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Logo BUSPAR 10 mg TABLETS

SCHEDULING STATUS
S5

PROPRIETARY NAME
(and dosage form)

BUSPAR 10 mg TABLETS

COMPOSITION
Tablets containing 10 mg
buspirone hydrochloride.

PHARMACOLOGICAL CLASSIFICATION
A 2.6.5 Tranquillizers, miscellaneous structures.

PHARMACOLOGICAL ACTION
BUSPAR, buspirone hydrochloride (an azapirone) is an anxiolytic agent. It is not chemically or pharmacologically related to the benzodiazepines and in animal studies it does not appear to interact directly with either the benzodiazepine or GABA receptors. In vitro pre-clinical studies have shown that buspirone has a high affinity for sertonin (5-HT
1A) receptors. However, in man, details of its mechanism of anxiolytic action remain to be elucidated.
In humans, BUSPAR is rapidly absorbed, reaching peak plasma levels 60 to 90 minutes after dosing. The mean plasma concentration of buspirone hydrochloride appears to be linearly related to the administered dose.
Administration of BUSPAR with food results in higher blood levels of unchanged buspirone, but the clinical significance of this finding is unknown. BUSPAR is approximately 95% bound by human plasma proteins. In pharmacokinetic studies mean plasma half-lives have varied from 2 to 11 hours.
BUSPAR is excreted primarily as metabolites of buspirone hydrochloride in the urine. Buspar is metabolised primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). Several hydroxylated derivatives of BUSPAR are produced along with 1-pyrimidinyl piperazine, which is pharmacologically active. The latter is approximately 20% as active as BUSPAR in animal models, predictive of anxiolytic activity in humans.
Buspirone clearance is reduced in patients with hepatic impairment as well as in patients with impaired renal function.

INDICATIONS
BUSPAR is indicated for the management of anxiety disorders with or without accompanying depression.

CONTRA-INDICATIONS
1. Patients hypersensitive to buspirone hydrochloride.
2. Pregnancy and during lactation.
3. Severe renal impairment.
4. Severe hepatic disease.
5. Patients with a history of seizure disorders.
6. Concomitant use with nefazodone (see Interactions)
7. Concomitant use with MAOIs, or within 14 days of discontinuing MAOI therapy.

WARNINGS
Buspar may lower convulsion threshold. Reports have described the occurrence of elevated blood pressure in patients receiving both Buspar and Monoamine Oxidase Inhibitors (phenelzine sulphate or tranylcypromine sulphate).

DOSAGE AND DIRECTIONS FOR USE
The usual starting dose is 5 mg given three times daily. This may be increased by 5 mg increments every two or three days, depending upon the therapeutic response, to a maximum daily dose of 60 mg. The usual effective daily dose is 20 to 30 mg in divided doses (see Precautions and Interactions).
In view of buspirone's low propensity to sedate and induce muscle relaxation, patients may not immediately notice the effects of the medication. Furthermore, clinical experience has also indicated that a few weeks treatment may be required before the full anxiolytic action is evident. Safety and efficacy of this medicine for prolonged use (more than six months) has not been established.
Grapefruit juice increases the plasma concentrations of buspirone. Patients taking BUSPAR should avoid consuming large quantities of grapefruit juice.
The usefulness of this medicine for the individual patient should be periodically reassessed.
Safety and effectiveness of BUSPAR in children below the age of 18 years has not been established.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects of BUSPAR are generally observed at the beginning of drug therapy and may subside with use of the medication and/or decreased dosage.
When patients receiving BUSPARwere compared with patients receiving placebo, headache, nervousness, light-headedness, nausea, excitement
, dizziness and sweating/clamminess were the only side-effects that occurred with significantly greater frequency in the Buspar group than in the placebo group.
Other side-effects reported include insomnia, dry mouth, blurred vision, tachycardia/palpitations, chest pain, decreased concentration/abnormal thinking, depression, confusion, dream disturbances, anger/hostility, nasal congestion, sore throat, tinnitus, abdominal distress, diarrhoea, constipation, vomiting, musculoskeletal aches, paresthesia/numbness, inco-ordination, tremor, fatigue/weakness, drowsiness, galactorrhoea, syncope, tunnel vision, urinary retention and female galactorrhoea . Hypersensitivity reactions including skin rash, pruritis, urticaria, ecchymosis and angioedema may occur.
BUSPAR should be used cautiously in patients with moderate hepatic or renal disease, with dosage adjustments.
BUSPAR has a low incidence of sedation. 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. Extrapyramidal symptoms, including dyskinesias (acute and delayed), dystonic reactions and cogwheel rigidity, depersonalisation, emotional lability, hallucinations, psychosis, ataxias , seizures, transient difficulty with recall and serotonin syndrome have occurred. It is prudent to avoid concomitant use of alcohol and buspirone.

