Usual Adult Dose for Spasticity

Oral:

• Initial dose: The following gradually increasing dosage regimen is suggested, but should be adjusted to suit individual patient requirements: 5 mg orally 3 times a day for 3 days, then 10 mg orally 3 times a day for 3 days, then 15 mg orally 3 times a day for 3 days, then 20 mg orally 3 times a day for 3 days
• Maintenance dose: Should be individualized.
• Maximum dose: 80 mg/day (20 mg orally 4 times a day)

Comments:

• The lowest dose compatible with an optimal response is recommended.
• Slowly withdraw therapy if benefits are not evident after a reasonable period.

Uses:

• For spasticity of multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity; patients should have reversible spasticity so therapy will aid in restoring residual function
• For spinal cord injuries and other spinal cord diseases

Usual Adult Dose for Cerebral Spasticity

INTRATHECAL SCREENING PHASE: Prior to pump implantation for chronic infusion, patients must show a positive response to an intrathecal bolus dose in a screening trial.

• First Screening Dose: 50 mcg (in a volume of 1 mL) administered into the intrathecal space by barbotage over at least 1 minute; observe patient for 4 to 8 hours for a positive response
• Second Screening Dose: (if no positive response to first screening dose): 75 mcg (in a volume of 1.5 mL) bolus dose administered 24 hours after the first screening dose; observe patient for 4 to 8 hours for a positive response
• Third Screening Dose: (if no positive response to second screening dose): 100 mcg (in a volume of 2 mL) bolus dose administered 24 hours after the second screening dose; observe patient for 4 to 8 hours for a positive response; if no positive response to third screening dose, the patient should not be considered for chronic intrathecal therapy

INTRATHECAL POST-IMPLANT DOSE TITRATION PERIOD:

• The screening dose that received a positive response should be doubled and administered over 24 hours, 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 24 hours.
• No dose increases should be given in the first 24 hours (i.e., until steady state is achieved).
• ADULT PATIENTS WITH SPASTICITY OF SPINAL CORD ORIGIN: After the first 24 hours, the daily dosage should be increased slowly by 10% to 30% increments and only once every 24 hours, until the desired 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 effect is achieved.

INTRATHECAL MAINTENANCE DOSING FOR SPASTICITY OF SPINAL CORD ORIGIN:

• 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 to maintain optimal response during chronic therapy
• Maintenance dosage for long term continuous infusion: 12 to 2003 mcg/day, with most patients adequately maintained on 300 to 800 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day.

MAINTENANCE DOSING FOR SPASTICITY OF CEREBRAL ORIGIN PATIENTS:

• 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; most patients require gradual increases in dose to maintain optimal response during chronic therapy.
• Maintenance dosage for long term continuous infusion: 22 to 1400 mcg/day, with most patients adequately maintained on 90 to 703 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day.

POTENTIAL NEED FOR DOSE ADJUSTMENTS IN CHRONIC USE:

• During long term treatment, approximately 5% of patients become refractory to increasing doses. There is not sufficient experience to make recommendations for tolerance treatment; however, tolerance has been treated on occasion, in hospital, by a "drug holiday" consisting of the gradual reduction of intrathecal dosing over a 2 to 4-week period and switching to alternative methods of spasticity management.
• After the "drug holiday," intrathecal dosing may be restarted at the initial continuous infusion dose.

Comments:

• Patients should first respond to a screening dose prior to consideration for long term infusion via an implantable pump.
• For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral 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 therapy.
• Determination of the optimal dose requires individual titration. The lowest dose with an optimal response should be used.
• A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms.
• 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).
• Careful dose titration is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function. Allowing occasional spasms may help support circulatory function, possibly prevent the formation of deep vein thrombosis, and optimize activities of daily living.
• Except in overdose related emergencies, dosing should 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 infusion.
• Monitor patients in a fully equipped environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be available for use in case of life-threatening or intolerable side effects.

Use: For the management of severe spasticity of cerebral or spinal origin

Usual Adult Dose for Spinal Spasticity

INTRATHECAL SCREENING PHASE: Prior to pump implantation for chronic infusion, patients must show a positive response to an intrathecal bolus dose in a screening trial.

• First Screening Dose: 50 mcg (in a volume of 1 mL) administered into the intrathecal space by barbotage over at least 1 minute; observe patient for 4 to 8 hours for a positive response
• Second Screening Dose: (if no positive response to first screening dose): 75 mcg (in a volume of 1.5 mL) bolus dose administered 24 hours after the first screening dose; observe patient for 4 to 8 hours for a positive response
• Third Screening Dose: (if no positive response to second screening dose): 100 mcg (in a volume of 2 mL) bolus dose administered 24 hours after the second screening dose; observe patient for 4 to 8 hours for a positive response; if no positive response to third screening dose, the patient should not be considered for chronic intrathecal therapy

INTRATHECAL POST-IMPLANT DOSE TITRATION PERIOD:

• The screening dose that received a positive response should be doubled and administered over 24 hours, 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 24 hours.
• No dose increases should be given in the first 24 hours (i.e., until steady state is achieved).
• ADULT PATIENTS WITH SPASTICITY OF SPINAL CORD ORIGIN: After the first 24 hours, the daily dosage should be increased slowly by 10% to 30% increments and only once every 24 hours, until the desired 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 effect is achieved.

INTRATHECAL MAINTENANCE DOSING FOR SPASTICITY OF SPINAL CORD ORIGIN:

• 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 to maintain optimal response during chronic therapy
• Maintenance dosage for long term continuous infusion: 12 to 2003 mcg/day, with most patients adequately maintained on 300 to 800 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day.

MAINTENANCE DOSING FOR SPASTICITY OF CEREBRAL ORIGIN PATIENTS:

• 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; most patients require gradual increases in dose to maintain optimal response during chronic therapy.
• Maintenance dosage for long term continuous infusion: 22 to 1400 mcg/day, with most patients adequately maintained on 90 to 703 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day.

POTENTIAL NEED FOR DOSE ADJUSTMENTS IN CHRONIC USE:

• During long term treatment, approximately 5% of patients become refractory to increasing doses. There is not sufficient experience to make recommendations for tolerance treatment; however, tolerance has been treated on occasion, in hospital, by a "drug holiday" consisting of the gradual reduction of intrathecal dosing over a 2 to 4-week period and switching to alternative methods of spasticity management.
• After the "drug holiday," intrathecal dosing may be restarted at the initial continuous infusion dose.

Comments:

• Patients should first respond to a screening dose prior to consideration for long term infusion via an implantable pump.
• For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral 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 therapy.
• Determination of the optimal dose requires individual titration. The lowest dose with an optimal response should be used.
• A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms.
• 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).
• Careful dose titration is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function. Allowing occasional spasms may help support circulatory function, possibly prevent the formation of deep vein thrombosis, and optimize activities of daily living.
• Except in overdose related emergencies, dosing should 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 infusion.
• Monitor patients in a fully equipped environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be available for use in case of life-threatening or intolerable side effects.

Use: For the management of severe spasticity of cerebral or spinal origin

Usual Pediatric Dose for Spasticity

12 years and older:
Oral:

• Initial dose: The following gradually increasing dosage regimen is suggested, but should be adjusted to suit individual patient requirements: 5 mg orally 3 times a day for 3 days, then 10 mg orally 3 times a day for 3 days, then 15 mg orally 3 times a day for 3 days, then 20 mg orally 3 times a day for 3 days
• Maintenance dose: Should be individualized.
• Maximum dose: 80 mg/day (20 mg orally 4 times a day)

Comments:

• The lowest dose compatible with an optimal response is recommended.
• Slowly withdraw therapy if benefits are not evident after a reasonable period.

Uses:

• For spasticity of multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity; patients should have reversible spasticity so therapy will aid in restoring residual function
• For spinal cord injuries and other spinal cord diseases

Usual Pediatric Dose for Cerebral Spasticity

4 years and older:

• The starting screening dose for pediatric patients is the same as in adult patients, (50 mcg); however, for very small patients, a screening dose of 25 mcg may be tried first:

INTRATHECAL SCREENING PHASE: Prior to pump implantation for chronic infusion, patients must show a positive response to an intrathecal bolus dose in a screening trial.

• First Screening Dose: 25 to 50 mcg (in a volume of 1 mL) administered into the intrathecal space by barbotage over at least 1 minute; observe patient for 4 to 8 hours for a positive response
• Second Screening Dose: (if no positive response to first screening dose): 75 mcg (in a volume of 1.5 mL) bolus dose administered 24 hours after the first screening dose; observe patient for 4 to 8 hours for a positive response
• Third Screening Dose: (if no positive response to second screening dose): 100 mcg (in a volume of 2 mL) bolus dose administered 24 hours after the second screening dose; observe patient for 4 to 8 hours for a positive response; if no positive response to third screening dose, the patient should not be considered for chronic intrathecal therapy

INTRATHECAL POST-IMPLANT DOSE TITRATION PERIOD:

• The screening dose that received a positive response should be doubled and administered over 24 hours, 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 24 hours.
• No dose increases should be given in the first 24 hours (i.e., until steady state is achieved).
• After the first 24 hours in pediatric patients, the daily dose should be increased slowly by 5% to 15% increments and only once every 24 hours, until the desired effect is achieved.

