Active ingredient: Baclofen Chemical name: (3RS)-4-amino-3-(4-chlorophenyl)butanoic acid Structural formula: Molecular formula: C10H12ClNO2 Molecular weight: 213.7 CAS Registry No. : 1134-47-0

DESCRIPTION

Baclofen is a derivative of gamma-aminobutyric acid (GABA). It is a white or almost white powder, slightly soluble in water, very slightly soluble in ethanol (96%), practically insoluble in acetone and in ether. It dissolves in dilute mineral acids and in dilute alkali hydroxides. Each Clofen 10 and Clofen 25 tablet contains baclofen 10 mg and baclofen 25 mg, as the active ingredient, respectively. The tablets also contain the following inactive ingredients: lactose, cellulose - microcrystalline, calcium hydrogen phosphate anhydrous, sodium starch glycollate, silica - colloidal anhydrous, magnesium stearate.

PHARMACOLOGY

Baclofen is an effective antispastic agent with a spinal site of action. Its mechanism of action and pharmacological properties are different from those of other antispastic agents. Baclofen also has central sites of action given the adverse event profile and general CNS depressant properties. Baclofen depresses monosynaptic and polysynaptic reflex transmission, probably by various actions, including stimulation of GABAb-receptors. This stimulation in turn inhibits the release of excitatory amino acids (glutamate and aspartate) in guinea pig preparations. Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. The clinical significance of this awaits clarification. In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of baclofen take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism and clonus. Baclofen, where indicated, improves the patient's mobility, making for greater independence, and facilitating passive and active physiotherapy. Baclofen stimulates gastric acid secretion.

Baclofen is rapidly and completely absorbed from the gastrointestinal tract. Maximum concentrations

of unchanged drug are achieved in plasma in 2 to 4 hours after an oral dose. The bioavailability of oral baclofen is 70-80%. Following oral administration of a single dose of 40 mg baclofen, a peak serum concentration between 500 to 600 nanogram/mL was reached. The serum concentration remains above 200 nanogram/mL for 8 hours. The onset of action is highly variable and may range from hours to weeks.

The distribution volume of baclofen amounts to 0.7 L/kg. In cerebrospinal fluid, the active substance attains concentrations approximately 8.5 times lower than in the plasma.

About 15% of the baclofen dose is metabolised in the liver. Deamination yields the main metabolite,

Approximately 70% of baclofen is eliminated in the urine in the unchanged form. The plasma elimination half-life of baclofen averages 3 to 4 hours. Within 72 hours, approximately 75% of the dose is excreted via the kidneys, approximately 5% of this quantity being in the form of metabolites. The remainder of the dose, including 5% as metabolites, is excreted in the faeces.

CONTRAINDICATIONS

PRECAUTIONS

Anxiety and confusional states, hallucinations, psychotic, manic or paranoid states, convulsions (status epilepticus), dyskinesia, tachycardia, hyperthermia and, as a rebound phenomenon, temporary aggravation of spasticity, have been reported upon the abrupt withdrawal of baclofen, especially after long-term medication. Postnatal convulsions have been reported after intrauterine exposure to oral baclofen (see Use in Pregnancy). Except in overdose-related emergencies or where serious adverse effects have occurred, treatment should therefore always be gradually withdrawn by successive dosage reduction over a period of approximately 1 to 2 weeks. If withdrawal symptoms occur, restarting baclofen therapy and withdrawing over a longer period may help to resolve withdrawal problems.

Patients suffering not only from spasticity but also from psychotic disorders, schizophrenia, depressive or manic disorders or confusional states should be treated cautiously with baclofen and kept under careful surveillance, because exacerbations of these conditions may occur.

Caution is needed in patients with epilepsy or other convulsive conditions, cortical or subcortical brain damage or significant EEG abnormalities, since ingestion of baclofen may cause deterioration of seizure control and EEG changes, and may precipitate convulsions. In patients with epilepsy and muscle spasticity, baclofen can be used under appropriate supervision, provided adequate anticonvulsive therapy is continued. Lowering of the convulsion threshold may occur and seizures have been reported occasionally after cessation of baclofen or with overdosage.

