Spasticity management CRG

Intrathecal Baclofen for the Management ofSevere Spasticity

SYNCHROMED® IIProgrammable Infusion System Clinical Reference Guide

April, 2004

Key Contacts

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IN THE U.S.

Medtronic offices are open from 8:00 a.m. to 5 p.m. Central Standard Time Mondaythrough Friday.

Emergency Technical Support: 1-800-707-0933

Medtronic Customer Service: 1-800-328-0810

Product Orders: 1-888-638-7627

Therapy Access (reimbursement): 1-877-940-2327

Patient Services: 1-800-510-6735

IN OTHER WORLD AREAS

Customer and Technical Services are available from the Medtronic offices within eachcountry. Contact information for country offices is provided on the back of this module.

Table of ContentsSpasticity: Assessment and Overall Management.................................................................................................................1

Spasticity Defined .......................................................................................................................................................................1Pathophysiology ............................................................................................................................................................................1Manifestations and Impact of Spasticity..................................................................................................................2Assessment of Spasticity.......................................................................................................................................................2Spasticity Management..........................................................................................................................................................3

Lioresal® Intrathecal ...........................................................................................................................................................4Description.......................................................................................................................................................................................4Indications........................................................................................................................................................................................4Pharmacodynamics...................................................................................................................................................................4Pharmacokinetics........................................................................................................................................................................5Available Concentrations.......................................................................................................................................................6Storage Requirements .............................................................................................................................................................6Stability/Compatibility in Pump ....................................................................................................................................6Demonstrated Safety and Efficacy ................................................................................................................................7

Patient Selection and Screening...................................................................................................................................7Goal ........................................................................................................................................................................................................7Review Patient Selection Criteria ...................................................................................................................................7Select the Patient........................................................................................................................................................................11Establish Objectives for Treatment..............................................................................................................................11Provide Patient and Caregiver Education ...............................................................................................................12Prepare for Screening Test ................................................................................................................................................12Conduct Screening Test.......................................................................................................................................................14Measurement Tools .................................................................................................................................................................16

Ongoing Patient Management.....................................................................................................................................19Dosing and Titration Guidelines...................................................................................................................................19Tolerance.........................................................................................................................................................................................22

Potential Adverse Effects .............................................................................................................................................22Adverse Reaction to Lioresal Intrathecal ...............................................................................................................22Withdrawal Symptoms and Treatment ..................................................................................................................23Overdose Symptoms and Treatment.........................................................................................................................25

Potential Adverse Events .............................................................................................................................................28System-Related ..........................................................................................................................................................................28Catheter-Related........................................................................................................................................................................28Procedure-Related....................................................................................................................................................................29Other ..................................................................................................................................................................................................29Drug-Related................................................................................................................................................................................29

References...........................................................................................................................................................................30Appendix ..............................................................................................................................................................................32

Spinal Origin vs. Cerebral Origin Spasticity Comparison Chart .........................................................33Patient Education Checklist For Screening Test ...............................................................................................35Lioresal Intrathecal Screening Test Assessment Form ...............................................................................36Drug Package Insert ...............................................................................................................................................................38

Brief Disclosure .................................................................................................................................................................47Index ..................................................................................................................................................................................48

Medtronic SynchroMed® II Programmable Infusion System Intrathecal Baclofen for theManagement of Severe Spasticity

Clinical Reference Guide i April, 2004

Spasticity: Assessment and Overall Management

Spasticity Although the pathophysiology of spasticity is not completely understood, itDefined is most commonly defined clinically as “…a motor disorder characterized

by a velocity-dependent increase in tonic stretch reflexes (‘muscle tone’)with exaggerated tendon jerks, resulting from hyperexcitability of thestretch reflex, as one component of the upper motor neuron syndrome.”1

The velocity-dependent nature of spasticity distinguishes it from otherforms of hypertonia, such as dystonia and rigidity. 2

Pathophysiology Spasticity represents a loss of balance in the central nervous system (CNS)between inhibitory and excitatory inputs into alpha motor neurons,leading to relative over-excitation of those neurons. It generally developswhen suprasegmental control over spinal cord segmental reflexes is lost,typically secondary to lesions in the motor cortex or long spinal tracts.3

Brain or spinal cord damage may prevent the release of GABA (gamma-aminobutyric acid) from interneurons, and thus inhibitory impulses.GABA is an inhibitory neurotransmitter that modulates excitatory inputat the alpha motor neuron.4

For a comparison of spinal-origin and cerebral-origin spasticity, pleasesee the Spinal-Origin vs. Cerebral-Origin Spasticity Comparison Chart inthe Appendix of this module.

A wide variety of factors can contribute to an increase in spasticity:

■ Infection (including urinary-tract infections)

■ Pain (e.g., from kidney stones)

■ Other noxious stimuli (e.g., from ingrown nails or overly-restrictiveclothing)

■ Skin ulcers

■ Constipation or bowel impaction

■ Menses

■ Deep vein thromboses

■ Fatigue or overall stress

■ Altered environment (e.g., changes in temperature or humidity)

■ Disease progression (e.g., as in multiple sclerosis)

■ Onset of new medical conditions

■ Changes in medication

■ Psychological issues


Clinical Reference Guide 1 April, 2004

Manifestations Symptoms and physiologic impairments associated with spasticity can and Impact of include the following:Spasticity ■ Increased muscle tone

■ Reduced range of motion about a joint, which can lead to fixedcontractures

■ Poor motor control

■ Muscle weakness

■ Fatigue

■ Pain (typically through increased muscle spasms)

■ Excessive metabolic requirements

Such impairments can cause significant functional limitations anddisability. Mobility, transfers, sitting, and activities of daily living (ADLs)are examples of areas that are often affected.5,6 Potential medical conse-quences include skin breakdown, falls, and psychiatric disturbances.

The impact of spasticity is not limited to the patient. Spasticity can pose amajor problem for caregivers as well.

In some circumstances the increased muscle tone of spasticity mayprovide some benefits to individual patients. For example, patients withlong-standing spasticity may have learned to rely on their excess tonewhen transferring. Other benefits may include:

■ Maintenance of muscle mass

■ Maintenance of posture

■ Increased venous blood return, which may help prevent the formationof deep vein thromboses

Assessment Details on the assessment of spasticity and associated symptoms (e.g.,of Spasticity spasms) are provided in the Patient Selection and Screening section later

in this module.

Many standardized tools are available for pediatric functional assessment,including the following: 7

■ Gross Motor Function Measure (GMFM)

■ Pediatric Evaluation of Disability Inventory (PEDI)

■ Functional Independence Measure for Children (WeeFIM)

■ Child Health Questionnaire (CHQ)

■ Pediatric Outcomes Instrument (PODCI)

■ Canadian Occupational Performance Measure (COPM)



Similarly, there are many tools available for adult functional assessment,including the following: 7

■ Functional Independence Measure (FIM)

■ Canadian Occupational Performance Measure (COPM)

■ SF-36 and SF-12

■ Sickness Impact Profile (SIP)

Spasticity Management of spasticity is most successful when it is based on goalsManagement that are:

■ Specific

■ Realistic

■ Reflective of the spasticity’s impact on function, comfort, andcaregiving

■ Set jointly by the patient, family, other caregivers, and multi-disciplinary health care team

■ Documented prior to the initiation of treatment

For more on goal setting, refer to the Establish Objectives for Treatmentsection in this module. As shown in Figure 1, effective management ofspasticity has evolved to a “spectrum of care” approach. ITBTM Therapy(Intrathecal Baclofen Therapy) is one component of this spectrum of care,and it can generally be implemented in parallel with other components.

