Buspirone is rapidly absorbed in man and undergoes extensive
first pass metabolism. Following oral administration, low peak
plasma levels of unchanged drug, of 1 to 6 ng/mL were observed
40 to 90 minutes after a single 20 mg dose. In a number of studies
performed in healthy volunteers, the mean half-life of buspirone
ranged from 2 to 3 hours up to approximately 11 hours with considerable
variation in individual values. Multiple dose studies suggest
that steady state plasma levels were usually achieved within a
few days. Buspirone is metabolized primarily by oxidation, producing
several hydroxylated derivatives and a pharmacologically active
metabolite, 1-pyrimidinylpiperazine (1-PP). Peak plasma levels
of 1-PP have been found to be higher than those of its parent
drug and its half-life to be approximately double that of unchanged
buspirone. In a single dose study using (14)C labeled buspirone,
29 to 63% of the dose was excreted in the urine within 24 hours,
primarily as metabolites, while fecal excretion accounted for
18 to 38% of the dose. 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.
The effect of food upon the bioavailability of buspirone was
studied in 8 subjects. The area under the plasma concentration
curve (AUC) and peak plasma concentration (C(max)) of unchanged
buspirone increased by 84% and 116% respectively when the drug
was administered with food, but the total amount of buspirone
immunoreactive material did not change. The significance of this
finding is not known, but it could indicate that food may decrease
the presystemic clearance of buspirone.
Buspirone had no effect on hepatic microsomal enzyme activity
when administered to rats for 5 days. In man, the effect of buspirone
on drug metabolism or concomitant drug disposition has not been
studied. The pharmacokinetics of buspirone in patients with hepatic
or renal dysfunction, and in the elderly, has also not been clearly
established.
--------------------------------------------------------------------------------
Indications
Short-term symptomatic relief of excessive anxiety in patients
with generalized anxiety disorder (psychoneurotic disorder).
Eight 3-way short-term, controlled clinical trials involving
buspirone, diazepam and placebo are considered central to the
evaluation of buspirone as an anxiolytic agent. In 4 of the 8
clinical trials, buspirone demonstrated a significant difference
from placebo. In the other 4 trials, there was no significant
difference between buspirone and placebo, but a significantly
greater improvement was observed in 2 of these trials with diazepam
than with placebo. The adverse effect profiles of buspirone and
diazepam in these clinical trials were, however, different.
--------------------------------------------------------------------------------
Contraindications
In patients hypersensitive to buspirone HCl.
Buspirone is contraindicated in patients with severe hepatic
or severe renal impairment.
--------------------------------------------------------------------------------
Warnings
The occurrence of elevated blood pressure in patients receiving
both buspirone and a MAO inhibitor has been reported. Therefore,
it is recommended that buspirone should not be used concomitantly
with a MAO inhibitor.
Since buspirone can bind to central dopaminergic receptors, the
possibility of acute and chronic changes in dopamine mediated
neurological function (e.g. dystonia, pseudo-parkinsonism, akathisia
and tardive dyskinesia) should be considered (see Precautions).
Since the effects of buspirone have not been evaluated in patients
with a history of convulsive disorders and since it lacks anticonvulsant
activity in animals, buspirone is not recommended for patients
with seizure disorders.
Use of Buspirone in Patients Previously Treated with a Benzodiazepine:
Patients who have previously taken benzodiazepines may be less
likely to respond to buspirone than those who have not. In 2 clinical
studies to date, substitution of buspirone did not ameliorate
or prevent withdrawal symptoms in either abrupt or gradual withdrawal
from various benzodiazepines following long-term use. Therefore,
if it is considered desirable to switch a patient who has been
receiving benzodiazepine therapy to buspirone, the benzodiazepine
should first be withdrawn gradually. A drug-free interval is desirable
between withdrawal of the benzodiazepine and initiation of buspirone,
in order to increase the likelihood of distinguishing between
benzodiazepine withdrawal effects and unrelieved anxiety due to
possible failure of buspirone in this category of patients.
Benzodiazepine 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. These symptoms may appear
as any combination of irritability, anxiety, agitation, insomnia,
tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like
symptoms without fever and, occasionally, seizures, and should
be treated symptomatically.
Pregnancy and Lactation:
The safety of buspirone during pregnancy and lactation has not
been established and, therefore, it should not be used in women
of childbearing potential or nursing mothers, unless, in the opinion
of the physician, the potential benefits to the patient outweigh
the possible hazards to the fetus. Buspirone and its metabolites
are excreted in milk in rats. The extent of excretion in human
milk has not yet been determined.
