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Baclofen (Intrathecal-Systemic)


VA CLASSIFICATION
Primary: MS200

Commonly used brand name(s): Lioresal Intrathecal.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antispastic. —

Indications

General considerations
Although the manufacturer does not recommend that long-term intrathecal baclofen therapy be initiated in patients with spasticity due to traumatic injury until at least 1 year after the injury {01} {22}, some USP Advisory panelists recommend use sooner than 1 year in these patients {24}.

Intrathecal baclofen may be used as an alternative to destructive neurosurgical procedures such as rhizotomies or phenol injections {01} {02} {03}.

Accepted

Spasticity, severe (treatment)—Intrathecal baclofen is indicated for the management of severe spasticity {01}. It is used for the treatment of spasticity of spinal origin, including spinal cord trauma and multiple sclerosis, in patients who do not respond to or tolerate oral therapy {01}. It is also used in patients with spasticity of cerebral origin {05} {09} {10} {11}, including traumatic brain injury and cerebral palsy {01} {04}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) {01}.
Molecular weight—
    213.66 {01} {17}


pH
    5 to 7 {01}.

Mechanism of action/Effect:

The precise mechanism of action of baclofen has not been fully determined {01}. Baclofen exerts its effects as an agonist at presynaptic GABA-B (bicuculline-insensitive) receptors {01} {02}. It acts mainly at the spinal cord level to inhibit the transmission of both monosynaptic and polysynaptic reflexes {01}, possibly by hyperpolarization of primary afferent fiber terminals, resulting in antagonism of the release of putative excitatory transmitters (i.e., glutamic and aspartic acids) {01} {02} {14}. Postsynaptic effects of baclofen have been demonstrated at concentrations above the therapeutic range {14}. In addition, actions at the supraspinal sites may be involved {01}.


Other actions/effects:

Baclofen has general central nervous system (CNS)–depressant actions {01}. Animal studies demonstrated that baclofen also may have antinociceptive effects, possibly by acting at spinal and supraspinal sites to decrease the responsiveness of nociceptive neurons, thereby resulting in analgesia {14} {15}.

Absorption:

Following intrathecal administration of baclofen, concurrent plasma concentrations are expected to be low (0 to 5 nanograms per mL [nanograms/mL]) {07}.

Distribution:

Limited pharmacokinetic data suggest that baclofen injected into the lumbar cerebrospinal fluid (CSF) migrates upward. The concentration declines progressively upward along the neuroaxis during continuous infusion of therapeutic doses, thereby resulting in a lumbar-cisternal baclofen concentration gradient of approximately 4:1 {01} {06}.

Half-life:

Elimination (CSF)—Following an intrathecal loading dose of 50 or 100 mcg over the first 4 hours: Approximately 1.5 hours {01} {02} {19}.


Onset of action:

Following intrathecal loading dose of 50 or 100 mcg over the first 4 hours—Approximately 0.5 to 1 hour {01} {11}.

Following intrathecal continuous infusion—Approximately 6 to 8 hours {01}.

Time to peak concentration:

Following intrathecal continuous infusion of 50 to 1200 mcg a day (time to CSF steady-state concentration)—Within 1 to 2 days {21}.

Peak serum concentration:

Following intrathecal continuous infusion of 50 to 1200 mcg a day (peak CSF steady-state concentration)—Approximately 130 to 1240 nanograms/mL {21}.

Time to peak effect:

Following intrathecal loading dose—Approximately 4 hours {01}.

Following continuous infusion—Approximately 24 to 48 hours {01}.

Duration of action:

Following intrathecal loading dose—Approximately 4 to 8 hours {01} {11}.

Elimination:
    Following a loading dose of 50 or 100 mcg, the CSF clearance of intrathecal baclofen was 30 mL per hour (mL/hour) {01}. CSF clearance of baclofen following intrathecal administration of a loading dose or continuous infusion approximates CSF turnover, which suggests that the elimination occurs by bulk flow removal of CSF {01} {02}.


Precautions to Consider

Tumorigenicity

Studies in animals to evaluate the tumorigenic potential of intrathecal baclofen have not been done {01}. However, a 2-year study found no increase in tumors in rats receiving oral baclofen at 30 to 60 times the oral maximum recommended human dose (MRHD) on a mg per kg of body weight (mg/kg) basis (10 to 20 times the MRHD on a mg per square meter of body surface area [mg/m 2] basis) {01}.

