buspar
Generic Name: (
BUSPIRONE HYDROCHLORIDE)
Dosage Type: tablet Organization: Bristol-Myers Squibb
(Patient Instruction Sheet Included)
DESCRIPTION
BuSpar® (buspirone hydrochloride tablets,
USP) 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 empirical formula C21H31N5O2•
HCl is represented by the following structural formula:
BuSpar is supplied as tablets for oral administration containing
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 and 30 mg tablets are provided in the DIVIDOSE® tablet
design. These tablets are scored so they can be either bisected or trisected.
Thus, a single 15 mg tablet can provide the following doses: 15 mg (entire
tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half
of a tablet), or 5 mg (one third of a tablet). A single 30 mg tablet can
provide the following doses: 30 mg (entire tablet), 20 mg (two thirds of a
tablet), 15 mg (one half of a tablet), or 10 mg (one third of a tablet). BuSpar
Tablets contain the following inactive ingredients: colloidal silicon dioxide,
lactose, magnesium stearate, microcrystalline cellulose, and sodium starch
glycolate. The 30 mg tablet also contains iron oxide.
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-HT1A)
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.
BuSpar 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 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 BuSpar 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
(Cmax) 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
BuSpar (buspirone hydrochloride) 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 14C-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 Cmax) 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
(Clcr = 10–70 mL/min/1.73 m2)
patients, steady-state AUC of buspirone increased 4-fold compared with healthy
(Clcr=80 mL/min/1.73 m2)
subjects (see PRECAUTIONS).
Race Effects
The effects of race on the pharmacokinetics of buspirone have not
been studied.
INDICATIONS AND USAGE
BuSpar is 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 BuSpar 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 BuSpar relieved anxiety in the presence of these coexisting
depressive symptoms. The patients evaluated in these studies had experienced
symptoms for periods of 1 month to over 1 year prior to the study, with an
average symptom duration of 6 months. Generalized Anxiety Disorder (300.02)
is described in the American Psychiatric Association's Diagnostic and Statistical
Manual, III1 as follows:
Generalized, persistent anxiety (of at least 1 month continual
duration), manifested by symptoms from three of the four following categories:
- Motor tension: shakiness, jitteriness, jumpiness, trembling, tension,
muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow,
strained face, fidgeting, restlessness, easy startle.
- Autonomic hyperactivity: sweating, heart pounding or racing, cold,
clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling
in hands or feet), upset stomach, hot or cold spells, frequent urination,
diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing,
pallor, high resting pulse and respiration rate.
- Apprehensive expectation: anxiety, worry, fear, rumination, and
anticipation of misfortune to self or others.
- Vigilance and scanning: hyperattentiveness resulting in distractibility,
difficulty in concentrating, insomnia, feeling "on edge," irritability, impatience.
The above symptoms would not be due to another mental disorder,
such as a depressive disorder or schizophrenia. However, mild depressive symptoms
are common in GAD.
The effectiveness of BuSpar 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 BuSpar for 1 year without ill effect. Therefore, the physician
who elects to use BuSpar for extended periods should periodically reassess
the usefulness of the drug for the individual patient.
CONTRAINDICATIONS
BuSpar is contraindicated in patients hypersensitive to buspirone
hydrochloride.
WARNINGS
The administration of BuSpar 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 BuSpar (buspirone hydrochloride)
has been added to a regimen including an MAOI. Therefore, it is recommended
that BuSpar not be used concomitantly with an MAOI.
Because BuSpar 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 BuSpar 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 BuSpar (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 BuSpar 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 BuSpar, it is advisable to withdraw patients
gradually, especially patients who have been using a CNS-depressant drug chronically,
from their prior treatment. Rebound or withdrawal symptoms may occur over
varying time periods, depending in part on the type of drug, and its effective
half-life of elimination.
The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs
can appear as any combination of irritability, anxiety, agitation, insomnia,
tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms
without fever, and occasionally, even as seizures.