Figure 1Spectrum of Care

for Management of Spasticity



Lioresal® Intrathecal

Description Baclofen is a drug that acts as a GABA agonist. GABAB receptors, locatedin the superficial layers of the spinal cord, are sensitive to baclofen.“Therefore administration of baclofen into the intrathecal space requiresthat the drug penetrate only a few millimeters to reach the receptors.”4

Its main effect is to reduce muscle spasticity. Lioresal Intrathecal(baclofen injection) is a sterile, pyrogen-free, isotonic muscle relaxant andantispastic solution free of antioxidants, preservatives or other potentiallyneurotoxic additives, and is indicated only for intrathecal administration.8

Lioresal Intrathecal is the only commercially available baclofen productwith clinical studies demonstrating its safe use for intrathecal adminis-tration. In addition, it is the only baclofen injection product approved foruse in the SynchroMed II Infusion System.

While the precise mechanism of action is not fully understood, it isknown that baclofen inhibits both monosynaptic and polysynaptic reflex-es at the spinal level. This is thought to decrease excitatory neurotrans-mitter release from primary afferent terminals, although actions atsupraspinal sites may also occur and contribute to its clinical effects.Baclofen is a structural analog of the inhibitory neurotransmitter GABA,and may exert its effects by stimulation of the GABAB receptor subtype.

Direct intrathecal delivery of baclofen produces CNS levels at least 10times higher than that achieved with oral baclofen.4 Although oralbaclofen acts at the spinal level, the amount of drug that penetrates theblood-brain barrier is often not sufficient to provide adequate effect andthe side effects may be intolerable.

Indications Lioresal Intrathecal is indicated for use in the management of severespasticity. Its intended use is by either a single bolus test dose (via spinalcatheter or lumbar puncture) or continuous infusion via an implantablepump approved by the U.S. Food and Drug Administration (FDA)specifically for the administration of Lioresal Intrathecal into theintrathecal space.8

Pharmaco- Refer to Table 1 for a pharmacodynamics overview of Lioresal Intrathecal.dynamics For additional information on Lioresal Intrathecal, see the Drug Package

Insert in the Appendix of this module.



Table 1Pharmacodynamics

of LioresalIntrathecal 8

Pharmaco- CSF clearance of Lioresal Intrathecal calculated from the intrathecal boluskinetics or continuous infusion studies approximates CSF turnover. This suggests

that elimination is by bulk-flow removal of CSF.8 Refer to Table 2 for asummary of Lioresal Intrathecal clearance data.

Table 2Lioresal Intrathecal

Clearance Data 8

Limited pharmacokinetics data suggest that a lumbar-cisternalconcentration gradient of about 4:1 is established along the neuroaxisduring baclofen infusion. This is based upon simultaneous CSF samplingvia cisternal and lumbar tap in 5 patients receiving continuous baclofeninfusion at the lumbar level at doses associated with therapeutic efficacy;the interpatient variability was great. The gradient was not altered byposition.8



Intrathecal Bolus ■ The onset of action is generally 30 to 60 minutes afteran intrathecal bolus.

■ Peak spasmolytic effect is seen at approximately fourhours after dosing and effects may last four to eighthours.

■ Onset, peak response, and duration of action may varywith individual patients depending on the dose andseverity of symptoms.

Continuous Infusion ■ Antispastic action is first seen at six to eight hours afterinitiation of continuous infusion.

■ Maximum activity is observed in 24 to 48 hours.

■ The onset, peak response, and duration of action aresimilar for pediatric and adult patients.¸

Intrathecal Bolus ■ After bolus lumbar injection of 50 to 100 microgramsof baclofen injection in seven patients, the average CSFelimination half-life was approximately 1.5 hours overthe first four hours.

■ The average CSF clearance was approximately 30 mL/hr.

Continuous Infusion ■ In a study involving ten patients on intrathecal baclofen,the mean CSF clearance for baclofen injection wasapproximately 30 mL/hour. Concurrent plasma concen-trations of baclofen during intrathecal administrationwere low (0–5 nanograms/mL).

■ Six pediatric patients (age 8-18 years) receiving intrathe-cal baclofen at doses of 77-400 micrograms/day hadplasma baclofen levels near or below 10 nanograms/mL.

Method Onset, Peak Response and Duration of Action

Delivery Method Onset, Peak Response and Duration of Action

Available FOR SCREENING TEST

Concentrations Lioresal Intrathecal is available in the United States in a single use 1 mLampule for screening tests in the concentration of 50 micrograms/mL.

FOR REFILL

In the United States, refill kits containing Lioresal Intrathecal are availablein single-use ampules in concentrations of 500 and 2000 micrograms/mL.If dilution is required, use sterile, preservative-free 0.9% pharmacy-gradesodium chloride for injection. The refill kits also contain sterile suppliesfor drug preparation and pump refill. Customers outside the United Statesmay be able to purchase Lioresal Intrathecal from Novartis. Whenpurchased from Novartis, the refill kit components are not included.

Storage Lioresal Intrathecal does not require refrigeration.Requirements ■ Do not store above 86° F (30°C).

■ Do not freeze.

■ Do not heat sterilize.

Do not fill the pump with drug that is cooler than room temperature.

Stability/ The Medtronic drug stability and material compatibility testing Compatibility conducted with Lioresal Intrathecal and the SynchroMed II Infusion in Pump System demonstrated the following:

STABILITY

■ Lioresal Intrathecal is stable in solution and potent at body temperature.

■ Lioresal Intrathecal is stable for 180 days at 37˚C in the implantableSynchroMed II Infusion System. Stability is defined as ≥90% of initialconcentration.

COMPATIBILITY

■ Device materials do not affect the quality of Lioresal Intrathecal.

■ Lioresal Intrathecal does not impact device operation.

Lioresal Intrathecal is the only baclofen injection drug product demonstratedto be safe and effective for use in the SynchroMed II Infusion System. Theuse of pharmaceutical products that are not specifically labeled for intrathe-cal administration via continuous infusion may cause damage to compo-nents of the infusion system. This could potentially lead to diminisheddevice performance, reduced therapy efficacy, or could jeopardize patientsafety. Seemingly similar products may contain preservatives, antimicro-bials or antioxidants or exhibit chemical properties that are not compatiblewith the SynchroMed II Infusion System.



Demonstrated Since early reports of clinical efficacy with Lioresal Intrathecal, multiple Safety and clinical studies have been conducted. Collectively, they have demonstrated:Efficacy ■ Clinically significant reductions in severe spasticity of cerebral origin

and spinal origin.9,10

■ Long-term safety and efficacy in patients with severe spasticity ofspinal origin.9,11

■ Long-term safety and efficacy in patients with severe spasticity ofcerebral origin.10,12

Patient Selection and Screening

Goal The overall goal for patient selection is to choose those patients most like-ly to experience therapeutic success while reducing the likelihood of risks,complications, and adverse events.

KEY TASKS

The key tasks involved with selection and screening include:

■ Review patient selection criteria.

■ Select the patient.

■ Establish objectives for treatment.

■ Provide patient and caregiver education.

■ Prepare for screening test.

■ Conduct screening test.

Review Patient The first key task involves reviewing indications and contraindications for Selection inclusion.Criteria Candidates for ITB Therapy (Figure 2) are patients who have:

■ A diagnosis of severe spasticity

■ Become refractory to oral baclofen or experienced intolerable sideeffects at effective doses (spasticity of spinal origin only)

■ Demonstrated positive response to a single bolus dose of LioresalIntrathecal during the screening test

■ Sustained a traumatic brain injury at least 1 year before considerationof long term therapy (spasticity of cerebral origin only)



Figure 2 Patient Selection

Algorithm



Yes

Patient Selection Algorithm:ITBTM Therapy for the Management of Severe Spasticity

of Cerebral and Spinal Origin

Step 2: EXCLUSION CRITERIA FOR ITB THERAPY

Step 1: INCLUSION CRITERIA FOR ITB THERAPY (INTRATHECAL BACLOFEN THERAPY)

CONTINUE TO STEP 2

Yes

Yes

Yes

+ response

No response

Yes

No

No

Step 3: GENERAL CLINICAL CONSIDERATIONS

STOP

Step 4: TEST SCREENING FLOW CHART

CONTINUE TO STEP 3

UC199704978cEN NP-3173© Medtronic, Inc. 2003All Rights ReservedPrinted in USA

See the accompanying Lioresal® Intrathecal (baclofen injection) drug package insert for full prescribing information.

