Lioresal 10 mg/ 25 mg Tablet.

Spasticity of the skeletal muscle due to multiple sclerosis; spastic conditions occurring in spinal-cord diseases of infectious, degenerative, traumatic, neoplastic, or unknown aetiology u2013 e.g. spastic spinal paralysis, amyotrophic lateral sclerosis, syringomyelia, transverse myelitis, traumatic paraplegia or paraparesis, and compression of the spinal cord. Spasticity of cerebral origin, e.g. following cerebrovascular accidents or in the presence of neoplastic or degenerative brain disease.

Treatment should always be initiated with small, gradually increasing doses of LIORESAL. The optimum daily dosage should be individually adapted to the patient's requirements in such a way that clonus, flexor and extensor spasms, and spasticity are reduced, but that a sufficient degree of muscle tone is maintained to permit active movements and adverse effects are avoided as far as possible. The score line on one side of 10 mg tablet is to divide the tablets into equal doses. The score line on the 25 mg tablet is only to facilitate breaking for ease of swallowing and not to divide into equal doses. In order to prevent excessive weakness and falling, LIORESAL should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion or whenever spasticity is used to maintain function. It may be important to maintain some degree of muscle tone and allow occasional spasms to help support circulatory function. LIORESAL should be taken during meals with a little liquid. The daily dosage should be given in at least 3 divided doses in adults, and 3 to 4 in children. If no benefit is apparent within 6 to 8 weeks of achieving the maximum dosage, a decision should be taken whether to continue with LIORESAL. 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. Abrupt discontinuation of the treatment should be avoided (see Section 4.4.)

Adults Treatment should, as a rule, be started with a dosage of 5 mg three times daily, which for the purpose of cautious dose titration, should subsequently be increased at three-day intervals by 5 mg three times daily until the requisite daily dosage has been attained, i.e.:

• 5 mg three times daily for 3 days
• 10 mg three times daily for 3 days
• 15 mg three times daily for 3 days
• 20 mg three times daily for 3 days

In certain patients reacting sensitively to medicines, it may be advisable to begin with a lower daily dosage (5 mg or 10 mg) and to raise this dosage more gradually. The optimum dosage generally ranges from 30 mg to 80 mg daily. Doses of more than 80 mg to 100 mg daily are not generally recommended although higher doses have been given to carefully supervised patients in hospital.

Children Treatment should usually be started with a very low dose, e.g., 0,3 mg/kg a day, in divided doses. The dosage should be raised cautiously, at about 1 to 2 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 mass. In children over 10 years of age, however, a maximum daily dosage of 2,5 mg/kg body mass may be given.

Renal impairment In patients with impaired renal function LIORESAL should be given with caution and at lower doses. These patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (e.g., somnolence, lethargy). In patients undergoing chronic haemodialysis, baclofen concentrations in plasma are elevated and therefore a particularly low dosage of LIORESAL should be selected, i.e., approximately 5 mg daily.

Geriatric patients (aged 65 years or above) Since unwanted effects are more likely to occur in elderly patients or in patients with spastic states of cerebral origin, in such cases it is recommended that a very cautious dosage schedule be adopted and that the patient be kept under appropriate surveillance.

Hepatic impairment No studies have been performed in patients with hepatic impairment under LIORESAL therapy. Liver does not play a significant role in the metabolism of baclofen after oral administration of LIORESAL. However, LIORESAL has the potential of elevating liver enzymes. LIORESAL should be prescribed with caution in patients with hepatic impairment.

• Known hypersensitivity to baclofen or to any of the excipients.
• Porphyria.

LIORESAL may be associated with dizziness, sedation, somnolence, visual disturbances and impaired concentration which may impair the patientu2019s reaction and may be aggravated by the simultaneous intake of alcohol or central nervous system depressant agents. Patients experiencing these adverse reactions should be advised to refrain from driving or using machines. Patients suffering from psychotic disorders, schizophrenia, depressive or manic disorders, confusional states or Parkinson's disease should be treated cautiously with LIORESAL and kept under careful surveillance, because exacerbations of these conditions may occur. Suicide and suicide-related events have been reported in patients treated with baclofen. Close supervision of patients with additional risk factors for suicide (e.g., alcohol use disorder, depression and/or a history of previous suicide attempts) should accompany therapy with LIORESAL. 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.

Special attention should be given to patients known to suffer from epilepsy since lowering of the convulsion threshold may occur and seizures have occasionally been reported in connection with the discontinuation of LIORESAL or with overdosage. Adequate anticonvulsive therapy should be continued and the patient carefully monitored. LIORESAL should be used with caution in patients with, or with a history of, peptic ulcers, as well as in those suffering from cerebrovascular diseases or from respiratory, hepatic, or renal failure. Patients with stroke tolerate LIORESAL poorly. LIORESAL should be used with caution in patients with pre-existing sphincter hypertonia as acute retention of urine may occur. In instances, elevated aspartate aminotransferase (AST), alkaline phosphatase (ALP), and glucose levels in the serum have been recorded. Appropriate laboratory tests should therefore be performed periodically in patients with liver disease or diabetes mellitus in order to ensure that no drug-induced changes in these underlying diseases have occurred.

Renal Impairment LIORESAL should be used with caution in patients with renal impairment (see section 4.2) Neurological signs and symptoms of overdose including clinical manifestations of toxic encephalopathy (e.g., confusion, somnolence, hallucination) have been observed in patients with renal impairment taking LIORESAL at doses of more than 5 mg per day. Patients with renal impairment should be closely monitored for prompt diagnosis of early signs and symptoms of toxicity (see section 4.9). Particular caution is required when combining LIORESAL with medicinal products which may significantly impact renal function. Renal function should be closely monitored and LIORESAL 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.

