LIORESAL INTRATHECAL INJECTION 50MICROGRAMS/1ML

Active substance: BACLOFEN

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PRODUCT SUMMARY
1.

NAME OF THE MEDICINAL PRODUCT

Lioresal ® Intrathecal Injection 50micrograms/1ml

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance
b-(Aminomethyl)-p-chlorohydrocinnamic acid (= baclofen), a racemic mixture of the
R, (-) and S, (+) isomers.
One ampoule of 1 ml contains 50 micrograms baclofen, (50 micrograms/ml).
For excipients see section 6.1 List of excipients

3.

PHARMACEUTICAL FORM
Solutions for intrathecal injection and intrathecal infusion.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Lioresal Intrathecal is indicated in patients with severe chronic spasticity of spinal or
cerebral origin (associated with injury, multiple sclerosis, cerebral palsy) who are
unresponsive to oral baclofen or other orally administered antispastic agents and/or
those patients who experience unacceptable side-effects at effective oral doses.
In patients with spasticity due to head injury a delay of at least one year before
treatment with Lioresal Intrathecal is recommended, to allow the symptoms of
spasticity to stabilise.
Lioresal Intrathecal may be considered as an alternative to ablative neurosurgical
procedures.
Paediatric population

Lioresal Intrathecal is indicated in patients aged 4 to <18 years with severe chronic
spasticity of cerebral origin or of spinal origin (associated with injury, multiple
sclerosis, or other spinal cord diseases) who are unresponsive to orally administered
antispastics (including oral baclofen) and/or who experience unacceptable side effects
at effective oral doses.
4.2

Posology and method of administration
Intrathecal administration of Lioresal through an implanted delivery system should
only be undertaken by physicians with the necessary knowledge and experience.
Specific instructions for implantation, programming and/or refilling of the
implantable pump are given by the pump manufacturers, and must be strictly adhered
to.
Lioresal Intrathecal 50 micrograms/1ml is intended for administration in single bolus
test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable
pumps suitable for continuous administration of Lioresal Intrathecal 10mg/20ml and
10mg/5ml into the intrathecal space (EU certified pumps). Establishment of the
optimum dose schedule requires that each patient undergoes an initial screening phase
with intrathecal bolus, followed by a very careful individual dose titration prior to
maintenance therapy.
Respiratory function should be monitored and appropriate resuscitation facilities
should be available during the introduction of treatment with Lioresal Intrathecal.
Intrathecal administration using an implanted delivery system should only be
undertaken by physicians with appropriate knowledge and experience. Specific
instructions for using the implantable pump should be obtained from the pump
manufacturers. Only pumps constructed of material known to be compatible with the
product and incorporating an in-line bacterial retentive filter should be used.
Adult Screening Phase
Prior to initiation of a chronic infusion, the patient's response to intrathecal bolus
doses administered via a catheter or lumbar puncture must be assessed. Low
concentration ampoules containing 50 micrograms baclofen in 1ml are available for
the purpose. Patients should be infection-free prior to screening, as the presence of a
systemic infection may prevent an accurate assessment of the response.
The usual initial test dose in adults is 25 or 50 micrograms, increasing step-wise by
25 microgram increments at intervals of not less than 24 hours until a response of
approximately 4 to 8 hours duration is observed. Each dose should be given slowly
(over at least one minute). In order to be considered a responder the patient must
demonstrate a significant decrease in muscle tone and/or frequency and/or severity of
muscle spasms.
The variability in sensitivity to intrathecal baclofen between patients is emphasised.
Signs of severe overdose (coma) have been observed in an adult after a single test
dose of 25 micrograms. It is recommended that the initial test dose is administered
with resuscitative equipment on hand.
Patients who do not respond to a 100 micrograms test dose should not be given
further dose increments or considered for continuous intrathecal infusion.