--------------------------------------------------------------------------------
Precautions
Effects on Cognitive and Motor Performance:
In controlled studies in healthy volunteers, single doses of buspirone
up to 20 mg had little effect on most tests of cognitive and psychomotor
function, although performance on a vigilance task was impaired
in a dose-related manner. The effect of higher single doses of
buspirone on psychomotor performance has not been investigated.
Ten mg of buspirone given 3 times daily for 7 days to healthy
volunteers produced considerable subjective sedation but no significant
effect on psychomotor performance (no vigilance tasks were used
in this study). It also caused transient dizziness, especially
on standing and walking.
Occupational Hazards:
Until further experience is obtained with buspirone, patients
should be warned not to operate an automobile or undertake activities
requiring mental alertness, judgment and physical coordination,
until they are reasonably certain that buspirone does not affect
them adversely.
Significant Interactions:
In laboratory studies in healthy volunteers, buspirone in doses
up to 20 mg did not potentiate the psychomotor impairment produced
by relatively modest doses of alcohol. However, decreased contentedness
or dysphoria was observed with a combination of alcohol and a
20 mg single dose of buspirone. Since no data are available on
concomitant use of higher doses of buspirone and alcohol, it is
prudent to advise patients to avoid alcohol during buspirone therapy.
Food increased the bioavailability of unchanged buspirone in
healthy subjects, possibly due to a reduced first-pass effect.
Concomitant use of MAO inhibitors and buspirone has been reported
to cause an increase in blood pressure. Therefore, concomitant
use of these medications is not recommended.
In a study in normal volunteers, no interaction of buspirone
with amitriptyline was seen. A similar study with buspirone and
diazepam showed an increase in the levels of nordiazepam.
In another 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.
There is 1 report suggesting that the concomitant use of trazodone
and buspirone may have caused 3- to 6-fold elevations in ALT (SGPT)
in a few patients. In a similar study, attempting to replicate
this finding, no interactive effect on hepatic transaminases was
identified.
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.
In vitro, buspirone does not displace tightly bound drugs like
phenytoin, propranolol and warfarin from serum proteins. However,
there has been 1 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.
There have been no reports to date of interference of buspirone
with commonly employed clinical laboratory tests.
Drug Abuse and Dependence:
Although preliminary animal and human investigations suggest that
buspirone may be significantly devoid of potential for producing
physical or psychological dependence, only extensive clinical
experience with the drug will provide conclusive evidence. Meanwhile,
physicians should carefully evaluate patients for a history of
drug abuse and follow such patients closely, observing them for
signs of buspirone misuse and abuse.
Patients with Impaired Hepatic or Renal Function:
Since it is metabolized by the liver and excreted by the kidneys,
buspirone should be used with caution in patients with a history
of hepatic or renal impairment. It is contraindicated in patients
with severe hepatic or renal impairment.
Children:
The safety and effectiveness of buspirone in individuals below
the age of 18 years have not been established.
Geriatrics:
Buspirone has not been systematically evaluated in older patients.
Although it would appear from limited pharmacokinetic and clinical
studies that buspirone does not behave differently in the elderly,
there is little known about the effects of buspirone in this age
group at doses above 30 mg/day. Therefore, it is recommended that
buspirone should be used in the elderly at doses not exceeding
30 mg/day for a duration not exceeding 4 weeks.
Neuroendocrine Effects:
Single doses of 30 mg or higher of buspirone resulted in significantly
elevated plasma prolactin and growth hormone concentrations in
normal volunteers. No effect was seen at lower doses. In another
study, no such increases were observed after buspirone was administered
in divided doses (10 mg t.i.d.) for 28 days.
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,
pseudoparkinsonism, 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.
--------------------------------------------------------------------------------
Adverse Effects
The most common adverse reactions encountered with buspirone are
dizziness, headache, drowsiness and nausea. During premarketing
clinical trials, approximately 10% of the patients discontinued
treatment due to an adverse event.
Adverse reactions reported include the following:
CNS:
Dizziness, headache, drowsiness, lightheadedness, insomnia, fatigue,
nervousness, decreased concentration, excitement, depression,
confusion, nightmares/vivid dreams, anger/hostility. Infrequently
(<1%) depersonalization, noise intolerance, euphoria/feeling
high, dissociative reaction, fear, loss of interest, dysphoria,
hallucinations, seizures, suicidal thoughts. Rarely, slurred speech,
claustrophobia, cold intolerance, stupor, psychosis.
Neurologic:
Paresthesia, weakness, incoordination, tremor, numbness. Infrequently,
muscle cramps and spasms, rigid/stiff muscles, involuntary movements,
akathisia, slowed reaction time. Rarely, tingling of limbs, stiff
neck, rigidity of jaw, ataxia.
