busPIRone HCl

Buspirone hydrochloride tablets, USP are indicated for the management of anxiety disorders or the short-term relief of the 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 hydrochloride tablets, USP has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD). Many of the patients enrolled in these studies also had coexisting depressive symptoms and buspirone hydrochloride tablets, USP relieved anxiety in the presence of these coexisting depressive symptoms. The patients evaluated in these studies had experienced symptoms for periods of 1 month to over 1 year prior to the study, with an average symptom duration of 6 months. Generalized Anxiety Disorder (300.02) is described in the American Psychiatric Association's Diagnostic and Statistical Manual, III1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of the four following categories: Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle. Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate. Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others. Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling "on edge," irritability, impatience. The above symptoms would not be due to another mental disorder, such as a depressive disorder or schizophrenia. However, mild depressive symptoms are common in GAD. The effectiveness of buspirone hydrochloride tablets, USP in long-term use, that is, for more than 3 to 4 weeks, has not been demonstrated in controlled trials. There is no body of evidence available that systematically addresses the appropriate duration of treatment for GAD. However, in a study of long-term use, 264 patients were treated with buspirone hydrochloride tablets, USP for 1 year without ill effect. Therefore, the physician who elects to use buspirone hydrochloride tablets, USP for extended periods should periodically reassess the usefulness of the drug for the individual patient.

The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 mg to 30 mg per day were commonly employed. The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food. When buspirone is to be given with a potent inhibitor of CYP3A4, the dosage recommendations described in the PRECAUTIONS, Drug Interactions section should be followed. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with buspirone hydrochloride tablets. Conversely, at least 14 days should be allowed after stopping buspirone hydrochloride tablets before starting an MAOI antidepressant CONTRAINDICATIONS and DRUG INTERACTIONS). Use of buspirone hydrochloride tablets with (Reversible) MAOIs, Such as Linezolid or Methylene Blue Do not start buspirone hydrochloride tablets in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered (see CONTRAINDICATIONS and DRUG INTERACTIONS). In some cases, a patient already receiving therapy with buspirone hydrochloride tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, buspirone hydrochloride tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with buspirone hydrochloride tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg per kg with buspirone hydrochloride tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see CONTRAINDICATIONS, WARNINGS and DRUG INTERACTIONS).

CONTRAINDICATIONS Buspirone hydrochloride tablets are contraindicated in patients hypersensitive to buspirone hydrochloride. 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 ADMINISTRATION AND DRUG INTERACTIONS ).

ADVERSE REACTIONS (See also PRECAUTIONS ) Commonly Observed The more commonly observed untoward events associated with the use of buspirone hydrochloride tablets 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 tablets are 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 tablets 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 tablets patients who participated in 4-week, controlled trials comparing buspirone hydrochloride tablets 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 Tablets (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 4 Weakness 2 -- Sweating/Clamminess 1 -- * Events reported by at least 1% of buspirone hydrochloride tablets patients are included. —Incidence less than 1%. Other Events Observed During the Entire Premarketing Evaluation of Buspirone Hydrochloride Tablets During its premarketing assessment, buspirone hydrochloride tablets were 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 tablets in the dose range for which buspirone hydrochloride tablets are being recommended (ie, the modal daily dose of buspirone hydrochloride tablets fell between 10 mg 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 tablets 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 ad …

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 ADMINISTRATION AND 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 t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and C max of buspirone 3.4-fold while diltiazem increased AUC and C max 5.5-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 max and 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 b.i.d.) 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 t.i.d. 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 gra …

DESCRIPTION Buspirone hydrochloride tablets, USP are an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. Buspirone hydrochloride is a white crystalline, water soluble compound with a molecular weight of 422.0. Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1­ piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride. The empirical formula C 21 H 31 N 5 O 2 • HCl is represented by the following structural formula: Buspirone hydrochloride tablets are supplied as tablets for oral administration containing 5 mg, 7.5 mg, 10 mg, 15 mg, or 30 mg of buspirone hydrochloride, USP (equivalent to 4.6 mg, 6.9 mg, 9.1 mg, 13.7 mg, and 27.4 mg of buspirone free base, respectively). The 5 mg and 10 mg tablets are scored so they can be bisected. Thus, the 5 mg tablet can also provide a 2.5 mg dose, and the 10 mg tablet can provide a 5 mg dose. The 15 mg and 30 mg tablets are provided in multi-scored tablet design. These tablets are scored so they can be either bisected or trisected. Thus, a single 15 mg tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half of a tablet), or 5 mg (one third of a tablet). A single 30 mg tablet can provide the following doses: 30 mg (entire tablet), 20 mg (two thirds of a tablet), 15 mg (one half of a tablet), or 10 mg (one third of a tablet). Buspirone hydrochloride tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and croscarmellose sodium. structure

OVERDOSAGE Signs and Symptoms In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers. As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. A few cases of overdosage have been reported, with complete recovery as the usual outcome. No deaths have been reported following overdosage with buspirone hydrochloride tablets alone. Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined. Toxicology studies of buspirone yielded the following LD 50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg. These dosages are 160 to 550 times the recommended human daily dose. Recommended Overdose Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined.

Buspirone Hydrochloride Tablets, USP are available as: 100 tablets in a HDPE bottle NDC: 42543-741-06 White to off white ovoid- rectangular uncoated functionally scored tablet with score line on one side and engraved '5' on the other side. 5 mg 500 tablets in a HDPE bottle NDC: 42543-741-07 1000 tablets in a HDPE bottle NDC: 42543-741-08 7.5 mg 100 tablets in a HDPE bottle NDC: 42543-787-06 White to off white colour, oval, biconvex tablets, debossed with 7.5 on one side and score line on other side. 500 tablets in a HDPE bottle NDC: 42543-787-07 30 tablets in a HDPE bottle NDC: 72189-458-30 White to off white ovoid- rectangular uncoated functionally scored tablet with score line on one side and engraved '10' on the other side. 10 mg 500 tablets in a HDPE bottle NDC: 42543-742-07 1000 tablets in a HDPE bottle NDC: 42543-742-08 60 tablets in a HDPE bottle NDC: 42543-743-03 White to off white rectangular uncoated functionally scored tablet with bisected score lines on one side and trisected score line with engraved '5' on each trisection of other side. The 15 mg tablet is in xx tablet design and functionally scored so that it can be either bisected or trisected. 15 mg 100 tablets in a HDPE bottle NDC: 42543-743-06 180 tablets in a HDPE bottle NDC: 42543-743-18 30 mg 60 tablets in a HDPE bottle NDC: 42543-744-03 White to off white rectangular uncoated functionally scored tablet with bisected score lines on one side and trisected score line with engraved '10' on each trisection of other side.