Information for the Patient
Lioresal Intrathecal
Pharmacology
The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen, calculated from intrathecal bolus or continuous infusion studies, approximate CSF turnover, suggesting elimination is by bulk-flow removal of CSF. Direct infusion into the spinal subarachnoid space bypasses absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
Intrathecal Bolus: After a bolus lumbar injection of 50 or 100 µg intrathecal baclofen in 7 patients, the average CSF elimination half-life was 1.51 hours over the first 4 hours and the average CSF clearance was approximately 30 mL/h.
After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 mL.
Continuous Infusion: A study, conducted in 10 patients, suggests that the mean CSF clearance for continuous intrathecal infusion of baclofen is approximately 30 mL/h.
Continuous intrathecal infusion daily doses of 50 to 1200 µg result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/mL at steady state. According to the half-life measured in the CSF, CSF steady-state concentrations will be reached within 1 to 2 days. 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 baclofen concentration gradient of about 4:1 is established during continuous baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap during continuous baclofen infusion at the lumbar level in doses associated with therapeutic efficacy; the interpatient variability was great. This is of clinical importance insofar as spasticity in the lower extremities can be effectively treated with little effect on the upper limbs and with fewer CNS adverse reactions due to effects on the brain centres.
Indications
For the management of patients with severe spasticity due to spinal cord injury or multiple sclerosis who are unresponsive to oral baclofen or who experience unacceptable side effects at effective oral doses.
Intrathecal baclofen therapy may be considered as an alternative to destructive neurosurgical procedures.
Prior to implantation of a device for chronic intrathecal infusion, patients must demonstrate a positive clinical response to an intrathecal baclofen screening trial (see Dosage).
Intrathecal baclofen has been used in patients with spasticity of cerebral origin, e.g., spasticity following hypoxic encephalopathy, head injury, or stroke; however, clinical experience is limited.
Precautions
There is inadequate systemic experience with the use of baclofen intrathecal in combination with other medications to predict specific drug-drug interactions. The combined use of morphine and intrathecal baclofen was responsible for hypotension in 1 patient. The potential for this combination to cause dyspnea or other CNS symptoms cannot be excluded.
The coadministration of other intrathecal agents with intrathecal baclofen has not been tested and the safety of these combinations is unknown.
The CNS depressant effects of alcohol and other compounds affecting the CNS may be additive to the effects of intrathecal baclofen.
When using oral baclofen, concurrent treatment with tricyclic antidepressants may potentiate the effect of baclofen, resulting in pronounced muscular hypotonia. Therefore, caution is advised when using intrathecal baclofen in this combination.
Since concomitant treatment with oral baclofen and antihypertensives is likely to increase antihypertensive effects, it is recommended that blood pressure is checked and if necessary, the dosage of antihypertensive medication adjusted accordingly.
Information to Be Provided to the Patient: See Information for the Patient.
Several patients over the age of 65 years have been treated with intrathecal baclofen during the clinical trials without specific problems. Elderly patients may be more susceptible to the side effects of oral baclofen in the titration stage and this may also apply to intrathecal baclofen. However, as doses are individually titrated there is not likely to be a particular problem in treating elderly patients.
Drowsiness has been reported in some patients on intrathecal baclofen. Patients should be cautioned regarding the operation of automobiles or dangerous machinery, and activities made hazardous by decreased alertness.
In mothers taking oral baclofen 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 intrathecal baclofen. As a general rule, nursing should be undertaken while a patient is receiving intrathecal baclofen only if the potential benefits outweigh the possible risks to the infant.
Patients with Special Diseases and Conditions: In patients with abnormal CSF flow, the spread of the drug and therefore, the distribution of antispastic activity may be inadequate.
Patients suffering from psychotic disorders, schizophrenia, confusional states, or Parkinson's disease should be treated cautiously with intrathecal baclofen and kept under careful surveillance, because exacerbations of these conditions have been observed with oral baclofen administration.
Special attention should be given to patients known to suffer from epilepsy since seizures have occasionally been reported during overdose with, and withdrawal from, intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen.
Intrathecal baclofen should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of intrathecal baclofen may cause an autonomic dysreflexic episode.
