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BUSPIRONE HYDROCHLORIDE 5 MG TABLETS

Active substance(s): BUSPIRONE HYDROCHLORIDE / BUSPIRONE HYDROCHLORIDE / BUSPIRONE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Buspirone hydrochloride 5 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg Buspirone (as hydrochloride).
Excipients with known effect:
Each 5mg tablets contains 75.840 mg lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White ovoid rectangular uncoated tablet with score line one side and plain on
other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Buspirone is indicated for the treatment of short-term management of anxiety
disorders and the relief of symptoms of anxiety with or without accompanying
symptoms of depression.

4.2

Posology and method of administration
Posology
The dosage should be individualised for each patient.
Adults (including older people): 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 30 mg daily in divided doses. The maximum
recommended dose is 45mg daily in divided doses.

Food 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.
Patients with Renal impairment
After 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.
Patients with 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.
Pediatric 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 section
5.2).
Method of administration
For oral administration

4.3

Contraindications
Buspirone is contraindicated in the following groups of patients.
• Hypersensitivity to the active substance or to any of the excipients
listed in section 6.1
• patients with epilepsy.
• acute intoxication with alcohol, hypnotics, analgesics, or antipsychotic
drugs.
• patients with severe renal or hepatic impairment. Severe renal
impairment can be defined as a creatinine clearance of 20ml/min or
below, or a plasma creatinine above 200µmol/l.

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 care in the following situations.
• acute narrow-angle glaucoma
• myasthenia gravis
• drug dependence
• patients with rare hereditary problems of galactose intolerance, the
lapp lactase deficiency or glucose – galactose malabsorption should not
take this medicine.
• patients with a history of renal or hepatic 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 20mg.
• buspirone does not exhibit cross-tolerance with benzodiazepines and
other common sedative/hypnotic agents. It will not block the
withdrawal syndrome often seen with cessation of therapy with these
agents. Patients should be gradually withdrawn from these agents
before initiating buspirone treatment.
Buspirone should not be used alone to treat depression, and may potentially
mask the clinical signs of depression.
Paediatric use
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).

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.
Potential for withdrawal reactions in sedative/hypnotic/anxiolytic drugdependent 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.
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
Buspirone tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the lapp lactase deficiency, or glucose-galactose
malabsorption should not take Buspirone tablets
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. 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, 1pyrimidinylpiperazine. 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 monotherapy 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 drugs

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
In some studies, administration of high doses of buspirone to pregnant animals
produced effects on survival, birth and weaning weights, although there was no
effect on foetal development. Since the relevance of this finding in humans has
not been established, buspirone is contraindicated in pregnancy and in lactation.

4.7

Effects on ability to drive and use machines
Buspirone has moderate influence on the ability to drive and use machines.
Attention is drawn to the risks associated with drowsiness or dizziness induced
by this drug (see section 4.8).

4.8

Undesirable effects
Side effects of buspirone, if they occur, are generally observed at the
beginning of drug therapy and usually subside with use of the medication
and/or decreased dosage.
Clinical experience
When 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 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and
not known (cannot be estimated from the available data).
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

Cardiac Disorders

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

common

tachycardia, chest pain

Respiratory, Thoracic and common
Mediastinal Disorders

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

common

fatigue

Administration Site
Conditions
* 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 at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose
Features:
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 include 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.
There is no specific antidote to buspirone. Buspirone is not removed by
haemodialysis. The stomach should be emptied as quickly as possible.
Treatment should be symptomatic and supportive. The ingestion of multiple
agents should be suspected.
Management:
Treatment should by symptomatic and supportive. 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Azaspirodecanedione derivatives, ATC code:
N05B E01
Buspirone is an azaspirodecanedione. The exact mechanism of Buspirone
anxioselective action is not fully known. It does not act on benzodiazepine
receptor sites and lacks sedative, anticonvulsant and muscle relaxant properties.
From animal studies it is known to interact with serotonin, noradrenaline
(norepinephrine), acetylcholine and dopamine systems of the brain. Buspirone
enhances the activity of specific noradrenergic and dopaminergic pathways,

whereas the activity of serotonin and acetylcholine are reduced.
5.2

Pharmacokinetic properties
Absorption: Buspirone hydrochloride is rapidly absorbed from the
gastrointestinal tract reaching peak plasma concentrations within 40 to 90
minutes after administration by mouth. Systemic bioavailability is low because
of extensive first-pass metabolism.
Distribution: Buspirone is about 95% bound to plasma proteins.
Metabolism: Metabolism in the liver is extensive via the cytochrome P450
isoenzyme CYP3A4. The elimination half-life of buspirone is usually about 2
to 4 hours but half-lives of up to 11 hours have been reported.
Elimination: Buspirone is excreted mainly as metabolites in the urine, and also
the faeces.
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
7.5 mg b.i.d
15 mg b.i.d

Cmax
2.9 – fold
2.1 – fold

AUC
1.8 – 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 in adults.
5.3

Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are
additional to that already included in other sections of the SPC

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Microcrystalline cellulose (Aavicel-PH-101)
Sodium starch glycolate
Microcrystalline cellulose (Aavicel-PH-200)
Colloidal silicon dioxide
Magnesium stearate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
The product is supplied in blister packs of white opaque PVC film and plain
aluminium blister foil.
Blister pack sizes: 20, 30, 40, 50, 60, 90 and 100 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Strides Arcolab International Ltd.
Unit 4, Metro Centre,
Tolpits Lane, Watford,
Hertfordshire WD 189SS
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 28176/0153

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/01/2015

10

DATE OF REVISION OF THE TEXT
30/01/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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