Pediatric Patients
The starting screening dose for pediatric patients is the same as in adult patients, i.e., 50 mcg. However, for very small patients, a screening dose of 25 mcg may be tried first.
Patients who do not respond to a 100 mcg intrathecal bolus should not be considered candidates for an implanted pump for chronic infusion.
Screening
Use the 1 mL screening syringe only (50 mcg per mL) for bolus injection into the subarachnoid space. For a 50 mcg bolus dose, use 1 mL of the screening syringe. Use 1.5 mL of 50 mcg per mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg per mL baclofen injection (2 screening syringes).
Maintenance
The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. For patients who require concentrations other than 500 mcg per mL, 1,000 mcg per mL, or 2,000 mcg per mL, baclofen injection must be diluted with sterile preservative free Sodium Chloride for Injection, USP.
Delivery Regimen
Baclofen injection is most often administered in a continuous infusion mode immediately following implant. For those patients implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of baclofen injection delivery. For example, patients who have increased spasms 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 time of desired clinical effect.
Post-Implant Dose Titration Period
To determine the initial total daily dose of baclofen injection following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved). 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).
Adult Patients with Spasticity of Spinal Cord Origin
After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10% to 30% increments and only once every 24 hours, until the desired clinical effect is achieved.
Adult Patients with Spasticity of Cerebral Origin
After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours, until the desired clinical effect is achieved.
Pediatric Patients
After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable side effects.
Additional Considerations Pertaining to Dosage Adjustment
Careful dose titration of baclofen injection 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. 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 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, either prior to screening or following implant and initiation of chronic baclofen injection 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.
Spasticity of Spinal Cord Origin Patients
The clinical goal is to maintain muscle tone as close to normal as possible, and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in lifestyle due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 10% to 40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10% to 20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement).
Maintenance dosage for long term continuous infusion of intrathecal baclofen has ranged from 12 mcg/day to 2,003 mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1,000 mcg/day. Determination of the optimal baclofen injection dose requires individual titration. The lowest dose with an optimal response should be used.
Spasticity of Cerebral Origin Patients
The clinical goal is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in lifestyle due to the alleviation of spasticity.
During periodic refills of the pump, the daily dose may be increased by 5% to 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10% to 20% if patients experience side effects. Many patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement).
Maintenance dosage for long term continuous infusion of intrathecal baclofen has ranged from 22 mcg/day to 1,400 mcg/day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients required daily doses greater than 1,000 mcg/day.
Pediatric Patients
Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed to require a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/day, with a range of 24 mcg/day to 1,199 mcg/day. Dosage requirement for pediatric patients over 12 years does not seem to be different from that of adult patients. Determination of the optimal baclofen injection dose requires individual titration. The lowest dose with an optimal response should be used.
Potential Need for Dose Adjustments in Chronic Use
During long term treatment, approximately 5% (28/627) of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this “tolerance” has been treated on occasion, in hospital, by a “drug holiday” consisting of the gradual reduction of intrathecal baclofen over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” intrathecal baclofen may be restarted at the initial continuous infusion dose.
Spasticity of Spinal Cord Origin
There were 16 deaths reported among the 576 U.S. patients treated with intrathecal baclofen 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, intrathecal baclofen 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 intrathecal baclofen 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 Multiple Sclerosis, 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 intrathecal baclofen contributed to these deaths. The third patient underwent three baclofen screening trials. His medical history included spinal cord injury, 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 intrathecal baclofen in pre-marketing studies as of March 1996. These deaths were not attributed to the therapy.
Most Common Adverse Reactions in Patients with Spasticity of Spinal Origin
In pre- and post-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia.
Adverse Reactions Associated with Discontinuation of Treatment
8/474 patients with spasticity of spinal cord origin receiving long term infusion of intrathecal baclofen in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse reactions. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations.
Fatalities - [see Warnings and Precautions (5.6)].
Incidence in Controlled Trials
Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions 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 intrathecal baclofen in two randomized, placebo-controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse reactions were reported among the 32 patients receiving placebo in these studies.
Events Observed during the Pre- and Post-marketing Evaluation of Intrathecal Baclofen
Adverse events associated with the use of intrathecal baclofen reflect experience gained with 576 patients followed prospectively in the United States. They received intrathecal baclofen 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 2,003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases and many of the adverse reactions reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions — hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache — appear clearly drug-related.
Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in Table 1. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post- marketing studies.
