Flexilax

Flexilax is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of Flexilax via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. Flexilax is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in pumps labeled for intrathecal administration of Flexilax.

Prior to implantation of a device for chronic intrathecal infusion of Flexilax, patients must show a response to Flexilax in a screening trial.

GABLOFEN is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of GABLOFEN via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. GABLOFEN is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in pumps labeled for intrathecal administration of GABLOFEN.

Prior to implantation of a device for chronic intrathecal infusion of GABLOFEN, patients must show a response to GABLOFEN in a screening trial.

Flexilax Aguettant is indicated in patients with severe chronic spasticity resulting from trauma, multiple sclerosis or other spinal cord disorders, who are unresponsive to oral Flexilax or other orally administered antispastic agents and/or those patients who experience unacceptable side effects at effective oral doses.

Flexilax Aguettant is effective in adult patients with severe chronic spasticity of cerebral origin, resulting e.g. from cerebral palsy, brain trauma or cerebrovascular accident; however, clinical experience is limited.

Paediatric population

Flexilax Aguettant is indicated in patients aged 4 to <18 years with severe chronic spasticity of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) who are unresponsive to orally administered antispastics (including oral Flexilax) and/or who experience unacceptable side effects at effective oral doses.

Flexilax is indicated in patients with severe chronic spasticity of spinal or cerebral origin (associated with injury, multiple sclerosis, cerebral palsy) who are unresponsive to oral baclofen or other orally administered antispastic agents and/or those patients who experience unacceptable side-effects at effective oral doses.

In patients with spasticity due to head injury a delay of at least one year before treatment with Flexilax is recommended, to allow the symptoms of spasticity to stabilise.

Flexilax may be considered as an alternative to ablative neurosurgical procedures.

Paediatric population

Flexilax is indicated in patients aged 4 to <18 years with severe chronic spasticity of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) who are unresponsive to orally administered antispastics (including oral baclofen) and/or who experience unacceptable side effects at effective oral doses.

Use Only In Pumps Labeled For Intrathecal Administration Of Flexilax

Flexilax is approved only for use in implantable pumps labeled for intrathecal administration of Flexilax. Refer to the manufacturer’s manual for specific instructions and precautions for programming the pump and/or refilling the reservoir. It is important to select the appropriate refill kit for the pump used to administer Flexilax. Flexilax is not to be compounded with other medications.

Screening Phase

Prior to pump implantation and initiation of chronic infusion of Flexilax, patients must demonstrate a positive clinical response to a Flexilax bolus dose administered intrathecally in a screening trial. The screening trial employs Flexilax at a concentration of 50 mcg/mL. A 1 mL syringe (50 mcg/mL) is available for use in the screening trial. The screening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space by barbotage over a period of not less than one minute. The patient is observed over the ensuing 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should be observed for an interval of 4 to 8 hours. If the response is still inadequate, a final bolus screening dose of 100 micrograms in 2 milliliters may be administered 24 hours later.

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.

Preparation Information

Screening

Use the 1 mL screening syringe only (50 mcg/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/mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/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/mL, 1,000 mcg/mL, 2,000 mcg/mL, or 3,000 mcg/mL, Flexilax must be diluted with sterile preservative free Sodium Chloride for Injection, USP.

Administration Information

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

The external surface of Flexilax prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. The use of Flexilax prefilled syringe in an aseptic setting (i.e., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended. For outpatient use, modify aseptic procedures to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the Flexilax prefilled syringe when filling the pump reservoir.

Delivery Regimen

Flexilax 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 Flexilax 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.

Dose Titration

Post-Implant Dose Titration Period

To determine the initial total daily dose of Flexilax 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 dosetitration 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 Flexilax 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 Flexilax 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 Flexilax 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.

Maintenance Therapy

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 Flexilax 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 Flexilax 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.

Use Only In Pumps Labeled For Intrathecal Administration Of GABLOFEN

GABLOFEN is approved only for use in implantable pumps labeled for intrathecal administration of GABLOFEN. Refer to the manufacturer’s manual for specific instructions and precautions for programming the pump and/or refilling the reservoir. It is important to select the appropriate refill kit for the pump used to administer GABLOFEN. GABLOFEN is not to be compounded with other medications.

Screening Phase

Prior to pump implantation and initiation of chronic infusion of GABLOFEN, patients must demonstrate a positive clinical response to a GABLOFEN bolus dose administered intrathecally in a screening trial. The screening trial employs GABLOFEN at a concentration of 50 mcg/mL. A 1 mL syringe (50 mcg/mL) is available for use in the screening trial. The screening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space by barbotage over a period of not less than one minute. The patient is observed over the ensuing 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should be observed for an interval of 4 to 8 hours. If the response is still inadequate, a final bolus screening dose of 100 micrograms in 2 milliliters may be administered 24 hours later.

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.

Preparation Information

Screening

Use the 1 mL screening syringe only (50 mcg/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/mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/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/mL, 1,000 mcg/mL, 2,000 mcg/mL, or 3,000 mcg/mL, GABLOFEN must be diluted with sterile preservative free Sodium Chloride for Injection, USP.

Administration Information

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

The external surface of GABLOFEN prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. The use of GABLOFEN prefilled syringe in an aseptic setting (i.e., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended. For outpatient use, modify aseptic procedures to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the GABLOFEN prefilled syringe when filling the pump reservoir.

Delivery Regimen

GABLOFEN 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 GABLOFEN 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.

Dose Titration

Post-Implant Dose Titration Period

To determine the initial total daily dose of GABLOFEN 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 dosetitration 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 GABLOFEN 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 GABLOFEN 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 GABLOFEN 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.

Maintenance Therapy

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 GABLOFEN 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 GABLOFEN 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.

Flexilax Aguettant 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 of Flexilax Aguettant into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. Intrathecal administration of Flexilax Aguettant through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to.

Efficacy of Flexilax intrathecal has been demonstrated in controller randomised studies with an EU certified pump. This is an implantable administration systems: a refillable reservoir is implanted beneath the skin, mostly into the abdominal wall. This system is connected to an intrathecal catheter that passes subcutaneously into the subarachnoid space.

Test phase.

