LIORESAL INTRATHECAL is for use in single bolus intrathecal
injections (via a catheter placed in the lumbar intrathecal space or injection
by lumbar puncture) and in implantable pumps approved by the FDA specifically
for the intrathecal administration of baclofen. Because of the possibility of
potentially life-threatening CNS depression, cardiovascular collapse, and/or
respiratory failure, physicians must be adequately trained and educated in
chronic intrathecal infusion therapy.
The pump system should not be implanted until the patient’s response to bolus
LIORESAL INTRATHECAL injection is adequately evaluated. Evaluation (consisting
of a screening procedure: see Dosage and Administration) requires that LIORESAL
INTRATHECAL be administered into the intrathecal space via a catheter or lumbar
puncture. Because of the risks associated with the screening procedure and the
adjustment of dosage following pump implantation, these phases must be conducted
in a medically supervised and adequately equipped environment following the
instructions outlined in the Dosage and Administration section.
Resuscitative equipment should be available.
Following surgical implantation of the pump, particularly during the initial
phases of pump use, the patient should be monitored closely until it is certain
that the patient’s response to the infusion is acceptable and reasonably stable.
On each occasion that the dosing rate of the pump and/or the concentration
of LIORESAL INTRATHECAL (baclofen injection) in the reservoir is adjusted, close
medical monitoring is required until it is certain that the patient’s response
to the infusion is acceptable and reasonably stable.
It is mandatory that the patient, all patient caregivers, and the physicians
responsible for the patient receive adequate information regarding the risks of
this mode of treatment. All medical personnel and caregivers should be
instructed in 1) the signs and symptoms of overdose, 2) procedures to be
followed in the event of overdose and 3) proper home care of the pump and
Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction, inadvertent subcutaneous injection, or dosing error. (See Drug Overdose Symptoms and Treatment.)
Extreme caution must be used when filling an FDA approved implantable pump. Such pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose.
Abrupt withdrawal of intrathecal baclofen, regardless of
the cause, has resulted in sequelae that included high fever, altered mental
status, exaggerated rebound spasticity and muscle rigidity that in rare cases
progressed to rhabdomyolysis, multiple organ-system failure, and death. In the
first 9 years of post-marketing experience, 27 cases of withdrawal temporally
related to the cessation of baclofen therapy were reported; six patients died.
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; human error may have played a causal or contributing role
in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to
withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures (see PRECAUTIONS).
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. Patients and caregivers
should be advised of the importance of keeping scheduled refill visits and
should be educated on the early symptoms of baclofen withdrawal.
All patients receiving intrathecal baclofen therapy are potentially at risk
for withdrawal. Early symptoms of baclofen withdrawal may include return of
baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical
characteristics of the advanced intrathecal baclofen withdrawal syndrome may
resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia,
neuroleptic-malignant syndrome, or other conditions associated with a
hypermetabolic state or widespread rhabdomyolysis.
Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially life-threatening
central nervous system and systemic effects of intrathecal baclofen withdrawal.
The suggested treatment for intrathecal baclofen withdrawal is the restoration
of intrathecal baclofen 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 baclofen, or
oral, enteral, or intravenous benzodiazepines may prevent potentially fatal
sequelae. Oral or enteral baclofen alone should not be relied upon to halt the
progression of intrathecal baclofen withdrawal.
Seizures have been reported during overdose and with withdrawal from LIORESAL
INTRATHECAL as well as in patients maintained on therapeutic doses of LIORESAL
Spasticity of Spinal Cord Origin: There
were 16 deaths reported among the 576 U.S. patients treated with LIORESAL
INTRATHECAL (baclofen injection) in pre- and post-marketing studies evaluated
as of December 1992. Because these patients were treated under uncontrolled
clinical settings, it is impossible to determine definitively what role, if any,
LIORESAL INTRATHECAL played in their deaths.
As a group, the patients who died
were relatively young (mean age was 47 with a range from 25 to 63), but the
majority suffered from severe spasticity of many years duration, were
nonambulatory, had various medical complications such as pneumonia, urinary
tract infections, and decubiti, and/or had received multiple concomitant
medications. A case-by-case review of the clinical course of the 16 patients
who died failed to reveal any unique signs, symptoms, or laboratory results that
would suggest that treatment with LIORESAL INTRATHECAL caused their deaths. Two
patients, however, did suffer sudden and unexpected death within 2 weeks of pump
implantation and one patient died unexpectedly after screening.
One patient, a 44 year-old male with MS, died in hospital on the second day
following pump implantation. An autopsy demonstrated severe fibrosis of the
coronary conduction system. A second patient, a 52 year-old woman with MS and a
history of an inferior wall myocardial infarction, was found dead in bed 12 days
after pump implantation, 2 hours after having had documented normal vital signs.
An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is
impossible to determine whether LIORESAL INTRATHECAL contributed to these
deaths. The third patient underwent three baclofen screening trials. His medical
history included SCI, aspiration pneumonia, septic shock, disseminated
intravascular coagulopathy, severe metabolic acidosis, hepatic toxicity, and
status epilepticus. Twelve days after screening (he was not implanted), he again
experienced status epilepticus with subsequent significant neurological
deterioration. Based upon prior instruction, extraordinary resuscitative
measures were not pursued and the patient died.
Spasticity of Cerebral Origin: There were three
deaths occurring among the 211 patients treated with LIORESAL INTRATHECAL in
pre-marketing studies as of March 1996. These deaths were not attributed to the
Children should be of sufficient body mass to accommodate the
implantable pump for chronic infusion. Please consult pump manufacturer's
manual for specific recommendations.
Safety and effectiveness in pediatric patients below the age of 4 have not
Patients should be infection-free prior to the screening trial
with LIORESAL INTRATHECAL (baclofen injection) because the presence of a
systemic infection may interfere with an assessment of the patient’s response to
bolus LIORESAL INTRATHECAL.
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 dosing.
Pump Dose Adjustment and Titration
In most patients, it will be necessary to increase the dose
gradually over time to maintain effectiveness; a sudden requirement for
substantial dose escalation typically indicates a catheter complication (i.e.,
catheter kink or dislodgement).
Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Subcutaneous injection may result in symptoms of a systemic overdose or early depletion of the reservoir. Refill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal.
Strict aseptic technique in filling is required to avoid bacterial
contamination and serious infection. A period of observation appropriate to the
clinical situation should follow each refill or manipulation of the drug
Extreme caution must be used when filling an FDA approved
implantable pump equipped with an injection port that allows direct access to
the intrathecal catheter. Direct injection into the catheter through the
catheter access port may cause a life-threatening overdose.
Additional considerations pertaining to dosage
adjustment: It may be important to titrate the dose to maintain some
degree of muscle tone and allow occasional spasms to: 1) help support
circulatory function, 2) possibly prevent the formation of deep vein thrombosis,
3) optimize activities of daily living and ease of care.
Except in overdose related emergencies, the dose of LIORESAL INTRATHECAL
should ordinarily be reduced slowly if the drug is discontinued for any reason.
An attempt should be made to discontinue concomitant oral antispasticity
medication to avoid possible overdose or adverse drug interactions, either prior
to screening or following implant and initiation of chronic LIORESAL INTRATHECAL
infusion. Reduction and discontinuation of oral anti-spasmotics should be done
slowly and with careful monitoring by the physician. Abrupt reduction or
discontinuation of concomitant antispastics should be avoided.
Drowsiness: Drowsiness has been reported in patients
on LIORESAL INTRATHECAL. Patients should be cautioned regarding the operation of
automobiles or other dangerous machinery, and activities made hazardous by
decreased alertness. Patients should also be cautioned that the central nervous
system depressant effects of LIORESAL INTRATHECAL (baclofen injection) may be
additive to those of alcohol and other CNS depressants.
Intrathecal mass: Cases of intrathecal mass at the tip of the implanted catheter have been reported,
most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms
associated with intrathecal 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. In patients with new
neurological signs or symptoms suggestive of an intrathecal 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 intrathecal mass.
Precautions in special patient populations: Careful
dose titration of LIORESAL INTRATHECAL is needed when spasticity is necessary to
sustain upright posture and balance in locomotion or whenever spasticity is used
to obtain optimal function and care.
Patients suffering from psychotic disorders, schizophrenia, or confusional
states should be treated cautiously with LIORESAL INTRATHECAL and kept under
careful surveillance, because exacerbations of these conditions have been
observed with oral administration.
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 (baclofen injection) may cause an autonomic
Because LIORESAL is primarily excreted unchanged by the kidneys, it should be
given with caution in patients with impaired renal function and it may be
necessary to reduce the dosage.
No specific laboratory tests are deemed essential for the management of patients
on LIORESAL INTRATHECAL.
There is inadequate systematic experience with the use of
LIORESAL INTRATHECAL in combination with other medications to predict specific
drug-drug interactions. Interactions attributed to the combined use of LIORESAL
INTRATHECAL and epidural morphine include hypotension and dyspnea.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
No increase in tumors was seen in rats receiving LIORESAL (baclofen USP) orally
for two years at approximately 30-60 times on a mg/kg basis, or 10-20 times
on a mg/m2 basis, the maximum oral dose recommended for
human use. Mutagenicity assays with LIORESAL have not been performed.
PREGNANCY CATEGORY C
LIORESAL (baclofen USP) given orally has been shown to increase
the incidence of omphaloceles (ventral hernias) in fetuses of rats given
approximately 13 times on a mg/kg basis, or 3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this
dose also caused reductions in food intake and weight gain in the dams.
This abnormality was not seen in mice or rabbits. There are no adequate and
well-controlled studies in pregnant women. LIORESAL should be used during
pregnancy only if the potential benefit justifies the potential risk to the
In mothers treated with oral LIORESAL (baclofen USP) in therapeutic doses, the
active substance passes into the breast milk. It is not known whether detectable
levels of drug are present in breast milk of nursing mothers receiving LIORESAL
INTRATHECAL. As a general rule, nursing should be undertaken while a patient is
receiving LIORESAL INTRATHECAL only if the potential benefit justifies the
potential risks to the infant.
Children should be of sufficient body mass to accommodate the
implantable pump for chronic infusion. Please consult pump manufacturer's manual
for specific recommendations.
Safety and effectiveness in pediatric patients below the age of 4 have not
been established. Considerations based on experience with oral
LIORESAL (baclofen USP)
A dose-related increase in incidence of ovarian cysts was observed in female
rats treated chronically with oral LIORESAL. Ovarian cysts have been found by
palpation in about 4% 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
estimated to occur spontaneously in approximately 1% to 5% of the normal female