Buspirone Hydrochloride 10 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Buspirone Hydrochloride 10 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: buspirone hydrochloride 10 mg. Excipient with known effect:
Each tablet contains 111.4 mg of lactose monohydrate. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
Buspirone Hydrochloride 10 mg Tablets are white, capsule shaped tablets, embossed “BR (breakline) 10” on one side, “G” on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Buspirone hydrochloride tablets are indicated for short-term treatment of general anxiety disorders and to relieve the symptoms of anxiety with or without accompanying depression.
4.2 Posology and method of administration
Posology
The dosage should be individualised for each patient.
The maximum recommended dose is 45 mg daily in divided doses.
Food increases the bioavailability of buspirone.
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 (see section 4.5).
Adults:
Initially, a dose of 5 mg two to three times daily is given. After several weeks, to allow for a lag period, this may be increased in increments of 5 mg at 2 to 3 day intervals according to the therapeutic response. After dosage titration, the usual daily dose is 15 to 30 mg per day in divided doses.
Older people:
Current data do not support a change in dosage regimen based on age or sex of the patient.
Paediatric population :
The therapeutic use of Buspirone in children has not been established. 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.
Renal impairment:
After a single administration to patients with mild to moderate renal insufficiency (creatinin clearance 20-49 ml/min/1,72m ) a slight increase in the buspirone blood levels was seen, without increase of the half-life time. In these patients buspirone hydrochloride Tablets 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 Hydrochloride Tablets 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 impairment:
As 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.
Method of administration For oral use.
Buspirone should be taken at the same time each day and consistently with or without food. Tablets should be taken with some fluid and should not be chewed.
4.3 Contraindications
Buspirone hydrochloride is contraindicated in:
• Hypersensitivity to the active substance or to any excipients listed in section 6.1.
• Severe renal (defined as creatinine clearance <20 ml/min/1.72 m or a plasma creatinine above 200 micromoles/litre) or severe hepatic insufficiency.
• Acute intoxication with alcohol, hypnotics, analgesics or antipsychotic drugs.
• Patients with epilepsy.
4.4 Special warnings and precautions for use
The administration of buspirone 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 has been added to a regimen including a MAOI. Therefore, it is recommended that buspirone not be used concomitantly with a MAOI.
Buspirone should be used with caution in patients with:
• Acute narrow-angle glaucoma.
• Myasthenia gravis.
• Drug dependence.
• History of hepatic or renal impairment.
• Alcohol use should be avoided, although buspirone has not been reported to potentiate the psychomotor impairment produced by alcohol. No data are available on concomitant use of alcohol and single doses of buspirone greater than 20 mg.
Buspirone should not be used alone to treat depression, and may potentially mask the clinical signs of depression.
Paediatric population
The long-term safety and effectiveness of buspirone have not been determined in individuals below 18 years of age. Buspirone is not recommended in children and adolescents (see section 4.2).
Potential for withdrawal reactions in sedative/hypnotic/anxiolytic drug-dependent patients
Because 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.
Drug abuse and dependence Buspirone is not a controlled substance.
Buspirone has shown no potential for drug abuse and dependence based on human and animal studies.
Cases of insomnia, anxiety, agitation, depersonalisation and paraesthesias are seen in a few patients on discontinuation of the therapy.
Long-term toxicity
Because its mechanism of action is not fully elucidated, long-term toxicity in the CNS or other organ systems cannot be predicted.
Lactose
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
The concomitant use of buspirone with other CNS-active drugs should be approached with caution.
Effect of other drugs on buspirone
Association not recommended:
MAO inhibitors:
Co-administration of MAO inhibitors may cause increases in blood pressure. Coadministration 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.
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.
In healthy volunteers no interaction with the tricyclic antidepressant amitriptyline was seen.
Protein Binding:
In vitro buspirone may displace less firmly protein-bound drugs like digoxin. The clinical significance of this property is unknown.
Cytochrome P450 3A4
Buspirone is metabolised by CYP 3A4. In vivo studies showed interactions with the strong inhibitors like Nefazodone, Erythromycin, Itraconazole and Verapamil. Dose adaptation should be considered in the case of buspirone is co-administered with strong CYP3A4 inhibitors like HIV protease inhibitors or Ketoconazole. Further dose adjustment should be based on clinical effects.
