- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe dosage should be individualised for each patient.Adults (including the elderly): the usual starting dosage is 5mg given two to three times per day. The dosage may be increased every 2-3 days. The usual therapeutic dosage is 15 to 30mg daily in divided doses. The maximum recommended dose should not exceed 60mg per dayFood increases the bioavailability of buspirone. Buspirone should be taken at the same time each day and consistently with or without food. If buspirone is administered with a potent CYP3A4 inhibitor, the initial dose should be lowered and only increased gradually after medical evaluation (see section 4.5).Grapefruit juice increases the plasma concentrations of buspirone. Patients taking buspirone should avoid consuming large quantities of grapefruit juice.
Renal impairmentAfter a single administration to patients with mild to moderate renal insufficiency (creatinin clearance 20-49 ml/min/1.72 m2) a slight increase in the buspirone blood levels was seen, without increase of the half-life time. In these patients buspirone should be administered with caution and a low dosage, two-times daily, is advised. The response and the symptoms of the patients should be evaluated carefully, before an eventual increase of the dosage is made. A single administration to anuretic patients causes an increase in the blood levels of the metabolite 1-pyrimidine/piperazine (1-PP), in which dialysis did not prove to have any influence on the buspirone levels, neither on the 1-PP levels. Buspirone should not be administered to patients with a creatinin clearance < 20 ml/min/1.72 m2), especially not to anuretic patients, because of the fact that increased and untreated levels of buspirone and its metabolites may occur.
Hepatic impairmentAs may be expected agents as buspirone used in patients with a reduced liver function show a reduced first pass effect. After a single administration to patients with liver cirrhosis, higher maximum concentrations of unchanged buspirone are seen, with an increase in the half life time. In these patients buspirone should be used with caution and individual dosages should be titrated with care to reduce the chance of central undesirable effects, which may occur because of high maximum concentrations of buspirone. Increased dosages should be considered carefully and only after 4-5 days experience with the prior dosage.
Elderly PatientsCurrent data do not support a change in dosage regimen based on age or sex of the patient
Paediatric population:Placebo-controlled trials, in which 334 patients were treated with buspirone for up to six weeks, have not shown buspirone at doses recommended for adults to be an effective treatment for generalised anxiety disorder in patients less than 18 years.Plasma concentrations of buspirone and its active metabolite were higher in paediatric patients, compared to adults given equivalent doses. (see 5.2, Pharmacokinetic Properties.)
Method of AdministrationFor oral administration
Drug abuse and dependenceBuspirone is not a controlled substance.Buspirone has shown no potential for drug abuse and dependence based on human and animal studies.
Potential for withdrawal reactions in sedative/hypnotic/anxiolytic drug-dependent patientsBecause buspirone 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, it is advisable to withdraw these drugs gradually, especially in patients who have been using a CNS-depressant drug chronically.
Long-term toxicityBecause its mechanism of action is not fully elucidated, long-term toxicity in the CNS or other organ systems cannot be predicted.
Association not recommended:MAO inhibitors: Co-administration of MAO inhibitors may cause increases in blood pressure. Co-administration of MAO inhibitors and buspirone is therefore not recommended (see section 4.4).Erythromycin: Concomitant administration of buspirone (10 mg as single dose) and erythromycin (1.5 g once daily for four days) in healthy volunteers increased the plasma concentrations of buspirone (Cmax increased 5-fold and AUC 6-fold). If buspirone and erythromycin are to be used in combination, a low dose of buspirone (e.g., 2.5 mg twice daily) is recommended. Subsequent dose adjustments of either drug should be based on clinical response.Itraconazole: Concomitant administration of buspirone (10 mg as single dose) and itraconazole (200 mg once daily for four days) in healthy volunteers increased the plasma concentrations of buspirone (Cmax increased 13-fold and AUC 19-fold). If buspirone and itraconazole are to be used in combination, a low dose of buspirone (e.g., 2.5 mg once daily) is recommended. Subsequent dose adjustments of either drug should be based on clinical response.
Association with precautions of use:Diltiazem: Concomitant administration of buspirone (10 mg as single dose) and diltiazem (60 mg three times daily) in healthy volunteers increased the plasma concentrations of buspirone (Cmax increased 5.3-fold and AUC 4-fold). 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: Concomitant administration of buspirone (10 mg as single dose) and verapamil (80 mg three times daily) in healthy volunteers increased the plasma concentrations of buspirone (Cmax and AUC increased 3.4-fold). Enhanced effects and increased toxicity of buspirone may be possible when buspirone is administered with verapamil. Subsequent dose adjustments of either drug should be based on clinical response.Rifampicin: Rifampicin induces the metabolism of buspirone via CYP3A4. Therefore, concomitant administration of buspirone (30 mg as single dose) and rifampicin (600 mg once daily for 5 days) in healthy volunteers decreased the plasma concentrations (Cmax decreased 84 % and AUC decreased 90 %) and the pharmacodynamic effect of buspirone.• Antidepressants - the occurrence of elevated blood pressure in patients receiving buspirone and monoamine oxidase inhibitors (phenelzine and tranylcypromine) has been reported. Buspirone should not be used concomitantly with a MAOI. In healthy volunteers no interaction with the tricyclic antidepressant amitriptyline was seen.• Baclofen, lofexidine, nabilone, antihistamines may enhance any sedative effect.