1. Spasticity due to spinal cord injury, multiple sclerosis, cerebral palsy, stroke or brain injury (1 year post trauma).

1. Infection is present at time of screening or implant.

2. Patient has a history of allergy (hypersensitivity) to oral baclofen.

Day 1Bolus: 50mcg

Please see reverse side of chart to review General Clinical Considerations.

Case-related considerations do not

support decision to proceed with screening test.

2. Spasticity is severe.

Patient presents with increase in tone that significantly interferes with movement and/or care, which may be accompanied by spasms.

3. Patient has sufficient body mass to support a pump.

4. Patient/family/caregivers and providers agree on treatment goals that are both explicit and suitable for the patient. Appropriate goals range from facilitating transfer and hygiene for dependent patients to improving ambulation for patients who are less severely disabled.

5. Patient/family/caregivers are motivated to achieve the treatment goals, and they are committed to meeting the follow-up care requirements.

+ response

No responseDay 2Bolus: 75mcg

+ response

No responseDay 3Bolus: 100mcg

Patientineligiblefor implant.

Implant

Implant

Implant

Figure 2 (cont.)Patient Selection

Algorithm



Step 3: GENERAL CLINICAL CONSIDERATIONS

Return to Step 3 (reverse side)

1. Prior Procedures Prior soft tissue lengthening procedures, tendon releases, and selective posterior rhizotomy are not contraindications to ITB Therapy.

2. Oral Antispasticity Medications Patients with spasticity of spinal origin should be refractory to oral baclofen or experience intolerable CNS side effects at effective doses. However, oral antispasticity medication is not a prerequisite for patients with spasticity of cerebral origin.

3. Seizures A history of seizures is not a contraindication to ITB Therapy.

4. Presence of Other Devices The presence of a ventriculoperitoneal (VP) shunt is not a contraindication to ITB Therapy.1

The telemetry signals produced by the pump programmer can cause sensing problems and inappropriate device responses with an implantable pacemaker or defibrillator.

7. Spasticity-related Pain ITB Therapy should be considered when patients experience spasticity-related pain.

8. Psychosocial Considerations The patient, family, and multidisciplinary health care team must establish, and agree on, appropriate therapeutic goals. Patient/family/caregivers must be committed to obtaining refills, PT, and other follow-up care on schedule.

5. Trunk and Cervical Weakness Among patients who have significant trunk or cervical weakness, spasticity or increased tone may be necessary for stabilization and maintenance of appropriate posture. The benefits of baclofen in reducing spasticity must be carefully weighed against the potential for loss of patientsí function if trunk or cervical tone is reduced.

6. Funtional Considerations Three features of ITB Therapy are particularly desirable and important to most patients:

Graduated Control of Spasticity and Flexible Dosing Patterns Use of a programmable infusion system permits clinicians to titrate dosage, providing graduated control of spasticity that not only meets the needs of individual patients at the time of implant, but that also can be adjusted whenever a change in dose is clinically indicated. It also enables physicians to deliver the drug on a variable schedule, e.g. providing greater spasticity control at night than during the day.

Effective Treatment for Upper and Lower Extremity Spasticity ITB Therapy reduces upper and lower extremity spasticity.1-2 Treatment may promote function and care among quadriplegic/tetraplegic as well as diplegic patients. Effects may vary based on catheter tip placement.3

Reversibility of Treatment Patients and their families can be reluctant to undergo destructive procedures. The reversible nature of ITB Therapy is especially important for these individuals.

Lioresal is a registered trademark of Novartis Pharmaceuticals Corporation.

1. Meythaler JM, Guin-Renfroe S, Law C, et al. Continuously infused intrathecal baciofen over 12 months for spastic hypertonia in adolescents and adults with cerebral palsy. Archives of Physical Medicine and Rehabiliation 2001; 82:155-161.2. Albright L, Gilmartin R, Swift D, et al. Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin. Journal of Neurosurgery 2003; 98:291-295.3. Penn RD. Intrathecal baclofen for spasticity of spinal origin: seven years of experience. Journal of Neurosurgery 1992; 77:236-240.4. Grabb PA, Guin-Renfroe S, Meythaler JM. Midthoracic catheter tip placement for intrathecal baclofen administration in children with quadriparetic spasticity. Neurosurgery 1999; 45:833-837.

®

PRECAUTIONS IN SPECIAL POPULATIONS

Lioresal Intrathecal should be used with caution in patients who needspasticity to sustain upright posture and balance in locomotion orwhenever spasticity is used to obtain increased function and care. Referto Table 3 for other precautions in special patient populations. Refer tothe Drug Package Insert in the Appendix of this module for additionalprescribing information.

Table 3Precautions in

Special PatientPopulations 8

CONTRAINDICATIONS

Lioresal Intrathecal is not recommended for intravenous, intramuscular,subcutaneous or epidural administration.8 Hypersensitivity to oralbaclofen is a contraindication to therapy. For contraindications related topump implant, see the contraindications for pump implant section of theSurgical Procedures module of this guide.



Autonomic ■ Lioresal Intrathecal should be used with caution in Dysreflexia patients with a history of autonomic dysreflexia.

■ The presence of nociceptive stimuli or abrupt baclofenwithdrawal may cause an autonomic dysreflexic episode.

Impaired Renal ■ Because oral baclofen is primarily excreted unchanged by theFunction kidneys, Lioresal Intrathecal should be given with caution

in patients with impaired renal function and it may benecessary to reduce the dosage.

Psychotic Disorders, ■ Patients suffering from psychotic disorders, schizophrenia, or Schizophrenia, or confusional states should be treated cautiously with Lioresal Confusional States Intrathecal and kept under careful surveillance; exacerbation

of these conditions has been observed with oral administration.

Pregnancy ■ Lioresal Intrathecal is in Pregnancy Category C. There are noadequate and well-controlled studies in pregnant women forintrathecal baclofen. Lioresal Intrathecal should be usedduring pregnancy only if the potential benefit justifies thepotential risk to the fetus.

Nursing Mothers ■ In mothers treated with oral baclofen in therapeutic doses,the active substance passes into the breast milk. It is notknown whether detectable levels of drug are present in breastmilk of nursing mothers receiving Lioresal Intrathecal; there-fore, use only if the potential benefit justifies the potentialrisks to the infant.

Pediatric Use ■ Children should be of sufficient body mass to accommodatean implantable programmable pump.

Condition Precautions

Select the Patient assessment is an essential step prior to selecting candidates forPatient ITB Therapy. Ideally, an interdisciplinary team conducts the assessment

so that all facets of the patient’s condition can be considered. Together,the team considers the whole person. For example, a neurologist maydiagnose severe spasticity, and the physical therapist may determine thatsome spasticity is beneficial for transfers. Reducing tone completely maymake the patient less functional. A team that works together providesoptimal care for the patient.

KEY TASKS FOR SELECTING THE PATIENT

■ Conduct a complete patient history and physical examination.

■ Evaluate the spasticity, spasms, clonus, and underlying strength.

■ Assess orthotic and other equipment needs.

■ Consult with caregivers and conduct additional patient assessmentas needed to determine:

– Level of independence

– Difficulty in caregiving tasks

– Functional status

– Activities of daily living (ADLs)

– Social support structure

■ Determine current medication use, including antispasmodics.

– Assess history of drug side effects and adverse events.

■ Establish realistic goals with patient, family, caregivers, and aninterdisciplinary spasticity management team.

■ Identify ITB Therapy candidates. (See the Review Patient SelectionCriteria section in this module for specific patient selection guidelinesfor spinal and cerebral origin spasticity.)