MAINTENANCE DOSING:
The same dosing recommendations for adults with spasticity of cerebral origin are used in pediatric patients 4 years and older:

• 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.

MAINTENANCE DOSAGE FOR LONG TERM CONTINUOUS INFUSION:

• Pediatric patients 4 to under 12 years may require a lower daily dose: 274 mcg/day, with a range of 24 to 1199 mcg/day
• Age 12 years and older: 22 to 1400 mcg/day, with most patients adequately maintained on 90 to 703 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day

POTENTIAL NEED FOR DOSE ADJUSTMENTS IN CHRONIC USE:

• During long term treatment, approximately 5% of patients become refractory to increasing doses. There is not sufficient experience to make recommendations for tolerance treatment; however, tolerance has been treated on occasion, in hospital, by a "drug holiday" consisting of the gradual reduction of intrathecal dosing over a 2 to 4-week period and switching to alternative methods of spasticity management.
• After the "drug holiday," intrathecal dosing may be restarted at the initial continuous infusion dose.

Comments:

• Patients should first respond to a screening dose prior to consideration for long term infusion via an implantable pump.
• For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral 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 therapy.
• Determination of the optimal dose requires individual titration. The lowest dose with an optimal response should be used.
• A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms.
• 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).
• Careful dose titration is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function. Allowing occasional spasms may help support circulatory function, possibly prevent the formation of deep vein thrombosis, and optimize activities of daily living.
• Except in overdose related emergencies, dosing should 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 infusion.
• Monitor patients in a fully equipped environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be available for use in case of life-threatening or intolerable side effects.

Use: For the management of severe spasticity of cerebral or spinal origin in pediatric patients 4 years and older

Usual Pediatric Dose for Spinal Spasticity

4 years and older:

• The starting screening dose for pediatric patients is the same as in adult patients, (50 mcg); however, for very small patients, a screening dose of 25 mcg may be tried first:

INTRATHECAL SCREENING PHASE: Prior to pump implantation for chronic infusion, patients must show a positive response to an intrathecal bolus dose in a screening trial.

• First Screening Dose: 25 to 50 mcg (in a volume of 1 mL) administered into the intrathecal space by barbotage over at least 1 minute; observe patient for 4 to 8 hours for a positive response
• Second Screening Dose: (if no positive response to first screening dose): 75 mcg (in a volume of 1.5 mL) bolus dose administered 24 hours after the first screening dose; observe patient for 4 to 8 hours for a positive response
• Third Screening Dose: (if no positive response to second screening dose): 100 mcg (in a volume of 2 mL) bolus dose administered 24 hours after the second screening dose; observe patient for 4 to 8 hours for a positive response; if no positive response to third screening dose, the patient should not be considered for chronic intrathecal therapy

INTRATHECAL POST-IMPLANT DOSE TITRATION PERIOD:

• The screening dose that received a positive response should be doubled and administered over 24 hours, 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 24 hours.
• No dose increases should be given in the first 24 hours (i.e., until steady state is achieved).
• After the first 24 hours in pediatric patients, the daily dose should be increased slowly by 5% to 15% increments and only once every 24 hours, until the desired effect is achieved.

MAINTENANCE DOSING:
The same dosing recommendations for adults with spasticity of cerebral origin are used in pediatric patients 4 years and older:

• 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.

MAINTENANCE DOSAGE FOR LONG TERM CONTINUOUS INFUSION:

• Pediatric patients 4 to under 12 years may require a lower daily dose: 274 mcg/day, with a range of 24 to 1199 mcg/day
• Age 12 years and older: 22 to 1400 mcg/day, with most patients adequately maintained on 90 to 703 mcg/day; there is limited experience with daily doses greater than 1000 mcg/day

POTENTIAL NEED FOR DOSE ADJUSTMENTS IN CHRONIC USE:

• During long term treatment, approximately 5% of patients become refractory to increasing doses. There is not sufficient experience to make recommendations for tolerance treatment; however, tolerance has been treated on occasion, in hospital, by a "drug holiday" consisting of the gradual reduction of intrathecal dosing over a 2 to 4-week period and switching to alternative methods of spasticity management.
• After the "drug holiday," intrathecal dosing may be restarted at the initial continuous infusion dose.

