SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Baclofen Tablets 10 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains baclofen 10 mg.

Excipient with known effect: Each tablet contains 40 mg lactose monohydrate For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

A 7 mm flat bevelled edge tablet marked “BN” breakline “10” on one side and “G” on the reverse.

4.1 Therapeutic indications

Baclofen is indicated 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.

Baclofen 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 baclofen 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 stabilized.

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

Posology

Before starting treatment with baclofen it is prudent to realistically assess the overall extent of the 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.

Once the maximum recommended dose has been reached, if the therapeutic effect is not apparent within 6 weeks a decision whether to continue with baclofen should be taken.

Discontinuation of the treatment should always be gradual by successively reducing the dosage over a period of approximately 1 to 2 weeks, except in overdose-related emergencies, or where serious adverse effects have occurred (see section 4.4).

Adults:

Treatment should be started with a dosage of 15 mg daily, preferably in divided doses. The following gradually increasing dosage regime is suggested, but should be adjusted to suit individual patient requirements.

5 mg    Three    times a    day for three    days

10 mg    Three times a    day for three    days

15 mg    Three times a    day for three    days

20 mg    Three times a    day for three    days

Satisfactory control of symptoms is usually obtained with doses up to 60 mg 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 100 mg 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 1 hour prior to the performance of specific tasks such as washing, dressing, shaving, physiotherapy, will often improve mobility.

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 the 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.

Patients with renal impairment:

In patients with impaired renal function or undergoing chronic haemodialysis, a particularly low dosage of baclofen should be selected i.e. approximately 5 mg daily.

Baclofen should be administered to end stage renal failure patients only if the expected benefit outweighs the potential risk. These patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (e.g. somnolence, lethargy) (see sections 4.4 and 4.9).

Patients with hepatic impairment:

No studies have been performed in patients with hepatic impairment receiving baclofen therapy. The liver does not play a significant role in the metabolism of baclofen after oral administration of baclofen (see section 5.2). However, baclofen has the potential of elevating liver enzymes. Baclofen should be prescribed with caution in patients with hepatic impairment.

Patients with spastic states of cerebral origin:

Unwanted effects are more likely to occur in these patients. It is therefore recommended that a cautious dosage schedule be adopted and that patients be kept under appropriate surveillance.

Paediatric population

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 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.

Baclofen tablets are not suitable for use in children below 33 kg body weight.

Method of administration

Baclofen should be taken during meals with a little liquid.

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.

Epilepsy

Baclofen may also exacerbate epileptic manifestations but can be employed provided appropriate supervision and adequate anticonvulsive therapy are maintained.

Others

Baclofen should be used with extreme care in patients already receiving antihypertensive therapy (see section 4.5).

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

Renal impairment

Signs of overdose have been observed in patients with renal impairment taking baclofen at doses of more than 5 mg per day. Baclofen should be used with caution in patients with renal insufficiency and should only be administered to patients with end-stage renal failure (CKD stage 5, GFR < 15 ml/min) if the expected benefit outweighs the potential risk (see section 4.2).

Cases of baclofen toxicity have been reported in patients with acute renal failure (see section 4.9).

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

Besides discontinuing treatment, unscheduled haemodialysis might be considered as a treatment alternative in patients with severe baclofen toxicity. Haemodialysis effectively removes baclofen from the body, alleviates clinical symptoms of overdose and shortens the recovery time in these patients.

Urinary disorders

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 patients.

Abrupt withdrawal

Anxiety and confusional state, delirium, hallucination, psychotic disorder, mania or paranoia, convulsion (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.

Neonatal convulsions have been reported after intrauterine exposure to oral baclofen (see section 4.6).

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.

Laboratory tests

In rare instances, elevated aspartate aminotransferase, 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.

Posture and balance

Baclofen should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion (see section 4.2).

Paediatric patients

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.

Excipients

Baclofen Tablets contain 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 Drugs causing Central Nervous System (CNS) depression

Increased sedation may occur when baclofen is taken concomitantly with other drugs causing CNS depression including other muscle relaxants (such as tizanidine), with synthetic opiates or with alcohol (see section 4.7).

The risk of respiratory depression is also increased. In addition, hypotension has been reported with concomitant use of morphine and intrathecal baclofen. Careful monitoring of respiratory and cardiovascular functions is essential, especially in patients with cardiopulmonary disease and respiratory muscles weakness.

Pre-treatment with baclofen may prolong the duration of fentanyl induced anaesthesia. Lithium

Concomitant use of oral baclofen and lithium resulted in aggravated hyperkinetic symptoms. Thus, caution should be exercised when baclofen is used concomitantly with lithium.

Antidepressants

During concomitant treatment with tricyclic antidepressants, the effect of baclofen may be potentiated, resulting in pronounced muscular hypotonia.

Antihypertensives

Since concomitant treatment with baclofen and anti-hypertensives is likely to increase the fall in blood pressure, the dosage of anti-hypertensive medication should be adjusted accordingly.

Agents reducing renal function

Drugs or medicinal products that can significantly affect renal function may reduce baclofen excretion leading to toxic effects (see Section 4.4).

Levodopa/dopa decarboxylase (DDC) inhibitor (Carbidopa)

In patients with Parkinson’s disease receiving treatment with baclofen and levodopa (alone or in combination with DDC inhibitor, carbidopa), there have been reports of mental confusion, hallucinations, nausea and agitation. Worsening of the symptoms of Parkinsonism has also been reported. Hence, caution should be exercised during concomitant administration of baclofen and levodopa/carbidopa.

4.6 Fertility, pregnancy and lactation

During pregnancy, especially in the first 3 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.