Possible Concerns Related to Buspirone's Binding to Dopamine Receptors
Because buspirone can bind to central dopamine receptors, a question
has been raised about its potential to cause acute and chronic changes in
dopamine-mediated neurological function (eg, dystonia, pseudo-parkinsonism,
akathisia, and tardive dyskinesia). Clinical experience in controlled trials
has failed to identify any significant neuroleptic-like activity; however,
a syndrome of restlessness, appearing shortly after initiation of treatment,
has been reported in some small fraction of buspirone-treated patients. The
syndrome may be explained in several ways. For example, buspirone may increase
central noradrenergic activity; alternatively, the effect may be attributable
to dopaminergic effects (ie, represent akathisia). See ADVERSE
REACTIONS: Postmarketing Experience.
Information for Patients
To assure safe and effective use of BuSpar, the following information
and instructions should be given to patients:
- 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 BuSpar.
- Inform your physician if you are pregnant, or if you are planning
to become pregnant, or if you become pregnant while you are taking BuSpar.
- 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 BuSpar (buspirone hydrochloride) consistently, either
always with or always without food.
- During your treatment with BuSpar, avoid drinking large amounts
of grapefruit juice.
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
Psychotropic Agents
MAO inhibitors: It is recommended
that BuSpar not be used concomitantly with MAO inhibitors
(see WARNINGS).
Amitriptyline: After addition of buspirone
to the amitriptyline dose regimen, no statistically significant differences
in the steady-state pharmacokinetic parameters (Cmax,
AUC, and Cmin) 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 (Cmax,
AUC, and Cmin) were observed for diazepam, but increases
of about 15% were seen for nordiazepam, and minor adverse clinical effects
(dizziness, headache, and nausea) were observed.
Haloperidol: In a study in normal
volunteers, concomitant administration of buspirone and haloperidol resulted
in increased serum haloperidol concentrations. The clinical significance of
this finding is not clear.
Nefazodone: (see Inhibitors
and Inducers of Cytochrome P450 3A4 [CYP3A4])
Trazodone: There is one report suggesting
that the concomitant use of Desyrel® (trazodone
hydrochloride) and buspirone may have caused 3- to 6-fold elevations on SGPT
(ALT) in a few patients. In a similar study attempting to replicate this finding,
no interactive effect on hepatic transaminases was identified.
Triazolam/Flurazepam: Coadministration
of buspirone with either triazolam or flurazepam did not appear to prolong
or intensify the sedative effects of either benzodiazepine.
Other Psychotropics: Because the effects
of concomitant administration of buspirone with most other psychotropic drugs
have not been studied, the concomitant use of buspirone with other CNS-active
drugs should be approached with caution.
Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4)
Buspirone has been shown in vitro to be metabolized
by CYP3A4. This finding is consistent with the in vivo interactions
observed between buspirone and the following:
Diltiazem and Verapamil: In a study of nine
healthy volunteers, coadministration of buspirone (10 mg as a single dose)
with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma
buspirone concentrations (verapamil increased AUC and Cmax of
buspirone 3.4-fold while diltiazem increased AUC and Cmax 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 Cmax 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 Cmax; 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 Cmax 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 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 Cmax 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 Cmax 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 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
Cmax; 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 Cmax (40%) and Tmax (2-fold),
but had minimal effects on the AUC of buspirone.
Protein Binding
In vitro, buspirone does not displace tightly
bound drugs like phenytoin, propranolol, and warfarin from serum proteins.
However, there has been one report of prolonged prothrombin time when buspirone
was added to the regimen of a patient treated with warfarin. The patient was
also chronically receiving phenytoin, phenobarbital, digoxin, and Synthroid®. In
vitro, buspirone may displace less firmly bound drugs like digoxin.
The clinical significance of this property is unknown.
Therapeutic levels of aspirin, desipramine, diazepam, flurazepam,
ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect
on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY).
Synthroid® is
the registered trademark of Abbott Laboratories.
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 BuSpar (buspirone hydrochloride) on labor and delivery
in women is unknown. No adverse effects were noted in reproduction studies
in rats.
Nursing Mothers
The extent of the excretion in human milk of buspirone or its metabolites
is not known. In rats, however, buspirone and its metabolites are excreted
in milk. BuSpar 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. (15-60 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 BuSpar 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 BuSpar 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 BuSpar 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 BuSpar 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 BuSpar (buspirone hydrochloride) patients
who participated in 4-week, controlled trials comparing BuSpar with placebo.