Monitoring of respiratory and cardiac function is essential during this phase,
especially in patients with cardiopulmonary disease and respiratory muscle weakness
or those being treated with benzodiazepine-type preparations or opiates, who are at
higher risk of respiratory depression.
Paediatric population Screening Phase
The initial lumbar puncture test dose for patients 4 to <18 years of age should be 2550 micrograms/day based upon age and size of the child. Patients who do not
experience a response may receive a 25 microgram/day dose escalation every 24
hours. The maximum screening dose should not exceed 100 micrograms/day in
paediatric patients.
Dose-Titration Phase
Once the patient's responsiveness to Lioresal Intrathecal has been established, an
intrathecal infusion may be introduced. Lioresal Intrathecal is most often
administered using an infusion pump which is implanted in the chest wall or
abdominal wall tissues. Implantation of pumps should only be performed in
experienced centres to minimise risks during the perioperative phase.
Infection may increase the risk of surgical complications and complicate attempts to
adjust the dose.
The initial total daily infused dose is determined by doubling the bolus dose which
gave a significant response in the initial screening phase and administering it over a
24 hour period. However, if a prolonged effect (i.e. lasting more than 12 hours) is
observed during screening the starting dose should be the unchanged screening dose
delivered over 24 hours. No dose increases should be attempted during the first 24
hours.
After the initial 24 hour period dosage should be adjusted slowly to achieve the
desired clinical effect. If a programmable pump is used the dose should be increased
only once every 24 hours; for non-programmable multi-dose reservoir pumps
intervals of 48 hours between dose adjustments are recommended. In either case
increments should be limited as follows to avoid possible overdosage:
Patients with spasticity of spinal origin:
daily dose
Patients with spasticity of cerebral origin:
dose.

10-30% of the previous
5-15% of the previous daily

If the dose has been significantly increased without apparent clinical effect pump
function and catheter patency should be investigated.
There is limited clinical experience using doses greater than 1000 micrograms/day.
It is important that patients are monitored closely in an appropriately equipped and
staffed environment during screening and immediately following pump implantation.
Resuscitative equipment should be available for immediate use in case of lifethreatening adverse reactions.
Adult Maintenance Therapy
The clinical goal is to maintain as normal a muscle tone as possible, and to minimise
the frequency and severity of spasms without inducing intolerable side effects. The
lowest dose producing an adequate response should be used. The retention of some
spasticity is desirable to avoid a sensation of "paralysis" on the part of the patient. In

addition, a degree of muscle tone and occasional spasms may help support circulatory
function and possibly prevent the formation of deep vein thrombosis.
In patients with spasticity of spinal origin maintenance dosing for long-term
continuous infusions of intrathecal baclofen has been found to range from 12 to 2003
micrograms/day, with most patients being adequately maintained on 300 to 800
micrograms/day.
In patients with spasticity of cerebral origin maintenance dosage has been found to
range from 22 to 1400 micrograms/day, with a mean daily dosage of 276 micrograms
per day at 12 months and 307 micrograms per day at 24 months.
Paediatric population Maintenance Therapy
In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial
maintenance dosage for long-term continuous infusion of Lioresal Intrathecal ranges
from 25 to 200 micrograms/day (median dose: 100 micrograms/day). The total daily
dose tends to increase over the first year of therapy, therefore the maintenance dose
needs to be adjusted based on individual clinical response. There is limited
experience with doses greater than 1,000 micrograms/day.
The safety and efficacy of Lioresal Intrathecal for the treatment of severe spasticity of
cerebral or spinal origin in children younger than 4 years of age have not been
established (also see section 4.4).
Delivery specifications
Lioresal Intrathecal ampoules of 20ml containing 500 micrograms/ml and 5ml
containing 2mg (2000micrograms)/ml are intended for use with infusion pumps. The
concentration to be used depends on the dose requirements and size of pump
reservoir. Use of the more concentrated solution obviates the need for frequent refilling in patients with high dosage requirements.
Delivery regimen
Lioresal Intrathecal is most often administered in a continuous infusion mode
immediately following implant. After the patient has stabilised with regard to daily
dose and functional status, and provided the pump allows it, a more complex mode of
delivery may be started to optimise control of spasticity at different times of the day.
For example, patients who have increased spasm at night may require a 20 % increase
in their hourly infusion rate. Changes in flow rate should be programmed to start two
hours before the desired onset of clinical effect.
Most patients require gradual dose increases to maintain optimum response during
chronic therapy due to decreased responsiveness or disease progression. In patients
with spasticity of spinal origin the daily dose may be increased gradually by 10-30%
to maintain adequate symptom control. Where the spasticity is of cerebral origin any
increase in dose should be limited to 20% (range: 5-20%). In both cases the daily
dose may also be reduced by 10-20% if patients suffer side effects.
A sudden requirement for substantial dose escalation is indicative of a catheter
complication (i.e. a kink or dislodgement) or pump malfunction.
In order to prevent excessive weakness the dosage of Lioresal Intrathecal should be
adjusted with caution whenever spasticity is required to maintain function.
During long-term treatment approximately 5% of patients become refractory to
increasing doses due to tolerance or drug delivery failure (see Section 4.4 – Special

Warnings and Precautions for Use “Treatment Withdrawal” section). This
“tolerance” may be treated by gradually reducing Lioresal Intrathecal dose over 2 to 4
week period and switching to alternative methods of spasticity management (e.g.
Intrathecal preservative-free morphine sulphate). Lioresal Intrathecal should be
resumed at the initial continuous infusion dose. Caution should be exercised when
switching from Lioresal Intrathecal to morphine and vice versa (see section 4.5).
Discontinuation
Except in overdose-related emergencies, the treatment with Lioresal Intrathecal
should always be gradually discontinued by successively reducing the dosage.
Lioresal Intrathecal should not be discontinued suddenly (see section 4.4).
Special populations
Renal impairment
No studies have been performed in patients with renal impairment receiving Lioresal
Intrathecal therapy. Because baclofen is primarily excreted unchanged by the kidneys
(see section 5.2) it should be given with special care and caution in patients with
impaired renal function (see section 4.4).
Hepatic impairment
No studies have been performed in patients with hepatic impairment receiving
Lioresal Intrathecal therapy. No dosage adjustment is recommended as the liver does
not play any significant role in the metabolism of baclofen after intrathecal
administration of Lioresal. Therefore, hepatic impairment is not expected to impact
the drug systemic exposure (see section 5.2).
Elderly population
Several patients over the age of 65 years have been treated with Lioresal Intrathecal
during the clinical trials without increased risks compared to younger patients.
Problems specific to this age group are not expected as doses are individually titrated.

4.3

Contraindications

Known hypersensitivity to baclofen or any of its excipients (see section 6.1)
The drug should not be administered by any route other than intrathecal.

4.4

Special warnings and precautions for use
Intrathecal baclofen therapy is valuable but hazardous. Careful pre-operative
assessment is mandatory.
The patient must be given adequate information regarding the risks of this mode of
treatment, and be physically and psychologically able to cope with the pump. It is
essential that the responsible physicians and all those involved in the care of the
patient receive adequate instruction on the signs and symptoms of overdose,

procedures to be followed in the event of an overdose and the proper home care of the
pump and insertion site.
Inflammatory mass at the tip of the implanted catheter: cases of inflammatory mass
at the tip of the implanted catheter that can result in serious neurological impairment,
including paralysis, have been reported. Although they have been reported with
Lioresal intrathecal, they have not been confirmed by contrast MRI or histopathology.
The most frequent symptoms associated with inflammatory mass are: 1) decreased
therapeutic response (worsening spasticity, return of spasticity when previously well
controlled, withdrawal symptoms, poor response to escalating doses, or frequent or
large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should
monitor patients on intraspinal therapy carefully for any new neurological signs or
symptoms. Clinicians should use their medical judgement regarding the most
appropriate monitoring specific to their patients’ medical needs to identify prodromal
signs and symptoms for inflammatory mass especially if using pharmacy
compounded drugs or admixtures that include opioids. In patients with new
neurological signs or symptoms suggestive of an inflammatory mass, consider a
neurosurgical consultation since many of the symptoms of inflammatory mass are not
unlike the symptoms experienced by patients with severe spasticity from their
disease. In some cases, performance of an imaging procedure may be appropriate to
confirm or rule-out the diagnosis of an inflammatory mass.
Pump Implantation
Patients should be infection-free prior to pump implantation because the presence of
infection may increase the risk of surgical complications. Moreover, a systemic
infection may complicate attempts to adjust the dose. A local infection or catheter
malplacement can also lead to drug delivery failure, which may result in sudden
Lioresal Intrathecal withdrawal and its related symptoms (see Section 4.4 – Special
Precautions for Use “Treatment Withdrawal” section).
Reservoir refilling
Reservoir refilling must be performed by trained and qualified personnel in
accordance with the instructions provided by the pump manufacturer. Refills should
be timed to avoid excessive depletion of the reservoir, as this would result in the
return of spasticity or potentially life-threatening symptoms of Lioresal Intrathecal
withdrawal (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal”
section).
When refilling the pump care should be taken to avoid discharging the contents of the
catheter into the intrathecal space.
Strict asepsis is required to avoid microbial contamination and infection.
Extreme caution must be taken when filling a pump equipped with an injection port
that allows direct access to the intrathecal catheter as a direct injection into the
catheter through the access port could cause a life-threatening overdose.
Precautions in paediatric patients
For patients with spasticity due to head injury, it is recommended not to proceed to
long-term Lioresal Intrathecal therapy until the symptoms of spasticity are stable (i.e.
at least one year after the injury).
Children should be of sufficient body mass to accommodate the implantable pump for
chronic infusion. Use of Lioresal Intrathecal in the paediatric population should be
only prescribed by medical specialists with the necessary knowledge and experience.

There is very limited clinical data regarding the safety and efficacy of the use of
Lioresal Intrathecal in children under the age of four years.
Precautions in special patient populations
In patients with abnormal CSF flow the circulation of drug and hence antispastic
activity may be inadequate.
Psychotic disorders, schizophrenia, confusional states or Parkinson’s disease
may be exacerbated by treatment with oral Lioresal. Patients suffering from these
conditions should therefore be treated cautiously and kept under close surveillance.
Special attention should be given to patients known to suffer from epilepsy as
seizures have occasionally been reported during overdose with, and withdrawal from,
Lioresal Intrathecal as well as in patients maintained on therapeutic doses.
Lioresal Intrathecal should be used with caution in patients with a history of
autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of
Lioresal Intrathecal may precipitate an autonomic dysreflexic episode.
Lioresal should be used with caution in patients with cerebrovascular or
respiratory insufficiency.
An effect of Lioresal Intrathecal on underlying, non-CNS related diseases is
unlikely because its systemic availability is substantially lower than after oral
administration. Observations after oral baclofen therapy suggest that caution should
be exercised in patients with a history of peptic ulcers and pre-existing sphincter
hypertonia.
Renal impairment
After oral Lioresal dosing severe neurological outcomes have been reported in
patients with renal impairment. Thus caution should be exercised while administering
Lioresal Intrathecal in patients with renal impairment.
In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the
serum have been recorded when using oral Lioresal.
Treatment withdrawal
Abrupt discontinuation of Lioresal Intrathecal, regardless of cause, manifested by
increased spasticity, pruritus, paraesthesia and hypotension, has resulted in sequelae
including a hyperactive state with rapid uncontrolled spasms, hyperthermia and
symptoms consistent with neuroleptic malignant syndrome, e.g. altered mental status
and muscle rigidity. In rare cases this has advanced to seizures/status epilepticus,
rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients
receiving intrathecal baclofen therapy are potentially at risk for withdrawal.
Some clinical characteristics associated with intrathecal baclofen withdrawal may
resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia,
neuroleptic-malignant syndrome, or other conditions associated with a
hypermetabolic state or widespread rhabdomyolysis.
Patients and caregivers should be advised of the importance of keeping scheduled
refill visits and should be educated on the signs and symptoms of baclofen
withdrawal particularly those seen early in the withdrawal syndrome.

In most cases, symptoms of withdrawal appeared within hours to a few days
following interruption of baclofen therapy. Common reasons for abrupt interruption
of intrathecal baclofen therapy included malfunction of the catheter (especially
disconnection), low volume in the pump reservoir and end of pump battery life.
Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention
to programming and monitoring of the infusion system, refill scheduling and
procedures, and pump alarms. The suggested treatment for intrathecal Lioresal
withdrawal is the restoration of intrathecal Lioresal at or near the same dosage as
before therapy was interrupted. However, if restoration of intrathecal delivery is
delayed, treatment with GABA-ergic agonist drugs such as oral or enteral Lioresal, or
oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae.
Oral or enteral Lioresal alone should not be relied upon to halt the progression of
intrathecal baclofen withdrawal.

4.5

Interaction with other medicinal products and other forms of interaction
The co-administration of other intrathecal agents with Lioresal Intrathecal is not
recommended.
An attempt should be made to reduce or discontinue concomitant oral antispastic
medications, preferably before initiating baclofen infusion. However, abrupt
reduction or discontinuation during chronic intrathecal baclofen therapy should be
avoided.
There is little experience with the use of Lioresal Intrathecal in combination with
systemic medications to be able to predict specific drug-drug interactions, although it
is suggested that the low baclofen systemic exposure after intrathecal administration
could reduce the potential for pharmacokinetic interactions (see section 5.2).
Experience with oral baclofen would suggest that:






Alcohol and other compounds affecting the CNS: There may be increased
sedation where Lioresal is taken concomitantly with other drugs acting on the
CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines,
anxiolytics) or with alcohol.
Tricyclic antidepressants: During concurrent treatment with tricyclic
antidepressants, the effect of Lioresal may be potentiated, resulting in
muscular hypotonia.
Antihypertensives: Since concomitant treatment with Lioresal and antihypertensives is likely to increase the fall in blood pressure, it may be
necessary to reduce the dosage of antihypertensive medication.
Levodopa: Concomitant use of oral Lioresal and levodopa/dopadecarboxylase (DDC) inhibitor resulted in increased risk of adverse events
like visual hallucinations, confusional state, headache and nausea. Worsening
of the symptoms of Parkinsonism has also been reported. Thus, caution
should be exercised when intrathecal Lioresal is administered to patients
receiving levodopa/DDC inhibitor therapy.

Morphine

The combined use of morphine and intrathecal baclofen has been responsible for
hypotension in one patient; the potential for this combination to cause dyspnoea or
other CNS symptoms cannot be excluded.
Anaesthetics
Concomitant use of intrathecal baclofen and general anaesthetics (e.g. fentanyl,
propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution
should be exercised when anaesthetics are administered to patients receiving
intrathecal Lioresal.

4.6

Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Oral
baclofen increases the incidence of omphaloceles (ventral hernias) in the
foetuses of rats at high doses. No teratogenic effects have been noted in mice
or rabbits.
A dose related increase in the incidence of ovarian cysts, and a less marked
increase in enlarged and/or haemorrhagic adrenals have been observed in
female rats treated for 2 years. The clinical relevance of these findings is not
known.
Lioresal Intrathecal should not be used during pregnancy unless the potential
benefit is judged to outweigh the potential risk to the foetus. Baclofen crosses
the placental barrier.
Lactation
In mothers taking oral 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. It is not known whether detectable
levels of drug are present in the breast milk of nursing mothers receiving
Lioresal Intrathecal.

4.7

Effects on ability to drive and use machines
Central nervous system (CNS) depressant effects such as somnolence and
sedation have been reported in some patients receiving intrathecal baclofen,
and patients should be advised to exercise due caution. Other listed events
include ataxia, hallucinations, vision blurred, diplopia and withdrawal
symptoms. Operating equipment or machinery may be hazardous.

4.8

Undesirable effects

Some of the adverse reactions listed below have been reported in patients with
spasticity of spinal origin but could also occur in patients with spasticity of cerebral
origin. Adverse reactions that are more frequent in either population are indicated
below.
Adverse drug reactions (Table 1) are listed according to system organ classes in
MedDRA. Within each system organ class, the adverse drug reactions are ranked
under headings of frequency, the most frequent reactions first. Within each
frequency grouping, adverse drug reactions are presented in order of decreasing
seriousness. In addition, the corresponding frequency category using the following
convention (CIOMS III) is also provided for each adverse drug reaction: very
common (≥1/10); common ( ≥1/100 to <1/10); uncommon ( ≥1/1,000 to <1/100);
rare ( ≥1/10,000 to<1/1,000); very rare (<1/10,000), and Not known (cannot be
estimated from available data).
Table 1

Adverse drug reactions

Metabolism and nutritional disorders
Uncommon:
Dehydration
Psychiatric disorders
Common:
Depression, anxiety, agitation.
Uncommon:
Suicidal ideation, suicide attempt, hallucinations, paranoia,
euphoric mood.
Not known:
Dysphoria
Nervous system disorders
Very common:
Somnolence
Common:
Convulsion, confusional state, sedation, dizziness, headache,
paraethesia, dysarthria, lethargy, insomnia, disorientation,
Uncommon:
Ataxia, memory impairment, nystagmus
(Convulsion and headache occur more often in patients with spasticity of cerebral origin than
in patients with spasticity of spinal origin).
Eye disorders
Common:
Accommodation disorder, vision blurred, diplopia.
Cardiovascular disorders
Uncommon:
Bradycardia,
Vascular disorders
Common:
Hypotension
Uncommon:
Hypertension, deep vein thrombosis, flushing, pallor.
Respiratory, thoracic and mediastinal disorders
Common:
Respiratory depression, pneumonia, dyspnoea .
Not known:
Bradypnoea
Gastrointestinal disorders
Common:
Nausea/vomiting, constipation, dry mouth, diarrhoea,
decreased appetite,increased salivation.
Uncommon:
Ileus, dysphagia,hypogeusia.
(Nausea and vomiting occur more often in patients with spasticity of cerebral origin than in
patients with spasticity of spinal origin).
Skin and subcutaneous tissue disorders
Common:
Urticaria/pruritus, facial and/or peripheral oedema.
Uncommon:
Alopecia,hyperhydrosis.
Musculoskeletal and connective tissue disorders
Very common:
Hypotonia
Common:
Hypertonia

Renal and urinary disorders
Common:
Urinary incontinence, urinary retention
(Urinary retention occurs more often in patients with spasticity of cerebral origin than in
patients with spasticity of spinal origin).
Reproductive system and breast disorders
Common:
Sexual dysfunction (Intrathecal Lioresal may compromise
erection and ejaculation. This effect is usually reversible on
withdrawal of Lioresal Intrathecal.)
General disorders and administration site conditions
Common:
Asthenia, pyrexia, pain, chills.
Uncommon:
Hypothermia.
Rare:
Life threatening withdrawal symptoms due to drug delivery
failure (see section 4.4 – Special warnings and precautions for
use “Treatment Withdrawal”).
Adverse events associated with the delivery system
Adverse events associated with the delivery system (inflammatory mass at the tip of
the catheter, catheter dislocation with possible complications, pocket infection,
meningitis, overdose due to wrong manipulation of the device) have been reported.

