Lioresal 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.

Lioresal 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 Lioresal 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

Lioresal 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.

Lioresal 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.

Treatment should be initiated with small doses of Lioresal and gradually increased. It is recommended that the lowest effective dose be used. The optimum dosage must be adapted to the patient’s requirements such that clonus, flexor and extensor spasms and spasticity are reduced while avoiding adverse effects as far as possible.

To prevent excessive weakness and falling, Lioresal must be used with caution when spasticity is needed to maintain upright posture and balance in locomotion or other functions. A certain degree of muscle tone and occasional spasms may be important in helping to support circulatory functions and potentially preventing deep vein thrombosis.

Close monitoring is required at the start of treatment so that potential adverse effects such as general muscle weakness, potentially abrupt loss of muscle tone (risk of falling), fatigue or confusion can be rapidly detected and the dose adjusted.

If baclofen is to be withdrawn after prolonged administration (longer than 2‑3 months), the dose should be reduced gradually over the course of approximately 3 weeks except in overdose-related emergencies or where serious adverse effects have occurred (see “Warnings and precautions”) as abrupt withdrawal is occasionally associated with anxiety, confusional states, hallucinations, cerebral seizures, dyskinesia, tachycardia or hyperthermia. Withdrawal of baclofen should be gradual due to the risk of a transient rebound effect involving increased spasm frequency and/or severity (see “Warnings and precautions”).

Continuation of treatment with Lioresal should be reconsidered if it has not proved successful within 6‑8 weeks of the patient reaching the maximum dose.

Adults

Treatment should be started with a dosage of 5 mg 3 times daily, given in 3 divided doses. Depending on the response each divided dose should be cautiously increased by 5 mg every 3 days. 30‑80 mg/d is considered the standard guideline value for the daily dose, but 100 to 120 mg/d may be given in isolated cases (with monitoring in hospital).

Special dosage instructions

Children and adolescents

Experience with Lioresal is limited in children and adolescents. The minimum age for treatment is 12 months.

Treatment usually starts at very low dosages (e.g. 0.3 mg/kg/d, given in 4 divided doses). The dosage should be cautiously increased at approximately 1‑2 week intervals until it meets the individual patient’s requirements. The daily dosage for maintenance therapy is 0.75‑2 mg/kg. The total daily dose for children under 8 years of age must not exceed a maximum of 40 mg/day. In children over 8 years of age a maximum daily dose of 60 mg/day may be given.

Elderly patients (aged 65 years or above) and patients with spasticity of cerebral origin

The dosage should be increased particularly slowly in elderly and weakened patients suffering from organic brain disorders, cardiovascular disorders, respiratory impairment or hepatic/renal impairment and in patients with spasticity of cerebral origin.

Use in renal impairment

Lioresal should be used with caution in patients with renal impairment. As baclofen plasma concentrations are elevated in patients undergoing chronic haemodialysis, a particularly low dose of Lioresal (approx. 5 mg/d) should be selected. Symptoms of overdose have been reported with doses of over 5 mg per day in this clinical situation (see “Overdose”).

Lioresal should not be used in patients with end-stage renal failure unless the expected benefit of further treatment outweighs the potential risk. These patients must be closely monitored for early signs of overdose (e.g. drowsiness, lethargy; see “Warnings and precautions” and “Overdose”).

Method of administration

Lioresal tablets should be taken at mealtimes with a small amount of liquid.

Psychiatric disorders

Caution and close medical supervision are required in patients with spasticity who also suffer from psychotic disorders, schizophrenia or confusional states as these conditions may be exacerbated.

Suicide and suicide-related events have been reported in patients treated with baclofen. In most cases patients had additional risk factors associated with an increased suicide risk, including a history of alcohol abuse, depression and/or attempted suicide. Patients with risk factors for suicide must be closely monitored during therapy with Lioresal. Patients (and their carers) must be instructed to look out for signs of clinical deterioration, suicidal behaviour/thoughts or unusual changes in behaviour and seek immediate medical assistance if these symptoms occur.

