WARNINGS
Tablets
Withdrawal:
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. 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 the intrathecal baclofen withdrawal syndrome.
Impaired Renal Function: Because baclofen
is primarily excreted unchanged through the kidneys, it
should be given with caution, and it may be necessary
to reduce the dosage.
Stroke: Baclofen has not significantly
benefited patients with stroke. These patients have also
shown p.o. tolerability to the drug.
Pregnancy: Baclofen has been shown to
increase the incidence of omphaloceles (ventral hernias)
in fetuses of rats given approximately 13 times the maximum
dose recommended for human use, at a dose which caused
significant reductions in food intake and weight gain
in dams. This abnormality was not seen in mice or rabbits.
There was also an increased incidence of incomplete sternebral
ossification in fetuses of rats given approximately 13
times the maximum recommended human dose, and an increased
incidence of unossified phalangeal nuclei of forelimbs
and hindlimbs in fetuses of rabbits given approximately
7 times the maximum recommended human dose. In mice, no
teratogenic effects were observed, although reductions
in mean fetal weight with consequent delays in skeletal
ossification were present when dams were given 17 or 34
times the human daily dose. There are no studies in pregnant
women. Baclofen should be used during pregnancy only if
the benefit clearly justifies the potential risk to the
fetus.
Injection
Baclofen injection 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 baclofen injection is adequately evaluated.
Evaluation (consisting of a screening procedure: see DOSAGE
AND ADMINISTRATION) requires that baclofen injection 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.
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 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 care givers,
and the physicians responsible for the patient receive
adequate information regarding the risks of this mode
of treatment. All medical personnel and care givers 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 insertion site.
Overdose: 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 CNS depression, excessive salivation,
dizziness, nausea and/or vomiting, somnolence, and cephalad
progression of hypotonia. Should overdose appear likely,
the patient should be taken immediately to a hospital
for assessment and emptying of the pump reservoir. In
the cases reported to date, overdose has generally been
related to pump malfunction or dosing error. (See OVERDOSAGE.)
Hallucinations: have occurred after
abrupt withdrawal of baclofen injection.
Seizures have been reported during overdose with and
withdrawal from baclofen injection as well as in patients
maintained on therapeutic doses of baclofen injection.
Fatalities
Spasticity of Spinal Cord Origin: There
were 16 deaths reported among the 576 U.S.patients treated
with the 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, baclofen injection 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 13
patients who died failed to reveal any unique signs, symptoms,
or laboratory results that would suggest that treatment
with baclofen injection caused their deaths. Two patients,
however, did suffer sudden and unexpected death within
2 weeks of pump implantation.
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
baclofen injection 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 detertioration. Based upon prior instruction,
extraordinary resusitative measures were not pursued and
the patient died.
Spasticity of Cerebral Origin: There
were three deaths occuring among the 211 patients treated
with baclofen intrathecal in pre-marketing studies as
of March, 1996. These deaths were not attributed to the
therapy.
PRECAUTIONS
Tablets
Safe use of baclofen in children under 12 has not been
established, and it is, therefore, not recommended for
use in children. Because of the possibility of sedation,
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 effects
of baclofen may be additive to those of alcohol and other
CNS depressants.
Baclofen should be used with caution where spasticity
is utilized to sustain upright posture and balance in
locomotion or whenever spasticity is utilized to obtain
increased function.
In patients with epilepsy, the clinical state and electroencephalogram
should be monitored at regular intervals, since deterioration
in seizure control and EEG have been reported occasionally
in patients taking baclofen. It is not known whether this
drug is excreted in human milk. As a general rule, nursing
should not be undertaken while a patient is on a drug
since many drugs are excreted in human milk.
A dose-related increase in incidence of ovarian cysts
and a less marked increase in enlarged and/or hemorrhagic
adrenal glands was observed in female rats treated chronically
with baclofen.
Ovarian cysts have been found by palpation in about 4%
of the multiple sclerosis patients that were treated with
baclofen 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 population.
Injection
Children should be sufficient in body mass to accomodate
the implantable pump for chronic infusion. Please consult
pump manufacturer's manual for specific recommendations.
The safe use of baclofen injection in children under
age 4 has not been established.
Screening
Patients should be infection-free prior to the screening
trial with baclofen injection because the presence of
a systemic infection may interfere with an assessment
of the patient's response to bolus baclofen injection.
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 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. 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 reservoir.
Extreme caution must be used when filling an
FDA approved implantable pump equipped with an injection
proof that allows direct access to the intrathecal catheter.
Direct injection into the catheter through the access
proof 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 in order
to: 1) help support circulatory function, 2) possibly
prevent the formation of deep vein thrombosis, and 3)
optimize activities of daily living and ease of care.
Except in overdose related emergencies, the dose of baclofen
injection 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, preferably prior to initiation
of baclofen injection infusion, with careful monitoring
by the physician. Abrupt reduction or discontinuation
of concomitant antispastics, however, during chronic baclofen
injection therapy should be avoided.
Drowsiness: Drowsiness has been reported
in patients on baclofen injection. 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
baclofen injection may be additive to those of alcohol
and other CNS depressants.
Precautions In Special Patient Populations
Careful dose titration of baclofen 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
baclofen injection and kept under careful surveillance,
because exacerbations of these conditions have been observed
with oral administration.
Baclofen injection should be used with caution in patients
with a history of autonomic dysreflexia. The presence
of nociceptive stimuli or abrupt withdrawal of baclofen
injection may cause an autonomic dysreflexic episode.
Because baclofen injection 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.
Laboratory Tests
No specific laboratory tests are deemed essential for
the management of patients on baclofen injection.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
No increase in tumors was seen in rats receiving 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 baclofen have not been performed.
Pregnancy Category C
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. Baclofen should be used during pregnancy only if
the potential benefit justifies the potential risk to
the fetus.
Nursing Mothers
In mothers treated with oral 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 baclofen
injection. As a general rule, nursing should be undertaken
while a patient is receiving baclofen injection only if
the potential benefit justifies the potential risks to
the infant.
Pediatric Use
Children should be of sufficient body mass to accomodate
the implantable pump for chronic infusion. Please consult
pump manufacturer's manual for specific recommendations.
The safe use of baclfen intrathecal in children under
age 4 has not been established.
Considerations Based On Experience With Oral
Baclofen USP
A dose-related increase in incidence of ovarian cysts was
observed in female rats treated chronically with oral baclofen.
Ovarian cysts have been found by palpation in about 4% of
the multiple sclerosis patients who were treated with oral
baclofen 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 population.
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