The frequencies were obtained from pooled data for 17 trials. The prescriber
should be aware that these figures cannot be used to predict the incidence
of side effects in the course of usual medical practice where patient characteristics
and other factors differ from those which prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained
from other clinical investigations involving different treatments, uses, and
investigators. Comparison of the cited figures, however, does provide the
prescribing physician with some basis for estimating the relative contribution
of drug and nondrug factors to the side-effect incidence rate in the population
studied.
TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED
CLINICAL TRIALS*
| (Percent of Patients Reporting) |
|---|
| Adverse Experience |
BuSpar
(n=477) |
Placebo
(n=464) |
|---|
| * Events reported by at least 1% of BuSpar patients
are included. |
| — Incidence less than 1%. |
| Cardiovascular |
|
|
| Tachycardia/Palpitations |
1 |
1 |
| CNS |
|
|
| Dizziness |
12 |
3 |
| Drowsiness |
10 |
9 |
| Nervousness |
5 |
1 |
| Insomnia |
3 |
3 |
| Lightheadedness |
3 |
— |
| Decreased
Concentration |
2 |
2 |
| Excitement |
2 |
— |
| Anger/Hostility |
2 |
— |
| Confusion |
2 |
— |
| Depression |
2 |
2 |
| EENT |
|
|
| Blurred
Vision |
2 |
— |
| Gastrointestinal |
|
|
| Nausea |
8 |
5 |
| Dry
Mouth |
3 |
4 |
| Abdominal/Gastric
Distress |
2 |
2 |
| Diarrhea |
2 |
— |
| Constipation |
1 |
2 |
| Vomiting |
1 |
2 |
| Musculoskeletal |
|
|
| Musculoskeletal
Aches/Pains |
1 |
— |
| Neurological |
|
|
| Numbness |
2 |
— |
| Paresthesia |
1 |
— |
| Incoordination |
1 |
— |
| Tremor |
1 |
— |
| Skin |
|
|
| Skin
Rash |
1 |
— |
| Miscellaneous |
|
|
| Headache |
6 |
3 |
| Fatigue |
4 |
4 |
| Weakness |
2 |
— |
| Sweating/Clamminess |
1 |
— |
Other Events Observed During the Entire Premarketing Evaluation of BuSpar
During its premarketing assessment, BuSpar 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
BuSpar in the dose range for which BuSpar is being recommended (ie, the modal
daily dose of BuSpar 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 BuSpar 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 BuSpar (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.
Cardiovascular
Frequent was nonspecific
chest pain; infrequent were syncope, hypotension, and hypertension; rare were
cerebrovascular accident, congestive heart failure, myocardial infarction,
cardiomyopathy, and bradycardia.
Central Nervous System
Frequent
were dream disturbances; infrequent were depersonalization, dysphoria, noise
intolerance, euphoria, akathisia, fearfulness, loss of interest, dissociative
reaction, hallucinations, involuntary movements, slowed reaction time, suicidal
ideation, and seizures; rare were feelings of claustrophobia, cold intolerance,
stupor, and slurred speech and psychosis.
EENT
Frequent were tinnitus, sore throat,
and nasal congestion; infrequent were redness and itching of the eyes, altered
taste, altered smell, and conjunctivitis; rare were inner ear abnormality,
eye pain, photophobia, and pressure on eyes.
Endocrine
Rare were galactorrhea and
thyroid abnormality.
Gastrointestinal
Infrequent were flatulence,
anorexia, increased appetite, salivation, irritable colon, and rectal bleeding;
rare was burning of the tongue.
Genitourinary
Infrequent were urinary
frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria;
rare were amenorrhea, pelvic inflammatory disease, enuresis, and nocturia.
Musculoskeletal
Infrequent
were muscle cramps, muscle spasms, rigid/stiff muscles, and arthralgias; rare
was muscle weakness.
Respiratory
Infrequent were hyperventilation,
shortness of breath, and chest congestion; rare was epistaxis.
Sexual Function
Infrequent
were decreased or increased libido; rare were delayed ejaculation and impotence.
