1 Name of Medicine
The active ingredient of Lioresal is a gamma-aminobutyric acid derivative, baclofen, or β-(aminomethyl)-p-chlorohydrocinnamic acid, a racaemic mixture of the R(-) and S(+) isomers.
2 Qualitative and Quantitative Composition
Baclofen is a white or almost white, odourless or practically odourless, crystalline powder. It is slightly soluble in water, very slightly soluble in methanol and insoluble in chloroform.
Lioresal tablets contain 10 mg or 25 mg baclofen. The tablets also contain the following excipients: colloidal anhydrous silica, microcrystalline cellulose, magnesium stearate, povidone, wheat starch.
Excipient with known effect. Wheat starch. Wheat starch may contain gluten, but only in trace amounts.
3 Pharmaceutical Form
Tablets containing baclofen 10 mg: white, round, flat with bevelled edges; marked with KJ and score, CG on reverse.
Tablets containing baclofen 25 mg: white, round, flat with bevelled edges; marked with UR and score, CG on reverse.
4 Clinical Particulars
4.9 Overdose
Signs and symptoms. Prominent features are signs of central nervous depression or encephalopathy: somnolence, depressed level of consciousness, respiratory depression due to absent respiratory movement, coma.
Also liable to occur are: confusion, hallucinations, agitation, abnormal electroencephalogram (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, tachycardia or cardiac arrhythmias, hypothermia, nausea, vomiting, diarrhoea, salivary hypersecretion; increased hepatic enzymes, sleep apnoea, rhabdomyolysis, tinnitus.
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.
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.
Symptomatic treatment should include the following:
Elimination of the drug from the gastrointestinal tract, e.g. 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 i.v., paying attention to increased muscle relaxation and possible respiratory insufficiency, if the patient is not already being artificially ventilated.
Haemodialysis (sometimes unscheduled) may be useful in severe poisoning associated with renal failure (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. 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.
Animal data. In two teratogenic studies in pregnant rats, baclofen has been shown to increase the incidence of omphalocoeles (ventral hernias) in fetuses, 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 fetuses.
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 fetal 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 fetuses revealed a marked increase in the absence of ossification of the phalangeal nuclei of fore-limbs and hind-limbs.
Carcinogenicity. 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 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 Lioresal 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.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. The chemical structure of baclofen is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSBACLFE.gif CAS number. 1134-47-0.
Empirical formula: C10H12ClNO2.
Molecular weight: 213.67.
7 Medicine Schedule (Poisons Standard)
Poison schedule: 4 - Prescription Only Medicine.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/LIORELST.gif