Nefazodone:
The co-administration 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). Patients using buspirone are advised to avoid drinking grapefruit juice.
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 buspirone'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.
Effect of buspirone on other drugs
Because of the high protein binding of Buspirone (around 95%) caution is advised when drugs with a high protein binding are given concomitantly. In vitro studies have shown that warfarin, phenytoin or propranolol are not displaced from plasma proteins by Buspirone.
Diazepam:
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of buspirone in pregnant women. Adverse effects have been reported only after the administration of high doses of the drug. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of buspirone during pregnancy.
The effect of buspirone on labour and delivery is unknown.
Breastfeeding
It is unknown whether buspirone or its metabolite/metabolites are excreted in human milk.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from buspirone therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
4.7 Effects on Ability to Drive and Use Machines
Preclinical and clinical studies did not show an adverse influence on responsiveness. However, it can not be excluded that Buspirone may influence responsiveness to such an extent that driving a vehicle or operating machines will be impaired. This applies especially at start of therapy and at change of dosage.
4.8 Undesirable effects
Undesirable effects most frequently reported include dizziness, headache, lightheadedness, nausea, nervousness, excitement, sweating and clamminess. Side effects, if they occur, are generally observed at the beginning of treatment and usually subside or disappear as treatment progresses and/or with dose lowering.
Clinical experience
When patients receiving buspirone were compared with patients receiving placebo, dizziness, headache, nervousness, lightheadedness, 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 to <1/10), rare (> 1/10,000 to < 1/1,000) and very rare (<1/10,000).
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, excitement. |
|
very rare |
psychotic disorder, hallucination, depersonalization, affect lability. | |
|
Nervous System disorders |
very common |
dizziness*, headache, somnolence, drowsiness, |
|
common |
Paraesthesia/numbness, coordination abnormal, coordination disturbances, tremor. | |
|
very rare |
serotonin syndrome, convulsion, extrapyramidal disorder, cogwheel rigidity, dyskinesia, dystonia, syncope, amnesia, ataxias, Parkinsonism, akathisia, restless leg syndrome, restlessness | |
|
Eye disorders |
common |
blurred vision. |
|
very rare |
tunnel vision. | |
|
Ear and labyrinth disorders |
common |
tinnitus. |
|
Cardiac disorders |
common |
tachycardia, chest pain, palpitations |
|
Respiratory, thoracic and mediastinal disorders |
common |
nasal congestion, nasal stuffiness, throat pain, 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, pruritus, alopecia | |
|
Musculoskeletal and connective tissue disorders |
common |
musculoskeletal pain |
|
Renal and urinary disorders |
very rare |
urinary retention |
|
ADVERSE DRUG EVENTS REPORTED DURING CLINICAL EXPERIENCE | ||
|
System Organ Class |
Frequency |
MedDRA Terms |
|
Reproductive system and breast disorders |
very rare |
galactorrhoea |
|
General disorders and administration site conditions |
common |
fatigue/weakness |
* Dizziness includes lightheadedness.
Reporting of suspected adverse reactions
Reporting 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).
4.9 Overdose
Symptoms
In normal volunteers, the maximum tolerated dose of buspirone was 375 mg/day. As the maximum dose levels were approached, the most commonly observed symptoms were nausea, vomiting, headache, dizziness, drowsiness, tinnitus, restlessness, miosis, and gastric distress. Mild bradycardia and hypotension have been reported. Extrapyramidal symptoms have been reported after therapeutic doses. Rarely convulsions may occur.
Management
Treatment should be symptomatic and supportive. The ingestion of multiple agents should be suspected. The benefit of gastric decontamination is uncertain. Consider activated charcoal if the patient presents within 1 hour of ingestion of more than 5mg/kg provided they are not too drowsy. No specific antidote exists. Buspirone hydrochloride is not removed by haemodialysis . The stomach should be emptied as quickly as possible.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anxiolytics, azaspirodecanedione derivatives, ATC code: NO5B E01
Buspirone is a member of the azapirone class of drugs. It has anxiolytic activity, but is largely lacking in sedative and muscle relaxant effects and anticonvulsant activity.