Prior to administering Flexilax as a continuous intrathecal infusion, patients must show a positive response to administration of an intrathecal test dose in an initial test phase. Usually, a bolus test dose is administered via lumbar puncture or an intrathecal catheter, in order to provoke a response. Patients should be infection-free prior to screening, as the presence of a sistemic infection may prevent an accurate assessment of the response. The initial dose is generally 25 or 50 micrograms; the dose is generally increased in increments of 25 micrograms at intervals of at least 24 hours, until a response lasting approximately 4 to 8 hours is obtained. The dose must be injected over at least one minute via barbotage.

Low-dose ampoules (0.05 mg/ml) are available for this test phase.

Resuscitative equipment must be on hand during injection of the first dose.

Patients are considered to be positive responders if they show a significant decrease in muscle tone and/or frequency and/or severity of spasms.

There is much variability with regard to sensitivity to intrathecal Flexilax.

Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25 micrograms.

Patients who do not respond to a 100-microgram test dose must not be given further doses and are not eligible for continuous intrathecal infusions.

Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depressions.

Paediatric population

Screening phase

The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25-50 μg/day based upon age and size of the child. Patients who do not experience a response may receive a 25 μg/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 μg/day in paediatric patients.

Titration phase.

Once the patient's response to Flexilax Aguettant has been established as positive via test doses, intrathecal infusion with a suitable administration system is introduced. Infection may increase the risk of surgical complications and complicate attempts to adjust the dose.

Following implantation, the initial total daily dose should be determined by doubling the dose that gave a positive effect in the test phase and administering it over a 24-hour period, unless the effect of the bolus dose is maintained for more than 12 hours. In this latter case, the initial daily dose should be similar to the dose in the test phase and should be administered over a 24-hour periodo The dose must not be increased during the first 24 hours. After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed l0-30%. Patients with spasticity of cerebral genesis: After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed 5 - 15%.

If a programmable pump is used, dosage should only be increased once every 24 hours. For non-programmable pumps attached to a 76 cm catheter and with a delivery rate of 1 mI/day, it is recommended that the response should only be evaluated at 48-hour intervals. If the daily dosage has been significantly increased without any clinical effect having been observed, pump functioning and catheter permeability should be verified.

Only limited experience is available with doses exceeding 1000 micrograms/day.

During the test phase, as well as during the titration period following implantation, patients should be closely monitored at an institution with all the necessary equipment and personnel. Resuscitative equipment must be on immediate stand-by in the event of any reaction that threatens the vital prognosis, or onset of very serious undesirable effects. In order to limit risks in the perioperative phase, the pump must only be implanted at centres with experienced personnel.

Maintenance therapy.

The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of “paralysis” on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis.

In patients with spasticity of spinai origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom controI. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%).

In both cases the daily dose may also be reduces by 10-20% if patients suffer side effects.

If a significant dose increase should suddenly be necessary, this is indicative of a catheter complication (kink or dislodgement) or pump malfunction.

For Iong-term maintenance treatment via continuous infusion, the intrathecal Flexilax dosage for patients with spasticity of spinal genesis is between 10 and 1000 micrograms/day, with an adequate response being achieved in most patients with 300-800 micrograms/day.

In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22 to 1400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.

Pediatric population:

In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of Flexilax Aguettant ranges from 25 to 200 mcg/day (median dose: 100 mcg/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.

The safety and efficacy of Intrathecal Flexilax for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established.

Around 5% of patients receiving long-term treatment become refractory to dose escalation. This may be due to therapeutic failure. There is insufficient experience available to make any recommendations on dealing with treatment failure. However, this phenomenon has occasionally been treated in hospital by a "drug holiday" consisting of the gradual reduction off Flexilax intrathecal over a period of 2 to 4 weeks and switching to alternative methods of spasticity therapy (e.g. intrathecal preservative-free morphine sulphate). After this period, sensitivity to Flexilax intrathecal may be re-established: treatment should be resumed at the initial continuous infusion dose, followed by a titration phase to avoid overdose.

Caution should be exercised when switching from Flexilax intrathecal to morphine and vice versa (see "Interactions").

Regular clinical monitoring is needed to assess the patient's dosage requirements, to check that the administration system is working properly and to note any undesirable effects or the presence of infection.

Discontinuation oftreatment.

Except in emergency cases associated with an overdose, treatment shouId be discontinued gradually with successive dose reductions. Flexilax Aguettant should not be abruptly discontinued (see "Special wamings and precautions").

Administration: particular specifications.

Ampoules of 10mg/5ml, 40mg/20ml and l0mg/20ml Flexilax Aguettant have been specially developed for infusion pumps.

The exact concentration to be selected depends on the total daily dose needed, as well as the minimum infusion rate of the pump. Please refer to the manufacturer's manual, which contains all specific recommendations.

Method ofadministration.

In most cases, Flexilax Aguettant is administered as a continuous infusion directly after implantation. Once the patient is stabilised in terms of daily dosage and functional aspects, and provided that the pump allows it, a switch can be made to a more complex method of administration, to allow optimal control over spasticity at different times of the day. For example, patients with increased night-time spasms may require a 20% increase in the hourly infusion rate. This altered rate of infusion must be programmed about 2 hours in advance of the expected clinical effect.

Every ampoule is exclusively single-use. Do not resterilize.

The medicinal product has to be visually inspected prior to use. Only clear solutions practically free from particles should be used.

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Intrathecal administration of Lioresal through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to.

Flexilax 50 micrograms/1ml 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 of Flexilax 10mg/20ml and 10mg/5ml into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy.

Respiratory function should be monitored and appropriate resuscitation facilities should be available during the introduction of treatment with Flexilax. Intrathecal administration using an implanted delivery system should only be undertaken by physicians with appropriate knowledge and experience. Specific instructions for using the implantable pump should be obtained from the pump manufacturers. Only pumps constructed of material known to be compatible with the product and incorporating an in-line bacterial retentive filter should be used.

Adult Screening Phase

Prior to initiation of a chronic infusion, the patient's response to intrathecal bolus doses administered via a catheter or lumbar puncture must be assessed. Low concentration ampoules containing 50 micrograms baclofen in 1ml are available for the purpose. Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response.

The usual initial test dose in adults is 25 or 50 micrograms, increasing step-wise by 25 microgram increments at intervals of not less than 24 hours until a response of approximately 4 to 8 hours duration is observed. Each dose should be given slowly (over at least one minute). In order to be considered a responder the patient must demonstrate a significant decrease in muscle tone and/or frequency and/or severity of muscle spasms.