Baclofen should be used with caution in patients with cerebrovascular or respiratory insufficiency, as these conditions may be exacerbated by baclofen.
Interaction of intrathecal baclofen with underlying, non CNS related diseases is unlikely because the systemic availability of the drug after intrathecal administration is substantially lower than after oral administration. Nevertheless, observations after oral baclofen therapy suggest that caution should be exercised in the following situations: history of peptic ulcers, pre-existing sphincter hypertonia, impaired hepatic or renal function.
In rare instances elevated AST, alkaline phosphatase and glucose levels in the serum have been recorded when using oral baclofen.
Clinical experience with intrathecal baclofen in patients under 18 years of age is limited and safe use in this age group has not been established.
Safe use of intrathecal baclofen during pregnancy has not been established. Baclofen crosses the placental barrier. High doses of oral baclofen are associated with an increased incidence of omphaloceles (abdominal hernias) in the fetuses of rats and of ossification defects in those of rats and rabbits. Therefore, the drug should be administered to pregnant patients or women of childbearing potential only when, in the judgment of the physician, the potential benefits outweigh the possible hazards.
Supplied
Each mL of clear, colorless solution contains: baclofen 0.5 mg for intrathecal administration. Nonmedicinal ingredients: sodium chloride and water for injection. Ampuls of 20 mL. Cartons of 1.
Each mL of clear, colorless solution contains: baclofen 0.05 mg for intrathecal administration. Nonmedicinal ingredients: sodium chloride and water for injection. Ampuls of 1 mL. Cartons of 5.
Each mL of clear, colorless solution contains: baclofen 2 mg for intrathecal administration. Nonmedicinal ingredients: sodium chloride and water for injection. Ampuls of 5 mL. Cartons of 5.
Protect from heat (store at 15 to 30°C). Do not freeze. Do not heat sterilize. Lioresal Intrathecal must be kept out of the reach and sight of children.
Contraindications
Known or suspected hypersensitivity to baclofen or to any of the excipients.
The drug should not be administered by the i.v., i.m., s.c. or epidural routes.
Warnings
Because of the possibility of potential life-threatening CNS depression, cardiovascular collapse and/or respiratory failure, physicians must be adequately trained in chronic intrathecal infusion therapy.
Specific instructions for programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to. Consult pump manufacturer's literature for information on the appropriate use and care of these devices.
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 (see Dosage).
Resuscitative equipment should be available.
The pump system should not be implanted until the patient's response to bolus intrathecal injection of intrathecal baclofen has been properly evaluated and found to be clinically safe and effective.
Following surgical implantation of the pump, particularly during the initial phase 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 intrathecal baclofen 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 and all those involved in the care of 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 (see Overdose: Symptoms and Treatment).
Abrupt Drug Withdrawal:
Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include 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.
Prevention of abrupt discontinuation of intrathecal baclofen 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. Special attention should be given to patients at apparent risk (e.g., spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information. (See Warnings.)
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 postmarketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; 6 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 CNS 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 baclofen, or oral, enteral, or i.v. benzodiazepines may prevent potentially fatal sequelae. Oral baclofen alone should not be relied upon to halt the progression of the effects of intrathecal baclofen withdrawal.
Seizures have been reported during overdose and with withdrawal from baclofen intrathecal as well as in patients maintained on therapeutic doses of baclofen intrathecal.
Therefore, except for serious adverse reactions and overdose related emergencies, the dose should always be reduced slowly when the drug is discontinued (over a period of approximately 1 to 2 weeks).
Adverse Effects
Rare: urticaria, alopecia, facial edema, diaphoresis.
Rare: urinary incontinence, sluggish bladder, bladder spasm, sexual dysfunction.
Occasional: sedation, accommodation disorders/double vision. Rare: respiratory depression, hypothermia, nystagmus, dysphagia, insomnia, somnolence, fatigue, decreased coordination, memory loss, confusion/disorientation, anxiety, depression, suicide ideation and attempt, euphoria, dysphoria, hallucinations, paranoia.
In addition to the more common adverse events reported above, the following adverse events were observed during clinical trials elsewhere or reported by clinicians using intrathecal baclofen on a humanitarian basis.
Rare: dry mouth, diarrhea, decreased appetite, dehydration, ileus, decreased taste.