Establish The objectives for treatment vary and must be realistic given the patient'sObjectives current level of function and disability.for Treatment

Ambulatory patients may seek to improve their balance, endurance, anduse of assistive devices. Non-ambulatory patients may seek to improvetransfers, ADLs, and quality of life. Goals for highly dependent patientsmay include facilitating care and reducing the incidence of contracturesand other complications of immobility.



Examples of spasticity management goals include:

■ Improve self-care 13,14

■ Improve gait 10,15

■ Improve functional ability and independence 6,13,16

■ Decrease pain associated with spasticity 17,18

■ Improve transfers 13,18

■ Improve sleep 10,13,17

■ Increase participation in rehabilitation activities 6,15

■ Prevent or decrease risk of contractures 15,17,19

■ Facilitate hygiene 14,15

■ Ease of nursing care 17,18

Provide Patient Patient education is critical to managing patient expectations and theand Caregiver long-term success of ITB Therapy. Education begins at the initialEducation assessment and continues throughout all phases of the therapy. The

Patient Education Checklist for Screening in the Appendix of this moduleprovides a detailed checklist of key patient education topics. The patientand caregiver need to understand their commitment to ITB Therapy. Forexample, they must keep scheduled refill appointments, report unusual orunexpected symptoms, etc.

Prepare for OBJECTIVEScreening Test The objective of the screening test is to assess patient response to a bolus

test dose of Lioresal Intrathecal and determine eligibility for long-termtherapy. A bolus dose of Lioresal Intrathecal is delivered by lumbar punc-ture or spinal catheter, and the patient’s response to the bolus dose isevaluated. Patients with a positive clinical response may be consideredcandidates for receiving an implant. Patients who do not respond to a 100microgram bolus or less are not considered candidates for ITB Therapy.An acceptable response should be determined for each patient in advanceof the screening test.



KEY CONSIDERATIONS FOR THE SCREENING TEST

The screening test must be conducted in a medically supervised and ade-quately equipped environment with immediate access to resuscitativeequipment. Prior to the screening test, be sure to do the following:

■ Educate patient and caregiver regarding the screening test procedure.For specific patient or caregiver information regarding the screeningtest, refer to the Patient Education Checklist for Screening in theAppendix of this module.

■ Prepare the following for the screening test:

■ IV access

■ Blood pressure cuff

■ Heart monitor

■ Pulse oximeter or apnea monitor

■ Consider titration or discontinuation of concomitant oral antispas-modic medications. Some physicians only hold the daily dose on theday of screening. Refer to the section on Withdrawal from OralAntispasmodics section of this module for more information.

■ Review team member roles and responsibilities for the screening test.

■ Review lumbar puncture procedure precautions.

■ Prepare for the possibility of significant hypotonia during screening asa result of the bolus injection. Following implant, the dose will be con-tinuously administered over a 24-hour period and titrated to meetindividual needs for function and care.

■ Review the Screening Test Procedure section of this module.

WITHDRAWAL FROM ORAL ANTISPASMODICS

Prior to screening or immediately following implant, an attempt should bemade to discontinue concomitant oral antispasmodic medications. Thisshould be done to avoid the risk of overdose or adverse drug interactionswith Lioresal Intrathecal.

Reduction and discontinuation of oral antispasmodics should be doneslowly and with careful monitoring by the physician. Abrupt or large-scale reductions in dose should be avoided.

If using oral baclofen, gradually reduce the dose. Rapid or abrupt with-drawal may result in seizures or hallucinations. Consult the prescribinginformation associated with the drugs you are managing for specificwithdrawal/weaning information.



If possible, develop a plan with a clinical pharmacist to slowly weanpatients off oral antispasmodics. The plan should include consideration ofthe following:

■ Timing (pre-screening or post-implant)

■ Patient condition (including other medical conditions)

■ Type of drug(s) and dose(s)

■ Prescribing information for each medication

■ Length of time drug has been prescribed/used

BENEFITS AND RISKS OF DISCONTINUING ORAL MEDICATION

Abrupt withdrawal of oral baclofen may result in seizures or hallucina-tions. 8 Carefully consider the withdrawal symptoms of other oralmedications, including combined effects. Consult the prescribinginformation for all current medications.

If, for safety reasons or patient comfort, the oral medications cannotbe withdrawn prior to screening, gradually taper the medications post-implant, while increasing Lioresal Intrathecal to a therapeutic dose.

Conduct Patients should be closely monitored in a fully equipped and staffedScreening environment throughout the entire screening test procedure. An apneaTest monitor or a pulse oximeter may be used. Resuscitative equipment

should be readily available.

Figure 2 contains an algorithm, which outlines the screening testprocedure.

1. If available, use the Lioresal Intrathecal screening ampule containing1 mL of Lioresal Intrathecal 50 micrograms/mL. Using sterile technique,prepare lumbar puncture tray and draw up medication in a 3–5 mLsyringe. (For information on a screening ampule available fromMedtronic, see the System Components module). Refer to Table 4 forinformation on the drug volume according to the desired screening dose.



NOTE:

Special attention must be given to recognizing the signs and symptomsof overdose, especially during the Screening Test. For specific informa-tion on management of overdose, see the Overdose Symptoms andTreatment section of this module.

Table 4Screening Test Dose

and Drug Volume

2. Evaluate patient’s spasticity and/or spasms prior to administering abolus dose of Lioresal Intrathecal. Ideally, the same evaluator should beused to assess patient response before, during, and after the screeningtest to eliminate consistency issues between evaluators.

3. By lumbar puncture, administer an initial screening test dose of 50micrograms (1 mL of solution) by barbotage over at least one minuteand/or follow the bolus with a minimum flush of 1 mL sterile, preser-vative-free 0.9% pharmacy-grade sodium chloride for injection. Aninitial test dose of 25 micrograms should be considered for patientswith multiple sclerosis.

■ The onset of action of Lioresal Intrathecal is 30 to 60 minutes afterdelivery of the intrathecal bolus.

■ Peak effect occurs approximately 4 hours after bolus dose; effectmay last 4 to 8 hours or longer.

■ Monitor the patient for a minimum of 4–8 hours and observe forresponse.

■ Continue to monitor until patient’s spasticity begins to return to baseline.

4. Determine the patient’s response to Lioresal Intrathecal by evaluatingchanges in muscle spasticity and spasms based on the assessmentform. The Ashworth and Spasm Scales may be used (Tables 5 and 6).



25 micrograms 0.5 mL




Screening Dose 50 micrograms/mL Amplue/s

NOTE:

The recommended concentration for the screening test is 50 micro-grams/mL. If a lower concentration of Lioresal Intrathecal is usedat the time of a screening test, the drug must be diluted with sterile,preservative-free 0.9% pharmacy-grade sodium chloride for injection.If the initial dose is 25 micrograms (pediatric patients or patients withmultiple sclerosis), adjust subsequent doses accordingly. Screeningdoses greater than 50 micrograms will require the use of 2 ampules.

5. If the clinical response is less than desired, a second bolus injection of75 micrograms (1.5 mL of the 50 micrograms/mL solution) may beadministered NO LESS THAN 24 hours after the first bolus. If theinitial dose was 25 micrograms, adjust the second dose accordingly.

■ Monitor the patient for minimum of 4–8 hours and observe forresponse. Continue to monitor until patient’s spasticity begins toreturn to baseline.

6. If the clinical response is again less than desired, a third bolus injec-tion of 100 micrograms (2 mL of the 50 micrograms/mL solution)may be administered NO LESS THAN 24 hours after the second bolus.Do not exceed a bolus dose of 100 micrograms. Patients who do notrespond to a 100 micrograms bolus of Lioresal Intrathecal should notbe considered candidates for ITB Therapy.

■ Monitor the patient for an interval of 4–8 hours and observe forresponse. Continue to monitor until patient’s spasticity begins toreturn to baseline.

