Special Populations

General

Information for Patients

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

1. 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.
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 BuSpar.
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.
5. You should take BuSpar (buspirone hydrochloride) consistently, either always with or always without food.
6. During your treatment with BuSpar, avoid drinking large amounts of grapefruit juice.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Drug/Laboratory Test Interactions

Buspirone hydrochloride may interfere with the urinary metanephrine/catecholamine assay. It has been mistakenly read as metanephrine during routine assay testing for pheochromocytoma, resulting in a false positive laboratory result. Buspirone hydrochloride should therefore be discontinued for at least 48 hours prior to undergoing a urine collection for catecholamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed in rats during a 24-month study at approximately 133 times the maximum recommended human oral dose; or in mice, during an 18-month study at approximately 167 times the maximum recommended human oral dose.

With or without metabolic activation, buspirone did not induce point mutations in five strains of Salmonella typhimurium (Ames Test) or mouse lymphoma L5178YTK+ cell cultures, nor was DNA damage observed with buspirone in Wi-38 human cells. Chromosomal aberrations or abnormalities did not occur in bone marrow cells of mice given one or five daily doses of buspirone.

Pregnancy: Teratogenic Effects

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).

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.

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.

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).

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.