The variability in sensitivity to intrathecal baclofen between patients is emphasised. Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25 micrograms. It is recommended that the initial test dose is administered with resuscitative equipment on hand.

Patients who do not respond to a 100 micrograms test dose should not be given further dose increments or considered for continuous intrathecal infusion.

Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depression.

Paediatric population Screening Phase

The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25-50 micrograms/day based upon age and size of the child. Patients who do not experience a response may receive a 25 microgram/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 micrograms/day in paediatric patients.

Dose-Titration Phase

Once the patient's responsiveness to Flexilax has been established, an intrathecal infusion may be introduced. Flexilax is most often administered using an infusion pump which is implanted in the chest wall or abdominal wall tissues. Implantation of pumps should only be performed in experienced centres to minimise risks during the perioperative phase.

Infection may increase the risk of surgical complications and complicate attempts to adjust the dose.

The initial total daily infused dose is determined by doubling the bolus dose which gave a significant response in the initial screening phase and administering it over a 24 hour period.

However, if a prolonged effect (i.e. lasting more than 12 hours) is observed during screening the starting dose should be the unchanged screening dose delivered over 24 hours. No dose increases should be attempted during the first 24 hours.

After the initial 24 hour period dosage should be adjusted slowly to achieve the desired clinical effect. If a programmable pump is used the dose should be increased only once every 24 hours; for non-programmable multi-dose reservoir pumps intervals of 48 hours between dose adjustments are recommended. In either case increments should be limited as follows to avoid possible overdosage:

If the dose has been significantly increased without apparent clinical effect pump function and catheter patency should be investigated.

There is limited clinical experience using doses greater than 1000 micrograms/day.

It is important that patients are monitored closely in an appropriately equipped and staffed environment during screening and immediately following pump implantation. Resuscitative equipment should be available for immediate use in case of life-threatening adverse reactions.

Adult Maintenance Therapy

The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of "paralysis" on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis.

In patients with spasticity of spinal origin maintenance dosing for long-term continuous infusions of intrathecal baclofen has been found to range from 12 to 2003 micrograms/day, with most patients being adequately maintained on 300 to 800 micrograms/day.

In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22 to 1400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.

Paediatric population Maintenance Therapy

In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of Flexilax ranges from 25 to 200 micrograms/day (median dose: 100 micrograms/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.

The safety and efficacy of Flexilax for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established.

Delivery specifications

Flexilax ampoules of 20ml containing 500 micrograms/ml and 5ml containing 2mg (2000micrograms)/ml are intended for use with infusion pumps. The concentration to be used depends on the dose requirements and size of pump reservoir. Use of the more concentrated solution obviates the need for frequent re-filling in patients with high dosage requirements.

Delivery regimen

Flexilax is most often administered in a continuous infusion mode immediately following implant. After the patient has stabilised with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimise 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 two hours before the desired onset of clinical effect.

Most patients require gradual dose increases to maintain optimum response during chronic therapy due to decreased responsiveness or disease progression. In patients with spasticity of spinal origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom control. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%). In both cases the daily dose may also be reduced by 10-20% if patients suffer side effects.

A sudden requirement for substantial dose escalation is indicative of a catheter complication (i.e. a kink or dislodgement) or pump malfunction.

In order to prevent excessive weakness the dosage of Flexilax should be adjusted with caution whenever spasticity is required to maintain function.

During long-term treatment approximately 5% of patients become refractory to increasing doses due to tolerance or drug delivery failure (see Section 4.4 - Special Warnings and Precautions for Use “Treatment Withdrawal” section). This “tolerance” may be treated by gradually reducing Flexilax dose over 2 to 4 week period and switching to alternative methods of spasticity management (e.g. Intrathecal preservative-free morphine sulphate). Flexilax should be resumed at the initial continuous infusion dose. Caution should be exercised when switching from Flexilax to morphine and vice versa.

Discontinuation

Except in overdose-related emergencies, the treatment with Flexilax should always be gradually discontinued by successively reducing the dosage. Flexilax should not be discontinued suddenly.

Special populations

Renal impairment

No studies have been performed in patients with renal impairment receiving Flexilax therapy. Because baclofen is primarily excreted unchanged by the kidneys it should be given with special care and caution in patients with impaired renal function.

Hepatic impairment

No studies have been performed in patients with hepatic impairment receiving Flexilax therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of Lioresal. Therefore, hepatic impairment is not expected to impact the drug systemic exposure.

Elderly population

Several patients over the age of 65 years have been treated with Flexilax during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated.

Flexilax is contraindicated in patients with a hypersensitivity to baclofen. Do not use Flexilax for intravenous, intramuscular, subcutaneous or epidural administration.

GABLOFEN is contraindicated in patients with a hypersensitivity to baclofen. Do not use GABLOFEN for intravenous, intramuscular, subcutaneous or epidural administration.

Hypersensitivity to the active substance(s) or to any of the excipient.

Epilepsy refractory to therapy.

The drug should not be administered by any route other than intrathecal.

Known hypersensitivity to baclofen or any of its excipients.

The drug should not be administered by any route other than intrathecal.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Life-Threatening Overdose During Pump Refills

Use extreme caution when filling pumps equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a lifethreatening overdose.

Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Carefully calculate refill intervals to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal.

Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.

Potential For Contamination Due To Non-Sterile External Surface Of Prefilled Syringe

Although the drug solution and pathway in the Flexilax prefilled syringes are sterile, the external surface of the prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. This has the potential to lead to contamination and consequent adverse reactions. The use of Flexilax prefilled syringe in an aseptic setting (e.g., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended, unless the external surface of the prefilled syringe is treated to ensure sterility. Flexilax supplied in vials may be used with conventional aseptic technique to fill intrathecal pumps prior to implantation. Procedures should also be put in place while refilling implantable intrathecal pumps in an outpatient setting to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the Flexilax prefilled syringe.

Prescriber, Caregiver And Patient Training And Screening Procedure/Post-Implantation Environment

Flexilax is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps labeled for intrathecal administration of Flexilax. Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy.

The pump system should not be implanted until the patient's response to bolus Flexilax injection is adequately evaluated. Evaluation (consisting of a screening procedure) requires that Flexilax be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section.

Resuscitative equipment should be available.

Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable.

On each occasion that the dosing rate of the pump and/or the concentration of Flexilax in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient’s response to the infusion is acceptable and reasonably stable.

It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.

