Baclofen 5mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Baclofen 5mg/5ml Oral Solution.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: Each 5ml contains 5mg baclofen.
Excipients: Sodium methyl parahydroxybenzoate (E219)
Sodium propyl parahydroxybenzoate (E217)
Liquid maltitol (E965)
For full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Oral solution.
A clear, almost colourless solution with a raspberry odour.
4 Clinical particulars
4.1 Therapeutic indications
For the relief of spasticity of voluntary muscle resulting from such disorders as: multiple sclerosis, other spinal lesions, e.g. tumours of the spinal cord, syringomyelia, motor neurone disease, transverse myelitis, traumatic partial section of the cord.
Also for the relief of spasticity of voluntary muscle arising from e.g. cerebrovascular accidents, cerebral palsy, meningitis, traumatic head injury.
Patient selection is important when initiating therapy; it is likely to be of most benefit in patients whose spasticity constitutes a handicap to activities and/or physiotherapy. Treatment should not be commenced until the spastic state has become stabilised.
Paediatric population :
Baclofen is indicated in patients 0 to <18 years for the symptomatic treatment of spasticity of cerebral origin, especially where due to infantile cerebral palsy, as well as following cerebrovascular accidents or in the presence of neoplastic or degenerative brain disease.
Baclofen is also indicated for the symptomatic treatment of muscle spasms occurring in spinal cord diseases of infectious, degenerative, traumatic, neoplastic, or unknown origin such as multiple sclerosis, spastic spinal paralysis, amyotrophic lateral sclerosis, syringomyelia, tranverse myelitis, traumatic paraplegia or paraparesis, and compression of the spinal cord.
4.2 Posology and method of administration
Before starting treatment with Baclofen 5mg/5ml Oral Solution it is prudent to realistically assess the overall extent of clinical improvement that the patient may be expected to achieve. Careful titration of dosage is essential (particularly in the elderly) until the patient is stabilised. If too high a dose is initiated or if the dosage is increased too rapidly side effects may occur. This is particularly relevant if the patient is ambulant in order to minimise muscle weakness in the unaffected limbs or where spasticity is necessary for support.
Adults
The following gradually increasing dosage regimen is suggested, but should be adjusted to suit individual patient requirements.
One 5ml spoonful (5mg) three times a day for three days
Two 5ml spoonfuls (10mg) three times a day for three days
Three 5ml spoonfuls (15mg) three times a day for three days
Four 5ml spoonfuls (20mg) three times a day for three days
Satisfactory control of symptoms is usually obtained with doses of up to 60mg daily, but a careful adjustment is often necessary to meet the requirements of each individual patient.
The dose may be increased slowly if required, but a maximum daily dose of more than 100mg is not advised unless the patient is in hospital under careful medical supervision. Small frequent dosage may prove better in some cases than larger spaced doses.
Also some patients benefit from the use of baclofen only at night to counteract painful flexor spasm. Similarly, a single dose given approximately one hour prior to performance of specific tasks such as washing, dressing, shaving, physiotherapy will often improve mobility.
Once the maximum recommended dose has been reached, if the therapeutic effect is not apparent within six weeks a decision whether to continue with baclofen should be taken.
Elderly
Elderly patients may be more susceptible to side effects, particularly in the early stages of introducing baclofen. Small doses should therefore be used at the start of treatment, the dose being titrated gradually against the response, under careful supervision. There is no evidence that the eventual average maximum dose differs from that in younger patients.
Paediatric population (0 to <18 years)
Treatment should usually be started with a very low dose (corresponding to approximately 0.3 mg/kg/day), in 2-4 divided doses (preferably in 4 divided doses).
The dosage should be raised cautiously, at about 1 week intervals, until it becomes sufficient for the child’s individual requirements. The usual daily dosage for maintenance therapy ranges between 0.75 and 2 mg/kg body weight. The total daily dose should not exceed a maximum of 40 mg/day in children below 8 years of age. In children over 8 years of age a maximum daily dose of 60 mg/day may be given.
