BUSPIRONE
DESCRIPTION:
BUSCALM (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:
ACTIONS/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.
BUSCALM is rapidly absorbed in man and undergoes extensive first-pass metabolism.
In a radiolabeled study, unchanged buspirone in the plasma accounted for only
about 1% of the radioactivity in the plasma. Following oral administration,
plasma concentrations of unchanged buspirone are very low and variable between
subjects. Peak plasma levels of 1 to 6 ng/mL have been observed 40 to 90 minutes
after single oral doses of 20 mg. The single-dose bioavailability of unchanged
buspirone when taken as a tablet is on the average about 90% of an equivalent
dose of solution, but there is large variability.
The effects of food upon the bioavailability of BUSCALM 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, but the
clinical significance of these findings is unknown.
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.
In man, approximately 95% of buspirone is plasma protein bound, but other highly
bound drugs, e.g., phenytoin, propranolol, and warfarin are not displaced by
buspirone from plasma protein In Vitro. However, In Vitro binding studies show
that buspirone does displace digoxin.
Buspirone is metabolized primarily by oxidation producing several hydroxylated
derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine
(1-PP). 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 BUSCALM do not exhibit high levels of 1-PP; mean
values are approximately 3ng/mL and the highest human blood level recorded among
108 chronically dosed patients was 17ng/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 to 40 mg is about 2 to 3 hours.
The pharmacokinetics of BUSCALM in patients with hepatic or renal dysfunction has
not been determined, nor has the effect of age. The effect of BUSCALM on drug
metabolism or concomitant drug disposition has not been investigated.
INDICATIONS AND USAGE:
BUSCALM 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 BUSCALM 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 BUSCALM 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 (REF. 1) 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 BUSCALM (buspirone hydrochloride, 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 BUSCALM for 1 year without ill effect. Therefore,
the physician who elects to use BUSCALM for extended periods should periodically
reassess the usefulness of the drug for the individual patient.
CONTRAINDICATIONS:
BUSCALM is contraindicated in patients hypersensitive to buspirone hydrochloride.
WARNINGS:
THE ADMINISTRATION OF BUSCALM 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 BUSCALM has been added to a regimen including an MAOI.
Therefore, it is recommended that BUSCALM not be used concomitantly with an MAOI.
Because BUSCALM 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 BUSCALM 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 BUSCALM 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 BUSCALM 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 BUSCALM, 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). Obviously, the question cannot
be totally resolved at this point in time. Generally, long-term sequelae of any
drug's use can be identified only after several years of marketing.
INFORMATION FOR PATIENTS
To assure safe and effective use of BUSCALM, the following information and
instructions should be given to patients:
1. Inform your physician about any medications, prescription or nonprescription,
alcohol, or drugs that you are now taking or plan to take during your treatment
with BUSCALM.
2. Inform your physician if you are pregnant, or if you are planning to become
pregnant, or if you become pregnant while you are taking BUSCALM.
3. Inform your physician if you are breast- feeding an infant.
4. Until you experience how this medication affects you, do not drive a car or
operate potentially dangerous machinery.
LABORATORY TESTS
There are no specific laboratory tests recommended.
DRUG INTERACTIONS
It is recommended that BUSCALM (buspirone hydrochloride, USP) Not be used
concomitantly with MAO inhibitors (See "WARNINGS"). Because the effects of
concomitant administration of BUSCALM with most other psychotropic drugs have not
been studied, the concomitant use of BUSCALM with other CNS-active drugs should
be approached with caution.
There is one report suggesting that the concomitant use of Desyrel(R) (trazodone
hydrochloride) and BUSCALM 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.
In a study in normal volunteers, concomitant administration of BUSCALM and
haloperidol resulted in increased serum haloperidol concentrations. The clinical
significance of this finding is not clear.
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.
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 BUSCALM 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.
BUSCALM administration to nursing women should be avoided if clinically possible.
PEDIATRIC USE
The safety and effectiveness of BUSCALM have not been determined in individuals
below 18 years of age.