Overdose

Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction or dosing error

Extreme caution must be used when filling the implantable pump.

Pumps should only be refilled through the reservoir refill septum. Use extreme caution when filling a pump which is equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose.

Withdrawal

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 post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six 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. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures.

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 central nervous system 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 or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Seizures have been reported during overdose and with withdrawal from intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen.

Possible Exacerbation Of Psychotic Disorders, Schizophrenia, Or Confusional States

Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with Flexilax and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.

Fatalities

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 premarketing studies as of March 1996. These deaths were not attributed to the therapy.

Use With Caution In Patients With A History Of Autonomic Dysreflexia

Flexilax should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Flexilax may cause an autonomic dysreflexic episode.

Infections

Patients should be infection-free prior to the screening trial with Flexilax because the presence of a systemic infection may interfere with an assessment of the patient’s response to bolus Flexilax. Patients should be infection-free prior to implantation of the pump because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing.

Drowsiness

Drowsiness has been reported in patients on intrathecal baclofen. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of intrathecal baclofen may be additive to those of alcohol and other CNS depressants.

Intrathecal Mass Formation

Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass.

Ovarian Cysts

A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

Nonclinical Toxicology

Carcinogenesis & Mutagenesis & Impairment Of Fertility

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m² basis, the maximum oral dose recommended for human use. Mutagenicity assays with baclofen have not been performed.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Flexilax should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m² basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

Labor & Delivery

The effect of baclofen on labor and delivery is unknown.

Nursing Mothers

At therapeutic oral doses, baclofen is excreted in human milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving Flexilax. Because of the potential for serious adverse reactions in nursing infants from Flexilax, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer’s manual for specific recommendations.

Safety and effectiveness in pediatric patients below the age of 4 have not been established.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Life-Threatening Overdose During Pump Refills

Use extreme caution when filling pumps equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a lifethreatening overdose.

Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Carefully calculate refill intervals to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal.

Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.

Potential For Contamination Due To Non-Sterile External Surface Of Prefilled Syringe

Although the drug solution and pathway in the GABLOFEN prefilled syringes are sterile, the external surface of the prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. This has the potential to lead to contamination and consequent adverse reactions. The use of GABLOFEN prefilled syringe in an aseptic setting (e.g., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended, unless the external surface of the prefilled syringe is treated to ensure sterility. GABLOFEN supplied in vials may be used with conventional aseptic technique to fill intrathecal pumps prior to implantation. Procedures should also be put in place while refilling implantable intrathecal pumps in an outpatient setting to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the GABLOFEN prefilled syringe.

Prescriber, Caregiver And Patient Training And Screening Procedure/Post-Implantation Environment

GABLOFEN is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps labeled for intrathecal administration of GABLOFEN. Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy.

The pump system should not be implanted until the patient's response to bolus GABLOFEN injection is adequately evaluated. Evaluation (consisting of a screening procedure) requires that GABLOFEN be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section.

Resuscitative equipment should be available.

Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable.

On each occasion that the dosing rate of the pump and/or the concentration of GABLOFEN in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient’s response to the infusion is acceptable and reasonably stable.

It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.

Overdose

Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction or dosing error

Extreme caution must be used when filling the implantable pump.

Pumps should only be refilled through the reservoir refill septum. Use extreme caution when filling a pump which is equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose.

Withdrawal

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 post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six 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. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures.

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 central nervous system 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 or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Seizures have been reported during overdose and with withdrawal from intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen.

Possible Exacerbation Of Psychotic Disorders, Schizophrenia, Or Confusional States

Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with GABLOFEN and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.

Fatalities

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 premarketing studies as of March 1996. These deaths were not attributed to the therapy.

Use With Caution In Patients With A History Of Autonomic Dysreflexia

GABLOFEN should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of GABLOFEN may cause an autonomic dysreflexic episode.

Infections

Patients should be infection-free prior to the screening trial with GABLOFEN because the presence of a systemic infection may interfere with an assessment of the patient’s response to bolus GABLOFEN. Patients should be infection-free prior to implantation of the pump because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing.

Drowsiness

Drowsiness has been reported in patients on intrathecal baclofen. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of intrathecal baclofen may be additive to those of alcohol and other CNS depressants.

Intrathecal Mass Formation

Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass.

Ovarian Cysts

A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

Nonclinical Toxicology

Carcinogenesis & Mutagenesis & Impairment Of Fertility

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m² basis, the maximum oral dose recommended for human use. Mutagenicity assays with baclofen have not been performed.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. GABLOFEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m² basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

Labor & Delivery

The effect of baclofen on labor and delivery is unknown.

Nursing Mothers

At therapeutic oral doses, baclofen is excreted in human milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving GABLOFEN. Because of the potential for serious adverse reactions in nursing infants from GABLOFEN, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer’s manual for specific recommendations.

Safety and effectiveness in pediatric patients below the age of 4 have not been established.

Medical management.

The pump should only be implanted after strict evaluation of the patient's response to Flexilax intrathecal bolus injections and/or dose titration. Given the risks associated with initial administration and dose adjustment of Flexilax intrathecal (general depression of CNS functions, cardiovascular collapse and/or respiratory depression), these steps must only be performed under medical surveillance at a centre with the required equipment, in compliance with the directives given in section "Posology and method of administration". Resuscitative equipment must be on immediate stand-by in the event of overdose symptoms that threaten the vital prognosis. Doctors must be adequately experienced in the chronic treatment with intrathecal infusions.

Patient surveillance.

The patient must be closely monitored after surgical implantation of the pump, especially during the initial phase of pump use and each time that its delivery rate and/or the Flexilax concentration in the reservoir are readjusted, until the patient's response to the infusion is acceptable and stabilised within reasonable limits.

It is essential that the risks of such a method of treatment are precisely known by the patient, doctors in charge of him/her and all caregivers. Ali persons participating in the treatment or care given to the patient must be clearly informed about the symptoms of under- and overdosing, procedures to be implemented in the event of intoxication, as well as the measures to be taken at home with regard to the pump and the insertion site.

For patients with spasticity due to head injury, it is recommended not to proceed to long-term Flexilax Aguettant therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Test phase.

Close monitoring of respiratory and cardiovascular functions is essential during the initial test phase, particularly in the presence of a cardiopulmonary condition or respiratory muscle weakness, as well as in patients concomitantly receiving benzodiazepine- or opiate-type medications, as the risk of respiratory depression is increased in such cases.