Mutagenicity

No mutagenicity assays have been done to evaluate the mutagenic potential of intrathecal baclofen {01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Studies done in rats have found that oral doses of baclofen 13 times higher than the MRHD on a mg/kg basis (3 times the MRHD on a mg/m 2 basis) resulted in an increase in the incidence of omphaloceles (ventral hernias) in fetuses of rats {01}. In addition, a reduction in weight gain and food intake occurred in the dams {01}. However, an increased incidence of omphaloceles did not occur in fetuses of rabbits or mice {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

Although orally administered baclofen is distributed into breast milk, it is not known whether intrathecal baclofen is distributed into breast milk. However, problems in humans have not been documented {01}.

Pediatrics

Children 4 years of age and older: Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of intrathecal baclofen in children. Children should be of sufficient body mass to accommodate the implantable pump for long-term infusion {01}.


Geriatrics


No information is available on the relationship of age to the effects of intrathecal baclofen in elderly patients. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dose or dosing interval in patients receiving intrathecal baclofen {01}. In addition, caution should be used in those elderly patients who may be especially susceptible to baclofen-induced central nervous system (CNS) toxicity {01}.


Dental

Prolonged use of intrathecal baclofen may decrease or inhibit salivary flow, contributing to the develoment of caries, periodontal disease, oral candidiasis, and oral discomfort.

Drug interactions and/or related problems
» Alcohol or
» CNS depression–producing medications, other (see Appendix II )     (concurrent use with intrathecal baclofen may enhance CNS depressant effects {28})


Opioid (narcotic) analgesics    (concurrent use of epidural morphine has been reported to result in hypotension and dyspnea {27}{28})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase
Aspartate aminotransferase (AST [SGOT])
Glucose    (values may be increased {28})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Autonomic dysreflexia {01}    (abrupt withdrawal of intrathecal baclofen may precipitate an episode of dysreflexia {27}{28})


Cerebrovascular insufficiency or
Respiratory insufficiency    (conditions may be exacerbated by baclofen {28})


» Communication difficulties or
» Spinal cord injuries, at or above T–6 or
» Withdrawal symptoms, history of    (may be at greater risk of withdrawal; special attention should be given to the maintenance of scheduled refill visits {26}{25})


Epilepsy    (baclofen may cause deterioration of seizure control {28})


Parkinson's disease    (condition may be exacerbated by baclofen {28})


» Psychiatric disorders, pre-existing {01}    (increased risk of baclofen-induced psychiatric disorders; careful monitoring is recommended)


» Renal function impairment {01}    (may result in increased concentrations of intrathecal baclofen in patients with renal function impairment; reduction in dosage may be required)


Hypersensitivity to baclofen {01}
Note: Caution is also required in patients who depend on spasticity to maintain upright posture and balance or to obtain and/or maintain increased body function for optimal function and care {01}.




Side/Adverse Effects

Note: Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death. {25} {26}
Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. {25}{26}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Seizures {01} {02}

Incidence less frequent or rare
    
Asthenia {01} {02} (muscle weakness)
    
central nervous system (CNS) effects {01} (mental depression; ringing or buzzing in ears)
    
hallucinations {01} (seeing, hearing, or feeling things that are not there)
    
respiratory depression {01} (shortness of breath or troubled breathing)
    
syncope {01} (fainting)
    
visual disturbances {01} (blurred vision; double vision )

Note: Ovarian cysts have been found in female patients treated with oral baclofen for up to one year {01}. However, there have been no reports to date of ovarian cysts in female patients using intrathecal baclofen {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation {01}
    
difficult urination {01}
    
dizziness {02}
    
headache {01} {02} —may be due to pump or catheter dislodgement or kinking {23}
    
hypotonia (muscle weakness)
    
nausea and/or vomiting {01}
    
paresthesia {01} (numbness or tingling in hands or feet)
    
somnolence {02} (sleepiness)

Incidence less frequent
    
Ataxia {01} (clumsiness, unsteadiness, trembling, or other problems with muscle control)
    
diarrhea {01}
    
dry mouth {01}
    
edema {01} (swelling of ankles, feet, or lower legs)
    
frequent urge to urinate {01}
    
hypotension {01} {02} (dizziness or lightheadedness, especially when getting up from a lying or sitting position )
    
infection at the implantation site {02} (irritation of the skin at the site where the pump is located)
    
insomnia {01} (difficulty sleeping)
    
pruritus {01} (itching of the skin)
    
sexual dysfunction {01}
    
slurred speech or other speech problems {01}
    
tremor {01} (trembling or shaking)



