| Lioresal® Intrathecal Injection 50micrograms/1ml Lioresal® Intrathecal Infusion 10mg/20ml Lioresal® Intrathecal Infusion 10mg/5ml | : : : | 3 years 5 years 3 years |
If alternative baclofen concentrations are required Lioresal Intrathecal may be diluted under aseptic conditions with sterile preservative-free sodium chloride for injections. The ampoules should not be mixed with other solutions for injection or infusion (dextrose has proved to be incompatible due to a chemical reaction with baclofen).
The compatibility of Lioresal Intrathecal with the components of the infusion pump (including the chemical stability of baclofen in the reservoir) and the presence of an in-line bacterial retentive filter should be confirmed with the pump manufacturer prior to use.
Sodium chloride; water for injections
Local tolerance
Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent.
Mutagenicity and carcinogenicty
Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. There was no evidence of a mutagenic potential of baclofen
A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or haemorrhagic adrenal glands was observed.
Repeated dose toxicity
Repeated intrathecal administration of baclofen was not associated with the development of inflammatory masses in studies in rats and dogs. No changes to the spinal cord and adjacent tissue and no signs of irritation or inflammation of the spinal cord and surrounding tissues were noted in either species.
Reproduction toxicity
Intrathecal baclofen is unlikely to have adverse effects on fertility or on prenatal or postnatal development based on oral studies in rats and rabbits. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Lioresal given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. Lioresal dosed orally has been shown to cause delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat fetuses at a high intraperitoneal dose.
Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.
Absorption
Direct infusion into the spinal subarachnoid space by-passes absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
Distribution
After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 ml.
With continuous intrathecal infusion daily doses of 50 to 1200 micrograms result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/ml at steady state. According to the half-life measured in the CSF, CSF steady-state concentrations will be reached within 1-2 days.
During intrathecal infusion the plasma concentrations do not exceed 5ng/ml, confirming that baclofen passes only slowly across the blood-brain barrier.
Elimination
The elimination half-life in the CSF after single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms baclofen ranges from 1 to 5 hours. Elimination half-life of baclofen after having reached steady-state in the CSF has not been determined.
After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance was about 30 ml/h.
At steady-state conditions during continuous intrathecal infusion, a baclofen concentration gradient is built up in the range between 1.8 : 1 and 8.7 : 1 (mean: 4 : 1) from lumbar to cisternal CSF. This is of clinical importance insofar as spasticity in the lower extremities can be effectively treated with little effect on the upper limbs and with fewer CNS adverse reactions due to effects on the brain centres.
Special populations
Elderly Patients
No pharmacokinetic data is available in elderly patients after administration of Lioresal Intrathecal. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower elimination but a similar systemic exposure to baclofen compared to young adults. However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.
Paediatrics
In paediatric patients, respective plasma concentrations are at or below 10 ng/mL.
Hepatic impairment
No pharmacokinetic data is available in patients with hepatic impairment after administration of Lioresal Intrathecal. However, as liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.
Renal impairment
No pharmacokinetic data is available in patients with renal impairment after administration of Lioresal Intrathecal. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment can not be excluded.
26 June 2017
Novartis Pharmaceuticals UK Limited
Trading as Ciba Laboratories
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
England.
Protect from heat (store below 30°C).
Medicines should be kept out of the reach and sight of children.
Colourless glass ampoules, glass type I, according to Ph. Eur.
| Lioresal® Intrathecal Injection 50micrograms/1ml Lioresal® Intrathecal Infusion 10mg/20ml Lioresal® Intrathecal Infusion 10mg/5ml | : : : | PL 00101/0500 PL 00101/0501 PL 00101/0502 |
Each ampoule is intended for single use only, and any unused solution should be discarded. Ampoules should not be either frozen or autoclaved.
| Lioresal® Intrathecal Injection 50micrograms/1ml Lioresal® Intrathecal Infusion 10mg/20ml Lioresal® Intrathecal Infusion 10mg/5ml | : : : | 31 January 2003 31 January 2003 3 September 2004 |