Comments:

• Patients should first respond to a screening dose prior to consideration for long term infusion via an implantable pump.
• For spasticity of spinal cord origin, chronic infusion via an implantable pump should be reserved for patients unresponsive to oral 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 therapy.
• Determination of the optimal dose requires individual titration. The lowest dose with an optimal response should be used.
• A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms.
• 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).
• Careful dose titration is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function. Allowing occasional spasms may help support circulatory function, possibly prevent the formation of deep vein thrombosis, and optimize activities of daily living.
• Except in overdose related emergencies, dosing should 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 infusion.
• Monitor patients in a fully equipped environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be available for use in case of life-threatening or intolerable side effects.

Use: For the management of severe spasticity of cerebral or spinal origin in pediatric patients 4 years and older

Renal Dose Adjustments

Use with caution. Dosage may need to be reduced.

Liver Dose Adjustments

Data not available

Dose Adjustments

Except in emergency cases associated with an overdose, treatment should be discontinued gradually with successive dose reductions. This drug should not be abruptly discontinued.

Precautions

US BOXED WARNINGS:
DO NOT DISCONTINUE THE INTRATHECAL FORMULATION OF THIS DRUG ABRUPTLY:

• Abrupt discontinuation 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 the intrathecal formulation 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 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 the oral or intrathecal formulation).
• Consult the technical manual of the implantable infusion system for additional post-implant clinician and patient information.

• ORAL: Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
• INTRATHECAL: Safety and effectiveness in pediatric patients below the age of 4 years have not been established.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis removes this drug from the body, alleviates clinical symptoms of overdose and shortens the recovery time in these patients.

Other Comments

Administration advice:

• The oral formulation of this drug should be taken with food.
• The specific concentration of this drug that should be used for intrathecal infusion depends on the total daily dose required as well as the delivery rate of the pump.
• Patients who do not respond (i.e., demonstrate a significant decrease in muscle tone and/or frequency and/or severity of spasms) following a 100 mcg intrathecal test dose should not be administered additional increases in dose or be considered for continuous intrathecal infusion.
• Over time during maintenance intrathecal therapy, many patients will require gradual dose increases to maintain the desired clinical effect. However, a sudden requirement for a significant increase in dose may signify a catheter complication or pump malfunction. Some patients may require a more complicated dose delivery which coincides with increased or decreased spasticity at different times of the day (e.g., increased infusion rate at night). Some patients may become refractory and develop tolerance to increasing doses. Cessation of intrathecal therapy for a few days may restore sensitivity. Treatment may be restarted at the initial continuous infusion rate and titrated accordingly.

General:

• The oral tablets and liquid are considered bioequivalent.
• In patients who do not exhibit an improvement in symptoms within 6 to 8 weeks of achieving the maximum dosage of the oral formulation, continuation of therapy should be reconsidered.
• The intrathecal formulation of this drug should be reserved for patients unresponsive to oral therapy, or those who experience intolerable central nervous system side effects at effective doses.
• The intrathecal injection is intended for administration in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable pumps suitable for continuous administration into the intrathecal space.
• Children should be of sufficient body mass to accommodate the intrathecal implantable pump for chronic infusion.
• The pump system should not be implanted until the patient response to bolus intrathecal injection and/or dose titration is adequately evaluated and found to be clinically safe and effective.
• The use of the intrathecal route of administration should only be undertaken by physicians adequately trained in chronic intrathecal infusion therapy, in a medically supervised and adequately equipped environment.
• Specific instructions for implanting, programming, and/or refilling of the implantable pump for intrathecal administration recommended by its manufacturer should be strictly adhered to.
• Do not administer the intrathecal formulation of this drug by any route apart from the intrathecal route.
• During the intrathecal dose titration phase, dose increases should occur once every 24 hours in patients with programmable pumps and every 48 hours in patients with nonprogrammable pumps.
• All patients on intrathecal therapy are at risk for withdrawal. Common reasons for abrupt interruption include malfunction of the catheter, low volume in the pump reservoir, and end of pump battery life; human error may play a causal or contributing role. 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 visits for pump refilling and be educated on early symptoms of withdrawal.
• For patients with spasticity due to traumatic brain injury, intrathecal therapy should be delayed until the symptoms of spasticity are stable (i.e., at least one year after the injury).
• No specific dose adjustment guidelines have been suggested for elderly patients; however, caution is recommended in dose selection.
• A suggested treatment of intrathecal baclofen withdrawal is restoration of treatment at or near the same dosage as before therapy was interrupted. If restoration of intrathecal therapy is delayed, treatment with GABA-ergic agonist drugs should be considered. Oral or enteral baclofen alone should not be relied upon to stop intrathecal baclofen withdrawal.

Storage requirements:

• Refer to the manufacturer product information.

Reconstitution/preparation techniques:

• Refer to the manufacturer product information.

Patient advice:

• This drug should be taken during meals with a glass of water.

Frequently asked questions

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