Those indicating the need for medical attention if they occur after medication is discontinued
    
Dysreflexia {01} (facial flushing; headache; increased sweating; slow heartbeat)
    
hallucinations {01} {02} (seeing, hearing, or feeling things that are not there)
    
rebound spasticity {02} ( increase in muscle spasms)
    
seizures {01} {02}





Overdose
For specific information on the agents used in the management of intrathecal baclofen overdose, see Physostigmine (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Asthenia{02} (muscle weakness)
    
dizziness, drowsiness, or lightheadedness{01}
    
excessive salivation{02} (increased watering of the mouth)
    
mental confusion{02}
    
nausea and/or vomiting{02}
    
respiratory depression{01}{02} (shortness of breath or troubled breathing)
    
seizures{01}{02}


Note: Special attention should be given to recognizing the signs and symptoms of overdose during the screening and dose titration phase of treatment. Extreme caution should be used when filling the implantable pump. These pumps should only be refilled through the reservoir refill septum. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. However, direct injection into the catheter access port may cause a life-threatening overdose.


Treatment of overdose
Turn the pump off and remove residual baclofen intrathecal solution from the pump {01}. If lumbar puncture is not contraindicated, withdrawal of 30 to 40 mL of cerebrospinal fluid (CSF) is recommended to reduce CSF baclofen concentration {01} {02} {22}. However, according to some USP Advisory panelists, this method is not effective in all cases of overdose {24}.

Specific treatment—Use of physostigmine to reverse the drowsiness and respiratory depression {01} {18}. Physostigmine has been associated with the induction of bradycardia, cardiac conduction disturbances, and seizures; therefore, it should be administered with caution {01}. See the package insert or the Physostigmine (Systemic) monograph for specific guidelines for use of this product.

Supportive care—May include maintaining an open airway, supporting ventilation, maintaining proper fluid and electrolyte balance, correcting hypotension, and controlling seizures {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Baclofen (Intrathecal-Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to baclofen





Use in children—Safe use in children up to 4 years of age has not been established






Use in the elderly—Caution should be used in those elderly patients who may be especially susceptible to baclofen-induced central nervous system (CNS) toxicity
Other medications, especially alcohol or CNS depression–producing medications
Other medical problems, especially autonomic dysreflexia, communication difficulties, history of withdrawal symptoms, pre-existing psychiatric disorders, renal function impairment, or spinal cord injuries at or above T-6

Proper use of this medication
» Importance of keeping scheduled refill visits

» Proper dosing

Precautions while using this medication
Regular visits to physician to check progress during therapy

» Avoiding alcohol or other CNS depressants during therapy unless approved by physician

» Caution when driving or doing anything else requiring alertness because of possible dizziness, drowsiness, lightheadedness, impairment of physical or mental abilities, false sense of well-being, or visual disturbances

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

Caution when getting up from a lying or sitting position


Side/adverse effects
Signs of potential side effects, especially asthenia, CNS effects, hallucinations, respiratory depression, seizures, syncope, and visual disturbances


General Dosing Information
Abrupt discontinuation of intrathecal baclofen may lead to severe side effects and, in some cases, fatalities. Prevention of abrupt discontinuation requires careful attention to proper 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.{25}{26}{27}

Intrathecal administration of baclofen requires the use of implantable pumps approved by the FDA {01}. Refer to the manufacturers manual for the implantable pump approved for intrathecal infusion and for more specific instructions and precautions for programming the pump and/or refilling the reservoir.

The pump may be programmed to administer higher doses at night to reduce spasms and lower doses during the day for patients who need some rigidity for ambulation {02}. Infusion rates may range from as low as 0.1 mL per hour (mL/hr) to as high as 1 mL/hr {02}. However, changes in flow rate should be programmed to start two hours before the time of the desired clinical effect {01}.
Guidelines for pump implantation:

   • Prescribing physicians should be trained and educated in long-term intrathecal infusion therapy {01}.
   • Prior to pump implantation and initiation of long-term infusion, patients must demonstrate a positive clinical response to a baclofen dose administered intrathecally during a screening period {01}.
   • Patients should be infection-free prior to the screening period {01}.
   • During the screening phase and dose-titration period immediately following implantation, patients must be monitored closely in a fully equipped and staffed environment {01}.
   • Strict aseptic technique in filling the implantable pump is required to avoid bacterial contamination and serious infection {01}.
   • Extreme caution should be used when filling an implantable pump. These pumps should only be refilled through the reservoir refill septum. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. However, direct injection into the catheter access port may cause a life-threatening overdose.
   • The maintenance dose may need to be adjusted during the first few months of therapy while patients adjust to changes in lifestyle due to the alleviation of spasticity {01}. A sudden large requirement for dose escalation may indicate a catheter complication {01}. Most patients will require gradual increases in dose over time to maintain optimal response during long-term therapy {01}. However, most patients obtain the optimal response within a year {24}.
   • For patients with programmable pumps who have achieved relatively satisfactory control of spasticity on continuous infusion, further benefit may be attained by using more complex dosing schedules for delivery of intrathecal baclofen {01}.
During long-term treatment with intrathecal baclofen, approximately 5% of patients became refractory to increasing doses {01}. Although there is insufficient experience of treatment for tolerance, tolerance has been treated in hospitalized patients with a drug holiday consisting of gradually reducing the dose of intrathecal baclofen over a 2- to 4-week period and switching to alternative methods of spasticity management {01} {20}. After a few days sensitivity to baclofen may return, then intrathecal baclofen should be restarted at the initial continuous infusion dose {01} {20}.


Parenteral Dosage Forms

Baclofen Injection

Usual adult and adolescent dose
Antispastic
Screening phase: Intrathecal, 50 mcg in a volume of 1 mL, administered into the intrathecal space by barbotage over a period of not less than one minute {01}.

Note: The patient should be monitored for four to eight hours for a positive response consisting of a significant decrease in muscle tone, frequency of spasms, and/or severity of spasms {01}. If the initial response is less than desired, a second dose of 75 mcg of baclofen in a volume of 1.5 mL may be administered intrathecally twenty-four hours after the first dose, and the patient should be monitored for an interval of four to eight hours. If a response is still inadequate, a final screening dose of 100 mcg in 2 mL may be administered twenty-four hours later {01}.
Patients who do not respond to a 100-mcg intrathecal screening dose should not be considered for implantation of a pump for long-term infusions {01}.

Post-implantation dose titration period: To determine the initial total daily dose of intrathecal baclofen following implantation, the screening dose that gave a positive effect should be doubled and administered over a twenty-four-hour period. However, if the efficacy of the loading dose was maintained for more than eight hours, the starting daily dose should be the screening dose delivered over a twenty-four-hour period {01}.




Spasticity of spinal cord origin—After the first twenty-four hours, the daily dose should be increased slowly by ten to thirty percent increments only once every twenty-four hours, until the desired clinical effect is achieved {01}.




Spasticity of cerebral origin—After the first twenty-four hours, the daily dose should be increased slowly by five to fifteen percent only once every twenty-four hours, until the desired clinical effect is achieved {01}.

Note: No dose increase should be given in the first twenty-four hours, until the steady state is achieved {01}.

Maintenance:


Spasticity of spinal cord origin—Intrathecal, 12 to 2003 mcg per day for long-term continuous infusion {01}.
Note: Most patients are adequately maintained on 300 to 800 mcg per day {01}. During periodic refills of the pump, the daily dose may be increased by ten to forty percent, but no more than forty percent, to maintain adequate symptom control {01}. However, there is limited experience with daily doses greater than 1000 mcg per day {01}.




Spasticity of cerebral origin—Intrathecal, 22 to 1400 mcg per day for long-term continuous infusion {01}.
Note: Most patients are adequately maintained on 90 to 703 mcg per day. During periodic refills of the pump, the daily dose may be increased by five to twenty percent, but no more than twenty percent, to maintain adequate symptom control.
The daily dose may be reduced by ten to twenty percent if patients experience intolerable side effects {01}.




Usual pediatric dose
Antispastic
Children 4 years of age and older: See Usual adult and adolescent dose for cerebral spasticity.

Note: In clinical trials, pediatric patients under 12 years of age required a lower daily dose than adults (average daily dose of 274 mcg per day) {01}. However, patients over 12 years of age had the same dosage requirements as adults.



Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


50 mcg per mL (Rx) [Lioresal Intrathecal{01}]


500 mcg per mL (Rx) [Lioresal Intrathecal{01}]


2000 mcg per mL (Rx) [Lioresal Intrathecal{01}]

Canada—


50 mcg per mL (Rx) [Lioresal Intrathecal{21}]


500 mcg per mL (Rx) [Lioresal Intrathecal{21}]


2000 mcg per mL (Rx) [Lioresal Intrathecal{21}]

Packaging and storage:
Store below 30 ºC (86 ºF), preferably between 15 and 30 ºC (59 and 86 ºF) {01}. Protect from freezing.