Abrupt Discontinuation Anxiety and confusional states, hallucinations, psychotic, manic or paranoid states, convulsions (status epilepticus), dyskinesia, tachycardia, hyperthermia, rhabdomyolysis and - as a rebound phenomenon - temporary aggravation of spasticity and hypertonia have been reported upon the abrupt withdrawal of LIORESAL, especially after long-term medication. Drug withdrawal reactions including postnatal convulsions in neonates have been reported after intrauterine exposure to oral LIORESAL. As a precautionary measure, LIORESAL administration to neonates with gradual tapering can help in controlling and preventing the withdrawal reactions (See section 4.6). Except in overdose - related emergencies or where serious adverse effects have occurred, treatment should therefore always be gradually discontinued by successively reducing the dosage (over a period of approximately one to two weeks). LIORESAL tablets contain wheat starch. Wheat starch may contain gluten, but only in trace amounts. Taking LIORESAL tablets is therefore considered safe for people with celiac disease.

Where LIORESAL is taken concomitantly with other medicines 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 LIORESAL may be potentiated, resulting in pronounced muscular hypotonia. Since concomitant treatment with LIORESAL and medicines that lower blood pressure is likely to increase the fall in blood pressure, the dosage of concomitant medications should be adjusted accordingly.

In patients with Parkinson's disease receiving treatment with LIORESAL and levodopa, (alone or in combination with dopa-decarboxylase (DDC) inhibitor, carbidopa), there have been reports of mental confusion, hallucinations, headaches, nausea and agitation. Worsening of the symptoms of Parkinsonism has also been reported. Hence, caution should be exercised during concomitant administration of LIORESAL and levodopa/carbidopa. Concomitant use of oral baclofen and lithium resulted in aggravated hyperkinetic symptoms. Thus, caution should be exercised when LIORESAL is used concomitantly with lithium. Drugs or medicinal products that can significantly impact renal function may reduce baclofen excretion leading to toxic effects.

There are no adequate and well-controlled studies in pregnant women. Baclofen crosses the placental barrier and should not be used during pregnancy. Drug withdrawal reactions including postnatal convulsions in neonates have been reported after intra-uterine exposure to oral LIORESAL (see section 4.4).

Breast - feeding In mothers taking LIORESAL 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.

Fertility There are no data available on the effect of baclofen on fertility in humans.

LIORESAL may cause dizziness, sedation, somnolence and visual impairment (see section 4.8) which may impair the patientu2019s reaction. Patients experiencing these adverse reactions should be advised to refrain from driving or using machines. LIORESAL can have a major influence on the ability to drive and use machines.

Unwanted effects occur mainly at the start of treatment (e.g., sedation, somnolence, drowsiness, fatigue and nausea), if the dose is raised too rapidly, if large doses are employed, or if the patient is an elderly person. 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 attacks of convulsions may possibly occur, particularly in epileptic patients. Certain patients have shown increased muscle spasticity as a paradoxical reaction to the medication. Many of the adverse CNS and genitourinary effects reported are known to occur in association with the underlying conditions being treated.

An undesirable degree of muscular hypotonia - making it more difficult for patients to walk or fend for themselves - may occur and may 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 heading of frequency, the most frequent first, using the following convention: very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1,000, < 1/100); rare (u2265 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports.

Table 1 Immune system disorders Not known: Hypersensitivity Psychiatric disorders Common Confusional state, hallucination, depression, insomnia, euphoric mood, nightmare Nervous System disorders Very Common: Sedation, somnolence, drowsiness, fatigue and nausea. Common: Dryness of the mouth, respiratory depression, exhaustion, dizziness, headache, ataxia, tremor, nystagmus, fatigue Rare: Paraesthesia, dysarthria, dysgeusia. Ear and labyrinth Disorders Uncommon: Tinnitus Eye Disorders Common Accommodation disorders, visual impairment Cardiac disorders Common Cardiac output decreased Not known: Bradycardia Vascular disorders Common Hypotension Gastrointestinal disorders Very common Nausea Common Gastrointestinal disorders, retching, vomiting, constipation, diarrhoea. Hepatobiliary disorders Rare: Hepatic function abnormal Skin and subcutaneous tissue disorders Common: Hyperhydrosis, rash. Not known: Urticaria, alopecia Musculoskeletal and connective tissue disorders Common: Muscular weakness, myalgia. Renal and urinary disorders Common: Pollakiuria, enuresis, dysuria. Rare: Urinary retention Reproductive system and breast disorders Rare: Erectile dysfunction. Not known: Sexual dysfunction General disorders and administration site conditions Very Rare Hypothermia Not known Drug withdrawal syndrome, swelling face, and peripheral oedema Investigations Not known: Blood glucose increased Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website, or via [email protected].

Prominent features are signs of central nervous depression: drowsiness, impairment of consciousness, respiratory depression, coma and tinnitus. Also liable to occur are: confusion, hallucinations, agitation, accommodation disorders, absent pupillary reflex; generalised muscular hypotonia, myoclonia, hyporeflexia or areflexia; convulsions; peripheral vasodilatation, hypotension or hypertension, bradycardia or tachycardia; hypothermia; nausea, vomiting, diarrhoea, hypersalivation; elevated LDH, AST, and AP values, sleep apnoea, rhabdomyolysis. A deterioration in the condition may occur if various substances or medicines 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, gastrointestinal disturbances, and respiratory or cardiovascular depression.