One case of suspected withdrawal reaction (generalised convulsions) has been reported in a week-old infant whose mother had taken oral baclofen 80 mg daily throughout her pregnancy. The convulsions, which were refractory to standard anticonvulsant treatment, ceased within 30 minutes of giving baclofen to the infant.

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 adverse effects such as dizziness, sedation, somnolence and

visual impairment (see section 4.8) which may impair the patient’s reaction. Patients experiencing these adverse reactions should be advised to refrain from driving or operating machinery.

4.8 Undesirable effects

Adverse 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 be ingested with food or a milk beverage.

Lowering of the convulsion threshold and convulsions may occur, particularly in epileptic patients.

In patients with a 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.

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).

Adverse reactions (Table 1) are ranked under the heading of frequency, the most frequent first, using the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000) and Not known (frequency cannot be estimated from the available data).

Nervous system disorders	sedation, somnolence	Dry mouth, respiratory depression, lightheadedness, fatigue, confusional state, dizziness, headache, insomnia, depression, euphoric mood, myalgia, muscular weakness, ataxia, tremor, nystagmus, hallucination, nightmare,	paraesthesia, dysarthria, dysgeusia
Eye disorders		accommodation disorder, visual impairment
Cardiac disorders		cardiac output decreased			bradycardia
Vascular disorders		hypotension
Gastrointestinal disorders	nausea	gastrointestinal disorder, retching, vomiting, constipation, diarrhoea	abdominal pain
Hepatobiliary disorders			hepatic function abnormal
Skin and subcutaneous tissue disorders		hyperhidrosis, rash			urticaria
Renal and urinary disorders		dysuria, pollakiuria, enuresis	urinary retention
Reproductive system and breast disorders			erectile dysfunction
General disorders and administration site conditions				hypothermia	drug withdrawal syndrome (see section 4.4)
Investigations					blood glucose increased

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: somnolence, depressed level of consciousness, respiratory depression, coma. Also liable to occur are: confusion, hallucination, agitation, accommodation disorder, impaired pupillary reflex, generalised muscular hypotonia, myoclonus, hyporeflexia or areflexia, convulsion, abnormal electroencephalogram (burst suppression pattern and triphasic waves), peripheral vasodilation, hypotension or hypertension, bradycardia, tachycardia or cardiac arrhythmia, hypothermia, nausea, vomiting, diarrhoea, hypersalivation, increased hepatic enzymes. Patients with renal impairment can develop signs of overdose even on low doses of oral baclofen (see sections 4.2 and 4.4).

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, and respiratory or cardiovascular depression.

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. Since the drug is excreted chiefly via the kidneys, generous quantities of fluid should be given, possibly together with a diuretic. Haemodialysis (sometimes unscheduled) may be useful in severe poisoning associated with renal failure (see section 4.4). In the event of convulsions diazepam should be administered cautiously I.V.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antispastic with spinal site attack, ATC code: M03B X01

Baclofen is an antispastic agent acting at the spinal level. A gamma-aminobutyric acid (GABA) derivative, chemically unrelated to other antispastic agents.

Baclofen depresses monosynaptic and polysynaptic reflex transmission, probably by stimulating the GABAB-receptors. This stimulation in turn inhibits 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 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 gastrointestinal tract. Following oral administration of single doses (10-30 mg) 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. The protein binding rate is approximately 30% and is constant in the concentration range of 10 nanogram/ml to 300 microgram/ml. 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

The plasma elimination half-life of baclofen averages 3 to 4 hours.

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 patients below 65 years of age. Following a single oral dose, elderly patients have slower elimination but a similar systemic exposure of baclofen compared to adults below 65 years of age. Extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetic difference between patients below 65 years of age and elderly patients.

Paediatric patients

Following oral administration of 2.5 mg Baclofen tablet in children (aged 2 to12 years), Cmax of 62.8±28.7 nanogram/ml, and Tmax in the range of 0.95-2h have been reported. Mean plasma clearance (Cl) of 315.9 ml/h/kg; volume of distribution (Vd) of 2.58 l/kg; and half-life (T1/2) of 5.10 h have been reported.

Hepatic impairment

No pharmacokinetic data are available in patients with hepatic impairment after administration of baclofen. However, as the liver does not play a significant role in the disposition of baclofen, it is unlikely that baclofen pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.

Renal impairment

No controlled clinical pharmacokinetic study is available in patients with renal impairment after administration of baclofen. Baclofen is predominantly eliminated unchanged in urine. Sparse plasma concentration data collected only in female patients under chronic hemodialysis or compensated renal failure indicate significantly decreased clearance and increased half-life of baclofen in these patients. Dosage adjustment of baclofen based on its systemic levels should be considered in renal impairment patients, and prompt hemodialysis is an effective means of reversing excess baclofen in systemic circulation

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 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.

6.1 List of excipients

The tablet contains:

-    microcrystalline cellulose

-    lactose monohydrate

-    anhydrous calcium hydrogen phosphate

-    colloidal anhydrous silica

-    magnesium stearate

-    sodium starch glycollate (type A)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in a dry place below 25°C in order to protect from light.

6.5 Nature and contents of container

Baclofen Tablets are available either in polypropylene containers with polyethylene caps (with optional polyethylene ullage filler, or in PVDC aluminium foil blisters. The pack sizes available in both pack types are 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168, 180 and for the polypropylene containers pack sizes of 50, 250 and 500 are also available.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited

T/A Mylan Station Close Potters Bar Hertfordshire EN6 1

8. MARKETING AUTHORISATION NUMBER

PL 4569/ 0158

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05/10/2005

10 DATE OF REVISION OF THE TEXT

06/07/2015