Preparation of dosage form:
Intrathecal baclofen may be prepared with sterile, preservative-free sodium chloride for injection {01}.

Note: For screening—A 50-mcg-per-mL concentration should be used for injection into the subarachnoid space {01}.
For maintenance—The solution must be diluted for patients who require concentrations other than 500 mcg per mL or 2000 mcg per mL {01}.




Revised: 02/20/2003



References
  1. Lioresal Intrathecal package insert (Medtronic—US), Rev 6/96, Rec 10/96.
  1. Lewis KS, Mueller WM. Intrathecal baclofen for severe spasticity secondary to spinal cord injury. Ann Pharmacother 1993; 27: 767-73.
  1. Albright AL. Neurosurgical treatment of spasticity: selective posterior rhizotomy and intrathecal baclofen. Stereotact Funct Neurosurg 1992; 58: 3-13.
  1. Rifici C, Kofler M, Kronenberg M, et al. Intrathecal baclofen application in patients with supraspinal spasticity secondary to severe traumatic brain injury. Funct Neurol 1994; 9: 29-33.
  1. Albright AL, Barron WB, Fasick MP, et al. Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993; 270: 2475-7.
  1. Kroin JS, Amjad A, York M, et al. The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 1993; 33(2): 226-30.
  1. Albright AL. Baclofen in the treatment of cerebral palsy. J Child Neurol 1996; 11: 77-83.
  1. Penn RD, Kroin JS. Long-term intrathecal baclofen infusion for treatment of spasticity. J Neurosurg 1987; 66: 181-5.
  1. Broseta G, Garcia-March MJ, Sanchez-Ledesma JA. Chronic intrathecal baclofen administration in severe spasticity. Stereotact Funct Neurosurg 1990; 54+55: 147-53.
  1. Muller H. Treatment of severe spasticity: results of a multicenter trial conducted in Germany involving the intrathecal infusion of baclofen by an implantable drug delivery system. Dev Med Child Neurol 1992; 34: 739-45.
  1. Albright AL, Cervi, Singletary J. Intrathecal baclofen for spasticity in cerebral palsy. JAMA 1991; 265(11): 1418-22.
  1. Albright AL. Spastic cerebral palsy. CNS Drugs 1995; 4(1): 17-27.
  1. Saltuari L, Kronenberg M, Maros MJ, et al. Long-term intrathecal baclofen treatment in supraspinal spasticity. Acta Neurol 1992; 14(3): 195-207.
  1. Davidoff R. Antispasticity drugs: mechanism of action. Ann Neurol 1985; 17: 107-16.
  1. Wuis EW. Spasticity and drug therapy. Pharm Weekbl Sci 1987; 9(5): 249-60.
  1. HOLD
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996. p. 74.
  1. Muller-Schwefe G, Penn RD. Physostigmine in the treatment of intrathecal baclofen overdose: report of three cases. J Neurosurg 1989; 71: 273-5.
  1. Sallerin-Caute B, Lazorthes Y, Monsarrat B, et al. CSF baclofen levels after intrathecal administration in severe spasticity. J Clin Pharmacol 1991; 40: 363-5.
  1. Coffey RJ, Cahill D, Steers W. Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multicenter study. J Neurosurg 1993; 78: 226-32.
  1. Lioresal Intrathecal package insert (Ciba-Geigy—Canada), Rev 9/94, Rec 11/96.
  1. Panel Comment, 7/97.
  1. Panel Comment, 7/97.
  1. Panel Comment, 7/97.
  1. Coffey, Robert J., M.D. , Important new drug warning [from Dear Doctor letter]. Medtronic Drug Delivery. 05/24/2002
  1. Fontana, Pier-Giorgio., PhD. , Important new drug warning [from Dear Doctor letter]. Novartis Pharmaceuticals Canada, Inc, Dorval, Quebec, Canada. 07/2002
  1. Product Information: Lioresal® Intrathecal, baclofen. Medtronic, Minneapolis, MN, (PI revised 2002) reviewed 10/2002.
  1. Product Monograph: PrLioresal® Intrathecal, baclofen. Novartis Pharmaceuticals Canada, Dorval, Quebec, (revised 06/27/1997) reviewed 10/2002.
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