Baclofen should be used with caution in patients with, peptic ulcers or with a history of peptic ulcers cerebrovascular diseases or respiratory or hepatic insufficiency porphyria a history of alcoholism diabetes mellitus (baclofen may increase blood glucose concentrations) hypertension (see INTERACTIONS WITH OTHER MEDICINES). Since unwanted effects are more likely to occur, a cautious dosage schedule should be adopted in elderly and patients with spasticity. Baclofen is not recommended in Parkinson's disease or spasticity arising from strokes, cerebral palsy or rheumatoid disorders.

Baclofen should be used with caution in patients who use spasticity to maintain an upright posture and balance in moving. If an undesirable degree of muscular hypotonia occurs, making it more difficult for patients to walk or fend for themselves, this can usually be relieved by adjusting the dosage (i.e. by reducing the doses given during the day and possibly increasing the evening dose). During treatment with baclofen, neurogenic disturbances affecting emptying of the bladder may improve, whereas in patients with pre-existing sphincter hypertonia, acute retention of urine may occur. The drug should, therefore, be used with caution in such cases.

Since baclofen is largely eliminated by the kidneys, a dosage reduction is advised to avoid drug accumulation. Clofen should be used with caution in patients with renal insufficiency and should only be administered to end stage renal failure patients only if the expected benefit outweighs the potential risk (see DOSAGE AND ADMINISTRATION -Renal impairment). 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. 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.

Because baclofen is partially metabolised in the liver, patients with impaired hepatic function should be periodically monitored with laboratory tests (see DOSAGE AND ADMINISTRATION - Monitoring Advice).

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

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

In two teratogenic studies in pregnant rats, baclofen has been shown to increase the incidence of omphaloceles (ventral hernias) in foetuses, at a dose of 20 mg/kg/day, which is maternotoxic. The relevance of this finding to humans is unknown. At the same dose there was also an increased incidence of incomplete sternebral ossification in the foetuses. In mice, no teratogenic effects were observed at a dose of 81.5 mg/kg/day given via the diet or up to 40 mg/kg/day given by gavage. At 40 mg/kg/day by gavage, a delay in foetal growth was associated with maternal anorexia. The lack of maternotoxicity seen in the dietary study suggests that the dose used was inadequate. In pregnant rabbits, oral doses up to 10 mg/kg/day were manifested as a sedative effect. Skeletal examination of foetuses revealed a marked increase in the absence of ossification of the phalangeal nuclei of fore limbs and hind limbs. There are no adequate and well-controlled studies in pregnant women. Baclofen crosses the placental barrier and should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. One case of suspected withdrawal reaction (generalized convulsions) has been reported in a week-old infant whose mother had taken baclofen during pregnancy. The convulsions, which were refractory to standard anticonvulsant treatment, ceased within 30 minutes of giving baclofen to infant.

Studies in lactating women are limited to one (1) patient. In this particular case, available evidence suggests that baclofen is found in quantities so small that undesirable effects in the infant would have been unlikely.

Baclofen should be given with extreme caution to children under 16 years, as only limited data are available.

A two year carcinogenicity study in rats found no evidence that baclofen had carcinogenic potential at oral doses up to 100 mg/kg/day. An apparently dose related increase in the incidence of ovarian cysts and of enlarged and/or haemorrhagic adrenals at the highest two doses (50 and 100 mg/kg/day) was observed in female rats. The clinical relevance of these findings is not known. Ovarian cysts have been found by palpation in about 5% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are known to occur spontaneously in a proportion of the normal female population.

Baclofen did not induce mutations in bacterial or mammalian cells in vitro, lacked DNA damaging activity in the sister chromatid exchange assay, and had no clastogenic activity in the nuclear anomaly test.

Baclofen may be associated with adverse effects such as dizziness, sedation, somnolence and visual disturbance (see ADVERSE EFFECTS) which may impair the patient's reaction. Patients experiencing these adverse reactions should be advised to refrain from driving or using machines. The patient's ability to react may be adversely affected by sedation and decreased alertness caused by baclofen. Patients should, therefore, exercise due caution when driving a vehicle or operating machinery.