Cases of misuse, abuse and dependency have been reported in association with baclofen. Caution is required in patients with a history of substance abuse and patients must be monitored for symptoms of baclofen misuse, abuse or dependency, e.g. dose increases, drug-seeking behaviour, development of a tolerance.

Epilepsy

Particular caution is indicated in patients with epilepsy as the seizure threshold may be reduced. There have been occasional reports of seizures associated with withdrawal or overdose of Lioresal. Appropriate anticonvulsive therapy should be continued and the patient should be closely monitored.

Other

Since adverse effects are more likely to occur in elderly patients and patients with spasticity of cerebral origin, a cautious dosage regimen should be used for these patients (see “Dosage/Administration”).

Use in renal impairment

Lioresal should be used with caution in patients with renal impairment and should not be administered to patients with end-stage renal failure unless the expected benefit of treatment outweighs the potential risk (see “Dosage/Administration”).

In patients with renal impairment who took Lioresal in dosages of more than 5 mg daily, neurological signs and symptoms of an overdose, including clinical manifestations of toxic encephalopathy (e.g. confusion, somnolence, hallucinations) have been observed. Patients with renal impairment should therefore be monitored closely so that early signs and symptoms of toxicities can be promptly diagnosed (see “Overdose”).

Particular caution is required when co-administering Lioresal with medicinal products that have an adverse effect on renal function. Under such circumstances renal function must be closely monitored and the daily dosage of Lioresal adjusted accordingly to prevent baclofen toxicity.

Use in hepatic impairment

No studies have been performed in patients with hepatic impairment on Lioresal therapy. The liver does not play a significant role in the metabolism of baclofen after oral administration of Lioresal (see “Pharmacokinetics”). However, Lioresal may elevate liver enzymes. Lioresal should be prescribed with caution to patients with hepatic impairment.

In addition to withdrawing treatment in patients exhibiting severe baclofen intoxication, additional haemodialysis may also be scheduled. Baclofen is removed from the body by haemodialysis. It reduces the clinical symptoms of overdose and shortens the patient’s recovery time.

Urinary retention

Neurogenic disturbances affecting the emptying of the bladder may improve during treatment with Lioresal; however, patients with pre-existing increased sphincter tone may experience acute urinary retention. The product should therefore be used with caution in such patients.

Particular caution is required when using baclofen in the elderly and in patients suffering from severe hepatic impairment, acute or chronic confusional states or disorders involving cerebral seizures.

It is primarily in the aftermath of a stroke that baclofen may be poorly tolerated and extreme caution is therefore required in such patients.

Caution is required when determining dosages in cases where spasticity is necessary for maintaining an upright gait and locomotive ability.

Lioresal should be used with caution in patients with gastric or duodenal ulcers (or a history thereof), cerebrovascular disease or respiratory, hepatic or renal impairment.

As there have been rare cases of elevated serum levels of aspartate aminotransferase, alkaline phosphatase and glucose, appropriate laboratory tests should be performed periodically in patients with liver disease or diabetes mellitus to ensure that no drug-induced changes have occurred in the underlying disease.

Lioresal tablets contain wheat starch; this may contain gluten, but only in trace amounts. The use of Lioresal tablets in patients with coeliac disease is therefore generally considered permissible. However, attention should be paid to possible gastrointestinal symptoms.

Postnatal convulsions have been reported after intrauterine exposure to oral Lioresal (see “Pregnancy/Breastfeeding”).

Abrupt withdrawal

Avoid abrupt withdrawal of baclofen. Abrupt withdrawal or abrupt dose reduction after several months of treatment with high doses of baclofen may lead to anxiety, concentration disorders, confusion, delirium, visual and acoustic hallucinations, psychotic disorders, agitation, mania, paranoia, seizures (status epilepticus), dyskinesia, tachycardia, hyperthermia, rhabdomyolysis and – as a rebound phenomenon – temporary aggravation of spasticity.

Drug withdrawal reactions, including postnatal convulsions, have been reported in neonates after intrauterine exposure to oral Lioresal. As a precautionary measure Lioresal can be administered to neonates and gradually withdrawn. This may help to control or prevent withdrawal reactions (see “Pregnancy/Breast-feeding”).