Its mechanism of action has yet to be fully explained. Evidence to date suggests that its activity is based on its effects on serotonin (5-HT) receptors. It acts as an agonist
of pre-synaptic and partial agonist of post-synaptic 5-HT1A subtype receptors. It is thought this initiates long-term changes in central 5-HT neurotransmission, producing the efficacy seen in the treatment of anxiety. Buspirone is thought to have antagonist activity at D2 receptors at the doses stipulated for anxious disorders, though it is unclear if this is linked to its anxiolytic activity.
Buspirone’s effects on GABAergic mechanisms are unclear. It does not directly interact with either the benzodiazepine-GABA receptor complex or GABA receptors. However, there is indirect evidence for Buspirone having a GABA antagonist-like action.
The onset of action can take 1-3 weeks and the full effect beyond 4 weeks has not been demonstrated.
There has been no evidence of pharmacodependence in studies performed in animals and on humans.
5.2 Pharmacokinetic properties
Absorption
Buspirone Hydrochloride is rapidly absorbed from the gastrointestinal tract and undergoes extensive pre-systematic metabolism (bioavailability 4%). Peak plasma levels are noted at approximately 60 minutes after oral administration range 30-150 minutes. Plasma concentration is related linearly to the dose given. Concomitant administration of food slows absorption slightly. Whilst this decreases pre-systematic metabolism, it is not deemed clinically significant.
Distribution
Equilibrium of plasma levels is reached after 3-5 days of repeated dosing, with around 95% bound to plasma proteins.
At steady state, the following doses of buspirone in children aged 6-12 years resulted in increases in Cmax (maximum concentration) and AUC (area under the curve), compared with adults, as shown in the table:
Dosage_Cmax_AUC
7.5 mg b.i.d 2.9 - fold 1.8 - fold
15 mg b.i.d 2.1 - fold 1.5 - fold
Across the dose range studied, the Cmax and AUC of 1-PP (the active metabolite of buspirone, 1-pyrimidinylpiperazine) in children were approximately double those of adults.
Biotransformation
Buspirone hydrochloride is extensively metabolised in the liver by cytochrome P450 3A4 to two main metabolites: 1-(2-pyrimidinyl)-piperazine and 5-hydroxyBuspirone. 1-(2-pyrimidinyl)-piperazine is pharmacologically active with approximately 20% of the potency of Buspirone, though it is unclear if it has any effect on buspirones overall anxiolytic action. The latter is present as both free and glucoroconjugated forms.
Elimination
The apparent plasma half-life for the elimination of Buspirone is 2 to 3 hours, range
1.5 - 7 hours with the elimination of the metabolites: 1-(2-pyrimidinyl)-piperazine and 5-hydroxyBuspirone and its glucuronide taking a little longer.
Elimination occurs mainly as metabolites and takes place largely in the first 24 hours following administration.
5.3 Preclinical safety data
Toxicity studies in several animal species have shown little evidence of undesirable effects, with toxic effects occurring only at levels well in excess of those recommended for clinical use.
No adverse effects have been described when buspirone hydrochloride has been tested in vitro and in vivo for carcinogenicity, mutagenicity and teratogenicity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Cellulose, microcrystalline Sodium starch glycolate Type A Silica, colloidal anhydrous Magnesium stearate
6.2. Incompatibilities
Not applicable.
6.3. Shelf life
36 months.
6.4. Special Precautions for Storage
Do not store above 25°C.
6.5. Nature and Contents of Container
HDPE tablet containers fitted with polypropylene caps and optional styrene wad in packs of 5, 7, 10, 15, 20, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 250 or 500 tablets.
PVC (250 pm) aluminium blister strips placed in cardboard cartons.
PVC/PVdC (285 pm) aluminium blister strips placed in cardboard cartons.
Blister strips will be available in packs of 20, 28, 30, 50, 56, 84, 90, 100, 112, 120, 168, or 180 tablets.
6.6 Special precautions for disposal and other handling
Not Applicable.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0369
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/02/2006
10 DATE OF REVISION OF THE TEXT
24/03/2015