BUSPIRONE HYDROCHLORIDE tablet

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Active ingredient:
BUSPIRONE HYDROCHLORIDE (UNII: 207LT9J9OC) (BUSPIRONE - UNII:TK65WKS8HL)
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Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 mon
Product summary:
NDC: 71335-1749-1 60 Tablets in a BOTTLE NDC: 71335-1749-2 30 Tablets in a BOTTLE NDC: 71335-1749-3 56 Tablets in a BOTTLE NDC: 71335-1749-4 90 Tablets in a BOTTLE NDC: 71335-1749-5 180 Tablets in a BOTTLE NDC: 71335-1749-6 15 Tablets in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
71335-1749-1, 71335-1749-2, 71335-1749-3, 71335-1749-4, 71335-1749-5, 71335-1749-6

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BUSPIRONE HYDROCHLORIDE- buspirone hydrochloride tablet

Bryant Ranch Prepack

----------

Buspirone Hydrochloride Tablets, USP

Rx Only

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

421.96. Chemically, buspirone hydrochloride is N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,1-

cyclopentanediacetamide monohydrochloride. The empirical formula C

H N O HCl is represented

by the following structural formula:

Each tablet, for oral administration, contains 5 mg, 10 mg, 15 mg or 30 mg of buspirone hydrochloride,

USP (equivalent to 4.6 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 tablets are scored such that they may be

bisected or trisected. Thus, a single 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). The 30 mg tablets

are scored such that they may be bisected or trisected. Thus, a single 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, USP contain the following inactive ingredients:

anhydrous lactose, colloidal silicon dioxide, 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 D -dopamine receptors. Some studies do suggest that

buspirone may have indirect effects on other neurotransmitter systems.

Buspirone hydrochloride tablets are rapidly absorbed in man and undergo 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 ng/mL 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 hydrochloride tablets 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

(see DOSAGE AND ADMINISTRATION).

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) (see PRECAUTIONS, Drug Interactions). 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 hydrochloride tablets 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 mg 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 (see PRECAUTIONS).

Renal Impairment

After multiple-dose administration of buspirone to renally impaired (Cl

= 10 to 70 mL/min/1.73 m )

patients, steady-state AUC of buspirone increased 4-fold compared with healthy (Cl

> 80 mL/min/1.73

m ) subjects (see PRECAUTIONS).

Race Effects

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

INDICATIONS AND USAGE

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, III

as follows:

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

three of the four following categories:

1. Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability,

inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle.

2. 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.

3. Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or

others.

4. 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.

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).

WARNINGS

The administration of buspirone hydrochloride 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 buspirone hydrochloride not be used concomitantly with an MAOI.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs,

SSRIs, and other serotonergic drugs, including buspirone, alone but particularly with concomitant use

of other serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin (in

particular, MAOIs, including reversible MAOIs such as linezolid and intravenous methylene blue), or

with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,

delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,

diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus,

hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting,

diarrhea). Patients should be monitored for emergence of serotonin syndrome.

The concomitant use of buspirone with MAOIs intended to treat depression is contraindicated.

Buspirone should also not be started in a patient who is being treated with reversible MAOIs such as

linezolid or intravenous methylene blue. All reports with methylene blue that provided information on

the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

There have been no reports involving the administration of methylene blue by other routes (such as oral

tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to

initiate treatment with a reversible MAOI such as linezolid or intravenous methylene blue in a patient

taking buspirone. Buspirone should be discontinued before initiating treatment with the reversible

MAOI (see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION and DRUG

INTERACTIONS).

If concomitant use of buspirone with a 5-hydroxytryptamine receptor agonist (triptan) is clinically

warranted, careful observation of the patient is advised, particularly during treatment initiation and dose

increases.

The concomitant use of buspirone with serotonin precursors (such as tryptophan) is not recommended.

Treatment with buspirone and any concomitant serotonergic or antidopaminergic agents, including

antipsychotics, should be discontinued immediately if the above events occur and supportive

symptomatic treatment should be initiated.

Because buspirone hydrochloride 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 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 do 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 tablets, 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.

Information for Patients

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

instructions should be given to patients:

1. 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.

2. Do not take an MAOI within 2 weeks of stopping buspirone unless directed to do so by your

physician.

3. Do not start buspirone if you stopped taking an MAOI in the last 2 weeks unless directed to do so by

your physician.

4. 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 hydrochloride tablets.

5. 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 hydrochloride tablets.

6. Inform your physician if you are breastfeeding an infant.

7. Until you experience how this medication affects you, do not drive a car or operate potentially

dangerous machinery.

8. You should take buspirone hydrochloride tablets consistently, either always with or always without

food.

9. During your treatment with buspirone hydrochloride tablets, 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 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

, AUC, and C

) 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

, 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 C

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

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 (e.g., 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug

dose of buspirone (e.g., 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

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 (e.g., 2.5 mg q.d.) 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 (e.g., 2.5 mg q.d.) 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 (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 and 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 hydrochloride tablets 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 hydrochloride tablets 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 b.i.d. (15 to 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 buspirone hydrochloride tablets to patients with severe

hepatic or renal impairment cannot be recommended (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS

(See also PRECAUTIONS)

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)

*

Buspirone

Placebo

Adverse Experience

(n = 477)

(n = 464)

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

Paresthesia

Incoordination

Tremor

Skin

Skin rash

Miscellaneous

Headache

Fatigue

Weakness

Sweating/Clamminess

- Incidence less than 1%.

Other Events Observed During the Entire Premarketing Evaluation of Buspirone Hydrochloride

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

buspirone is being recommended (i.e., the modal daily dose of buspirone hydrochloride fell between 10

mg and 30 mg for 70% of the patients studied) and for whom safety data were systematically collected.

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

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