BUSPIRONE HCL- buspirone hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
Buspirone hydrochloride (UNII: 207LT9J9OC) (Buspirone - UNII:TK65WKS8HL)
Available from:
Rebel Distributors Corp.
INN (International Name):
Buspirone hydrochloride
Composition:
Buspirone hydrochloride 5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Buspirone hydrochloride tablets 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 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 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, lll1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of
Product summary:
Buspirone HCl Tablets USP are supplied as follows: 5 mg tablets: White, oval, biconvex, scored tablets, debossed WATSON and 657, in bottles of 100, 500, and 1000. 10 mg tablets: White, oval, biconvex, scored tablets, debossed WATSON and 658, in bottles of 100, 500, and 1000. 15 mg tablets: White, oval shaped, scored tablets, debossed with the Watson logo and 718, and scoring on both sides so it can be either bisected or trisected, in bottles of 60, 180, 500, and 1000. Store at 20° - 25°C (68°- 77°F). [See USP controlled room temperature]. Protect from temperatures greater than 30°C (86°F). Dispense in a tight, light-resistant container as defined in USP/NF.
Authorization status:
Abbreviated New Drug Application
Authorization number:
21695-172-00, 21695-172-60, 21695-217-30, 21695-217-60, 21695-256-60, 21695-256-90

BUSPIRONE HCL- buspirone hydrochloride tablet

Rebel Distributors Corp.

----------

Buspirone HCl Tablets USP

Revised: October 2007

Rx only

DESCRIPTION

Buspirone hydrochloride is 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 molecular formula C

H N O HCl is

represented by the following structural formula:

Each tablet for oral administration contains 5 mg, 10 mg, or 15 mg of buspirone hydrochloride USP

(equivalent to 4.6 mg, 9.1 mg, and 13.7 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 tablet is provided in a special tablet design. This tablet

is scored so it 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). In addition, each tablet contains the following inactive ingredients: colloidal silicon

dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch

glycolate.

CLINICAL PHARMACOLOGY

The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine

anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent

sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown

that buspirone has a high affinity for serotonin (5-HT

) receptors. Buspirone has no significant affinity

for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in

preclinical models.

Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that

buspirone may have indirect effects on other neurotransmitter systems.

Buspirone is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled

study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma.

Following oral administration, plasma concentrations of unchanged buspirone are very low and variable

between subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes after single

oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tablet is

on the average about 90% of an equivalent dose of solution, but there is large variability.

The effects of food upon the bioavailability of buspirone have been studied in eight subjects. They

were given a 20 mg dose with and without food; the area under the plasma concentration-time curve

(AUC) and peak plasma concentration (C

) of unchanged buspirone increased by 84% and 116%

respectively, but the total amount of buspirone immunoreactive material did not change. This suggests

that food may decrease the extent of presystemic clearance of buspirone. (SeeDOSAGE AND

ADMINISTRATION section.)

A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear pharmacokinetics.

Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged

buspirone than would be predicted from results of single-dose studies.

An in vitro protein binding study indicated that approximately 86% of buspirone is bound to plasma

proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23%, while

flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether

these drugs cause similar effects on plasma levels of free buspirone in vivo, or whether such changes,

if they do occur, cause clinically significant differences in treatment outcome. An in vitro study

indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and

propranolol from plasma protein, and that buspirone may displace digoxin.

Buspirone is metabolized primarily by oxidation, which in vitro has been shown to be mediated by

cytochrome P450 3A4 (CYP3A4). (SeePRECAUTIONS, Drug Interactions section.) Several

hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are

produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity

of buspirone, but is present in up to 20-fold greater amounts. However, this is probably not important in

humans: blood samples from humans chronically exposed to buspirone do not exhibit high levels of 1-

PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108

chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large

doses of buspirone without signs of toxicity.

In a single-dose study using

C-labeled buspirone, 29% to 63% of the dose was excreted in the urine

within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The

average elimination half-life of unchanged buspirone after single doses of 10 to 40 mg is about 2 to 3

hours.

Special Populations

Age and Gender Effects

After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC

and C

) were observed between elderly and younger subjects or between men and women.

Hepatic Impairment

After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC

of buspirone increased 13-fold compared with healthy subjects (seePRECAUTIONS section).

Renal Impairment

After multiple-dose administration of buspirone to renally impaired (CIcr = 10-70 mL/min/1.73 m )

patients, steady-state AUC of buspirone increased 4-fold compared with healthy (Clcr ≥80 mL/min/1.73

m ) subjects (seePRECAUTIONS section).

Race Effects

The effects of race on the pharmacokinetics of buspirone have not been studied.

INDICATIONS AND USAGE

Buspirone hydrochloride tablets 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 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 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, lll1 as follows:

Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from

three of the four following categories:

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 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 for 1 year without ill effect. Therefore, the physician who elects to use

buspirone for extended periods should periodically reassess the usefulness of the drug for the

individual patient.

CONTRAINDICATIONS

Buspirone tablets are contraindicated in patients hypersensitive to buspirone hydrochloride.

