BUSPIRONE HYDROCHLORIDE- buspirone hydrochloride tablet

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Active ingredient:
BUSPIRONE HYDROCHLORIDE (UNII: 207LT9J9OC) (BUSPIRONE - UNII:TK65WKS8HL)
Available from:
Carilion Materials Management
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 hydrochloride tablets 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 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 du
Product summary:
Product: 68151-1437 NDC: 68151-1437-0 1 TABLET in a PACKAGE
Authorization status:
Abbreviated New Drug Application
Authorization number:
68151-1437-0

BUSPIRONE HYDROCHLORIDE- buspirone hydrochloride tablet

Carilion Materials Management

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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. Chemically, buspirone

hydrochloride is N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,1-cyclopentanediacetamide

monohydrochloride, which can be represented by the following structural formula:

H N O HCl M.W. 421.96

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 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 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 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:

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 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 for 1 year without ill effect.

Therefore, the physician who elects to use buspirone hydrochloride tablets 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 tablets to a patient taking a monoamine oxidase

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.

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 tablets 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 tablets 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 tablets 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 tablets 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 tablets, the following information and

instructions should be given to patients:

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Psychotropic Agents

Do not take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if

you are not sure if you take an MAOI, including the antibiotic linezolid.

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

physician.

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

by your physician.

Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs

that you are now taking or plan to take during your treatment with buspirone hydrochloride tablets.

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.

Inform your physician if you are breastfeeding an infant.

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

dangerous machinery.

You should take buspirone hydrochloride tablets consistently, either always with or always

without food.

During your treatment with buspirone hydrochloride tablets, avoid drinking large amounts of

grapefruit juice.

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

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, 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

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 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 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 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)

Bus pirone

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

*Events reported by at least 1% of buspirone 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 is being recommended (i.e., 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 adverse events were

reported. In the absence of appropriate controls in some of the studies, a causal relationship to

buspirone hydrochloride treatment cannot be determined. The list includes all undesirable events

reasonably associated with the use of the drug.

The following enumeration by organ system describes events in terms of their relative frequency of

reporting in this data base. Events of major clinical importance are also described in the

PRECAUTIONS section.

The following definitions of frequency are used: Frequent adverse events are defined as those

occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000

patients, while rare events are those occurring in less than 1/1000 patients.

Cardiovas cular

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.

Gas trointes tinal

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.

Mus culos keletal

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

weakness.

Res piratory

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.

Mis cellaneous

Infrequent were weight gain, fever, roaring sensation in the head, weight loss, and malaise; rare were

alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs.

Postmarketing Experience

Postmarketing experience has shown an adverse experience profile similar to that given above.

Voluntary reports since introduction have included rare occurrences of allergic reactions (including

urticaria), angioedema, cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions

(including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis,

emotional lability, serotonin syndrome, transient difficulty with recall, urinary retention, visual changes

(including tunnel vision), parkinsonism, akathisia, restless leg syndrome, and restlessness. Because of

the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone hydrochloride

tablets 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 hydrochloride tablets

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 hydrochloride tablets cause 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 hydrochloride tablets 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 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

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 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).

HOW SUPPLIED

Product: 68151-1437

NDC: 68151-1437-0 1 TABLET in a PACKAGE

REFERENCES

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. Z 12/2016

PATIENT INFORMATION

BUSPIRONE HYDROCHLORIDE TABLETS

Rx only

HOW TO USE:

BUSPIRONE HYDROCHLORIDE TABLETS, 15 mg

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

dosage to obtain the proper response.

This 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:

American Psychiatric Association, Ed.: Diagnostic and Statistical Manual of Mental Disorders—

III, American Psychiatric Association, May 1980.

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

the appropriate tablet score (groove) as shown below. Then, with the tablet score facing you, apply

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

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. H 12/2016

PATIENT INFORMATION

BUSPIRONE HYDROCHLORIDE TABLETS

Rx only

HOW TO USE:

BUSPIRONE HYDROCHLORIDE TABLETS, 30 mg

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

dosage to obtain the proper response.

This 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 30 mg tablet:

30 mg (the entire tablet)

20 mg (two-thirds of a tablet)

15 mg (one-half of a tablet)

10 mg (one-third of a tablet)

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

the appropriate tablet score (groove) as shown below. Then, with the tablet score facing you, apply

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

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. H 12/2016

Buspirone 5 MG TAB

BUSPIRONE HYDROCHLORIDE

buspirone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 151-1437(NDC:0 0 9 3-0 0 53)

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) (BUSPIRONE -

UNII:TK6 5WKS8 HL)

BUSPIRONE

HYDROCHLORIDE

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

Product Characteristics

Color

WHITE (white to o ff-white)

S core

2 pieces

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

TV;53

Contains

Packag ing

Carilion Materials Management

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 151-1437-0

1 in 1 PACKAGE; Type 0 : No t a Co mbinatio n Pro duct

0 2/28 /20 0 2

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 750 22

0 2/28 /20 0 2

Labeler -

Carilion Materials Management (079239644)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Carilio n Materials Management

0 79 239 6 44

REPACK(6 8 151-1437)

Revised: 7/2017

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