INTERACTIONS WITH OTHER MEDICINES

Increased sedation may occur where baclofen is taken concomitantly with other drugs causing CNS depression including other muscle relaxants (such as tizanidine), with synthetic opiates or with alcohol (see PRECAUTIONS). The risk of respiratory depression is also increased.

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

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

The concurrent use of baclofen with monoamine oxidase inhibitors (MAOIs) may result in increased CNS-depressant and hypotensive effects. Caution is recommended and dosage of one or both agents may require reduction. Since baclofen may increase blood glucose concentrations, dosage adjustments of insulin and/or oral hypoglycaemic agents may be necessary during and after concurrent therapy. Studies in rats indicate that the agonistic effects of baclofen on gastric acid secretion are potentiated by diazepam.

Since concomitant treatment with baclofen and antihypertensive agents is likely to increase the risk of hypotension, the dosage of antihypertensive medication should be adjusted accordingly.

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, headaches, 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.

Drugs or medical products that can significantly impact renal function may reduce baclofen excretion leading to toxic effects (see PRECAUTIONS - Impaired renal function).

ADVERSE EFFECTS

Unwanted effects mainly occur at the start of treatment (e.g. sedation, somnolence), if the dosage is increased too quickly, if large doses are used, or if the patient is elderly. They are often transitory and can be attenuated or eliminated by reducing the dosage. They may necessitate withdrawal of the medication. In patients with a history of psychiatric illness, cortical or organic brain disorders, or with cerebrovascular disorders (such as stroke), as well as elderly patients, adverse reactions may be more serious. It is often difficult to distinguish whether some of these are drug effects or manifestations of the diseases under treatment. Psychiatric manifestations can occur in acute or chronic toxicity due to baclofen. Lowering of the convulsion threshold and convulsions may occur, particularly in epileptic patients (see PRECAUTIONS). Certain patients have shown increased muscle spasticity as a paradoxical reaction to the medication. 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 (>=1/1,000, <1/100); rare (>=1/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).

Cardiac disorders

Common:cardiac output decreased Rare:arrhythmias, palpitations, chest pain Not known:bradycardia

Vascular disorders

Common:hypotension Rare:dyspnoea, ankle oedema

Gastrointestinal disorders

Very common:nausea (particularly at the start of treatment) Common:gastrointestinal disorder, constipation, diarrhoea, retching, vomiting Rare:colicky abdominal pain, anorexia

Hepatobiliary disorders

Rare:hepatic function abnormal

Nervous system disorders

Very common:sedation, somnolence Common:respiratory depression, fatigue, confusional state, dizziness, personality changes, vertigo, headache, insomnia, euphoric mood, depression, muscular weakness, ataxia, tremor, hallucination, nightmare, myalgia, nystagmus, dry mouth, tinnitus Rare:paresthesiae, dysarthria, dysgeusia, syncope, dyskinesia, coma, taste disturbances Very rare:hypothermia

Eye disorders

Common:accommodation disorders, visual impairment

Skin and subcutaneous tissue disorders

Common:hyperhidrosis, rash, pruritus Not known:urticaria

Renal and urinary disorders

Common:pollakiuria, dysuria, enuresis Rare:urinary retention, nocturia, haematuria

Reproductive system and breast disorders

Rare:erectile dysfunction, inability to ejaculate

General disorders and administration site conditions

Very rare:hypothermia Not known:drug withdrawal syndrome

Investigations

Not known:blood glucose increase

Miscellaneous

Rare:nasal congestion, weight gain

DOSAGE AND ADMINISTRATION

Treatment with baclofen should always be started in hospital, using small doses which are then gradually increased stepwise. The lowest dose compatible with an optimal response is recommended. The optimum daily dosage should be individually adapted to each patient's requirements, so that clonus, flexor and extensor spasms, and spasticity are reduced, at the same time retaining enough muscle tone to permit active movements and avoiding adverse effects as far as possible. In order to prevent excessive weakness and falling, baclofen 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. Abrupt discontinuation of treatment should be avoided (see PRECAUTIONS). Clofen should be taken during meals with a little liquid. In adults Clofen should be given in at least three divided doses daily.

