Buspirone Hydrochloride (000551)

CATEGORIES:

FDA DRUG CLASS: Antianxiety

BRAND NAMES: Ansial (Spain); Ansiced ^*; Ansitec (Brazil); Anxinil (Taiwan); Anxiolan (Thailand); Barpil (Thailand); Bespar (Germany, Greece); Biron (New-Zealand); Busirone (Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic-of-Yemen, Saudi-Arabia, Syria, United-Arab-Emirates); Buspar (US); Buspirone (Greece); Kallmiren (Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic-of-Yemen, Saudi-Arabia, Syria, United-Arab-Emirates); Narol (Spain); Nerbet (Chile); Neurosine (Mexico); Normaton (Colombia, Guatemala, Honduras); Paxon (Chile); Relac (Taiwan); Sburol (Korea); Tutran (Colombia);
(International brand names outside U.S. in italics)
^* Indicates foreign drugs without region specification at time of publication.

COST OF THERAPY: $ 245.73 (Anxiety; Tablet; 5 mg; 3/day; 120 days)


DESCRIPTION:

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_1A) 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.

Buspirone HCl 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 buspirone HCl 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_max) 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 buspirone HCl 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 to 40 mg is about 2 to 3 hours.

The pharmacokinetics of buspirone HCl in patients with hepatic or renal dysfunction has not been determined, nor has the effect of age. The effect of buspirone HCl on drug metabolism or concomitant drug disposition has not been investigated.

INDICATIONS AND USAGE:

Buspirone HCl 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 buspirone HCl 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 HCl 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 one 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 HCl 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 HCl for 1 year without ill effect. Therefore, the physician who elects to use buspirone HCl for extended periods should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS:

Buspirone HCl is contraindicated in patients hypersensitive to buspirone hydrochloride.

WARNINGS:

The administration of buspirone HCl to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard. There have been reports of the occurrence of elevated blood pressure when buspirone HCl has been added to a regimen including an MAOI. Therefore, it is recommended that buspirone HCl not be used concomitantly with an MAOI.

Because buspirone HCl 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 HCl 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 HCl 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 HCl 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 buspirone HCl, 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.

To assure safe and effective use of buspirone HCl, the following information and instructions should be given to patients:

Laboratory Tests

There are no specific laboratory tests recommended.

Buspirone is not known to interfere with commonly employed clinical laboratory tests.

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.

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.

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.

The effect of buspirone HCl on labor and delivery in women is unknown. No adverse effects were noted in reproduction studies in rats.

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 HCl administration to nursing women should be avoided if clinically possible.

The safety and effectiveness of buspirone HCl have not been determined in individuals below 18 years of age.

Buspirone HCl has not been systematically evaluated in older patients; however, several hundred elderly patients have participated in clinical studies with buspirone HCl 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 buspirone HCl was 15 mg per day, the same as that in the total sample of patients treated with buspirone HCl.

Since buspirone HCl 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 buspirone hydrochloride not be used concomitantly with MAO inhibitors (See WARNINGS.) Because the effects of concomitant administration of buspirone HCl with most other psychotropic drugs have not been studied, the concomitant use of buspirone HCl with other CNS-active drugs should be approached with caution.

There is one report suggesting that the concomitant use of trazodone hydrochloride (Desyrel) and buspirone HCl 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 buspirone HCl 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 levothyroxine sodium. In vitro, buspirone may displace less firmly bound drugs like digoxin. The clinical significance of this property is unknown.

ADVERSE REACTIONS:

(See also PRECAUTIONS)

The more commonly observed untoward events associated with the use of buspirone HCl not seen at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, lightheadedness, and excitement.

One guide to the relative clinical importance of adverse events associated with buspirone HCl 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 HCl 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.

The table that follows (TABLE 1) enumerates adverse events that occurred at a frequency of 1% or more among buspirone HCl patients who participated in 4-week, controlled trials comparing buspirone HCl 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.

TABLE 1 Treatment-Emergent Adverse Experience Incidence In Placebo-Controlled Clinical Studies*
(Percent of Patients Reporting)

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, 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.
Neurological: Infrequent: were involuntary movements and slowed reaction time; 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.



Post-Introduction 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, cogwheel rigidity, dystonic reactions, ecchymosis, emotional lability, tunnel vision, and urinary retention. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone HCl treatment has not been determined.

DRUG ABUSE AND DEPENDENCE:

Controlled Substance Class: Buspirone HCl is not a controlled substance.

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 HCl 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 HCl 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 buspirone HCl misuse or abuse (eg, development of tolerance, incrementation of dose, drug-seeking behavior).

OVERDOSAGE: