Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antispastic with spinal site attack, ATC code: M03B X01 
Lioresal is an antispastic agent acting at the spinal level. A gamma-aminobutyric acid (GABA) derivative, Lioresal is chemically unrelated to other antispastic agents.

Lioresal depresses monosynaptic and polysynaptic reflex transmission, probably by stimulating the GABAB-receptors, this stimulation in turn inhibiting the release of the excitatory amino acids glutamate and aspartate. Neuromuscular transmission is unaffected by Lioresal.

The major benefits of Lioresal stem from its ability to reduce painful flexor spasms and spontaneous clonus thereby facilitating the mobility of the patient, increasing his independence and helping rehabilitation.

Lioresal 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption: Lioresal (baclofen) is rapidly and completely absorbed from the gastro- intestinal tract. No significant difference between the liquid and tablet formulations is observed in respect of Tmax, Cmax and bioavailability. Following oral administration of single doses (10-30mg) 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, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive.

Elimination/excretion: The plasma elimination half-life of baclofen averages 3 to 4 hours.

Baclofen is eliminated largely in unchanged form. Within 72 hours, approximately 75% of the dose is excreted via the kidneys with about 5% of this amount as metabolites.

Special populations

Elderly patients (aged 65 years or above)
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
LIO API MAY24 V2                                                                     Page 8 of 10 Following oral administration of 2.5 mg Lioresal tablet in children (aged 2 to12 years), Cmax of 62.8±28.7 nanogram/mL, and Tmax in the range of 0.95-2 h 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 Lioresal. 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 Lioresal. 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.