Skin
Infrequent were edema, pruritus,
flushing, easy bruising, hair loss, dry skin, facial edema, and blisters;
rare were acne and thinning of nails.
Clinical Laboratory
Infrequent
were increases in hepatic aminotransferases (SGOT, SGPT); rare were eosinophilia,
leukopenia, and thrombocytopenia.
Miscellaneous
Infrequent were weight gain,
fever, roaring sensation in the head, weight loss, and malaise; rare were
alcohol abuse, bleeding disturbance, loss of voice, and hiccoughs.
Postmarketing Experience
Postmarketing experience has shown an adverse experience profile
similar to that given above. Voluntary reports since introduction have included
rare occurrences of allergic reactions (including urticaria), angioedema,
cogwheel rigidity, dizziness (rarely reported as vertigo), dystonic reactions
(including dystonia), ataxias, extrapyramidal symptoms, dyskinesias (acute
and tardive), ecchymosis, emotional lability, serotonin syndrome, transient
difficulty with recall, urinary retention, visual changes (including tunnel
vision), parkinsonism, akathisia, restless leg syndrome, and restlessness.
Because of the uncontrolled nature of these spontaneous reports, a causal
relationship to BuSpar treatment has not been determined.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
BuSpar (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 BuSpar 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 BuSpar 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 BuSpar misuse or abuse (eg, 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 BuSpar 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 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 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.
HOW SUPPLIED
BuSpar® (buspirone hydrochloride tablets,
USP) Tablets, 5 mg and 10 mg (white, ovoid-rectangular with score, MJ logo,
strength and the name BuSpar embossed) are available in bottles of 100.
5 mg tablets
NDC 0087-0818-41 Bottles of 100
10 mg tablets
NDC 0087-0819-41 Bottles of 100
Tablets, 15 mg white, in the DIVIDOSE® tablet
design imprinted with the MJ logo, are available in bottles of 60 and 180.
Tablets, 30 mg pink, in the DIVIDOSE® tablet design
imprinted with the MJ logo, are available in bottles of 60. The 15 mg and
30 mg tablets are scored so that they can be either bisected or trisected.
The 15 mg tablet has ID number 822 on one side and on the reverse side, the
number 5 on each trisect segment. The 30 mg tablet has ID number 824 on one
side and on the reverse side, the number 10 on each trisect segment.
15 mg tablets
NDC 0087-0822-32 Bottles of 60
NDC 0087-0822-33 Bottles
of 180
30 mg tablets
NDC 0087-0824-81 Bottles of 60
US Patent No. 5,015,646
Store at 25° C (77° F); excursions permitted between 15° C to 30°
C (59° F to 86° F) [see USP controlled room temperature]. Dispense in a tight,
light-resistant container (USP).
REFERENCE
- American Psychiatric Association, Ed.: Diagnostic and
Statistical Manual of Mental Disorders—III, American Psychiatric Association,
May 1980.
Bristol-Myers Squibb Company
Princeton,
NJ 08543 USA
1200451
Rev March 2007
BuSpar®
(buspirone
HCl, USP)
Patient Instruction Sheet
HOW TO USE:
BuSpar®
(buspirone
HCl, USP)
15 mg and 30 mg Tablets
in
convenient DIVIDOSE® tablet form
Response to buspirone varies among individuals. Your physician
may find it necessary to adjust your dosage to obtain the proper response.
This DIVIDOSE 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: |
|
If your doctor
prescribed the
15 mg
tablet: |
|
30 mg
(the entire tablet) |
|
15 mg
(the entire tablet) |
|
20 mg
(two thirds of a tablet) |
|
10 mg
(two thirds of a tablet) |
|
10 mg
(one third of a tablet) |
|
5 mg
(one third of a tablet) |
|
15 mg
(one half of a tablet) |
|
7.5 mg
(one half of a tablet) |
|
| |
# 822 on 15 mg and |
|
| |
824 on 30 mg tablet |
|
To break a DIVIDOSE 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).
Bristol-Myers Squibb Company
Princeton,
NJ 08543 USA
1200451
Rev March 2007
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Revised: 05/2007Bristol-Myers Squibb