Patients with impaired renal function
In patients with impaired renal function or undergoing chronic haemodialysis, a particularly low dosage of baclofen should be selected i.e. approximately 5mg daily. Signs of overdose have been observed in patients with renal impairment taking oral baclofen at doses more than 5mg per day.
Patients with spastic states of cerebral origin
Unwanted effects are more likely to occur in these patients. It is therefore recommended that a very cautious dosage schedule be adopted and that patients be kept under appropriate surveillance.
4.3 Contraindications
Hypersensitivity to baclofen or to any of the excipients, peptic ulceration.
4.4 Special warnings and precautions for use
Psychotic disorders, schizophrenia, depressive or manic disorders, confusional states or Parkinson’s disease may be exacerbated by treatment with baclofen. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.
Baclofen may also exacerbate epileptic manifestations but can be employed provided appropriate supervision and adequate anticonvulsive therapy are maintained. It should be used with extreme care in patients already receiving antihypertensive therapy, (see Section 4.5 Interactions).
Should be used with caution in patients suffering from diabetes, porphyria, cerebrovascular accidents, from respiratory, hepatic or renal impairment or with a history of peptic ulceration.
Should be used with caution in the elderly.
Signs of overdose have been observed in patients with renal impairment taking more than 5mg baclofen per day.
Under treatment with baclofen neurogenic disturbances affecting emptying of the bladder may show an improvement. In patients with pre-existing sphincter hypertonia, acute retention of urine may occur; the drug should be used with caution in such cases.
This medicine contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate. Parahydroxybenzoates may cause allergic reactions (possibly delayed allergic reactions). It also contains maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
There is very limited clinical data on the use of Baclofen in children under the age of one year. Use in this patient population should be based on the physician’s consideration of individual benefit and risk therapy.
Abrupt Withdrawal:
Anxiety and confusional states, hallucinations, psychotic, manic or paranoid states, convulsions (status epilepticus), dyskinesia, tachycardia, hyperthermia and as rebound phenomenon temporary aggravation of spasticity have been reported with abrupt withdrawal of baclofen, especially after long term medication. Treatment should always, (unless serious adverse effects occur), therefore be gradually discontinued by successively reducing the dosage over a period of about 1-2 weeks.
Since in rare instances elevated AST, alkaline phosphatase and glucose levels in serum have been recorded, appropriate laboratory tests should be performed in patients with liver diseases or diabetes mellitus in order to ensure that no drug induced changes in these underlying diseases have occurred.
4.5 Interaction with other medicinal products and other forms of interaction
Where baclofen is taken concomitantly with other drugs acting on the CNS, with synthetic opiates or with alcohol, increased sedation may occur.
The risk of respiratory depression is also increased. Careful monitoring of respiratory and cardiovascular functions is essential especially in patients with cardiopulmonary disease and respiratory muscle weakness.
During concurrent treatment with tricyclic antidepressants, the effect of baclofen may be potentiated, resulting in pronounced muscular hypotonia.
Baclofen possibly aggravates hyperkinesis caused by lithium and the effect of baclofen is enhanced by lithium.
Since concomitant treatment with baclofen and anti-hypertensives is likely to increase the fall in blood pressure, the dosage of antihypertensive medication should be adjusted accordingly. Hypotension has been reported in one patient receiving morphine and intrathecal baclofen.
Enhanced hypotensive effect when baclofen given with nitrates and diuretics.
The effects of baclofen are possibly modified by memantine.
Excretion of baclofen is possibly reduced by Ibuprofen and other NSAIDs (increased risk of toxicity).
In patients with Parkinson’s disease receiving treatment with baclofen and levodopa plus carbidopa, there have been reports of mental confusion, hallucinations, nausea and agitation.
4.6 Pregnancy and lactation
During pregnancy, especially in the first three months, baclofen should only be employed if its use is of vital necessity. The benefits of the treatment for the mother must be carefully weighed against the possible risks for the child. Baclofen crosses the placental barrier.
In mothers taking baclofen in therapeutic doses, the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.
4.7 Effects on ability to drive and use machines
Baclofen may be associated with dizziness, sedation, somnolence and visual disturbances (see section 4.8 Undesirable effects) which may impair the patient’s reaction. Patients experiencing these adverse reactions should be advised to refrain from driving or using machines.