Autonomic:
Dry mouth, sweating/clamminess, blurred vision, constipation.
Infrequently, urinary frequency, retention and burning, flushing.
Cardiovascular:
Tachycardia, chest pain, palpitations. Infrequently, syncope,
hypotension, hypertension. Rarely, congestive heart failure, cerebrovascular
accident, myocardial infarction, cardiomyopathy, bradycardia,
EKG change.
Gastrointestinal:
Nausea, gastrointestinal distress, diarrhea, vomiting. Infrequently,
flatulence, increased appetite, anorexia, hypersalivation, rectal
bleeding, irritable colon. Rarely, burning tongue.
Respiratory:
Nasal congestion. Infrequently, shortness of breath, chest congestion,
difficulty breathing, hyperventilation. Rarely, epistaxis.
Endocrine:
Infrequently, decreased and increased libido, weight gain, weight
loss, menstrual irregularity/breakthrough bleeding. Rarely, delayed
ejaculation, impotence, galactorrhea, amenorrhea, thyroid abnormality.
Allergic or Toxic:
Skin rash, sore throat. Infrequently, edema/facial edema, pruritus,
chills/fever. Rarely, photophobia, erythema, flu-like symptoms.
Clinical Laboratory:
Infrequently, increases in liver enzymes. Rarely, eosinophilia,
leukopenia, thrombocytopenia.
Miscellaneous:
Tinnitus, muscle aches/pains. Infrequently, redness/itching of
eyes, altered taste/smell, roaring sensation in head, malaise,
easy bruising, dry skin, arthralgia, blisters, hair loss. Rarely,
acne, thinning of nails, sore eyes, inner ear abnormality, pressure
on eyes, nocturia, enuresis, hiccups, voice loss, alcohol abuse.
Post Introduction Clinical Experience:
Post-marketing experience in the US has shown an adverse experience
profile similar to that given above. Additional reports have included
rare occurrences of allergic reaction, cogwheel rigidity, dystonic
reaction, ecchymosis, emotional lability and tunnel vision. Because
of the uncontrolled nature of these spontaneous reports, a causal
relationship to buspirone treatment has not been determined.
--------------------------------------------------------------------------------
Overdose
Symptoms:
In clinical pharmacology trials, buspirone up to 400 mg/day was
administered to healthy male volunteers. As this dose was approached,
the following symptoms were observed in descending order of frequency:
drowsiness, ataxia, nausea and vomiting, dizziness, clammy feeling,
difficulty thinking, feeling high, rushing sensation, gastric
distress, headache, itching, miosis, hypotension, tremor, incoordination,
insomnia and hallucinations. In a dose ranging study in acute
psychotic patients, up to 2400 mg/day was administered. Dizziness,
nausea and vomiting were the most common adverse effects. One
patient developed extrapyramidal symptoms at 600 mg/day.
Treatment:
There is no specific antidote for buspirone. Management should,
therefore, be symptomatic and supportive. Any patient suspected
of having taken an overdose should be admitted to a hospital as
soon as possible, and the stomach emptied by gastric lavage. Respiration,
pulse and blood pressure should be monitored, as in all cases
of drug overdosage. As with the management of intentional overdosage
with any drug, the ingestion of multiple agents should be suspected.
In 6 anuric patients, hemodialysis either had no effect on the
pharmacokinetics of buspirone or decreased its clearance.
--------------------------------------------------------------------------------
Dosage
Dosage should be individually adjusted, according to tolerance
and response.
The recommended initial dose is 5 mg 2 to 3 times daily. This
may be titrated according to the needs of the patient and the
daily dose increased by 5 mg increments every 2 to 3 days up to
a maximum of 45 mg daily in divided doses. The usual therapeutic
dose is 20 to 30 mg daily in 2 or 3 divided doses.
Geriatrics:
Limited pharmacokinetic and clinical data have shown no difference
in the effects of buspirone between elderly patients and healthy
adult volunteers. However, until more information has accumulated
in the elderly, it is recommended that the maximum daily dose
should not exceed 30 mg for a duration not exceeding 4 weeks.
Note:
If buspirone is administered to patients with compromised hepatic
or renal function, careful monitoring will be required together
with appropriate dosage adjustment.
--------------------------------------------------------------------------------
Supplied
Each white, biconvex, rectangular pillow shaped tablet with BUSPAR
raised on one side and BL logo, bisect score and 10 on the other
side contains: Buspirone HCl 10 mg. Bottles of 100. |