Any infection must be excluded prior to the test phase with Flexilax Aguettant, as a systemic infection might falsify the evaluation of the patient's response to the Flexilax Aguettant injection.

Pump implantation.

The patient must be free from infection prior to pump implantation, as the risk of postoperative complications would be increased. Furthermore, a systemic infection could complicate dose adjustment. A local infection or catheter misplacement can also cause interruption of drug delivery, which may result in abrupt Flexilax Aguettant withdrawal, accompanied by its symptoms (see "Interruption of treatment").

Filling the reservoir.

This must be performed by trained and fully qualified personnel, in accordance with the manufacturer's instructions. Intervals between each refill should be carefully calculated to avoid depletion of the reservoir, which would lead to severe recurrence of spasticity or potentially life-threatening symptoms of Flexilax Aguettant withdrawal (see "Interruption of treatment"). Filling should be performed under strictly aseptic conditions, in order to avoid any microbial contamination or any serious CNS infection. There should be an observation period, adapted to the clinical situation, after each refill or handling of the reservoir.

Extreme caution is required when filling an implantable pump fitted with a port with direct access to the intrathecal catheter, as direct injection into the catheter may lead to an overdose threatening the vital prognosis.

Dose adjustment: additional comments.

Flexilax Aguettant must be used with caution to avoid excessive weakness or a fall when a certain degree of spasticity is needed for standing up and gait balance, or whenever spasticity contributes to functional maintenance. It may be important to retain a certain amount of muscle tone and to tolerate occasional spasms, in order to facilitate circulatory function and prevent possible formation of deep vein thrombosis.

Whenever possible, all concomitant oral antispasmodic medications shouId be discontinued to avoid a possible overdose or undesirable interactions; preferably prior to initiating the Flexilax Aguettant infusion and under close medical surveillance. However, any abrupt reduction or discontinuation of the concomitant antispasmodic medication should be avoided during chronic treatment with Flexilax Aguettant.

Precautions in special populations.

Precautions in paediatric patients

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of intrathecal Flexilax in the paediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use of Flexilax Intrathecal in children under the age of four years.

Trascutaneous catheter insertion during the pump implantation and the presence of a PEG tube increase the incidence of infections in children.

Special patient groups

In patients with slowed CSF circulation due, for exampIe, to blockage caused by inflammation or trauma, the delayed migration of Flexilax Aguettant can reduce the antispastic efficacy and boost the adverse reactions.

In patients with impaired renal function, the dosage may need to be reduced to take account of the clinical condition or the level of reduced renal clearance.

Patients with psychotic disorders, schizophrenia, confusional states or Parkinson' s disease must be cautiously treated with Flexilax Aguettant and undergo strict surveillance whenever exacerbation of such conditions has been observed following oral Flexilax administration. Patients with epilepsy must be particularly monitored, as seizures may occasionally occur in the event of an overdose or withdrawal of the medication and even during maintenance treatment at therapeutic doses of Flexilax Aguettant.

Flexilax Aguettant must be used with caution in patients with a history of autonomic dysreflexia. Nociceptive stimulation or abrupt withdrawal of Flexilax Aguettant may precipitate such episodes.

The same caution is required in the presence of cerebrovascular or respiratory insufficiency, as Flexilax can aggravate such states.

Flexilax Aguettant is unlikely to have any effect on underlying, non-CNS related diseases, as systemic bioavailability of the product following intrathecal administration is considerably lower than with the oral route.

Based on observations made during Flexilax treatment via the oral route, caution is recommended in the following cases: history of gastro duodenal ulcers, pre-existing sphincter hypertonia, renal impairment.

With oral Flexilax, rare cases of elevated SGOT (AST), alkaline phosphatase and blood glucose levels have been recorded.

Elderly Patients

Several patients over 65 years of age have been treated with Flexilax intrathecal during clinical studies without any specific problems. Elderly patients are more likely to experience undesirable effects with oral Flexilax in the titration phase and this may also apply to Flexilax Aguettant. However, as optimal dose finding is individualised, treatment of elderly patients is unlikely to pose any specific problems.

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, i.e. essentialIy "sodium free".

Interruption of treatment.

Abrupt discontinuation of Flexilax intrathecal, for whatever reason, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has given rise to sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia and symptoms consistent with neuroleptic malignant syndrome (NMS), e.g. confused mental state and muscle rigidity. In rare cases, this has progressed to epileptic seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients receiving treatment with intrathecal Flexilax are potentially at risk for withdrawal. Some clinical characteristics associated with intrathecal Flexilax withdrawal can resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome (NMS) or other conditions associated with status hypermetabolicus or extensive rhabdomyolysis.

Patients and their caregivers must be advised of the importance of keeping a timetable for refill visits and must be alerted to the signs and symptoms of Flexilax withdrawal, particularly those that appear early on during the withdrawal syndrome.

In most cases, withdrawal symptoms appeared within a few hours after discontinuation of intrathecal Flexilax treatment. Common reasons for abrupt withdrawal of intrathecal Flexilax treatment included catheter malfunctioning (especially disconnection), excessively low volume in the pump reservoir and end of pump battery life; in some cases, human error may have been to blame or played a contributing role. Prevention of abrupt withdrawal of intrathecal Flexilax requires careful attention to programming and surveillance of the infusion system, refill scheduling/procedures and pump alarms.

It is extremely important that the manufacturer' s instructions for implantation, pump programming and/or refilling of the reservoir should be strictly followed.

Discontinuation

Except in overdose-related emergencies, the treatment with Flexilax should always be gradually discontinued by successively reducing the dosage. Flexilax should not be discontinued suddenly.

Special populations

Renal impairment

No studies have been performed in patients with renal impairment receiving Flexilax therapy. Because baclofen is primarily excreted unchanged by the kidneys it should be given with special care and caution in patients with impaired renal function.

Hepatic impairment

No studies have been performed in patients with hepatic impairment receiving Flexilax therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of Lioresal. Therefore, hepatic impairment is not expected to impact the drug systemic exposure.

Elderly population

Several patients over the age of 65 years have been treated with Flexilax during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated.

Known hypersensitivity to baclofen or any of its excipients.

The drug should not be administered by any route other than intrathecal.

Intrathecal baclofen therapy is valuable but hazardous. Careful pre-operative assessment is mandatory.

