Baclofen
Indications: Multiple sclerosis; Spasticity; Spasticity, secondary to brain trauma; Spasticity, secondary to cerebral palsy; Spasticity, secondary to multiple sclerosis; Spinal cord disease; Trauma, spinal cord
DESCRIPTION:
Baclofen is a muscle relaxant and antispastic. Its chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid.
Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.
CLINICAL PHARMACOLOGY:
Tablets
The precise mechanism of action of baclofen is not fully known. Baclofen is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. In studies with animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. Baclofen is rapidly and extensively absorbed and eliminated. Absorption may be dose-dependent, being reduced with increasing doses. Baclofen is excreted primarily by the kidney in unchanged form and there is relatively large intersubject variation in absorption and/or elimination.
Injection
The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and may exert its effects by stimulation of the GABAB, receptor subtype.
Baclofen injection when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration.
In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.
Pharmacodynamics of Baclofen Injection
Adult Patients: The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms.
Pediatric Patients: The onset, peak, and duration of action is similar to those seen in adult patients.
Continuous Infusion: Baclofen injection's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours.
No additional information is available for pediatric patients.
Pharmacokinetics of Baclofen Injection
The pharmacokinetics of CSF clearance of baclofen injection calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF.
Intrathecal Bolus: After a bolus lumbar injection of 50 or 100 mcg baclofen injection in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 ml/hour.
Continuous Infusion: The mean CSF clearance for baclofen injection was approximately 30 ml/hour in a study involving ten patients on continuous intrathecal infusion.
Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0-5 ng/ml).
Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 ia established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the inter-patient variability was great. The gradient was not altered by position.
Six pediatric patients (age 6-18 years) receiving continuous intrathecal baclofen infusion at doses of 77-400 mcg/day had plasma baclofen levels near or below 10 ng/ml.
INDICATIONS AND USAGE:
Tablets
Baclofen is useful for the alleviation of signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. Patients should have reversible spasticity so that baclofen treatment will aid in restoring residual function.
Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases.
Baclofen is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.
The efficacy of baclofen in stroke, cerebral palsy, and Parkinson's disease has not been established and, therefore, it is not recommended for these conditions.
Injection
Baclofen injection is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long-term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of baclofen intrathecal via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long-term intrathecal baclofen therapy. Baclofen injection is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of baclofen injection into the intrathecal space.
Spasticity of Spinal Cord Origin: Evidence supporting the efficacy of baclofen injection was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of baclofen injection to placebo. In patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis, baclofen injection was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms.
Spasticity of Cerebral Origin: Evidence supporting the efficacy of baclofen injection was obtained in randomized, controlled investigations that compared the effects of a single intrathecal dose of baclofen injection to placebo in patients with severe spasticity associated with cerebral palsy or brain injury. In both cases, an intrathecal dose of baclofen injection was superior to a placebo in reducing spasticity, as measured by the Ashworth scale. In patients with brain injury, baclofen injection was superior to placebo in both principal outcomes of change from baseline in the Ashworth rating of spasticity and the frequency of spasms.
Baclofen injection therapy may be considered an alternative to destructive neurosurgical procedures. Prior to implantation of a device for chronic intrathecal infusion of baclofen intrathecal, patients must show a response to baclofen injection in a screening trial (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS:
Tablets and Injection
Hypersensitivity to baclofen.
Injection
Hypersensitivity to baclofen. Baclofen injection is not recommended for intravenous, intramuscular, or epidural administration.
WARNINGS:
Tablets
a. Abrupt Drug Withdrawal: Hallucinations and seizures have occurred on abrupt withdrawal of baclofen. Therefore, except for serious adverse reactions, the dose should be reduced slowly when the drug is discontinued.
b. 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.
c. Stroke: Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.
d. 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 port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the 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 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.
DRUG INTERACTIONS:
Injection
There is inadequate systematic experience with the use of baclofen injection in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of baclofen injection and epidural morphine include hypotension and dyspnea.
ADVERSE REACTIONS:
Tablets
The most common is transient drowsiness (10-63%). In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions are dizziness (5-15%), weakness (5-15%) and fatigue (2-4%). Others reported:
Neuropsychiatric: Confusion (1-11%), headache (4-8%), insomnia (2-7%); and, rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure.
Cardiovascular: Hypotension (0.9%). Rare instances of dyspnea, palpitation, chest pain, syncope.
Gastrointestinal: Nausea (4-12%), constipation (2-6%); and, rarely, dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool.
Genitourinary: Urinary frequency (2-6%); and, rarely, enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria.
Other: Instances of rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion.