WARNINGS

The administration of buspirone 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

has been added to a regimen including an MAOI. Therefore, it is recommended that buspirone not be

used concomitantly with an MAOI. Because buspirone has no established antipsychotic activity, it

should not be employed in lieu of appropriate antipsychotic treatment.

PRECAUTIONS

General

Interference with Cognitive and Motor Performance

Studies indicate that buspirone is less sedating than other anxiolytics and that it does not produce

significant functional impairment. However, its CNS effects in any individual patient may not be

predictable. Therefore, patients should be cautioned about operating an automobile or using complex

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.

machinery until they are reasonably certain that buspirone treatment does not affect them adversely.

While formal studies of the interaction of buspirone 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 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, 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 (e.g., 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 (i.e.,

represent akathisia). See ADVERSE REACTIONS: Postmarketing Experience section.

Information for Patients

To assure safe and effective use of buspirone hydrochloride tablets, the following information and

instructions should be given to patients:

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Psychotropic Agents

MAO Inhibitors: It is recommended that buspirone hydrocloride not be used concomitantly with MAO

inhibitors (seeWARNINGS section).

Amitriptyline: After addition of buspirone to the amitriptyline dose regimen, no statistically significant

differences in the steady-state pharmacokinetic parameters (C

, AUC, and C

) of amitriptyline or its

metabolite nortriptyline were observed.

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 buspirone.

Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you

become pregnant while you are taking buspirone.

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.

You should take buspirone consistently, either always with or always without food.

During your treatment with buspirone, avoid drinking large amounts of grapefruit juice.

Diazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant

differences in the steady-state pharmacokinetic parameters (C

, AUC, and C

) 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 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

of buspirone 3.4-fold while diltiazem increased

AUC and Cmax 5.3-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

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

; 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

and 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 every 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 b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma

buspirone concentrations (increases up to 20-fold in C

and up to 50-fold in AUC) and statistically

significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP. With 5

mg b.i.d. 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

were observed for nefazodone (8%) and its metabolite HO-NEF (11%). Subjects

receiving buspirone 5 mg b.i.d. and nefazodone 250 mg b.i.d. 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 every 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

; 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

(40%) and T

(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 levothyroxine sodium. 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

(seeCLINICAL PHARMACOLOGY section).

Drug/Laboratory Test Interactions

Buspirone is not known to interfere with commonly employed clinical laboratory tests.

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: Teratogenic Effects

Pregnancy Category B: 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 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. Buspirone 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 7.5-30 mg b.i.d. (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 (seeCLINICAL

PHARMACOLOGY, Special Populations section).

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 buspirone to patients with severe hepatic or renal

impairment cannot be recommended (seeCLINICAL PHARMACOLOGY section).

ADVERSE REACTIONS

(See alsoPRECAUTIONS)

Commonly Observed

The more commonly observed untoward events associated with the use of buspirone 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 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 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 patients who participated in 4-week, controlled trials comparing buspirone 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)

Bus pirone

Placebo

(n = 477)

(n = 464)

Adverse Experience

Cardiovascular

Tachycardia/Palpitations

Dizziness

Drowsiness

Nervousness

Insomnia

Lightheadedness

Decreased Concentration

Excitement

Anger/Hostility

Confusion

Depression

EENT

Blurred Vision

Gastrointestinal

Nausea

Dry Mouth

Abdominal/Gastric Distress

Diarrhea

Constipation

Vomiting

Musculoskeletal

Musculoskeletal Aches/Pains

Neurological

Numbness

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

- Incidence less than 1%.

Numbness

Paresthesia

Incoordination

Tremor

Skin

Skin Rash

Miscellaneous

Headache

Fatigue

Weakness

Sweating/Clamminess

Other Events Observed During the Entire Premarketing Evaluation of Buspirone

During the premarketing assessment, buspirone 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 in the dose range for which buspirone hydrochloride is being

recommended (i.e., the modal daily dose of buspirone 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 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 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 data base. Events of major clinical importance are also described in

thePRECAUTIONS 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,

ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional lability,

serotonin syndrome, transient difficulty with recall, urinary retention, and 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 treatment has not

been determined.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Buspirone hydrochloride is not a controlled substance.

Physical and Psychological Dependence

In human and animal studies, buspirone has shown no potential for abuse or diversion and there is no

evidence that it causes tolerance, or either physical or psychological dependence. Human volunteers

with a history of recreational drug or alcohol usage were studied in two double-blind clinical

investigations. None of the subjects were able to distinguish between buspirone and placebo. By

contrast, subjects showed a statistically significant preference for methaqualone and diazepam. Studies

in monkeys, mice and rats have indicated that buspirone lacks potential for abuse.

Following chronic administration in the rat, abrupt withdrawal of buspirone did not result in the loss of

body weight commonly observed with substances that cause physical dependency.

Although there is no direct evidence that buspirone causes physical dependence or drug-seeking

behavior, it is difficult to predict from experiments the extent to which a CNS-active drug will be

misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate

patients for a history of drug abuse and follow such patients closely, observing them for signs of

buspirone misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking

behavior).