The patient must be given adequate information regarding the risks of this mode of treatment, and be physically and psychologically able to cope with the pump. It is essential that the responsible physicians and all those involved in the care of the patient receive adequate instruction on the signs and symptoms of overdose, procedures to be followed in the event of an overdose and the proper home care of the pump and insertion site.

Inflammatory mass at the tip of the implanted catheter: cases of inflammatory mass at the tip of the implanted catheter that can result in serious neurological impairment, including paralysis, have been reported. Although they have been reported with Flexilax, they have not been confirmed by contrast MRI or histopathology. The most frequent symptoms associated with inflammatory mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. Clinicians should use their medical judgement regarding the most appropriate monitoring specific to their patients' medical needs to identify prodromal signs and symptoms for inflammatory mass especially if using pharmacy compounded drugs or admixtures that include opioids. In patients with new neurological signs or symptoms suggestive of an inflammatory mass, consider a neurosurgical consultation since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an inflammatory mass.

Pump Implantation

Patients should be infection-free prior to pump implantation because the presence of infection may increase the risk of surgical complications.- Special Precautions for Use “Treatment Withdrawal” section).

Reservoir refilling

Reservoir refilling must be performed by trained and qualified personnel in accordance with the instructions provided by the pump manufacturer. Refills should be timed to avoid excessive depletion of the reservoir, as this would result in the return of spasticity or potentially life-threatening symptoms of - Special Precautions for Use “Treatment Withdrawal” section).

When refilling the pump care should be taken to avoid discharging the contents of the catheter into the intrathecal space.

Strict asepsis is required to avoid microbial contamination and infection.

Extreme caution must be taken when filling a pump equipped with an injection port that allows direct access to the intrathecal catheter as a direct injection into the catheter through the access port could cause a life-threatening overdose.

Precautions in paediatric patients

For patients with spasticity due to head injury, it is recommended not to proceed to long-term Flexilax therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of Flexilax in the paediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use of Flexilax in children under the age of four years

Precautions in special patient populations

In patients with abnormal CSF flow the circulation of drug and hence antispastic activity may be inadequate.

Psychotic disorders, schizophrenia, confusional states or Parkinson's disease may be exacerbated by treatment with oral Lioresal. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.

Special attention should be given to patients known to suffer from epilepsy as seizures have occasionally been reported during overdose with, and withdrawal from, Flexilax as well as in patients maintained on therapeutic doses.

Flexilax should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Flexilax may precipitate an autonomic dysreflexic episode.

Lioresal should be used with caution in patients with cerebrovascular or respiratory insufficiency.

An effect of Flexilax on underlying, non-CNS related diseases is unlikely because its systemic availability is substantially lower than after oral administration. Observations after oral baclofen therapy suggest that caution should be exercised in patients with a history of peptic ulcers and pre-existing sphincter hypertonia.

Renal impairment

After oral Lioresal dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering Flexilax in patients with renal impairment.

In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral Lioresal.

Treatment withdrawal

Abrupt discontinuation of Flexilax, regardless of cause, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has resulted in sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia and symptoms consistent with neuroleptic malignant syndrome, e.g. altered mental status and muscle rigidity. In rare cases this has advanced to seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal.

Some clinical characteristics associated with intrathecal baclofen withdrawal may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.

Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the signs and symptoms of baclofen withdrawal particularly those seen early in the withdrawal syndrome (e.g. priapism).

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.

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. The suggested treatment for intrathecal Lioresal withdrawal is the restoration of intrathecal Lioresal 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 or enteral Lioresal, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral Lioresal alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Scoliosis

The onset of scoliosis or worsening of a pre-existing scoliosis has been reported in patients treated with Flexilax. Signs of scoliosis should be monitored during treatment with Flexilax.

Onset of drowsiness has been reported in some patients on Flexilax intrathecal treatment. Patients must be urged to exercise caution when driving their car, using hazardous machinery or performing any potentially hazardous activity in case of reduced alertness.

Central nervous system (CNS) depressant effects such as somnolence and sedation have been reported in some patients receiving intrathecal baclofen, and patients should be advised to exercise due caution. Other listed events include ataxia, hallucinations, vision blurred, diplopia and withdrawal symptoms. Operating equipment or machinery may be hazardous.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In a recent clinical study, 153 adult and pediatric patients with spasticity of spinal cord or cerebral origin were treated with Flexilax 3,000 mcg/mL. The adverse reactions seen in this study were similar to that found with lower concentrations of Flexilax.

Spasticity Of Spinal Cord Origin

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 -.

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

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.

Spasticity Of Cerebral Origin

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, placebocontrolled 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

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.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In a recent clinical study, 153 adult and pediatric patients with spasticity of spinal cord or cerebral origin were treated with Gablofen 3,000 mcg/mL. The adverse reactions seen in this study were similar to that found with lower concentrations of Gablofen.

Spasticity Of Spinal Cord Origin

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 -.

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

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.

Spasticity Of Cerebral Origin

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, placebocontrolled 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

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.

In many cases, a causal link between the effects observed and Flexilax administration cannot be established, as most of the undesirable effects reported may also be associated with the underlying disease. Nevertheless, some commonly reported reactions (drowsiness, dizziness, headache, nausea, hypotension, hypotonia) seem to be drug-related. These effects are mostly transient and primarily occur during the test phase or with changes in concentrations.

Table 1.

Undesirable effects are ranked according to system class and frequency, within each frequency grouping, undesirable effects are presented in order of decreasing seriousness, according to the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000)

Undesirable effects due to the administration system (e.g. catheter dislodgement, local infection, meningitis, overdose due to incorrect manipulation of the system) are not mentioned here.

In a screening trial the presence of a PEG tube increased the incidence of deep infections in children.

Some of the adverse reactions listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse reactions that are more frequent in either population are indicated below.

Adverse drug reactions (Table 1) are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (>1/10); common ( >1/100 to <1/10); uncommon ( >1/1,000 to <1/100); rare ( >1/10,000 to<1/1,000); very rare (<1/10,000), and Not known (cannot be estimated from available data).

Table 1 Adverse drug reactions

Adverse events associated with the delivery system

Adverse events associated with the delivery system (inflammatory mass at the tip of the catheter, catheter dislocation with possible complications, pocket infection, meningitis, overdose due to wrong manipulation of the device) have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (www.mhra.gov.uk/yellowcard)

Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of Flexilax after a period of interruption in therapy.