Following abrupt withdrawal of the intrathecal formulation of Lioresal a clinical picture has been described that resembles autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.

Withdrawal of baclofen following long-term use (longer than 2‑3 months) must be gradual, extending over the course of about 3 weeks, except in emergencies or where serious adverse effects have occurred.

Posture and balance

Lioresal should be used with caution when spasticity is needed to maintain upright posture and balance in locomotion (see “Dosage/Administration”).

Gluten intolerances (incl. coeliac disease) and wheat allergy

The wheat starch in this medicinal product contains only very small amounts of gluten and it is very unlikely that this will cause problems in patients with coeliac disease.

One 10 mg tablet contains no more than 6.1 micrograms gluten. One 25 mg tablet contains no more than 8.3 micrograms gluten.

Patients who have a wheat allergy (not equatable to coeliac disease) must not take this medicinal product.

Levodopa/dopa decarboxylase (DDC) inhibitor (carbidopa)

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

Medicinal products causing central nervous system (CNS) depression

Increased sedation may occur when Lioresal is co-administered with other drugs causing CNS depression, including other muscle relaxants (such as tizanidine), synthetic opiates or alcohol (see “Effects on ability to drive and use machines” and “Warnings and precautions”). The risk of respiratory depression is also increased. In addition, hypotension has been reported with concomitant use of morphine and intrathecal baclofen. Close monitoring of respiratory and cardiovascular function is particularly important in patients with cardiopulmonary disease or respiratory muscle weakness.

Concomitant consumption of alcohol is particularly to be avoided since Lioresal interacts unpredictably with alcohol.

Antidepressants

Concomitant treatment with tricyclic antidepressants may potentiate the effect of Lioresal, resulting in pronounced muscular hypotonia.

Lithium

Concomitant use of oral Lioresal and lithium has resulted in severe hyperkinetic symptoms. Caution is therefore indicated when Lioresal is used concomitantly with lithium.

Antihypertensives

Since concomitant treatment with antihypertensives is likely to enhance the fall in blood pressure, the dosage of antihypertensive medication should be adjusted accordingly.

Medicinal products reducing renal function

Coadministration of medicinal products that affect renal function may lead to a toxic overdose due to a reduction in baclofen excretion.

4.6 Fertility, Pregnancy and lactation

There is insufficient clinical data available on the use of this product in pregnant women.

Reproductive toxicity has been observed in animal studies (see “Preclinical data”). The medicinal product crosses the placental barrier. Lioresal must not be administered during pregnancy unless clearly necessary.

Fetotoxicity

Drug withdrawal reactions, including postnatal convulsions, have been reported in neonates after intrauterine exposure to oral Lioresal (see “Warnings and precautions”).

Breast-feeding

Only small amounts of baclofen pass into the breast milk. There are no detailed data on possible adverse effects on the infant and the substance should therefore not be used during breast-feeding.

Fertility

There are no data available on the effect of baclofen on human fertility. In animals baclofen did not impair male or female fertility at non-toxic doses (see “Preclinical data”).

During treatment with baclofen the patient’s ability to drive or use machines may be considerably impaired. This is particularly true when alcohol is consumed during treatment. The attending physician should therefore decide at the start of treatment whether or not the patient should be permitted to drive vehicles, use machines or perform other potentially dangerous activities, taking into account the individual patient’s reactions and the current dosage.

Lioresal may cause adverse effects such as light-headedness, sedation, drowsiness, dizziness and visual impairment (see “Adverse effects”), which may impair the patient’s reactions. Patients experiencing such adverse effects should be instructed not to drive or use machines.

Specific instructions should be given to patients working in hazardous environments.

Adverse effects occur mainly at the start of treatment (e.g. sedation, drowsiness) and in cases where the dose is increased too rapidly, treatment is withdrawn abruptly following prolonged use or high doses are administered. They are often transient and can be reduced or eliminated by reducing the dose. They are rarely severe enough to require withdrawal of the product. Generally, adverse effects are likely to be more severe in patients with a history of psychiatric disorders, patients with cerebrovascular disorders (e.g. stroke) and elderly patients.