INTERACTIONS:
CNS Depressants
: Caution should be exercised in patients receiving Central Nervous System depressants including barbiturates. There is an additive risk of central nervous system depression when these medicines are taken together.
Benzodiazepines: Concomitant use of BUSPAR with diazepam resulted in elevation of blood nordiazepam (desmethyldiazepam) levels and with haloperidol in elevated haloperidol levels. Caution should be exercised if BUSPAR is considered for concomitant use with those benzodiazepines metabolized to nordiazepam (eg. diazepam, prazepam, chlordiazepoxide, clorazepate) and with haloperidol or other butyrophenones.
Because BUSPAR does not exhibit cross-tolerance with benzodiazepines and other sedative/hypnotic medicines, it will not block possible withdrawal symptoms seen with cessation of therapy with these medicines. Therefore, before starting therapy with BUSPAR, it is advisable to withdraw patients gradually, especially patients who have been using a Central Nervous System depressant medicine chronically, from their prior treatment. Rebound or withdrawal symptoms may occur over varying time periods, depending in part on the type of medicine, and its effective half-life of elimination. In patients in whom a benzodiazepine washout period is not feasible, gradual benzodiazepine taper/withdrawal may be overlapped by buspirone therapy over a few weeks in anxious patients requiring continued therapy.
Potential Interaction with Drugs that Inhibit Cytochrome P450 3A4 (CYP3A4):
Buspirone has been shown in vitro to be metabolised by CYP3A4. This is consistent with the interaction observed between buspirone and erythromycin, itraconazole and nefazodone and drugs that inhibit this isozyme. Consequently if BUSPAR is to be used in combination with a potent inhibitor of CYP3A4, a low dose of buspirone (eg 2,5 mg b.d.) is recommended. Subsequently dose adjustments of either drug should be based on clinical response.
Nefazodone: The co-administration of buspirone (2,5 mg or 5 mg b.d) and nefazodone (250 mg b.d) to healthy volunteers resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of buspirone metabolite, 1-pyrimidinylpiperazine. With 5mg b.d. doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%).
Other SSRIs: Seizures have been reported rarely in patients taking buspirone and SSRIs. Minimal experience with the combination of buspirone and SSRI antidepressants have shown no major safety problems.
Erythromycin: The co-administration of buspirone (10 mg as a single dose) and erythromycin (1,5 g/day for 4 days) to healthy volunteers increased plasma buspirone concentrations (5-fold increase in Cmax and a 6-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increase in adverse events attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg 2,5 mg b.d) is recommended. Subsequent dose adjustments of either drug should be based on clinical response.
Diltiazem: Enhanced effects and increased toxicity of buspirone may be possible when buspirone is administered with diltiazem. Subsequent dose adjustments of either drug should be based on clinical response.
Verapamil: Enhanced effects and increased toxicity of buspirone may be possible when buspirone is administered with verapamil.. Sunsequent dose adjustments of either drug should be based on clinical response
Rifampicin: Coadministration of BUSPAR with rifampicin decreases the plasma concentrations and pharmacodynamic effects of buspirone
Grapefruit Juice:
Co-administration of BUSPAR (10mg as a single dose) with double-strength grapefruit juice (200 mL t.d.s. for 2 days) increased plasma buspirone concentrations (4,3-fold increase in Cmax and 9,2-fold increase in AUC). Patients receiving buspirone should avoid consuming large amounts of grapefruit juice. (see Dosage and Directions for Use).
Other inhibitors and Inducers of CYP3A4:
When administered with a potent inhibitor of CYP3A4, a low dose of buspirone, used cautiously, is recommended. When used in combination with a potent inducer of CYP3A4, an adjustment of the dosage of buspirone may be necessary to maintain buspirone’s anxiolytic affect.
Itraconazole: The co-administration of buspirone (10 mg as a single dose) and itraconazole (200 mg/day for 4 days) to healthy volunteers increased plasma buspirone concentrations (13-fold increase in Cmax and 19-fold increase in AUC). These pharmacokinetic interactions were accompanied by an increased incidence of adverse events attributable to buspirone. If the two drugs are to be used in combination, a low dose of buspirone (eg 2,5 mg b.d) is recommended. Subsequent dose adjustments of either drug should be based on clinical response.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The following were most commonly observed with overdosage: nausea, vomiting, dizziness, central nervous system depression, drowsiness, miosis and gastric distress.
Treatment:
General symptomatic and supportive measures should be administered along with immediate gastric lavage. BUSPAR is not removed by haemodialysis; the metabolite 1-PP is partially removed by haemodialysis There is no specific antidote known for BUSPAR.

IDENTIFICATION
BUSPAR 10 mg: White, biconvex rectangular pillowshape tablet with bisect and "10" impressed on one side of the tablet.

PRESENTATION
Plastic securitainers containing 60 Buspar 10 mg tablets

STORAGE INSTRUCTIONS
Store in a cool place under 25°C. Protect from light.
Keep tightly closed.
Keep out of the reach of children.

REGISTRATION NUMBERS
Buspar 10 mg tablets : R/2.6.5/183

NAME AND BUSINESS ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd*
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
April 2003

Updated on this site: June 2005
Source: Pharmaceutical Industry

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