This information is intended for use by health professionals

1. Name of the medicinal product

Lyflex 5mg/5ml Oral Solution

Baclofen 5mg/5ml Sugar Free Oral Solution

2. Qualitative and quantitative composition

Each 5ml of oral solution contains 5mg baclofen.

Excipient(s) with known effect

Each 5 ml of this medicine contains 3.2 g sorbitol, liquid (non-crystallising), 6.8 mg methyl hydroxybenzoate, 0.57 mg propyl hydroxybenzoate and 3.8 mg sodium.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Oral solution

Clear yellowish liquid with an odour and flavour of raspberry

4. Clinical particulars
4.1 Therapeutic indications

Baclofen is indicated for the relief of voluntary muscle spasticity resulting from disorders such 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.

Baclofen Oral Solution is also indicated in adults and children 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 treatment with Baclofen Oral Solution; 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, transverse myelitis, traumatic paraplegia or paraparesis, and compression of the spinal cord.

4.2 Posology and method of administration

Baclofen Oral Solution is particularly suitable for children or those adults who are unable to take tablets. Dosage titration can be achieved more precisely with the oral solution.

Before initiating treatment with Baclofen Oral Solution it is advisable to assess realistically the overall extent of clinical improvement that the patient may be expected to achieve with treatment. Careful titration of dosage is essential (particularly in the elderly) until the patient is stabilised. If too high a dose is used initially or if increases in dosage are too rapid 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

It is recommended that treatment is started with a gradually increasing dosage regimen as follows. However, this may be adjusted to meet individual patient requirements:

5mg three times a day for three days

10mg three times a day for three days

15mg three times a day for three days

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 doses may prove better in some cases than larger spaced doses. Also, some patients benefit from the use of Baclofen Oral Solution only at night to counteract painful flexor spasm. Similarly, a single dose given approximately 1 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 6 weeks consideration should be made by the physician as to whether to continue treatment with Baclofen Oral Solution .

Elderly

Elderly patients may be more susceptible to side effects, particularly in the early stages of starting treatment with Baclofen Oral Solution. 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 a 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 dose 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 hemodialysis, a particularly low dosage of Baclofen should be selected i.e. approx. 5mg daily.

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 the active substance or to any of the excipients listed in section 6.1.

Peptic ulceration.

4.4 Special warnings and precautions for use

Psychiatric and nervous system disorders

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.

Suicide and suicide-related events have been reported in patients treated with baclofen. In most cases, the patients had additional risk factors associated with an increased risk of suicide including alcohol use disorder, depression and/or a history of previous suicide attempts. Close supervision of patients with additional risk factors for suicide should accompany drug therapy. Patients (and caregivers of patients) should be alerted about the need to monitor for clinical worsening, suicidal behaviour or thoughts or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Cases of misuse, abuse and dependence have been reported with baclofen. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of baclofen misuse, abuse or dependence e.g. dose escalation, drug-seeking behaviour, development of tolerance.

Epilepsy

Baclofen may also exacerbate epileptic manifestations but can be used provided appropriate supervision and adequate anticonvulsive therapy are maintained. Baclofen should be used with extreme care in patients already receiving antihypertensive therapy, (see Interactions).

Others

Baclofen should be used with caution in patients suffering from cerebrovascular accidents or from respiratory or hepatic impairment.

Renal impairment

Baclofen should be used with caution in patients with renal impairment and should be administered to end stage renal failure patients only if the expected benefit outweighs the potential risk (See section 4.2 Posology and method of administration). Neurological signs and symptoms of overdose including clinical manifestations of toxic encephalopathy (e.g. confusion, disorientation, somnolence and depressed level of consciousness) have been observed in patients with renal impairment taking oral baclofen at doses of more than 5mg per day. Patients with impaired renal function should be closely monitored for prompt diagnosis of early symptoms of toxicity.

Particular caution is required when combining baclofen to drugs or medicinal products that can significantly impact renal function. Renal function shall be closely monitored, and baclofen daily dosage adjusted accordingly to prevent baclofen toxicity.

During 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.

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 of therapy.

Abrupt withdrawal

Treatment should always, (unless serious adverse effects occur), be gradually discontinued by successively reducing the dosage over a period of about 1-2 weeks. Anxiety and confusional state, delirium, hallucinations, psychotic disorder, mania or paranoia, convulsion (status epilepticus), dyskinesia, tachycardia, hyperthermia, rhabdomyolysis and temporary aggravation of spasticity as a rebound phenomenon have been reported with abrupt withdrawal of baclofen, especially after long term medication.

Since in rare instances elevated SGOT, 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.

Excipients:

This medicine contains 3.2 g sorbitol, liquid (non-crystallising) in each 5 ml which is equivalent to 0.44 g/ml. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. Sorbitol may cause gastrointestinal discomfort and a mild laxative effect.

This medicine contains methyl hydroxybenzoate and propyl hydroxybenzoate which may cause allergic reaction (possibly delayed).

This medicine contains less than 1 mmol sodium (23 mg) in 5 ml solution, that is to say essentially 'sodium-free'.

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.

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.