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 Flexilax; 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.

Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of GABLOFEN after a period of interruption in therapy.

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 GABLOFEN; 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.

The patient must be closely monitored for any signs and symptoms of overdose throughout the entire treatment, particularly during the initial test phase and titration phase, but also when administration of Flexilax Aguettant is resumed after brief suspension.

Signs of overdose may appear suddenly or insidiously.

Symptoms of overdose: excessive muscular hypotonia, drowsiness, lightheadedness, dizziness, sedation, epileptic seizures, loss of consciousness, ptyalism, nausea and vomiting.

Respiratory depression, apnoea and coma occur in the event of a major overdose.

Serious overdose may occur, for example, if the catheter contents inadvertently pass into the intrathecal space during verification of catheter permeability/positioning. Programming errors, excessively rapid dose increases and concomitant treatment with oral Flexilax represent other possible causes of overdose. Pump malfunction should also be investigated.

Treatment

There is no specific antidote for the treatment of overdose with Flexilax Aguettant. The following measures are usually taken:

1) Drain any remaining bacIofen from the pump as quickly as possible.

2) If necessary, intubate patients with respiratory depression, until the drug is eliminated.

Certain reports suggest that physostigmine is capable of abolishing the central nervous effects, particularly drowsiness and respiratory depression.

However, caution must be exercised when intravenousIy injecting physostigmine, as it might induce epileptic seizures, bradycardia and cardiac conduction disturbances. A test can be performed with 1-2 mg physostigmine IV over a period of 5 to 10 minutes. During this time, patients should be subject to strict surveillance. Repeated doses of 1 mg can be given at 30 to 60minute intervals, in order to maintain adequate ventilation and vigilance if the patient responds favourably.

Physostigmine may be ineffective in cases of massive overdose and the patient may have to be placed under artificial ventilation.

Provided that lumbar puncture is not contraindicated, evacuation of 30-40 ml CSF can be considered at an early stage of intoxication, in order to reduce the Flexilax concentration within the CSF.

Maintenance of cardiovascular function. During seizures: cautious IV injection of diazepam.

Physostigmine is only recommended for severe toxicity not responsive to supportive measures.

In children a dose of 0.02 mg/kg physostigmine may be administered iv at a rate not exceeding 0.5 mg per minute. This dose may be repeated at 5 to l0 minute intervals until a therapeutic effect is obtained or a total dose of 2 mg has been administered.

Special attention should be given to recognising the signs and symptoms of overdosage at all times, but especially during the initial "screening" and "dose-titration" phases and also during reintroduction of Flexilax after an interruption of therapy.

Signs of overdose may appear suddenly or (more usually) insidiously.

Symptoms of overdose: excessive muscular hypotonia, drowsiness, light-headedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea and vomiting.

Respiratory depression, apnoea, and coma result from serious overdosage. Seizures may occur with increasing dosage or, more commonly, during recovery from an overdose. Serious overdose may occur through the inadvertent delivery of the catheter contents, errors in pump programming, excessively rapid dose increases or concomitant treatment with oral baclofen. Possible pump malfunction should also be investigated.

Treatment

There is no specific antidote for treating overdoses of intrathecal baclofen. Any instructions provided by the pump manufacturer should be followed, and the following steps should generally be undertaken:

- Where a programmable continuous infusion pump is used further delivery of baclofen should be halted immediately by removal of residual drug solution from the reservoir.

- If it is possible to do so without surgical intervention the intrathecal catheter should be disconnected from the pump as soon as possible, and infusion fluid allowed to drain back together with some CSF (up to 30-40ml is suggested).

- Patients with respiratory depression should be intubated if necessary, and ventilated artificially if required. Cardiovascular functions should be supported and in the event of convulsions, iv diazepam cautiously administered.

- Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate should be monitored.

Pharmacotherapeutic group: antispastic with a spinal site of attack

Muscle Relaxants, Other Centrally Acting Agents

ATC code: M03B X01

Pharmacodynamics.

Flexilax slows down mono- and polysynaptic reflex transmission in the spinal cord, by stimulating GABA_B receptors. The chemical structure of Flexilax is analogous to that of gamma-aminobutyric acid (GABA), which is a neurotransmitter inhibitor.

Neuromuscular transmission is not altered by Flexilax. Flexilax has an antinociceptive action. In neurological diseases accompanied by musculoskeletal spasms, the properties of Flexilax manifest not only in the form of an effect on reflex muscle contractions, but also as a marked reduction in the intensity of painful spasms and clonus. Flexilax improves patient mobility, providing them with greater autonomy, and facilitates physiotherapy.

Flexilax depresses the CNS in general, causing sedation, somnolence, as well as respiratory and cardiovascuIar depression.

Flexilax Aguettant can be regarded as an alternative to destructive neurosurgical procedures.

Flexilax, introduced directly into the intrathecal space, allows treatment of spasticity at doses at least 400 to 1,000 times lower than they would be via the oral route.

Intrathecal bolus.

The medicinal product usually starts to act half an hour to one hour after administration of a single intrathecal dose. The peak spasmolytic effect manifests around 4 hours post-dose and its action lasts for 4 to 8 hours. Onset of action, peak response and duration of effect can vary between individual patients, depending on the dose, severity of symptoms and the method and rate of administration.

Continuous infusion.

The antispasmodic effect of Flexilax starts 6 to 8 hours following initiation of the continuous infusion and reaches its peak within 24 to 48 hours.

Antispastic with a spinal site of attack: (ATC Code: M03B X01).

Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABA_ß receptors. Baclofen is a chemical analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of Lioresal take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Lioresal improves the patient's mobility, makes it easier for him/her to manage without aid, and facilitates physiotherapy.

Consequent important gains include improved ambulation, prevention and healing of decubitus ulcers, and better sleep patterns due to elimination of painful muscle spasms. In addition, patients experience improvement in bladder and sphincter function and catheterisation is made easier, all representing significant improvements in the patient's quality of life. Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.

Baclofen when introduced directly into the intrathecal space, permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.

Intrathecal bolus:

The onset of action is generally half an hour to one hour after administration of a single intrathecal dose. Peak spasmolytic effect is seen at approximately 4 hours after dosing, the effect lasting 4 to 8 hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms and the method and speed of drug administration.

Continuous infusion:

Baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed within 24 to 48 hours.