Association to be taken into account:SSRI: The combination of buspirone and selective serotonin reuptake inhibitors (SSRI) was tested in a number of clinical trials on more than 300,000 patients. Although no severe toxicities were observed, there were rare cases of seizures in patients that took SSRI and buspirone concomitantly.Separate cases of seizures in patients administered combination therapy with buspirone and SSRIs have been reported from regular clinical use.Buspirone should be used with caution in combination with serotonergic drugs (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, lithium and St. John's Wort) as there are isolated reports of serotonin syndrome occurring in patients on concomitant SSRI therapy. If this condition is suspected, treatment with buspirone should be immediately discontinued and supportive symptomatic treatment should be initiated.Protein Binding: In vitro buspirone may displace less firmly protein-bound drugs like digoxin. The clinical significance of this property is unknown.Nefazodone: The coadministration of buspirone (2.5 or 5 mg twice daily) and nefazodone (250 mg twice daily) 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 5-mg twice daily doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and mCPP (9%). Slight increases in Cmax were observed for nefazodone (8%) and its metabolite HO-NEF (11%).The side effect profile for subjects receiving buspirone 2.5 mg twice daily and nefazodone 250 mg twice daily was similar to that for subjects receiving either drug alone. Subjects receiving buspirone 5 mg twice daily and nefazodone 250 mg twice daily experienced side effects such as lightheadedness, asthenia, dizziness, and somnolence. It is recommended that the dose of buspirone be lowered when administered with nefazodone. Subsequent dose adjustments of either drug should be based on clinical response.Grapefruit juice: Concomitant administration of buspirone 10 mg and grapefruit juice (double strength 200 ml for 2 days) in healthy volunteers increased the plasma concentrations of buspirone (Cmax increased 4.3-fold and AUC 9.2-fold).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, e.g. phenobarbital, phenytoin, carbamazepine, St. John's wort, an adjustment of the dosage of buspirone may be necessary to maintain busprione's anxiolytic effect.Fluvoxamine: In short-term treatment with fluvoxamine and buspirone doubled buspirone plasma concentrations are observed compared to mono-therapy with buspirone.Trazodone: Concomitant administration of trazodone showed a 3-6 fold increase of ALT in some patients.Cimetidine: The concomitant use of buspirone and cimetidine has shown a slight increase in the 1-(2-pyrimidinyl)-piperazine metabolite of Buspirone. Because of the high protein binding of Buspirone (around 95%) caution is advised when drugs with a high protein binding are given concomitantly.Baclofen, lofexidine, nabilone, antihistamines may enhance any sedative effect.In vitro studies have shown that buspirone does not displace warfarin, digoxin, phenytoin, or propranolol from plasma proteins.Effect of buspirone on other drugsDiazepam: After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed.Haloperidol: Concomitant administration of haloperidol and buspirone can increase haloperidol serum levels.Digoxin: In humans, approximately 95% of buspirone is plasma protein bound. In vitro, buspirone does not displace tightly bound drugs (ie warfarin) from serum proteins. However, in vitro, buspirone may displace less firmly protein-bound drugs like digoxin. The clinical significance of this property is unknown.There are reports on increases in the prothrombin time after the addition of buspirone to a treatment regimen containing warfarin.
Clinical experienceWhen patients receiving buspirone were compared with patients receiving placebo, dizziness, headache, nervousness, lightheaded-ness, nausea, excitement, and sweating/clamminess were the only side effects occurring with significantly greater frequency (p <0.10) in the buspirone group than in the placebo group.The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), and very rare (<1/10000).
|ADVERSE DRUG EVENTS REPORTED DURING CLINICAL EXPERIENCE|
|System Organ Class||Frequency||MedDRA Terms|
|Psychiatric Disorders||common||nervousness, insomnia, disturbance in attention, depression, confusional state, sleep disorder, anger|
|very rare||psychotic disorder, hallucination, depersonalization, affect lability|
|Nervous System Disorders||very common||dizziness*, headache, somnolence|
|common||paraesthesia, vision blurred, coordination abnormal, tremor, tinnitus|
|very rare||serotonin syndrome, convulsion, tunnel vision, extrapyramidal disorder, cogwheel rigidity, dyskinesia, dystonia, syncope, amnesia, ataxias, Parkinsonism, akathisia, restless leg syndrome, restlessness|
|Cardiac Disorders||common||tachycardia, chest pain|
|Respiratory, Thoracic and Mediastinal Disorders||common||nasal congestion, pharyngolaryngeal pain|
|Gastrointestinal Disorders||common||nausea, abdominal pain, dry mouth, diarrhoea, constipation, vomiting|
|Skin and Subcutaneous Tissue Disorders||common||cold sweat, rash|
|rare||angioneurotic oedema, ecchymosis, urticaria|
|Musculoskeletal and Connective Tissue Disorders||common||musculoskeletal pain|
|Renal and Urinary Disorders||very rare||urinary retention|
|Reproductive System and Breast Disorders||very rare||galactorrhoea|
|General Disorders and Administration Site Conditions||common||fatigue|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard
|7.5mg b.i.d||2.9 - fold||1.8 - fold|
|15mg b.i.d||2.1 - fold||1.5 - fold|
Actavis UK Ltd
Actavis UK Ltd, a subsidiary of Accord Healthcare Ltd, Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
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