Some of the CNS and genitourinary symptoms may be related to the underlying disease rather than to the drug therapy.
The following laboratory tests have been found to be abnormal in a few patients receiving baclofen: increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.
Injection
Commonly Observed in Patients with Spasticity of Spinal Origin: In pre- and post-marketing clinical trials, the most commonly observed adverse events associated with the use of baclofen intrathecal which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions, and hypotonia.
Associated With Discontinuation of Treatment: 8/474 patients with spasticity of spinal cord origin receiving long term infusion of baclofen injection in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse events. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynocological fibroids (1), and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their reatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations.
Fatalities: see WARNINGS.
Spasticity of Spinal Cord Origin
Incidence in Controlled Trials: Experience with baclofen injection obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving baclofen injection in two randomized, placebo-controlled trials: Hypertension (2), dizziness (2), headache (2), dyspnea (1). No adverse events were reported among the 32 patients receiving placebo in these studies.
Events Observed During the Pre- and Post-Marketing Evaluation of Baclofen Injection: Adverse events associated with the use of baclofen injection reflect experience gained with 576 patients followed prospectively in the United States. They received baclofen injection for periods of one day (screening) (N=576) to over eight years (maintenance) (N=10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day.
Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of baclofen injection cannot be reliably assessed in many cases and many of the adverse events reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions--drowsiness, dizziness, headache, nausea, hypotension, hypotonia and coma--appear clearly drug-related.
Adverse experiences reported during all domestic studies (both controlled and uncontrolled) are shown in the following table (TABLE 1). None of these adverse experiences led to a discontinuation of treatment.
TABLE 1 Incidence Of Most Frequent (1%) Adverse Events In Patients With Spasticity Of Spinal Origin In Prospectively Monitored Clinical Studies
Adverse Event
Hypotonia
Somnolence
Dizziness
Paresthesia
Nausea/Vomiting
Headache
Constipation
Convulsions
Urinary Retention
Dry Mouth
Accidental Injury
Asthenia
Confusion
Death
Pain
Speech Disorder
Hypotension
Ambylopia
Diarrhea
Hypoventilation
Coma
Impotence
Peripheral Edema
Urinary Incontinence
Insomnia
Anxiety
Depression
Dyspnea
Fever
Pneumonia
Urinary Frequency
Urticaria
Anorexia
Diplopia
Dysaulonomia
Hallucinations
Hypertension
In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to baclofen injection has been reported. The following adverse events, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported.
Central Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependance, incoordination, paranoid reaction and ptosis.
Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis.
Cardiovascular: Postural Hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.
Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus, and rhinitis.
Urogenital: Hematuria and kidney failure.
Skin and Appendages: Alopecia and sweating.
Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration, and hyperglycemia.
Special Senses: Abnormal vision, abnormality of accomodation, photophobia, taste loss, and tinnitus.
Body As A Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome, and overdose.
Hemic and Lymphatic System: Anemia
Spasticity of Cerebral Origin
Commonly Observed: In pre-marketing clinical trials, the most commonly observed adverse events associated with the use of baclofen injection which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, fever, urinary retention, and hypotonia.
Associated with Discontinuation of Treatment: Nine of 211 patients receiving baclofen injection in pre-marketing clinical studies in the U.S. discontinued long term infusion due to adverse events associated with intrathecal therapy.
The nine adverseevents leading to discontinuation were: three causes of infection, two cases of CSF leaks, two cases of menigitis, one case of drainage, and one case of unmanageable trunk control.
Fatalities: Three deaths, none of which were attributed to baclofen injection, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See WARNINGSon other deaths reported in spinal spasticity patients.
Incidence in Controlled Trials: Experience with baclofen injection obtained in parallel, placebo controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following events occurred among the 62 patients receiving baclofen injection in two randomized, placebo controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolencec, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.
Events observed during the Pre-Marketing Evaluation of Baclofen Injection: Adverse events associated with the use of baclofen injection reflect experience gained with a total of 211 U.S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received baclofen injection for periods of one day (screening) (N=211) to 84 months (maintenance) (N=1). The usual screening bolus dose administered prior to pump implantation in these studies was 50-75 mcg. The maintenance dose ranged from 22 mcg to 1400 mcg per day. Doses used in this patient population for long term infusion are generally lower than those required for patients with spasticity of spinal cord origin.
Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of baclofen injection cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions - somnolence, dizziness, headache, nausea, hypotension, hypotonia, and coma - appear clealy drug-related.
The most frequent (1%) adverse events reported during all clinical trials are shown in TABLE 2. Nine patients discontinued long term treatment due to adverse events.