As a rule, treatment should be started with a dose of 5 mg three times daily, subsequently increased at three-day intervals by 5 mg three times daily (ie. the dosage regimen is 5 mg three times a day for three days, then 10 mg three times a day for three days, etc.) until the optimum response has been attained. In certain patients reacting sensitively to drugs, it may be advisable to begin with a lower daily dose (5 or 10mg), increased by smaller steps at longer intervals. The optimum dosage generally ranges from 30 to 75 mg daily, although occasionally in hospitalised patients daily doses up to 100 mg may be necessary. If no benefit is apparent within 6 to 8 weeks of achieving the maximum dosage, a decision whether or not to continue treatment with baclofen should be made. 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 PRECAUTIONS).

In patients with impaired renal function or undergoing chronic haemodialysis, low doses (ie. approximately 5 mg daily) should be used. Signs and symptoms of overdosage have been reported with doses above 5 mg daily in this setting (see OVERDOSAGE). Clofen should only be administered to end stage renal failure patients when benefit outweighs risk. These patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (e.g. somnolence, lethargy) (see OVERDOSAGE).

No studies have been performed in patients with hepatic impairment under baclofen therapy. Baclofen should be prescribed with caution in patients with hepatic impairment (see PRECAUTIONS).

Since unwanted effects are more likely to occur in elderly patients (due to increased risk of renal function impairment and CNS toxicity), a very cautious dosage schedule should be adopted and the patient kept under appropriate surveillance. Toxicity due to baclofen may be taken for uraemic encephalopathy.

Baclofen should be given with extreme caution to children under 16 years, as only limited data are available. Clofen tablets are not suitable for use in children below 33 kg body weight.

Since in rare instances elevated AST, alkaline phosphatase or glucose levels in the serum have been recorded, appropriate laboratory tests should be performed periodically in patients with liver diseases or diabetes mellitus, in order to ensure that no drug-induced changes in these underlying diseases have occurred. Careful monitoring of respiratory and cardiovascular function is essential especially in patients with cardiopulmonary disease and respiratory muscle weakness.

OVERDOSAGE

Prominent features are signs of central nervous depression: drowsiness, impairment of consciousness, respiratory depression due to absent respiratory movement, coma. Also liable to occur are: confusion, hallucinations, agitation, EEG changes (burst suppression pattern and triphasic waves), accommodation disorders, impaired pupillary reflex; generalised muscular hypotonia, myoclonus, hyporeflexia or areflexia; convulsions; peripheral vasodilatation, hypotension or hypertension, bradycardia or tachycardia or cardiac arrthythmias; hypothermia; nausea, vomiting, diarrhoea, hypersalivation; increased hepatic enzymes. 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. Adult patients have ingested up to 1,125 mg of baclofen and survived. Ingestion of 1,250 to 2,500 mg by one patient was fatal. Serious poisoning has occurred with doses of 150 and 300 mg in adults.

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. Symptomatic treatment should include the following: elimination of the drug from the gastrointestinal tract eg. administration of activated charcoal; if necessary, saline laxatives since the drug is excreted chiefly via the kidneys, generous quantities of fluid should be given, possibly together with a diuretic measures in support of cardiovascular functions in the case of respiratory muscle weakness, administration of artificial respiration in the event of convulsions, diazepam should be administered cautiously intravenously, paying attention to increased muscle relaxation, and possible respiratory insufficiency, if the patient is not already being artificially ventilated. haemodialysis (some times unscheduled) may be useful in severe poisoning associated with renal failure (see PRECAUTIONS). Contact the Poisons Information Centre on 131126 (Australia) for advice on management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

10mg tablet: white, flat bevelled edged, marked "BN" breakline "10" on one side and "G" on the other; available in bottles of 100s.

25mg tablet: white, flat bevelled edged, marked "BN" breakline "25" on one side and "G" on the other; available in bottles of 100s.

POISON SCHEDULE OF THE MEDICINE

NAME AND ADDRESS OF THE SPONSOR

(ABN 93 002 359 739) Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 www.alphapharm.com.au

NAME OF THE MEDICINE