Table 1: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Spinal Origin in Prospectively Monitored Clinical Trials
|
|
|
|
Adverse Reactions | Percent
N=576
Screening* | Percent
N=474
Titration† | Percent
N=430
Maintenance‡ |
| Hypotonia
| 5.4
| 13.5
| 25.3
|
| Somnolence
| 5.7
| 5.9
| 20.9
|
| Dizziness
| 1.7
| 1.9
| 7.9
|
| Paresthesia
| 2.4
| 2.1
| 6.7
|
| Nausea and Vomiting
| 1.6
| 2.3
| 5.6
|
| Headache
| 1.6
| 2.5
| 5.1
|
| Constipation
| 0.2
| 1.5
| 5.1
|
| Convulsion
| 0.5
| 1.3
| 4.7
|
| Urinary Retention
| 0.7
| 1.7
| 1.9
|
| Dry Mouth
| 0.2
| 0.4
| 3.3
|
| Accidental Injury
| 0.0
| 0.2
| 3.5
|
| Asthenia
| 0.7
| 1.3
| 1.4
|
| Confusion
| 0.5
| 0.6
| 2.3
|
| Death
| 0.2
| 0.4
| 3.0
|
| Pain
| 0.0
| 0.6
| 3.0
|
| Speech Disorder
| 0.0
| 0.2
| 3.5
|
| Hypotension
| 1.0
| 0.2
| 1.9
|
| Ambylopia
| 0.5
| 0.2
| 2.3
|
| Diarrhea
| 0.0
| 0.8
| 2.3
|
| Hypoventilation
| 0.2
| 0.8
| 2.1
|
| Coma
| 0.0
| 1.5
| 0.9
|
| Impotence
| 0.2
| 0.4
| 1.6
|
| Peripheral Edema
| 0.0
| 0.0
| 2.3
|
| Urinary Incontinence
| 0.0
| 0.8
| 1.4
|
| Insomnia
| 0.0
| 0.4
| 1.6
|
| Anxiety
| 0.2
| 0.4
| 0.9
|
| Depression
| 0.0
| 0.0
| 1.6
|
| Dyspnea
| 0.3
| 0.0
| 1.2
|
| Fever
| 0.5
| 0.2
| 0.7
|
| Pneumonia
| 0.2
| 0.2
| 1.2
|
| Urinary Frequency
| 0.0
| 0.6
| 0.9
|
| Urticaria
| 0.2
| 0.2
| 1.2
|
| Anorexia
| 0.0
| 0.4
| 0.9
|
| Diplopia
| 0.0
| 0.4
| 0.9
|
| Dysautonomia
| 0.2
| 0.2
| 0.9
|
| Hallucinations
| 0.3
| 0.4
| 0.5
|
| Hypertension
| 0.2
| 0.6
| 0.5
|
In addition to the more common (1% or more) adverse reactions reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to intrathecal baclofen from foreign studies has been reported. The following adverse reactions, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported:
Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilatation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, 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 accommodation, 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.
Most Common Adverse Reactions
In pre-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.
Adverse Reactions Associated with Discontinuation of Treatment
Nine of 211 patients receiving intrathecal baclofen in pre-marketing clinical studies in the U.S. discontinued long-term infusion due to adverse reactions associated with intrathecal therapy.
The nine adverse reactions leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1).
Fatalities
Three deaths, none of which were attributed to intrathecal baclofen, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients.
Incidence in Controlled Trials
Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following adverse reactions occurred among the 62 patients receiving intrathecal baclofen in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.
Events Observed during the Pre-marketing Evaluation of Intrathecal Baclofen
Adverse events associated with the use of intrathecal baclofen 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 intrathecal baclofen 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 mcg to 75 mcg. The maintenance dose ranged from 22 mcg to 1,400 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 intrathecal baclofen cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions — somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma — appear clearly drug-related.
The most frequent (≥1%) adverse reactions reported during all clinical trials are shown in Table 2. Nine patients discontinued long term treatment due to adverse reactions.