The seizure threshold may be lowered and seizures may occur particularly in epileptic patients.

Some patients have shown increased muscle spasticity as a paradoxical reaction to the medicinal product.

Frequency: 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), isolated cases.

Table 1 Tabulated summary of adverse drug reactions

* Drug withdrawal syndrome, including postnatal convulsions, has also been reported after intrauterine exposure to oral Lioresal.

Reporting of suspected adverse reactions

Reporting suspected adverse effects after authorisation of the medicinal product is very important. It allows continued monitoring of the risk-benefit ratio of the medicinal product. Healthcare professionals are asked to report any suspected new or serious adverse effects.

To report any side effect(s):

·         Saudi Arabia

-          The National Pharmacovigilance Centre (NPC):

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

Symptoms

The most prominent features are CNS depression: drowsiness, clouding of consciousness, coma, respiratory depression.

The following may also occur:

abnormal EEG (burst suppression pattern, triphasic waves), accommodation disorders, impaired pupillary reflex, generalised muscular hypotonia, myoclonus, hyporeflexia or areflexia, peripheral vasodilation, hypotension or hypertension, bradycardia or tachycardia, cardiac arrhythmias, hypothermia, nausea, vomiting, diarrhoea, salivary hypersecretion, increased hepatic enzymes (LDH, SGOT and ALP), sleep apnoea, rhabdomyolysis, tinnitus.

The patient’s condition may deteriorate if various substances or drugs acting on the central nervous system (e.g. alcohol, diazepam, tricyclic antidepressants) have been taken concomitantly.

Treatment

No specific antidote is known.

Intensive monitoring of the patient must begin as soon as there are any signs of baclofen overdose. Supportive measures and symptomatic treatment are indicated for complications such as hypotension, hypertension, convulsions, gastrointestinal disorders and respiratory or cardiovascular depression.

Due to the risk of respiratory impairment intensive monitoring of respiratory function is indicated, with artificial respiration if necessary.

Haemodialysis should be performed in patients with severe baclofen intoxication and renal failure (see “Warnings and precautions”). As baclofen is excreted primarily via the kidneys, sufficient fluids should be given. Forced diuresis should be used where necessary.

Physostigmine may reverse CNS effects. However, caution is required as physostigmine can cause cardiac conduction disturbances, bradycardia and/or epileptic seizures.

ATC code

M03BX01

Mechanism of action

Lioresal is an antispastic with a spinal site of action. Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABA_B receptors, inhibiting the release of the excitatory amino acids glutamate and aspartate.

Pharmacodynamics

Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. In neurological diseases associated with skeletal muscle spasticity the clinical effects of Lioresal take the form of beneficial action on reflex muscle contractions and marked relief of painful spasms, automatism and clonus. Lioresal improves patient mobility, facilitating daily activities, catheterisation and physiotherapy. Prevention and accelerated healing of decubitus ulcers, improved sleep (due to elimination of painful muscle spasms) and improved bladder and sphincter function have been reported as indirect effects of treatment with Lioresal and can improve the patient’s quality of life.

Baclofen stimulates gastric acid secretion.

Clinical efficacy

Not applicable.

Absorption

Baclofen is rapidly and completely absorbed from the gastrointestinal tract.

Following oral administration of single doses of 10, 20 and 30 mg baclofen mean peak active substance plasma concentrations of about 180, 340 and 650 ng/ml, respectively, were reached within 0.5‑1.5 h. The corresponding areas under the serum concentration curves (AUC) were approximately 1135, 2345 and 3353 ng × h/ml and increased proportionally to the dose.

Distribution

The volume of distribution of baclofen is 0.7 l/kg. Serum protein binding is approximately 30% and remains constant in the concentration range of 10 ng/ml to 300 μg/ml. In the cerebrospinal fluid the active substance attains concentrations that are approximately 8.5 times lower than in the plasma.