4.8 Undesirable effects
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
Unwanted effects occur mainly at the start of treatment (e.g. sedation, somnolence and nausea) if the dosage is raised too rapidly, if large doses are employed, or in elderly patients. They are often transitory and can be attenuated or eliminated by reducing the dosage; they are seldom severe enough to necessitate withdrawal of the medication.
Should nausea persist following a reduction in dosage, it is recommended that Baclofen 5mg/5ml Oral Solution be ingested with food or a milk beverage.
In patients with a case history of psychiatric illness or with cerebrovascular disorders (e.g. stroke) as well as in elderly patients, adverse reactions may assume a more serious form.
Lowering of the convulsion threshold and convulsions may occur, particularly in epileptic patients.
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Psychiatric disorders | |
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Common: |
Hallucinations, agitation, anxiety, confusional state, insomnia, euphoria, depression, nightmares |
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Nervous system disorders | |
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Very common: |
Sedation, somnolence. |
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Common: |
Convulsions, light-headedness, lassitude, exhaustion, dizziness, headache, ataxia, tremor, nystagmus, dry mouth. |
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Rare: |
Paraesthesia, dysarthria, dysgeusia. |
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Eye disorders | |
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Common: |
Accommodation disorders, visual disturbances. |
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Cardiac disorders | |
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Common: |
Cardiac output decreased. |
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Vascular disorders | |
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Common: |
Hypotension. |
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Respiratory, thoracic and mediastinal disorders | |
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Common: |
Respiratory depression |
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Gastrointestinal disorders | |
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Very common: |
Nausea. |
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Common: |
Gastro-intestinal disturbance, retching, vomiting, constipation, diarrhoea. |
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Rare: |
Abdominal pain. |
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Hepatobiliary disorders | |
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Rare: |
Hepatic function abnormal. |
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Skin and subcutaneous tissue disorders | |
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Common: |
Angioedema, pruritis, urticaria, rash, hyperhidrosis, |
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Musculoskeletal, connective tissue and bone disorders | |
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Common: |
Muscular weakness, myalgia, muscular hypotonia |
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Renal and urinary disorders | |
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Common: |
Polyuria, enuresis, dysuria. |
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Rare: |
Urinary retention. |
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Reproductive system and breast disorders | |
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Rare: |
Erectile dysfunction. |
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General disorders and administration site conditions | |
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Common: |
Fever |
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Very rare: |
Hypothermia |
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Investigations | |
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Rare: |
Blood sugar changes |
Certain patients have shown increased spasticity as a paradoxical reaction to the medication.
An undesirable degree of muscular hypotonia - making it more difficult for patients to walk or fend for themselves - may occur and can usually be relieved by re-adjusting the dosage (i.e. by reducing the doses given during the day and possibly increasing the evening dose).
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
Symptoms
Prominent features are signs of central nervous depression: drowsiness, impairment of consciousness, respiratory depression, coma. Also liable to occur are: confusion, hallucinations, agitation, accommodation disorders, absent pupillary reflex; generalised muscular hypotonia, myoclonia, hyporeflexia or areflexia; convulsions; peripheral vasodilatation, hypotension, bradycardia; hypothermia; nausea, vomiting, diarrhoea, hypersalivation; elevated LDH, AST and ALP values.
Patients with renal impairment can develop signs of overdose even on low doses of baclofen (see Section 4.2 Posology and method of administration and
4.4 Special warnings and special precautions for use.)
A deterioration in the condition may occur if various substances or drugs acting on the central nervous system (e.g. alcohol, diazepam, tricyclic antidepressants) have been taken at the same time.
Treatment
No specific antidote is known.
Supportive measures and symptomatic treatment should be given for complications such as hypotension, hypertension, convulsions, respiratory or cardiovascular depression.
After ingestion of a potentially toxic amount, activated charcoal should be considered. In the early period after ingestion charcoal should be considered in adults who ingested more than 100mg baclofen within 1 hour, and in children who have ingested more than 5mg/kg baclofen within 1 hour. Gastric decontamination (e.g. gastric lavage) should be considered in individual cases, especially in the early period (60 minutes) after ingestion of a potentially life-threatening overdose. Comatose or convulsing patients should be intubated prior to the initiation of gastric decontamination.