USE IN THE ELDERLY
BUSCALM has not been systematically evaluated in older patients; however, several
hundred elderly patients have participated in clinical studies with BUSCALM and
no unusual adverse age-related phenomena have been identified. In 87 elderly
patients for whom dosage data were available, the modal total daily dose of
BUSCALM was 15 mg per day, the same as that in the total sample of patients
treated with BUSCALM.
USE IN PATIENTS WITH IMPAIRED HEPATIC OR RENAL FUNCTION
Since BUSCALM is metabolized by the liver and excreted by the kidneys, its
administration to patients with severe hepatic or renal impairment cannot be
recommended.
DRUG INTERACTIONS:
It is recommended that BUSCALM (buspirone hydrochloride, USP) not be used
concomitantly with MAO inhibitors (See "WARNINGS"). Because the effects of
concomitant administration of BUSCALM with most other psychotropic drugs have not
been studied, the concomitant use of BUSCALM with other CNS-active drugs should
be approached with caution.
There is one report suggesting that the concomitant use of Desyrel(R) (trazodone
hydrochloride) and BUSCALM 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.
In a study in normal volunteers, concomitant administration of BUSCALM and
haloperidol resulted in increased serum haloperidol concentrations. The clinical
significance of this finding is not clear.
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.
(See Also PRECAUTIONS).
ADVERSE REACTIONS:
COMMONLY OBSERVED
The more commonly observed untoward events associated with the use of BUSCALM 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
BUSCALM 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 BUSCALM 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 BUSCALM patients who participated in 4-week, controlled trials
comparing BUSCALM 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)
BUSCALM PLACEBO
ADVERSE EXPERIENCE (N=477) (N=464)
Cardiovascular
Tachycardia/Palpitations 1 1
CNS
Dizziness 12 3
Drowsiness 10 9
Nervousness 5 1
Insomnia 3 3
Lightheadedness 3 --
Decreased Concentration 2 2
Excitement 2 --
Anger/Hostility 2 --
Confusion 2 --
Depression 2 2
EENT
Blurred Vision 2 --
Gastrointestinal
Nausea 8 5
Dry Mouth 3 4
Abdominal/Gastric Distress 2 2
Diarrhea 2 --
Constipation 1 2
Vomiting 1 2
Musculoskeletal
Musculoskeletal Aches/Pains 1 --
Neurological
Numbness 2 --
Paresthesia 1 --
Incoordination 1 --
Tremor 1 --
Skin
Skin Rash 1 --
Miscellaneous
Headache 6 3
Fatigue 4 4
Weakness 2 --
Sweating/Clamminess 1 --
* Events reported by at least 1% of BUSCALM (buspirone hydrochloride, USP)
patients are included.
-- Incidence less than 1%.
OTHER EVENTS OBSERVED DURING THE ENTIRE PREMARKETING EVALUATION OF BUSCALM
During its premarketing assessment, BUSCALM 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 BUSCALM in
the dose range for which BUSCALM is being recommended (i.e., the modal daily dose
of BUSCALM fell between 10 and 30 mg for 70% of the patients studied) and for
whom safety data were systematically collected. The conditions and duration of
exposure to BUSCALM 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 BUSCALM 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.
POSTINTRODUCTION CLINICAL EXPERIENCE
Postmarketing experience has shown an adverse experience profile similar to that
given above. Voluntary reports since introduction have included rare occurrences
of allergic reactions (including urticaria), angioedema, cogwheel rigidity,
dizziness (rarely reported as vertigo), dystonic reactions, ataxias,
extrapyramidal symptoms, dyskinesias (acute and tardive), ecchymosis, emotional
lability, serotonin syndrome, transient difficulty with recall, urinary
retention, and visual changes (including tunnel vision). Because of the
uncontrolled nature of these spontaneous reports, a causal relationship to
BUSCALM (buspirone hydrochloride, USP) treatment has not been determined.
DRUG ABUSE AND DEPENDENCE:
CONTROLLED SUBSTANCE CLASS
BUSCALM 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 BUSCALM 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 BUSCALM 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 BUSCALM
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
BUSCALM alone. Rare cases of intentional overdosage with a fatal outcome were
invariably associated with ingestion of multiple drugs and/or alcohol, and a
casual relationship 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 to
30 mg per day were commonly employed.
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