Occasional: bradycardia. Rare: deep vein thrombosis, skin flushing, paleness, pulmonary embolism.
Overdose
Signs of overdose may appear suddenly or insidiously.
Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea and/or vomiting and cephalad progression of hypotonia. Respiratory depression, apnea, and coma result from serious overdosage.
Serious overdose may occur, for example, by inadvertent delivery of catheter contents during catheter patency/position analysis. Errors in programming, excessively rapid dose increases, and concomitant treatment with oral baclofen are other possible causes of overdosage. Possible pump malfunction should also be investigated.
Symptoms of severe intrathecal baclofen overdose (coma) were reported in a sensitive adult patient after receiving a 25 µg intrathecal bolus dose.
There is no specific antidote for treating overdoses of intrathecal baclofen, however, the following steps should generally be undertaken. 1) Residual 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.
If lumbar puncture is not contraindicated, consideration should be given in the early stage of the intoxication to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.
Institute measures to support cardiovascular function.
In the event of convulsions, administer diazepam i.v. with caution.
Anecdotal reports suggest that i.v. physostigmine may reverse central side effects, notably drowsiness and respiratory depression.
Caution in administering physostigmine i.v. is advised, however, because its use has been associated with the induction of seizures, bradycardia, and cardiac conduction disturbances, a test dose of 0.5 mg i.v. is given initially. Give 1 to 2 mg slowly i.v. (over 2 minutes). Patients should be monitored closely during this time. If no clinical changes or cholinergic signs occur within 15 to 30 minutes, an additional 1 to 2 mg may be cautiously administered. Repeat doses of 1 to 2 mg i.v. every 30 minutes up to 2 hours. Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.
As the CNS effects of physostigmine may wear off rapidly, it is important to monitor the patient continuously.
Physostigmine is the only drug of this class that may be used. Neostigmine should not be used as it does not have any CNS effects.
If symptoms of cholinergic toxicity develop, physostigmine should be discontinued.
Dosage
The first dose should be performed with resuscitative equipment on stand-by.
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 available for immediate use in case of life-threatening or intolerable adverse reactions. Implantation of pumps should only be performed in experienced centres in order to minimize the risks in the perioperative phase.
Screening Phase: Prior to initiation of chronic infusion of intrathecal baclofen, patients must demonstrate a response to intrathecal baclofen bolus in a screening trial. A test bolus dose of baclofen is usually administered via a lumbar puncture or an intrathecal catheter to elicit a response. For this purpose low concentration ampuls of 0.05 mg/mL are available.
The usual initial test dose is 25 µg or 50 µg and is stepped up by 25 µg increments at least 24 hours apart, until an approximately 4 to 8 hour response is observed; the dose should be given by barbotage over at least 1 minute. If an adverse reaction occurs at a dose of 25 µg, a lower dose, such as 10 µg may be tested.
Patients should demonstrate a positive clinical response in order to be considered responders to treatment. A positive clinical response is characterized by a significant decrease in muscle tone and/or frequency and/or severity of spasms. There is great variability in sensitivity to intrathecal baclofen.
Patients who do not respond to a 100 µg test dose should not be given further increases of dose or be considered for continuous intrathecal infusion. However, in rare instances some patients, particularly those with spasticity of cerebral origin, have received higher test bolus doses.
Dose Titration Phase: After confirmation that the patient is responsive to intrathecal baclofen by means of test bolus doses, intrathecal infusion is established using a suitable delivery system (see Drug delivery devices).
To determine the initial total daily dose of intrathecal baclofen following implant, the screening dose which 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 12 hours. In this case the starting daily dose should be the screening dose delivered over a 24 hour period. No dose increases should be administered in the first 24 hours.
After the first 24 hours, the dosage should be adjusted slowly on a daily basis to achieve the desired effect, with dosage increments limited to 10 to 30% to avoid possible overdosing. With programmable pumps, the dose should be increased only once every 24 hours. For nonprogrammable pumps with a 76 cm catheter delivering 1 mL/day, intervals of 48 hours are suggested for evaluation of response. If the daily dose has been significantly increased and no clinical effect is achieved, check for proper pump function and catheter patency.
