The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs, SSRIs, and other serotonergic drugs, including buspirone, alone but particularly with concomitant use of other serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin (in particular, MAOIs, including reversible MAOIs such as linezolid and intravenous methylene blue), or with antipsychotics or other dopamine antagonists.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for emergence of serotonin syndrome.
The concomitant use of buspirone with MAOIs intended to treat depression is contraindicated. Buspirone should also not be started in a patient who is being treated with reversible MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. There have been no reports involving the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a reversible MAOI such as linezolid or intravenous methylene blue in a patient taking buspirone. Buspirone should be discontinued before initiating treatment with the reversible MAOI (see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION AND DRUG INTERACTIONS).
If concomitant use of buspirone with a 5-hydroxytryptmine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of buspirone with serotonin precursors (such as tryptophan) is not recommended.
Treatment with buspirone and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Because buspirone hydrochloride tablets have no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment.
Studies indicate that buspirone hydrochloride tablets are 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 hydrochloride tablets 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.
Because buspirone hydrochloride tablets do 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 hydrochloride tablets, 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.
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). See ADVERSE REACTIONS: Postmarketing Experience.
To assure safe and effective use of buspirone hydrochloride tablets, the following information and instructions should be given to patients:
- Do not take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
- Do not take an MAOI within 2 weeks of stopping buspirone unless directed to do so by your physician.
- Do not start buspirone if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
- 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 buspirone hydrochloride tablets.
- Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking buspirone hydrochloride tablets.
- 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 buspirone hydrochloride tablets consistently, either always with or always without food.
- During your treatment with buspirone hydrochloride tablets, avoid drinking large amounts of grapefruit juice.
There are no specific laboratory tests recommended.
The use of monoamine oxidase inhibitors (MAOIs) intended to treat depression with buspirone or within 14 days of stopping treatment with buspirone is contraindicated because of an increased risk of serotonin syndrome and/or elevated blood pressure. The use of buspirone within 14 days of stopping an MAOI intended to treat depression is also contraindicated.
Starting buspirone in a patient who is being treated with reversible MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS AND DOSAGE AND ADMINISTRATION).
After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max , AUC, and C min ) of amitriptyline or its metabolite nortriptyline were observed.
After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max , AUC, and C min ) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed.
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.
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.
Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine.
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.
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:
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 C max of buspirone 3.4-fold while diltiazem increased AUC and C max 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.
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 C max 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 (e.g., 2.5 mg b.i.d.) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.
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