If it has been determined that the patient is a candidate for ITB Therapy,the next step will be pump implant. Refer to the Surgical Proceduresmodule of this guide for information related to pump implant includingPre-operative Patient Education.

Information on determining the initial starting dose can be found inthe Dosing and Titration Guidelines section of this module.

Measurement Spasticity and related symptoms can be measured in several ways,Tools including:

■ Ashworth and Modified Ashworth scales

■ Spasm and reflex scales

■ Passive quantitative tests

■ Active tests of movement

ASHWORTH SCALE SCORES

Practitioners often use the Ashworth or Modified Ashworth Scale(Table 5) to quantify the amount of muscle tone a patient has in variousmuscle groups. These scales provide a means for measuring resistance topassive involuntary movement that the examiner objectively rates whenmoving a limb. For a sample evaluation form, refer to the Lioresal IntrathecalScreening Test Assessment Form in the Appendix of this module.



The Ashworth Scale was used in Lioresal Intrathecal clinical trials to assesspatient response. In clinical trials, a positive response to the screening testwas defined as a 2-point drop in the average lower extremity Ashworthscores in spasticity of spinal origin and a 1-point drop in spasticity ofcerebral origin. An excessive loss of tone during the screening test is notconsidered a contraindication to receiving ITB Therapy.

Muscles with the greatest amount of spasticity should be tested. Typically,the following muscle groups are assessed: hip abduction, hip flexion, kneeflexion and extension, and ankle dorsiflexion. An average score for onlythe lower extremities should be calculated. The upper extremities shouldalso be assessed but are not included in the average score. There is notalways a reduction in upper extremity spasticity during the screeningtest, but there may be an effect once the patient receives ITB Therapywith an implanted pump, depending on the catheter tip location.20

Table 5Ashworth Scale andModified Ashworth

Scale21



S

Score Criteria Score Criteria

1 No increase in tone. 0 No increase in tone.

2 Slight increase in tone, giving a 1 Slight increase in muscle tone,“catch” when moved in flexion manifested by a catch andor extension. release, or by minimal resistance

at the end of the range of motion(ROM) when the affected parts(s)is moved into flexion orextension.

3 More marked increase in tone 1+ Slight increase in muscle tone,but affected parts(s) easily flexed. manifested by a catch, followed

by minimal resistance through-out the remainder (less thanhalf) of the ROM.

4 Considerable increase in tone; 2 More marked increase in musclepassive movement difficult. tone through most of the ROM,

but the affected part(s) is easilymoved.

5 Affected parts(s) rigid in flexion 3 Considerable increase in muscle or extension. tone, passive movement is

difficult.

4 Affected part(s) is rigid inflexion or extension.

Ashworth Scale Modified Ashworth Scale

SPASM SCALE

A spasm scale is an assessment tool to quantify spasm frequency(Table 6).

Table 6Spasm Scale6

PASSIVE QUANTITATIVE TESTS

The clinician manually or mechanically manipulates the patient’s limbs toassess the velocity of the stretch, resistance to the stretch, and if possible,the electromyographic response (EMG).

ACTIVE TESTS

The evaluator observes patient movement in an attempt to establish ifspasticity is interfering with voluntary movement. Gait analysis andergometers can measure direct interference with movement. Indirectinterference with movement is measured by observing everydaymovements and how they affect the spasticity or spasms in othermuscle groups.



Score Criteria

0 No spasms

1 No spontaneous spasms (except with vigorous motor stimulation)

2 Occasional spontaneous spasms and easily induced spasms

3 More than 1 but less than 10 spontaneous spasms per hour

4 More than 10 spontaneous spasms per hour

Spasm Scale

Ongoing Patient Management

Dosing and INITIAL DOSETitration The initial dosing recommendations are the same for patients withGuidelines cerebral and spinal origin spasticity. A concentration of 500 micro-

grams/mL is recommended for use at initial implant to allow fordelivering a dose as low as 24 micrograms/day. No dose increases shouldbe given in the first 24 hours (i.e., until a steady state is achieved). Table 7describes how the starting dose is determined based on the duration ofeffect obtained from the screening test dose.

Table 7Starting Drug Dose

at Implant

TITRATION PERIOD (FIRST 60 DAYS)

The titration period is the first 60 days after pump implantation.

Key Tasks:

■ Conduct post-operative assessment

■ Titrate intrathecal drug dose (Table 8)

■ Adjust oral medications

■ Monitor patient for side effects, signs of overdose, andunderdose/withdrawal.



Less than 8 hrs Double the amount of the effective Continuous over 24 hrsscreening dose

Greater than 8 hrs Same as the effective screening Continuous over 24 hrsdose

Screen Dose Initial Dose Duration ofDuration of Effect At Implant Delivery

Table 8Post-Implant Dosing

Guidelines8

Note: Additional clinical studies have shown that dosage requirements for children andadolescents do not seem to be different from that of adult patients. Average daily doses at3 months after pump implantation were 153.1, 179.6, and 142.8 micrograms/day for ages<12, 12-15, and ≥ 16, respectively.12

MAINTENANCE PERIOD

The maintenance period begins 60 days after implantation. The goal ofthe maintenance period dosing is to maintain muscle tone as close tonormal as possible, and to reduce the frequency and severity of spasmswithout inducing intolerable side effects. Depending on the individualresponse and goals of each patient, dose adjustments may continue for6 months or more. See Table 8 for a comparison of dosing guidelines.



Increase slowly by 10-30%increments no more thanonce every 24 hours untildesired clinical effect isachieved.

Effect first seen at 6-8hours after initiation ofcontinuous infusion.

Maximum effect seen in24-48 hours.

Increase slowly by 10-40%increments no more thanonce every 24 hours.

Dosing ranges in clinicalstudies: Range: 12-2003micrograms/day Range formost patients: 300-800micrograms/day

Increase slowly by 5-15%no more than once every24 hours until desiredclinical effect is achieved.

Effect first seen at 6-8 hoursafter initiation of continuousinfusion.


Increase slowly by 5-20%no more than once every24 hours.

Dosing ranges in clinicalstudies: Range: 22-1400micrograms/day Range formost patients: 90-703micrograms/day

Increase slowly by 5-15%no more than once every24 hours until desired effectis achieved.

Effect first seen at 6-8 hoursafter initiation of continuousinfusion.


Increase slowly by 5-20% nomore than once every 24hours.

Dosing ranges in clinicalstudies: Range: 24-1199micrograms/day Pediatricpatients over 12 years: sameas adults.

Spinal Origin Cerebral Origin Pediatric (under 12)

TITRATION

MAINTENANCE

Titrate the dose for each patient based on the patient’s specific goals andneeds, but always use the lowest dose required to achieve an optimalresponse. During the maintenance period, it is important to continueeducation for the patient and caregiver to ensure understanding of allpatient requirements. Suggested topics are as follows:

■ Symptoms of infection

■ Managing drug side effects

■ Signs and symptoms of drug overdose, underdose and withdrawal

■ Hazards of driving and operating machinery

■ Potential effects of alcohol and other CNS depressants

■ Importance of attending all appointments, especially for pump refills

■ Concomitant therapies and/or medications

■ Emergency procedures

■ Importance of calling physician when pump alarms are activated

Dose Reduction

If the patient begins to experience uncomfortable or intolerable sideeffects, reduce the drug dose by 10–20% each day until the side effects arediminished or gone. Reduce the dose slowly to minimize the possibility ofbaclofen withdrawal.

Flex Dosing

Spasticity can often be managed more effectively by programming thepump to deliver medication at different rates throughout the day. Forexample:

■ Some patients may want less tone early in the morning so dressingis easier, but need more tone during the day for ambulating andtransferring.

■ Patients who have increased spasms at night may require up to a 20%increase in their hourly infusion rate. Changes in flow rate should beprogrammed to start two hours before the time of desired clinicaleffect.8 For more information on Flex dosing with the SynchroMed IIprogrammable pump, refer to the Patient Scenarios section of theProgramming module of this guide and the 8870 SynchroMed IIProgramming Guide.