The clinical goal is to maintain muscle tone as close to normal as possible, and to minimize the frequency and severity of spasms without inducing intolerable side effects.
There is limited experience with doses greater than 1000 µg/day.
Maintenance Therapy: The lowest dose giving an adequate response should be used. Most patients require gradual increases in dose over time to maintain optimum response during chronic therapy due to decreased responsiveness to therapy or to progress of the disease.
The daily dose may be gradually increased by 10 to 30% to maintain adequate symptom control by adjusting the dosing rate of the pump and/or the concentration of intrathecal baclofen in the reservoir. The daily dose may also be reduced by 10 to 20% if patients experience side effects. A sudden requirement for substantial dose escalation suggests a catheter complication (i.e., catheter kink or dislodgment) or pump malfunction.
Maintenance dosage for long-term continuous infusion of intrathecal baclofen ranges from 10 to 1200 µg/day, most patients being adequately maintained on 300 to 800 µg/day. The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. Please consult pump manufacturer's manual for specific recommendations.
During long-term treatment approximately 10% of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for tolerance management; however, in 17 patients, the use of a “drug holiday” by switching for 10 to 14 days to intrathecal preservative-free morphine sulfate has been reported as an effective approach to the management of tolerance. After a few days the sensitivity to baclofen may be restored; treatment should be resumed at the initial continuous infusion dose and followed by a titration phase to avoid overdose accidents. This must be performed in a hospital unit.
Regular clinical review remains a necessity throughout to assess dosage requirements, functioning of the delivery system, and monitoring for possible adverse drug reactions or evidence of infection.
Delivery Regimen: Intrathecal baclofen is most often administered in a continuous infusion mode immediately following implant. After the patient has stabilized with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimize control of spasticity at different times of the day. For example, patients who have increased spasm at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start 2 hours before the time of desired clinical effect.
Drug Delivery Devices: Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to. Consult pump manufacturer's literature for information on the appropriate use and care of these devices.
Evidence demonstrating the efficacy of intrathecal baclofen was obtained using the Medtronic SynchroMed Programmable Infusion System. Other pumps proven to be suitable for intrathecal baclofen administration may be used.
The Medtronic SynchroMed Programmable Infusion System, that is an implantable drug delivery system with refillable reservoirs which, after general or local anesthesia, is implanted in a s.c. pocket usually on the abdominal wall. This device is connected to an intrathecal catheter that passes s.c. to the subarachnoid space.
The Medtronic SynchroMed Programmable Infusion System has an 18 mL drug reservoir and may be programmed to different flow rates such as single bolus, periodic boluses, continuous and complex continuous. However, the lithium battery of the pump has a life span of 3 to 4 years and therefore requires replacement.
Intrathecal baclofen proved to be stable in the implanted SynchroMed Programmable Infusion System for 11 weeks.
Details regarding the availability and use of this drug delivery device can be obtained from the manufacturers: Medtronic of Canada Ltd., 6733 Kitimat Road, Mississauga, Ontario, L5N 1W3. 1-800-268-5346; Fax: 1-905-826-6620.
General guidelines regarding the use of all implantable systems are located under Precautions.
Before using other systems, it must be confirmed that the technical specifications, including chemical stability of baclofen in the reservoir fulfil the requirements for safe and effective use of intrathecal baclofen. Please consult pump manufacturer's manual for this information.
Parenteral Products: Instructions for use/handling: Intrathecal baclofen is intended for intrathecal injection and continuous intrathecal infusion as indicated by the delivery specifications of the infusion system.
Each ampul is intended for single use only. Discard any unused portion.
Parenteral drug products should be inspected for particulate matter and discoloration prior to administration whenever solution and container permit.
The concentration to be used depends upon the total daily dose required as well as the delivery rate of the pump. Please consult manufacturer's manual for specific recommendations.
For patients who require concentrations other than 0.05 mg/mL, 0.5 mg/mL or 2 mg/mL, intrathecal baclofen must be diluted, under aseptic conditions, with sterile preservative-free sodium chloride injection and used immediately.
As a rule baclofen ampuls for intrathecal administration should not be mixed with other infusion or injection solutions. Dextrose proved to be incompatible due to a chemical reaction with baclofen.