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 alone. Rare cases of intentional overdosage with a fatal outcome were invariably

associated with ingestion of multiple drugs and/or alcohol, and a casual relationship of buspirone could

not be determined. Toxicology studies of buspirone yielded the following LD50 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.

DOSAGE AND ADMINISTRATION

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 to 30 mg per day were commonly employed.

The bioavailability of buspirone is increased when given with food as compared to the fasted state

(seeCLINICAL PHARMACOLOGY section). 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 thePRECAUTIONS, Drug Interactions section should be followed.

HOW SUPPLIED

Buspirone HCl Tablets USP are supplied as follows:

5 mg tablets: White, oval, biconvex, scored tablets, debossed WATSON and 657, in bottles of 100, 500,

and 1000.

10 mg tablets: White, oval, biconvex, scored tablets, debossed WATSON and 658, in bottles of 100,

500, and 1000.

15 mg tablets: White, oval shaped, scored tablets, debossed with the Watson logo and 718, and scoring

on both sides so it can be either bisected or trisected, in bottles of 60, 180, 500, and 1000.

Store at 20° - 25°C (68°- 77°F). [See USP controlled room temperature]. Protect from temperatures

greater than 30°C (86°F).

Dispense in a tight, light-resistant container as defined in USP/NF.

Reference

1. American Psychiatric Association. Ed.: Diagnostic and Statistical Manual of Mental Disorders - lll.

American Psychiatric Association, May 1980.

Manufactured for:

Watson Laboratories, Inc.

Corona, CA 92880 USA

Manufactured by:

Patheon Pharmaceuticals Inc.

Cincinnati, OH 45215 USA

Revised: October 2007

Buspirone HCl Tablets USP

Patient Instruction Sheet

Rx only

HOW TO USE:

Buspirone HCl Tablets USP

Response to buspirone varies among individuals. Your physician may find it necessary to adjust your

dosage to obtain the proper response.

The 15 mg tablet design makes dosage adjustments easy. Each tablet is scored and can be broken

accurately to provide any of the following dosages.

If your doctor prescribed the 15 mg tablet:

15 mg (the entire tablet)

10 mg (two thirds of a tablet)

7.5 mg (one half of a tablet)

5 mg (one third of a tablet)

To break the tablet accurately and easily, hold the tablet between your thumbs and index fingers close to

the appropriate tablet score (groove) as shown in the photo. Then, with the tablet score facing you,

apply pressure and snap the tablet segments apart (segments breaking incorrectly should not be used).

Manufactured for:

Watson Laboratories, Inc.

Corona, CA 92880 USA

Manufactured by:

Patheon Pharmaceuticals Inc.

Cincinnati, OH 45215 USA

Revised: October 2007

Repackaged by:

Rebel Distributors Corp.

Thousand Oaks, CA 91320

Principal Display Panel

BUSPIRONE HCL

buspirone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:216 9 5-256 (NDC:0 59 1-0 6 57)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Buspiro ne hydro chlo ride (UNII: 20 7LT9 J9 OC) (Buspiro ne - UNII:TK6 5WKS8 HL)

Buspiro ne hydro chlo ride

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

la cto se mo no hydra te (UNII: EWQ57Q8 I5X)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

white

S core

2 pieces

S hap e

OVAL

S iz e

8 mm

Flavor

Imprint Code

WATSON;6 57

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:216 9 5-256 -6 0

6 0 in 1 BOTTLE

2

NDC:216 9 5-256 -9 0

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 74253

0 3/28 /20 0 1

BUSPIRONE HCL

buspirone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:216 9 5-217(NDC:0 59 1-0 6 58 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Buspiro ne hydro chlo ride (UNII: 20 7LT9 J9 OC) (Buspiro ne - UNII:TK6 5WKS8 HL)

Buspiro ne hydro chlo ride

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

la cto se mo no hydra te (UNII: EWQ57Q8 I5X)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

white

S core

2 pieces

S hap e

OVAL

S iz e

11mm

Flavor

Imprint Code

WATSON;6 58

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:216 9 5-217-30

30 in 1 BOTTLE

2

NDC:216 9 5-217-6 0

6 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 74253

0 3/28 /20 0 1

BUSPIRONE HCL

buspirone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:216 9 5-172(NDC:0 59 1-0 718 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Buspiro ne hydro chlo ride (UNII: 20 7LT9 J9 OC) (Buspiro ne - UNII:TK6 5WKS8 HL)

Buspiro ne hydro chlo ride

15 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

la cto se mo no hydra te (UNII: EWQ57Q8 I5X)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

white

S core

3 pieces

S hap e

OVAL

S iz e

11mm

Flavor

Imprint Code

WATSON;718

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

Rebel Distributors Corp.

1

NDC:216 9 5-172-6 0

6 0 in 1 BOTTLE

2

NDC:216 9 5-172-0 0

10 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 74253

0 3/28 /20 0 1

Labeler -

Rebel Distributors Corp. (118802834)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Rebel Distributo rs Co rp.

118 8 0 28 34

RELABEL, REPACK

Revised: 9/2010

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