The intrathecal nature of administration and decelerated circulation of cerebrospinal fluid (CSF) must be taken into account when interpreting the following kinetic parameters.

Absorption.

Direct infusion into the cerebrospinal fluid allows absorption processes to be avoided and allows the substance to come into contact, via adsorption, with receptor sites in the dorsal horn of the spinal cord.

Distribution.

Following a single intrathecal bolus injection/short-term infusion, the volume of distribution is between 22 and 157 ml, calculated from levels present in the CSF. When given as continuous intrathecal infusions, daily doses of 50 to 1200 micrograms produce Flexilax steady-state concentrations of 130 - 1240 ng/ml in lumbar CSF. According to the half-life measured in the CSF, steady state CSF concentrations are reached within 1 to 2 days. During intrathecal infusion, plasma concentrations do not exceed 5 ng/ml, which confirms that the passage of Flexilax through the blood-brain barrier is slow.

Elimination.

Following a single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms Flexilax, the CSF elimination half-life ranges from 1 to 5 hours. The CSF elimination half-life of Flexilax at steady state has not been determined.

Mean CSF clearance is approximately 30 ml/h after both a single bolus injection and continuous infusion in the lumbar subarachnoid space using an implantable pump.

During continuous intrathecal infusion, once steady state has been reached, a Flexilax concentration gradient is built up in the range between 1.8 : 1 and 8.7 : 1 (mean = 4 : 1) between lumbar CSF and subarachnoid cisternal CSF. This is of clinical importance, as spasticity of the lower extremities can be effectively treated without greatly influencing the upper limbs, with fewer adverse centrai nervous effects due to the drug's action on the brain centres.

Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.

Absorption

Direct infusion into the spinal subarachnoid space by-passes absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.

Distribution

After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 ml.

With continuous intrathecal infusion daily doses of 50 to 1200 micrograms 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 1-2 days.

During intrathecal infusion the plasma concentrations do not exceed 5ng/ml, confirming that baclofen passes only slowly across the blood-brain barrier.

Elimination

The elimination half-life in the CSF after single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms baclofen ranges from 1 to 5 hours. Elimination half-life of baclofen after having reached steady-state in the CSF has not been determined.

After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance was about 30 ml/h.

At steady-state conditions during continuous intrathecal infusion, a baclofen concentration gradient is built up in the range between 1.8 : 1 and 8.7 : 1 (mean: 4 : 1) from lumbar to cisternal CSF. 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.

Special populations

Elderly Patients

No pharmacokinetic data is available in elderly patients after administration of Flexilax. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower elimination but a similar systemic exposure to baclofen compared to young adults. However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.

Paediatrics

In paediatric patients, respective plasma concentrations are at or below 10 ng/mL.

Hepatic impairment

No pharmacokinetic data is available in patients with hepatic impairment after administration of Flexilax. However, as liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.

Renal impairment

No pharmacokinetic data is available in patients with renal impairment after administration of Flexilax. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment can not be excluded.

A 2-year study with rats (oral route) has shown that Flexilax is not carcinogenic. This study showed a dose-dependent increase in the incidence of ovarian cysts and a less marked increase in the incidence of hypertrophic and/or haemorrhagic adrenal glands. The clinical relevance of these findings is not known. In vivo and in vitro mutagenesis tests have shown no mutagenic effect.

Oral Flexilax increases the incidence of omphaloceles (ventral hemias) in the foetuses of rats at high doses. No teratogenic effects have been noted in mice.

An increased incidence of incomplete stemebral ossification in fetuses of rats given high doses oral Flexilax was observed. High doses oral Flexilax also increased the incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in rabbit fetuses.

Local tolerance

Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent.

Mutagenicity and carcinogenicty

Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. There was no evidence of a mutagenic potential of baclofen

A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or haemorrhagic adrenal glands was observed.

Repeated dose toxicity

Repeated intrathecal administration of baclofen was not associated with the development of inflammatory masses in studies in rats and dogs. No changes to the spinal cord and adjacent tissue and no signs of irritation or inflammation of the spinal cord and surrounding tissues were noted in either species.

Reproduction toxicity

Intrathecal baclofen is unlikely to have adverse effects on fertility or on prenatal or postnatal development based on oral studies in rats and rabbits. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Lioresal given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. Lioresal dosed orally has been shown to cause delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat fetuses at a high intraperitoneal dose.

Dextrose has been shown to be incompatible with Flexilax, as a chemical reaction occurs between the two substances.

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If alternative baclofen concentrations are required Flexilax may be diluted under aseptic conditions with sterile preservative-free sodium chloride for injections. The ampoules should not be mixed with other solutions for injection or infusion (dextrose has proved to be incompatible due to a chemical reaction with baclofen).

The compatibility of Flexilax with the components of the infusion pump (including the chemical stability of baclofen in the reservoir) and the presence of an in-line bacterial retentive filter should be confirmed with the pump manufacturer prior to use.

Any remaining product must be disposed of.

Instructions for useloperating instructions.

Flexilax Aguettant is designed for intrathecal injections and continuous infusions and is administered according to the specifications accompanying each infusion system.

Stability.

Flexilax intrathecal has been shown to be stable for 180 days in implantable EU certified pumps.

Wherever possible prior to administering them, medicinal products for parenteral use should be checked for the presence of particulate matter and any changes in colour.

Specific instructions for administration

The exact concentration to be selected depends on the total daily dose needed, as well as the minimum infusion rate of the pump. Please refer to the manufacturer's user manual for all specific recommendations.

Dilution.

If users wish to obtain concentrations other than 50, 500 or 2000 micrograms/ml, Flexilax Aguettant must be diluted under aseptic conditions in a sterile and preservative-free sodium chloride solution for injections.

Administration systems.

Several systems have been used for long-term administration of Flexilax intrathecal. Among these, EU certified pumps can be mentioned, which are implantable systems equipped with refillable reservoir, and which are implanted - under local or general anaesthetic - under the skin or into a pocket mostly in the abdominal wall. These systems are connected to an intrathecal catheter that passes subcutaneously into the subarachnoid space.

Before using these systems, users should ensure that the tecnica specifications, as well as the chemical stability of Flexilax in the reservoir, fulfil the conditions required for intrathecal administration of Flexilax intrathecal.

Each ampoule is intended for single use only, and any unused solution should be discarded. Ampoules should not be either frozen or autoclaved.