Drugs which may produce renal insufficiency e.g. ibuprofen may reduce baclofen excretion leading to toxic effects. 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 Fertility, pregnancy and lactation

Pregnancy

During pregnancy, especially in the first 3 months, baclofen should only be used 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.

Breast-feeding

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 would be expected.

4.7 Effects on ability to drive and use machines

Baclofen has major influence on the ability to drive and use machines.

The patient's reactions may be adversely affected by baclofen induced sedation or decreased alertness. Patients should therefore exercise due caution. Operating equipment or machinery may be hazardous.

4.8 Undesirable effects

Unwanted effects occur mainly at the start of treatment, 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 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.

Nervous system disorders

Very common (≥1/10): particularly at the start of treatment daytime sedation, drowsiness, and nausea.

Common (≥1/100 to <1/10): respiratory depression, light-headedness, lassitude, exhaustion, mental confusion, dizziness, headache, insomnia, euphoria, depression, muscular weakness, ataxia, tremor, hallucinations, nightmares, myalgia, nystagmus, dry mouth, dysgeusia.

Uncommon (≥ 1/1,000 to <1/100): paraesthesia, dysarthria. Lowering of the convulsion threshold and convulsions may occur, particularly in epileptic patients.

Not known (cannot be estimated from the available data): sleep apnoea syndrome*.

*Cases of central sleep apnoea syndrome have been observed with baclofen at high doses (≥ 100 mg) in patients who are alcohol dependent.

Eye disorders

Common (≥1/100 to <1/10): accommodation disorders, visual disturbance.

Gastrointestinal disorders

Very common (≥1/10): nausea.

Common (≥1/100 to <1/10): mild gastro-intestinal disturbances constipation, diarrhoea, retching and vomiting.

Uncommon (≥ 1/1,000 to <1/100): abdominal pain.

Vascular disorders

Common (≥1/100 to <1/10): hypotension, diminished cardiovascular function.

Renal and uninary disorders

Very common (≥1/10): frequency of micturition, enuresis, dysuria.

Uncommon (≥ 1/1,000 to <1/100): urinary retention, impotence.

Hepato-biliary disorders

Uncommon (≥ 1/1,000 to <1/100): disorders of hepatic function.

Skin and subcutaneous tissue disorders

Common (≥1/100 to <1/10): hyperhydrosis, skin rash.

General disorders and administration site conditions

Very rare (<1/10,000): hypothermia.

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).

The excipient sorbitol may have a mild laxative effect when taken in large amounts and hydroxybenzoates may cause allergic reactions which may be possibly delayed.

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/yellowcardor search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Prominent features of overdosage are signs of central nervous depression: drowsiness, impairment of consciousness, respiratory depression, coma. Also liable to occur are: confusion, hallucinations, agitation, convulsion, abnormal electroencephalogram (burst suppression pattern and triphasic waves), accommodation disorder, impaired pupillary reflex; generalised muscular hypotonia, myoclonia, hyporeflexia or areflexia; convulsions; peripheral vasodilatation, hypotension or hypertension, bradycardia or tachycardia, or cardiac arrhythmia,; hypothermia; nausea, vomiting, diarrhoea, salivary hypersecretion; increased hepatic enzymes, SGOT and AP values, rhabdomyolysis.

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.

Elimination of the drug from the gastro-intestinal tract (induction of vomiting, gastric lavage; comatose patients should be intubated prior to gastric lavage), administration of activated charcoal; if necessary, saline aperient; in respiratory depression, administration of artificial respiration, also measures in support of cardiovascular functions. 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

Pharmacotherapeutic group: Musculo-skeletal system; Muscle-relaxants, centrally acting agents; other centrally acting agents, ATC code: M 03 BX 01

Baclofen is an antispastic agent acting at the spinal level. It is a gamma-aminobutyric acid (GABA) derivative, with a similar chemical structure, but differing in action.

Baclofen depresses monosynaptic and polysynaptic reflex transmission, probably by stimulating the GABA beta 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 their independence and helping rehabilitation.

Baclofen also exerts an antinociceptive effect. General wellbeing 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 reached after 0.5 to 3.0 hours and the 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, β-(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.

A 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

Sorbitol, liquid (non-crystallising) (E 420)

Methyl hydroxybenzoate (E 218)

Propyl hydroxybenzoate (E 216)

Raspberry flavour (contains propylene glycol (E 1520))

Carmellose Sodium

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

2 years

Use within 56 days of first opening

Baclofen Oral Solution may be diluted with purified water. The shelf life of the diluted solution is 14 days when stored not above 25°C.

6.4 Special precautions for storage

Do not store above 25°C

Store in the original container

Do not refrigerate or freeze

6.5 Nature and contents of container

Pharmaceutical grade type III amber glass bottle with child resistant and tamper evident polypropylene faced cap with an EPE liner

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Chemidex Pharma Limited

Trading as Chemidex Generics

Egham Business Village

Crabtree Road

Egham

Surrey TW20 8RB

8. Marketing authorisation number(s)

PL 17736/0061

9. Date of first authorisation/renewal of the authorisation

24 May 2004

10. Date of revision of the text

25/09/2019