Tolerance Some patients may become refractory to increasing doses of LioresalIntrathecal. Sufficient experience is not available to make firm recommen-dations for management of tolerance; however, tolerance has been treatedon occasion with a “drug holiday” using the following methods.8

■ Gradually reduce Lioresal Intrathecal over a 2–4 week period andswitch to an alternative method of spasticity management.Intrathecal baclofen reduction should be carefully managed to reducethe risk of withdrawal. See the Withdrawal Symptoms and Treatmentsection of this module for more information.

■ After the “drug holiday”, restart Lioresal Intrathecal at the initialcontinuous dose.

Potential Adverse EffectsIn pre- and post-market clinical trials with Lioresal Intrathecal, thefollowing adverse effects have been reported:

Adverse Patients vary in their sensitivity to Lioresal Intrathecal. The mostReaction to commonly observed side effects associated with Lioresal Intrathecal are:Lioresal ■ HypotoniaIntrathecal ■ Somnolence

■ Nausea/vomiting■ Headache■ Dizziness

A more detailed list of side effects, cautions, and warnings associated withLioresal Intrathecal can be found in the Drug Package Insert in theAppendix of this module.



Patients must consult their physician before engaging in activitiesinvolving pressure or temperature changes (e.g., scuba diving, saunas,hot tubs, hyperbaric chambers, airline flights, skydiving, non-pressurizedaircraft, etc.). Pressure and temperature changes can cause temporaryunderinfusion or overinfusion and result in a clinically significant under-dose or overdose. Refer to the Flow Rate Accuracy section of the SystemComponents module of this guide for more information regarding theeffects of temperature and pressure on the SynchroMed II pump.

! WARNING

Withdrawal SYMPTOMS OF WITHDRAWALSymptoms and Baclofen underdose usually precedes signs of withdrawal. EarlyTreatment symptoms of baclofen underdose include:

■ Return to baseline spasticity■ Pruritus ■ Hypotension■ Paresthesias

Abrupt withdrawal of intrathecal baclofen may be life threatening.Symptoms include, but may not be limited to:

■ High fever■ Altered mental status■ Exaggerated rebound spasticity and muscle rigidity

In rare instances, if withdrawal is left untreated, the following may result:

■ Rhabdomyolysis■ Multiple organ system failure■ Death

An advanced case of intrathecal baclofen withdrawal syndrome mayresemble the following conditions.22

■ Autonomic dysreflexia■ Sepsis (infection)■ Malignant hyperthermia■ Neuroleptic-malignant syndrome■ Other conditions associated with hypermetabolic state

For information of possible causes of underdose or withdrawal, refer tothe Managing Complications section of the Therapy Maintenance moduleof this guide.





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MINIMIZING RISK OF UNDERDOSE AND WITHDRAWAL

To safeguard against underdose and withdrawal:

■ Educate staff, patient, and family regarding signs, symptoms,prevention and management of underdose.

■ Instruct staff on emergency procedures.■ Ensure accurate programming of the pump.■ In the US, a wallet-sized emergency medication information card is

available from your Medtronic Representative.

More information about Lioresal Intrathecal withdrawal symptoms can befound in the Drug Package Insert in the Appendix of this module.

Overdose SYMPTOMS OF BACLOFEN OVERDOSESymptoms Clinicians must be especially alert to the signs and symptoms of overdose,and Treatment especially during the screening test, post-implant dose titration, and

whenever ITB Therapy has been interrupted and reintroduced. Signs andsymptoms of overdose include:

■ Drowsiness■ Lightheadedness■ Dizziness■ Somnolence■ Respiratory depression■ Seizures■ Rostral progression of hypotonia ■ Loss of consciousness progressing to coma.

MINIMIZING RISK OF OVERDOSE

To safeguard against overdose:

■ Educate staff, patient, and family regarding signs, symptoms,prevention and management of overdose.

■ Instruct staff on emergency procedures.■ Monitor patients for signs of overdose during the screening test, dose

titration, and each time the dose is adjusted.■ Instruct staff to be prepared to manage CNS depression and

respiratory failure.■ Perform screening test and dose adjustments in a medically

supervised and adequately equipped environment.■ Ensure accurate programming of the pump.■ In the US, a wallet-sized emergency medication information card is

available from your Medtronic Representative.



More information about overdose symptoms can be found in the DrugPackage Insert in the Appendix of this module. For information ofpossible causes of overdose refer to the Managing Complications sectionof the Therapy Maintenance module of this guide.





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. J N

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EMER

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PRO

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FO

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VER

DO

SE

Potential Adverse Events

The adverse events associated with the use of this system may include,but may not be limited to, the events that follow:

System- ■ Cessation of theray due to end of device service life or componentRelated failure

■ Change in flow performance characteristics due to component failure■ Inability to program the device due to clinician programmer failure

or loss of telemetry■ Catheter access port failure due to component failure

Catheter- ■ Changes in catheter performance due to catheter kinking, catheter Related disconnection, catheter leakage, catheter breakage, complete or partial

catheter occlusion, catheter dislodgement or migration, or catheterfibrosis or hygroma.



Procedure- ■ Inaccessible reservoir fill port or catheter access port due to pumpRelated being implated upside down (inverted) or too deep

■ Pocket seroma, hematoma, or erosion■ Post-lumbar puncture (spinal) headache■ Cerebrospinal fluid (CSF) leak leading to CSF subcutaneous collection

or rare central nervous system (CNS) pressure-related problems■ Radiculitis■ Arachnoiditis■ Bleeding■ Spinal cord damage■ Meningitis■ Medical complications■ Anesthesia complications■ Damage to the pump, catheter, and catheter access system due to

improper handling and filling before, during, or after implantation■ Infection■ Reservoir contamination

Other ■ Local and systemic drug toxicity and related side effects■ Body rejection phenomena■ Surgical replacement of the pump or catheter due to complications■ Pump inversion (“flipping”)

Drug- ■ LocalRelated ■ Complications due to use of drugs not approved and/or formulated for

intraspinal delivery. Formulations must be sterile and preservative free.■ Complications due to using drugs not in accordance with drug labeling■ Inflammatory mass formation at the tip of the implanted catheter in

patients who receive intraspinal morphine or other opioid drugs.

Also refer to the following sections of this module for more informationon other drug-related adverse effects: Adverse Reaction to LioresalIntrathecal, Withdrawal Symptoms and Treatment, and OverdoseSymptoms and Treatment.



References1. Lance JW: Synopsis. In: Feldman RG, Young RR, Koella WP, eds.

Spasticity: Disordered Motor Control. Chicago: Year Book MedicalPublishers. 1980: 480-485.

2. Sanger TD, Delgado MR, Gaebler-Spira, D, et al. Classification andDefinition of Disorders Causing Hypertonia in Childhood. Pediatrics.2003;111(1):89-97.

3. Meythaler JM. Concept of spastic hypertonia. Phys Med Rehabil Clin NAm. 2001;12(4):725-732.

4. Albright AL. Spastic Cerebral Palsy: Approaches to Drug Treatment.CNS Drugs. 1995; 4(1): 17-27.

5. Delisa JA, Little J. Managing spasticity. American Family Physician.1982; 26(3): 117-22.

6. Savoy SM, Gianino JM. Intrathecal Baclofen Infusion: An InnovativeApproach for Controlling Spasticity. Rehab Nurs. 1993; 18(2): 105-113.

7. Guidelines for the Rehabilitation Team. Minneapolis, MN: Medtronic,Inc., 1998, UC9502736EN.

8. LIORESAL® INTRATHECAL (baclofen injection) [package insert].Manufactured by Novartis Pharma AG, Basle, Switzerland, forMedtronic, Inc., Minneapolis, MN 55432-5604 USA. 2002. (Lioresal® is aregistered trademark of Novartis Pharmaceuticals Corporation.)