Table 2: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Cerebral Origin
|
|
|
|
Adverse Reactions | Percent
N=211
Screening* | Percent
N=153
Titration† | Percent
N=150
Maintenance‡ |
| Hypotonia
| 2.4
| 14.4
| 34.7
|
| Somnolence
| 7.6
| 10.5
| 18.7
|
| Headache
| 6.6
| 7.8
| 10.7
|
| Nausea and Vomiting
| 6.6
| 10.5
| 4.0
|
| Vomiting
| 6.2
| 8.5
| 4.0
|
| Urinary Retention
| 0.9
| 6.5
| 8.0
|
| Convulsion
| 0.9
| 3.3
| 10.0
|
| Dizziness
| 2.4
| 2.6
| 8.0
|
| Nausea
| 1.4
| 3.3
| 7.3
|
| Hypoventilation
| 1.4
| 1.3
| 4.0
|
| Hypertonia
| 0.0
| 0.7
| 6.0
|
| Paresthesia
| 1.9
| 0.7
| 3.3
|
| Hypotension
| 1.9
| 0.7
| 2.0
|
| Increased Salivation
| 0.0
| 2.6
| 2.7
|
| Back Pain
| 0.9
| 0.7
| 2.0
|
| Constipation
| 0.5
| 1.3
| 2.0
|
| Pain
| 0.0
| 0.0
| 4.0
|
| Pruritus
| 0.0
| 0.0
| 4.0
|
| Diarrhea
| 0.5
| 0.7
| 2.0
|
| Peripheral Edema
| 0.0
| 0.0
| 3.3
|
| Thinking Abnormal
| 0.5
| 1.3
| 0.7
|
| Agitation
| 0.5
| 0.0
| 1.3
|
| Asthenia
| 0.0
| 0.0
| 2.0
|
| Chills
| 0.5
| 0.0
| 1.3
|
| Coma
| 0.5
| 0.0
| 1.3
|
| Dry Mouth
| 0.5
| 0.0
| 1.3
|
| Pneumonia
| 0.0
| 0.0
| 2.0
|
| Speech Disorder
| 0.5
| 0.7
| 0.7
|
| Tremor
| 0.5
| 0.0
| 1.3
|
| Urinary Incontinence
| 0.0
| 0.0
| 2.0
|
| Urination Impaired
| 0.0
| 0.0
| 2.0
|
The more common (1% or more) adverse reactions reported in the prospectively followed 211 patients exposed to intrathecal baclofen have been reported. In the total cohort, the following adverse reactions, not described in Table 2, and arranged in decreasing order of frequency, and classified by body system, were reported:
Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.
Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.
Cardiovascular: Bradycardia.
Respiratory: Apnea, dyspnea and hyperventilation.
Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis.
Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer.
Special Senses: Abnormality of accommodation.
Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia.
Hemic and Lymphatic System: Leukocytosis and petechial rash.
Risk Summary
There are no adequate data on the developmental risk associated with the use of baclofen injection in pregnant women.
In animal studies, oral administration of baclofen to pregnant rats produced an increase in fetal malformations (see Data). There are no animal data on developmental risk associated with baclofen administered via continuous intrathecal infusion.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Baclofen given orally to pregnant rats has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at a dose associated with maternal toxicity. This abnormality was not seen in mice or rabbits.
Risk Summary
There is insufficient information regarding levels of baclofen in milk of nursing mothers receiving baclofen injection. There are no adequate data on the effects of baclofen injection on the breastfed infant or on milk production. At recommended oral doses, baclofen is present in human milk and withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped or when breastfeeding is stopped.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for baclofen injection and any potential adverse effects on the breastfed infant from baclofen injection or from the underlying maternal condition.
Symptoms of Intrathecal Baclofen Overdose
Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus.
Treatment Suggestions for Overdose
There is no specific antidote for treating overdoses of baclofen injection; however, the following steps should ordinarily be undertaken:
- 1)
Residual intrathecal baclofen solution should be removed from the pump as soon as possible.
- 2)
Patients with respiratory depression should be intubated if necessary, until the drug is eliminated.
Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia.
Physostigmine Doses for Adult Patients
Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur.
Physostigmine Doses for Pediatric Patients
Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than
0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained.
Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.
If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.
Intrathecal Bolus
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 response and duration of action are similar to those seen in adult patients.
Continuous Infusion
Adult Patients
Intrathecal baclofen'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.
Pediatric Patients
No additional information on continuous infusions is available for pediatric patients.
Intrathecal Bolus
After a bolus lumbar injection of 50 mcg or 100 mcg intrathecal baclofen 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 intrathecal baclofen 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 to 5 ng/mL). Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 is 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 interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL.
Carcinogenesis
No increase in tumors was seen in rats receiving baclofen orally for two years.
Mutagenesis
Mutagenicity assays with baclofen have not been performed.
Impairment of Fertility
Studies to assess the potential for adverse effects of baclofen on fertility have not been conducted.
Spasticity of Spinal Cord Origin
Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen 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
The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed.
Risks Related to Sudden Withdrawal of Baclofen Injection
Advise patients and caregivers that sudden withdrawal of baclofen injection, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organ-system failure, and death. Inform patients that early symptoms of baclofen injection withdrawal may include increased spasticity, itching, and tingling of extremities. If baclofen injection withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment.
Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug.
Baclofen Injection Overdose
Inform patients and their caregivers that baclofen injection overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump.
Operation of Automobiles and Other Dangerous Machinery
Advise patients that baclofen injection may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness.
Increased Risk of Drowsiness with Alcohol and Other CNS Depressants
Inform patients and their caregivers that the drowsiness associated with baclofen injection use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use.
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SAGENT®
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Schaumburg, IL 60195 (USA)
Made in India
©2021 Sagent Pharmaceuticals, Inc.
June 2021
SAGENT Pharmaceuticals ®