4.9

Overdose

Special attention should be given to recognising the signs and symptoms of
overdosage at all times, but especially during the initial "screening" and
"dose-titration" phases and also during reintroduction of Lioresal Intrathecal after an
interruption of therapy.
Signs of overdose may appear suddenly or (more usually) insidiously.
Symptoms of overdose: excessive muscular hypotonia, drowsiness, light-headedness,
dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive
salivation, nausea and vomiting.
Respiratory depression, apnoea, and coma result from serious overdosage. Seizures
may occur with increasing dosage or, more commonly, during recovery from an
overdose. Serious overdose may occur through the inadvertent delivery of the
catheter contents, errors in pump programming, excessively rapid dose increases or
concomitant treatment with oral baclofen. Possible pump malfunction should also be
investigated.
Treatment
There is no specific antidote for treating overdoses of intrathecal baclofen. Any
instructions provided by the pump manufacturer should be followed, and the
following steps should generally be undertaken:


Where a programmable continuous infusion pump is used further delivery of
baclofen should be halted immediately by removal of residual drug solution
from the reservoir.






If it is possible to do so without surgical intervention the intrathecal catheter
should be disconnected from the pump as soon as possible, and infusion fluid
allowed to drain back together with some CSF (up to 30-40ml is suggested).
Patients with respiratory depression should be intubated if necessary, and
ventilated artificially if required. Cardiovascular functions should be
supported and in the event of convulsions, i.v. diazepam cautiously
administered.
Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate
should be monitored.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Antispastic with a spinal site of attack: (ATC Code: M03B X01).
Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the
spinal cord by stimulating the GABAß receptors. Baclofen is a chemical analogue of
the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Neuromuscular transmission is not affected by baclofen. Baclofen exerts an
antinociceptive effect. In neurological diseases associated with spasm of the skeletal
muscles, the clinical effects of Lioresal take the form of a beneficial action on reflex
muscle contractions and of marked relief from painful spasm, automatism, and clonus.
Lioresal improves the patient's mobility, makes it easier for him/her to manage
without aid, and facilitates physiotherapy.
Consequent important gains include improved ambulation, prevention and healing of
decubitus ulcers, and better sleep patterns due to elimination of painful muscle
spasms. In addition, patients experience improvement in bladder and sphincter
function and catheterisation is made easier, all representing significant improvements
in the patient's quality of life. Baclofen has been shown to have general CNS
depressant properties, causing sedation, somnolence, and respiratory and
cardiovascular depression.
Baclofen when introduced directly into the intrathecal space, permits effective
treatment of spasticity wih doses at least 100 times smaller than those for oral
administration.
Intrathecal bolus:
The onset of action is generally half an hour to one hour after administration of a
single intrathecal dose. Peak spasmolytic effect is seen at approximately 4 hours after
dosing, the effect lasting 4 to 8 hours. Onset, peak response, and duration of action
may vary with individual patients depending on the dose and severity of symptoms
and the method and speed of drug administration.

Continuous infusion:
Baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous
infusion. Maximum efficacy is observed within 24 to 48 hours.

5.2.

Pharmacokinetic properties
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 patient 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.

5.3

Preclinical safety data
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.
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.
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.
Muagenicity assays in vitro and in vivo showed no evidence of mutagenic
effects.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride; water for injections.

6.2

Incompatibilities

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.

6.3

Shelf life
3 years.

6.4

Special precautions for storage

Protect from heat (store below 30°C).
Medicines should be kept out of the reach and sight of children.

6.5

Nature and contents of container
Colourless glass ampoules, glass type I, according to Ph. Eur.

6.6

Instructions for use/handling
Each ampoule is intended for single use only, and any unused solution should
be discarded. Ampoules should not be either frozen or autoclaved.

ADMINISTRATION DATA
7.

MARKETING AUTHORISATION HOLDER
Novartis Pharmaceuticals UK Limited
Trading as Ciba Laboratories
Frimley Business Park

Frimley
Camberley
Surrey
GU16 7SR
England.

8.

MARKETING AUTHORISATION NUMBER
PL 00101/0500

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21 September 1997

10

DATE OF REVISION OF THE TEXT
03/09/13

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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