9. Penn R. Intrathecal Baclofen for Spasticity of Spinal Origin: SevenYears of Experience. J Neurosurg. 1992; 77: 236-240.

10. Gilmartin R, Bruce D, Storrs B., et al. Intrathecal Baclofen forManagement of Spastic Cerebral Palsy: Multicenter Trial. J ChildNeurology 2000; 15(2): 71-77.

11. Coffey R, Cahill D, Steers W, et al. Intrathecal Baclofen for IntractableSpasticity of Spinal Origin: Results of a Long-Term Multicenter Study.J Neursurg. 1993; 78: 226-232.

12. Albright, AL, Gilmartin R, Swift D, et al. Long-Term IntrathecalBaclofen Therapy for Severe Spasticity of Cerebral Origin. J Neurosurg.2003; 98: 291-295.

13. Campbell S, Almeida G, Penn Ret al. The Effects of IntrathecallyAdministered Baclofen on Function in Patients with Spasticity.Physical Therapy. 1995; 75(5); 352-362.

14. Albright, AL. Intrathecal Baclofen in Cerebral Palsy MovementDisorders. J Child Neurology. 1996; 11 (Supplement 1): S29-S35.



15. Francisco, G. Intrathecal Baclofen Therapy for Stroke-RelatedSpasticity. Top Stroke Rehabil. 2001; 8(1):36-46.

16. Meythaler J, Guin-Renfroe S, Law C, et al. Continuously InfusedIntrathecal Baclofen Over 12 Months for Spastic Hypertonia inAdolescents and Adults with Cerebral Palsy. Arch Phys Med Rehabil.2001; 82: 155-161.

17. Gianino J. Intrathecal Baclofen for Spinal Spasticity: Implications forNursing Practice. J Neurosci Nurs. 1993; 25(4): 254-264.

18. Ordia J, Fischer E, Adamski E, et al. Continuous Intrathecal BaclofenInfusion by Programmable Pump in 131 Consecutive Patients withSevere Spasticity of Spinal Origin. Neuromod. 2002; 5(1):16-24.

19. Gerszten P, Albright AL, Johnstone G. Intrathecal Baclofen Infusionand Subsequent Orthopedic Surgery in Patients with Spastic CerebralPalsy. J Neurosurg. 1998; 88:1009-1013.

20. Barry MJ, Albright AL, Schultz B. Intrathecal Baclofen in the Role ofthe Physical Therapist. Pediatric Physical Therapy. 2000; 12(2):77-86.

21. Bohannon R, Smith M. Interrater Reliability of a Modified AshworthScale of Muscle Spasticity. Physical Therapy. 1987; 67(2): 206-207.

22. Coffey RJ, Edgar TS, Francisco GE, et al. Abrupt Withdrawal fromIntrathecal Baclofen: Recognition and Management of a PotentiallyLife-Threatening Syndrome. Arch Phys Med Rehabil. 2002; (83): 735-741.



AppendixSpinal Origin vs. Cerebral Origin Spasticity Comparison Chart ......................33

Patient Education Checklist For Screening Test ............................................................35

Lioresal Intrathecal Screening Test Assessment Form ............................................36

Drug Package Insert ............................................................................................................................38



Spinal Origin vs. Cerebral Origin Spasticity Comparison Chart



Spasticity ■ Usually symmetrical in lower extremities. ■ Asymmetrical in muscle groups andextremities.

■ Average Ashworth 4–5 (in clinical trials). ■ Average Ashworth 3–4 (in clinical trials).

■ Severe spasms. ■ Brain injury patients may have spasms;spastic cerebral palsy may have clonusbut not usually spasms.

Patient Selection ■ Severe spasticity. ■ SAME

■ Responds to ≤ 100 microgram bolus of ■ SAMELioresal Intrathecal.

■ Cannot be hypersensitive to baclofen. ■ SAME

■ Free of infection. ■ SAME

■ Unresponsive to oral baclofen or ■ Prior oral antispasmodic use is not intolerable side effects at effective doses. required.

■ In traumatic brain injury, wait 1-yearpost injury.

Screening ■ Begin with a 50 microgram bolus; if ■ SAMETest Dosing inadequate response is seen, proceed to

a 75 microgram bolus 24 hours later.If the response is still inadequate, a100 microgram bolus can be given24 hours later.

■ In very small children and in patients ■ In very small children, a 25 microgramwith multiple sclerosis, a 25 microgram bolus may be considered.bolus may be considered.

■ Onset of action 30 to 60 minutes after ■ SAMEbolus injection. Peak spasmolyticresponse is 4 hours post injection.

Initial Dosing ■ Double the effective screening test dose ■ SAMEif the effect lasts 8 hours or less.

■ If the effect lasts more than 8 hours, use ■ SAMEsame dose as the effective screeningtest dose.

Spasticity of Spinal Origin Spasticity of Cerebral OriginPatients Patients

Spinal Origin vs. Cerebral Origin Spasticity Comparison Chart - Continued



Post-Implant ■ No dosing increases during first 24 hours. ■ SAMEDose Titration

■ Increase 10–30% once every 24 hours ■ Increase 5-15% once every 24 hoursuntil desired clinical effect is achieved. until desired clinical effect is achieved.

■ Response action first seen 6–8 hours ■ SAMEafter initiation of continuous infusion.Peak response observed in 24–48 hours.

Maintenance ■ Maintain muscle tone as close to normal ■ SAMEPeriod Goals as possible. (1–2 Ashworth scale)

■ Minimize frequency and severity ■ SAMEof spasms.

Maintenance ■ 10–40% increases no more than once ■ 5-20% increases no more than oncePeriod Dosing every 24 hours. every 24 hours.

■ Clinical Experience: ■ In pediatric patients over 12, doses didRange: 12–2003 micrograms/day not seem to be different than adultTypical Range: 300–800 micrograms/day cerebral origin spasticity patients

■ Clinical Experience:Range: 22–1400 micrograms/dayTypical Range: 90–703 micrograms/day

■ Clinical Experience:Pediatric patients (under 12) seem torequire lower daily doses.Range: 24-1199 micrograms/day

Dose Reductions ■ 10-20% reduction slowly ■ SAME

Flex Mode ■ Patients who have increased spasms at ■ May use variable programmingnight may require up to a 20% increase throughout the day (i.e., more drugin their hourly infusion rate. Changes in during morning for dressing and lessflow rate should be programmed to start later when transferring).two hours before the time of desiredclinical effect.

Adverse Events ■ The most common drug adverse events reported were hypotonia, somnolence, nauseaand vomiting, headache, and dizziness.

■ The most common procedural/system-related complications were catheter-relatedkinks, breaks, or dislodgements. Other events included pocket seroma, infections,and/or programming errors.