Metabolism

Baclofen is metabolised to only a minor extent. Deamination yields the main metabolite, the pharmacologically inactive beta-(p-chlorophenyl)-gamma-hydroxybutyric acid.

Elimination

The mean plasma elimination half-life is 3‑4 h. Baclofen is excreted largely in unchanged form. Within 72 h approximately 75% of the dose is excreted renally, 5% of which in the form of metabolites. The remainder of the dose, including 5% as metabolites, is excreted via the faeces.

Pharmacokinetics in special patient populations

Elderly patients (>65 years of age)

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 exhibit slower elimination of, but a similar systemic exposure to, baclofen compared to adults below 65 years of age. Extrapolation of these data to multi-dose treatment suggests no significant pharmacokinetic differences between patients below 65 years of age and elderly patients.

Children

Following oral administration of 2.5 mg Lioresal tablets to children (aged 2 to 12 years) C_max was 62.8±28.7 ng/ml and T_max was 0.95‑2 h. Mean plasma clearance (Cl) was 315.9 ml/h/kg, the volume of distribution (Vd) was 2.58 l/kg and the half-life (T_1⁄2) was 5.10 h.

Hepatic impairment

No pharmacokinetic data are available after administration of Lioresal in patients with hepatic impairment. 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 extent in patients with hepatic impairment.

Renal impairment

No data from controlled clinical pharmacokinetic studies is available after administration of Lioresal in patients with renal impairment. Baclofen is predominantly eliminated unchanged in the urine. Sparse plasma concentration data collected only in female patients under chronic haemodialysis or following compensated renal failure indicate significantly decreased clearance and an increased half-life of baclofen in these patients. Dose adjustment of baclofen based on its systemic levels should be considered in patients with renal impairment; prompt haemodialysis is an effective means of reducing increased baclofen concentrations in the systemic circulation.

Reproductive toxicity

Oral baclofen showed no adverse effects on fertility or postnatal development at non-maternally toxic doses in rats. Baclofen is not teratogenic in rats at doses at least 0.4 times the maximum oral adult dose. Oral Lioresal increased the incidence of omphaloceles (hernias of the abdominal wall) in rat fetuses at doses approximately 1.6 times the maximum oral adult dose. This malformation was not observed in mice or rabbits. Parenteral administration of high doses of GABA agonists, including baclofen (2.4 times the maximum human dose), induced spina bifida-type malformations in rats. Oral Lioresal has been shown to cause delayed fetal growth (bone ossification) at maternally toxic doses in mice, rats and rabbits (0.8 to 1.6 times the maximum oral adult dose).

Mutagenicity and carcinogenicity

Baclofen showed no genotoxic potential in tests in bacteria, mammalian cells, yeast and Chinese hamsters.

Baclofen showed no carcinogenic potential in a 2-year study in rats. A dose-dependent increase in the incidence of ovarian cysts and an increase in enlarged and/or haemorrhagic adrenals at the maximum dose (50‑100 mg/kg, corresponding to 4 times the maximum human dose) were observed in female rats given baclofen for 2 years.

·         10 mg tablet (scored)

61 mg wheat starch [contains ≤100 ppm gluten], microcrystalline cellulose (E460), colloidal anhydrous silica (E551), magnesium stearate, povidone

·         25 mg tablet (scored)

83 mg wheat starch [contains ≤100 ppm gluten], microcrystalline cellulose (E460), colloidal anhydrous silica (E551), magnesium stearate, povidone

None known

Lioresal 10 mg tablets should be stored in the original pack. Store below 30°C. Protect from moisture.

Lioresal 25 mg tablets should be stored in the original pack. Do not store above 25°C. Protect from moisture.Keep out of the reach of children.

Tablets 10mg circular, flat, white to faint yellowish tablets, uncoated, with bevelled edges, having the monogram CG on one side and the letters KJ and a break line on the other.

Tablets 25mg: circular, flat, white to faint yellowish tablets, uncoated, with bevelled edges, having the monogram CG on one side and the letters UR and a break line on the other.

In PVC blister packs of 50 tablets

There is no specific instruction for use/handling