/Hypnotic/Anxiolytic Drug-Dependent Patients Because buspirone hydrochloride does not exhibit cross-tolerance with benzodiazepines and other common sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with these drugs. Therefore, before starting therapy with buspirone hydrochloride, it is advisable to withdraw patients gradually, especially patients who have been using a CNS-depressant drug chronically, from their prior 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. The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms without fever, and occasionally, even as seizures. Possible Concerns Related to Buspirone's Binding to Dopamine Receptors 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 (eg, dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia). Clinical experience in controlled trials has failed to identify any significant neuroleptic-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 (ie, represent akathisia). See ADVERSE REACTIONS: Postmarketing Experience. Information for Patients To assure safe and effective use of Bucapsol TMcapsules, the following information and instructions should be given to patients: • Do not take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. • Do not take an MAOI within 2 weeks of stopping buspirone unless directed to do so by your physician. • Do not start buspirone if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. • Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with Bucapsol TMcapsules. • Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking Bucapsol TMcapsules. • Inform your physician if you are breast-feeding an infant. • Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery. • If you have difficulty swallowing capsules, Bucapsol TMcapsules can be opened and the contents sprinkled on a small amount of applesauce (about 1-2 tablespoons). The drug-applesauce mixture should be swallowed immediately. • You should take Bucapsol TMcapsules consistently, either always with or always without food. • During your treatment with Bucapsol TMcapsules, avoid drinking large amounts of grapefruit juice. Laboratory Tests There are no specific laboratory tests recommended. Drug Interactions Psychotropic Agents MAO inhibitors: The use of monoamine oxidase inhibitors (MAOIs) 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. (see WARNINGS, DOSAGE AND ADMINISTRATIONand CONCOMITANT DRUG) Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max, AUC, and C min) of amitriptyline or its metabolite nortriptyline were observed. Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max, AUC, and C min) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol: In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone: [see Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)] Trazodone: There is one report suggesting that the concomitant use of Desyrel ®(trazodone hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/Flurazepam: Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other Psychotropics: Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg three times a day) or diltiazem (60 mg three times a day) increased plasma buspirone concentrations (verapamil increased AUC and C maxof buspirone 3.4-fold while diltiazem increased AUC and C max5.5-fold and 4-fold, respectively). Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in C maxand 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg two times per day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength three times a day for 2 days) increased plasma buspirone concentrations (4.3-fold increase in C max; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in C maxand 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg once a day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg two times per day) with nefazodone (250 mg two times per day) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in C maxand up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5-mg two times per day doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in C maxwere observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects receiving buspirone 5 mg two times per day and nefazodone 250 mg two times per day experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg once a day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in C max; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Inhibitors and Inducers of CYP3A4 : Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Drugs Cimetidine: Coadministration of buspirone with cimetidine was found to increase C max(40%) and T max(2-fold), but had minimal effects on the AUC of buspirone. Protein Binding In vitro, buspirone does not displace tightly bound drugs like phenytoin, propranolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid ®. In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY). Drug/Laboratory Test Interactions Buspirone hydrochloride 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. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18-month study at approximately 167 times the maximum recommended human oral dose. With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone. Pregnancy No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose. In humans, however, adequate and well-controlled studies during pregnancy have not been performed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of buspirone hydrochloride on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats. Nursing Mothers The extent of the excretion in human milk of buspirone or its metabolites is not known. In rats, however, buspirone and its metabolites are excreted in milk. Bucapsol TMcapsules administration to nursing women should be avoided if clinically possible. Pediatric Use The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6-week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5 mg to 30 mg two times per day (15–60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population. Geriatric Use In one study of 6632 patients who received buspirone for the treatment of anxiety, 605 patients were ≥65 years old and 41 were ≥75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). Review of spontaneously reported adverse clinical events has not identified differences between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. There were no effects of age on the pharmacokinetics of buspirone (see CLINICAL PHARMACOLOGY: Special Populations). Use in Patients With Impaired Hepatic or Renal Function Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of Bucapsol TMcapsules to patients with severe hepatic or renal impairment cannot be recommended (see CLINICAL PHARMACOLOGY). Commonly Observed The more commonly observed untoward events associated with the use of buspirone hydrochloride not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Associated with Discontinuation of Treatment One guide to the relative clinical importance of adverse events associated with buspirone hydrochloride is provided by the frequency with which they caused drug discontinuation during clinical testing. Approximately 10% of the 2200 anxious patients who participated in the buspirone hydrochloride premarketing clinical efficacy trials in anxiety disorders lasting 3 to 4 weeks discontinued treatment due to an adverse event. The more common events causing discontinuation included: central nervous system disturbances (3.4%), primarily dizziness, insomnia, nervousness, drowsiness, and lightheaded feeling; gastrointestinal disturbances (1.2%), primarily nausea; and miscellaneous disturbances (1.1%), primarily headache and fatigue. In addition, 3.4% of patients had multiple complaints, none of which could be characterized as primary. Incidence in Controlled Clinical Trials The table that follows enumerates adverse events that occurred at a frequency of 1% or more among buspirone hydrochloride patients who participated in 4-week, controlled trials comparing buspirone hydrochloride with placebo. The frequencies were obtained from pooled data for 17 trials. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Comparison of the cited figures, however, does provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS* (Percent of Patients Reporting) Adverse Experience Buspirone Hydrochloride (n=477) Placebo (n=464) Cardiovascular • Tachycardia/Palpitations 1 1 CNS • Dizziness 12 3 • Drowsiness 10 9 • Nervousness 5 1 • Insomnia 3 3 • Lightheadedness 3 - • Decreased Concentration 2 2 • Excitement 2 - • Anger/Hostility 2 - • Confusion 2 - • Depression 2 2 EENT • Blurred Vision 2 - Gastrointestinal • Nausea 8 5 • Dry Mouth 3 4 • Abdominal/Gastric Distress 2 2 • Diarrhea 2 - • Constipation 1 2 • Vomiting 1 2 Musculoskeletal • Musculoskeletal Aches/Pains 1 - Neurological • Numbness 2 - • Paresthesia 1 - • Incoordination 1 - • Tremor 1 - Skin • Skin Rash 1 - Miscellaneous • Headache 6 3 • Fatigue 4 • Weakness 2 - • Sweating/Clamminess 1 - *Events reported by at least 1% of buspirone hydrochloride patients are included. -Incidence less than 1% Other Events Observed During the Entire Premarketing Evaluation of Bucapsol TMCapsules During its premarketing assessment, buspirone hydrochloride was evaluated in over 3500 subjects. This section reports event frequencies for adverse events occurring in approximately 3000 subjects from this group who took multiple doses of buspirone hydrochloride in the dose range for which buspirone hydrochloride is being recommended (ie, the modal daily dose of buspirone hydrochloride fell between 10 and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected. The conditions and duration of exposure to buspirone hydrochloride varied greatly, involving well- controlled studies as well as experience in open and uncontrolled clinical settings. As part of the total experience gained in clinical studies, various adverse events were reported. In the absence of appropriate controls in some of the studies, a causal relationship to buspirone hydrochloride treatment cannot be determined. The list includes all undesirable events reasonably associated with the use of the drug. The following enumeration by organ system describes events in terms of their relative frequency of reporting in this database. Events of major clinical importance are also described in the PRECAUTIONS section. The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients. Cardiovascular Frequent was nonspecific chest pain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heart failure, myocardial infarction, cardiomyopathy, and bradycardia. Central Nervous System Frequent were dream disturbances; infrequent were depersonalization, dysphoria, noise intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative reaction, hallucinations, involuntary movements, slowed reaction time, suicidal ideation, and seizures; rare were feelings of claustrophobia, cold intolerance, stupor, and slurred speech and psychosis. EENT Frequent were tinnitus, sore throat, and nasal congestion; infrequent were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; rare were inner ear abnormality, eye pain, photophobia, and pressure on eyes. Endocrine Rare were galactorrhea and thyroid abnormality. Gastrointestinal Infrequent were flatulence, anorexia, increased appetite, salivation, irritable colon, and rectal bleeding; rare was burning of the tongue. Genitourinary Infrequent were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia. Musculoskeletal Infrequent were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare was muscle weakness. Respiratory Infrequent were hyperventilation, shortness of breath, and chest congestion; rare was epistaxis. Sexual Function Infrequent were decreased or increased libido; rare were delayed ejaculation and impotence. Skin Infrequent were edema, pruritus, flushing, easy bruising, hair loss, dry skin, facial edema, and blisters; rare were acne and thinning of nails. Clinical Laboratory Infrequent were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia, leukopenia, and thrombocytopenia. Miscellaneous Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs. Postmarketing Experience Postmarketing experience has shown an adverse experience profile similar to that given above. Voluntary reports since introduction have included rare occurrences of allergic reactions (including urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions (including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes (including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone hydrochloride treatment has not been determined. To report SUSPECTED ADVERSE REACTIONS, contact Pangea Pharmaceuticals, LLC at 1-855-892-8224 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Psychotropic Agents MAO inhibitors: The use of monoamine oxidase inhibitors (MAOIs) 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. (see WARNINGS, DOSAGE AND ADMINISTRATIONand CONCOMITANT DRUG) Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max, AUC, and C min) of amitriptyline or its metabolite nortriptyline were observed. Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max, AUC, and C min) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed. Haloperidol: In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations. The clinical significance of this finding is not clear. Nefazodone: [see Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)] Trazodone: There is one report suggesting that the concomitant use of Desyrel ®(trazodone hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients. In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified. Triazolam/Flurazepam: Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Other Psychotropics: Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution. Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and Verapamil: In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg three times a day) or diltiazem (60 mg three times a day) increased plasma buspirone concentrations (verapamil increased AUC and C maxof buspirone 3.4-fold while diltiazem increased AUC and C max5.5-fold and 4-fold, respectively). Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil. Subsequent dose adjustment may be necessary and should be based on clinical assessment. Erythromycin: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in C maxand 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg two times per day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Grapefruit Juice: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength three times a day for 2 days) increased plasma buspirone concentrations (4.3-fold increase in C max; 9.2-fold increase in AUC). Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice. Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in C maxand 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg once a day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Nefazodone: In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg two times per day) with nefazodone (250 mg two times per day) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in C maxand up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5-mg two times per day doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%). Slight increases in C maxwere observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects receiving buspirone 5 mg two times per day and nefazodone 250 mg two times per day experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg once a day) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Rifampin: In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in C max; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Inhibitors and Inducers of CYP3A4 : Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone, or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect. Other Drugs Cimetidine: Coadministration of buspirone with cimetidine was found to increase C max(40%) and T max(2-fold), but had minimal effects on the AUC of buspirone. Protein Binding In vitro, buspirone does not displace tightly bound drugs like phenytoin, propranolol, and warfarin from serum proteins. However, there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin. The patient was also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid ®. In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown. Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY).

Buspirone hydrochloride 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.