Since the drug is excreted chiefly via the kidneys, generous quantities of fluid should be given, possibly together with a diuretic. In the event of convulsions diazepam should be administered cautiously i.v.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Muscle relaxants, other centrally acting agents, ATC code: M03BX01
Baclofen is an antispastic agent acting at the spinal level. A gamma-aminobutyric acid (GABA) derivative, baclofen is chemically unrelated to other antispastic agents.
Baclofen depresses monosynaptic and polysynaptic reflex transmission, probably by stimulating the GABAb receptors, this stimulation in turn inhibiting the release of the excitatory amino acids glutamate and aspartate. Neuromuscular transmission is unaffected by baclofen.
The major benefits of baclofen stem from its ability to reduce painful flexor spasms and spontaneous clonus thereby facilitating the mobility of the patient, increasing his independence and helping rehabilitation.
Baclofen also exerts an antinociceptive effect. General well being is often improved and sedation is less often a problem than with centrally acting drugs.
Baclofen stimulates gastric acid secretion.
5.2 Pharmacokinetic properties
Absorption
Baclofen is rapidly and completely absorbed from the gastro-intestinal tract. No significant difference between the liquid and tablet formulations is observed in respect of tmax, cmax and bioavailability. Following oral administration of single doses (10-30mg) peak plasma concentrations are recorded after 0.5 to 1.5 hours and areas under the serum concentration curves are proportional to the dose.
Distribution
The volume of distribution of baclofen is 0.7 l/kg and the protein binding rate is approximately 30%. In cerebrospinal fluid active substance concentrations are approximately 8.5 times lower than in the plasma.
Biotransformation
Baclofen is metabolised to only a minor extent. Deamination yields the main metabolite, P-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive.
Elimination/excretion
The plasma elimination half-life of baclofen averages 3 to 4 hours. The serum protein binding rate is approximately 30%.
Baclofen is eliminated largely in unchanged form. Within 72 hours, about 75% of the dose is excreted via the kidneys with about 5% of this amount as metabolites.
Elderly
The pharmacokinetics of baclofen in elderly patients are virtually the same as in young subjects. The peak plasma concentrations of baclofen in elderly patients are slightly lower and occur later than in healthy young subjects but the AUCs are similar in the two groups.
5.3 Preclinical safety data
Baclofen increases the incidence of omphaloceles (ventral hernias) in the foetuses of rats given approximately 13 times the maximum oral dose (on a mg/kg basis) recommended for human use. This was not seen in mice or rabbits.
An apparently dose related increase in the incidence of ovarian cysts, and a less marked increase in enlarged and/or haemorrhagic adrenals have been observed in female rats treated for 2 years. The clinical relevance of these findings is not known.
Experimental evidence to date suggests that baclofen does not possess either carcinogenic or mutagenic properties.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium methyl parahydroxybenzoate (E219)
Sodium propyl parahydroxybenzoate (E217)
Raspberry flavour (contains nature identical flavouring substances, propylene glycol and maltol)
Carmellose sodium Liquid maltitol (E965)
Citric acid monohydrate Sodium citrate dihydrate Purified water.
6.2 Incompatibilities
None known
6.3 Shelf life
Unopened: Three years.
Opened: One month
6.4 Special precautions for storage
Store in the original container. Do not store above 25°C. Do not refrigerate or freeze.
6.5 Nature and contents of container
Amber glass bottle and tamper evident HDPE child resistant closure with EPE saranex faced liner.
Pack size 300 ml.
6.6 Special precautions for disposal
There is no specific instruction for use/handling.
7 MARKETING AUTHORISATION HOLDER
Dalkeith Laboratories Limited
2 Park Street
Woburn
Bedfordshire
MK17 9PG
8 MARKETING AUTHORISATION NUMBER(S)
PL 17496/0024
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/08/2010
10 DATE OF REVISION OF THE TEXT
13/07/2015