Spasticity of Spinal Origin Spasticity of Cerebral OriginPatients Patients

Patient It important to involve the patient, family members, and all caregivers inEducation the education process. The following are key topics that should be covered Checklist prior to the actual screening test:For Screening ■ Educate patients, their families and caregivers about the benefits andTest risks of the therapy, specifically:

■ Potential adverse events■ Symptoms of underdose, overdose and withdrawal

■ Explain the four stages of ITB Therapy and the goals for each phase

■ Explain the screening test procedure, what is required, and what toexpect:

■ Informed consent■ Test duration ■ Instructions for management of existing medication■ The individuality of response to the screening test dose(s)■ Realistic, patient-specific goals for the test■ Excessive hypotonia (flaccidity) may be experienced, but this is not

considered a contraindication to pump implant■ A pump implant may be appropriate in patients who do not obtain

an ideal response

■ Explain the role of patient, family, caregiver(s), and the spasticity man-agement team members, specifically:

■ Importance of a responsible patient and/or caregiver during themaintenance phase of therapy

■ Expectation that the patient/caregiver will schedule and keep refillappointments, monitor for and report adverse events, and bemindful of the potential interaction of intrathecal baclofen withCNS depressants

■ Discuss the management plan for existing medications, includingwithdrawal of oral antispasmodics



Situation Total Prime Volume = Both pump and catheter are Both pump and cather impl anted or replaced

Patient selection Determine appropriate candidates for screening test

Screening test Determine appropriate candidates for pump implant

Implant Provide the patient with long-term therapy

Maintenance therapy Monitor patient progress and achieve optimum effectwith minimal side effects; replace pump as needed

Phase Goal

Lioresal Intrathecal (Baclofen Injection) Screening Test Assessment Form



sam

ple

LIORESAL® INTRATHECAL (baclofen injection)

Screening Test Assessment Form

Date ___________________________

Solution given via:

Dose Given

_______ mcg

Time

Respirations/minute

Pulse/minute

Blood Pressure

Spasticity Scores

Wrist Flexion

Wrist Extension

Elbow Flexion

Elbow Extension

Hip Adduction

Hip Abduction

Hip Flexion

Knee Extension

Knee Flexion

Ankle Dorsiflexion

Plantar Flexion

Average Upper Extremity

Average Lower Extremity

Time of Injection

Pre-Bolus 1/2 Hr. afterbolus

1 Hr. afterbolus

2 Hrs. afterbolus

3 Hrs. afterbolus

4 Hrs. afterbolus

6 Hrs. afterbolus

8 Hrs. afterbolus

12 Hrs. after bolus

Circle device(s) used:

Apnea Monitor Pulse Oximiter Heart Monitor

Lumbar Puncture ______ Intrathecal Catheter _____ Clinician ___________________________

L R L R L R L R L R L R L R L R L R

Overall Spasm Score*

COMMENTS: (Side effects, patient comments, clinician observations)

SCALE Used:

(comments continued on back)

Lioresal Intrathecal (Baclofen Injection) Screening Test Assessment Form (cont.)



sam

ple

Ashworth Scale

Modified Ashworth Scale

Spasm Scale

Other Medications During Screening (include 6 hours prior to injection through 12 hours post injection)

Time Medication

COMMENTS (continued):

Score

Score

Criteria

Criteria

No increase in toneSlight increase in tone, giving a “catch” when the affected part(s) is moved in flexion or extensionMore marked increase in tone but affect part(s) easily flexedConsiderable increase in tone-passive movement difficultAffected part(s) rigid in flexion or extension

12345

01

1+

234

Score CriteriaNoneNo spontaneous spasms; vigorous sensory and motor stimulation results in spasmsOccasional spontaneous spasms and easily induced spasmsGreater than one but less than ten spontaneous spasms per hourGreater than ten spontaneous spasms per hour

01234

Dose Time Medication Dose Time Medication Dose

No increase in tone.Slight increase in muscle tone, manifested by a catch and release, or by minimal resistance at the end of the ROM when the affected part(s) is moved into flexion or extension.Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM.More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved.Considerable increase in muscle tone, passive movement difficult.Affected part(s) rigid in flexion or extension.

DrugPackageInsertLIORESAL® INTRATHECAL(baclofen injection)

DESCRIPTIONLIORESAL INTRATHECAL (baclofen injection) is a muscle relaxant and antispastic. Its chemical name is 4-amino-3-(4-chlorophenyl) butanoic acid, and its structural formula is:Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66.It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.LIORESAL INTRATHECAL is a sterile, pyrogen-free, isotonic solution free of antioxidants, preservatives or otherpotentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37° C andcompatible with CSF. Each milliliter of LIORESAL INTRATHECAL contains baclofen U.S.P. 50 mcg, 500 mcg or 2000mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.0 - 7.0. Each ampule is intended for SINGLE USEONLY. Discard any unused portion. DO NOT AUTOCLAVE.

CLINICAL PHARMACOLOGYThe precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits bothmonosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferentterminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of theinhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype.LIORESAL INTRATHECAL when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved withresultant plasma concentrations 100 times less than those occurring with oral administration.In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of seda-tion with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.Pharmacodynamics of LIORESAL INTRATHECAL:Intrathecal Bolus:Adult Patients: The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen atapproximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary withindividual patients depending on the dose and severity of symptoms.Pediatric Patients: The onset, peak response and duration of action is similar to those seen in adult patients.Continuous Infusion:LIORESAL INTRATHECAL’S antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observedin 24 to 48 hours.Continuous Infusion: No additional information is available for pediatric patients.Pharmacokinetics of LIORESAL INTRATHECAL:The pharmacokinetics of CSF clearance of LIORESAL INTRATHECAL calculated from intrathecal bolus or continuous infusion studies approxi-mates CSF turnover, suggesting elimination is by bulkflow removal of CSF.Intrathecal Bolus: After a bolus lumbar injection of 50 or 100 mcg LIORESAL INTRATHECAL in seven patients, the average CSF eliminationhalf-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 ml/hour.Continuous Infusion: The mean CSF clearance for LIORESAL INTRATHECAL (baclofen injection) was approximately 30 ml/hour in a studyinvolving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration areexpected to be low (0-5 ng/ml).Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 is established along the neuroaxis duringbaclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infu-sion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered byposition.Six pediatric patients (age 8-18 years) receiving continuous intrathecal baclofen infusion at doses of 77-400 mcg/day had plasma baclofenlevels near or below 10 ng/ml.



Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mentalstatus, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-systemfailure and death.Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusionsystem, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keepingscheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given topatients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oralor intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patientinformation (see WARNINGS).

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INDICATIONSLIORESAL INTRATHECAL is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathe-cal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of LIORESALINTRATHECAL via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerableCNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injurybefore consideration of long term intrathecal baclofen therapy. LIORESAL INTRATHECAL (baclofen injection) is intended for use by the intrathecalroute in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifi-cally for the administration of LIORESAL INTRATHECAL into the intrathecal space.Spasticity of Spinal Cord Origin: Evidence supporting the efficacy of LIORESAL INTRATHECAL was obtained in randomized, controlled investigationsthat compared the effects of either a single intrathecal dose or a three day intrathecal infusion of LIORESAL INTRATHECAL to placebo in patientswith severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. LIORESAL INTRATHECAL was superior to placebo on bothprincipal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms.Spasticity of Cerebral Origin: The efficacy of LIORESAL INTRATHECAL was investigated in three controlled clinical trials; two enrolled patients withcerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of51 patients with cerebral palsy, provided strong, statistically significant results; LIORESAL INTRATHECAL was superior to placebo in reducing spas-ticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury.Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The laststudy, however, did not provide data that could be reliably analyzed.LIORESAL INTRATHECAL therapy may be considered an alternative to destructive neurosurgical procedures. Prior to implantation of a device forchronic intrathecal infusion of LIORESAL INTRATHECAL, patients must show a response to LIORESAL INTRATHECAL in a screening trial (seeDosage and Administration).

CONTRAINDICATIONSHypersensitivity to baclofen. LIORESAL INTRATHECAL is not recommended for intravenous, intramuscular, subcutaneous or epidural administration.

WARNINGSLIORESAL INTRATHECAL is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbarpuncture) and in implantable pumps approved by the FDA specifically for the intrathecal administration of baclofen. Because of the possibility ofpotentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educatedin chronic intrathecal infusion therapy.The pump system should not be implanted until the patient’s response to bolus LIORESAL INTRATHECAL injection is adequately evaluated.Evaluation (consisting of a screening procedure: see Dosage and Administration) requires that LIORESAL INTRATHECAL be administered into theintrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage fol-lowing pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following theinstructions 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 cer-tain 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 LIORESAL INTRATHECAL (baclofen injection) in the reservoir isadjusted, 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 care givers, and the physicians responsible for the patient receive adequate information regarding therisks of this mode of treatment. All medical personnel and care givers should be instructed in 1) the signs and symptoms of overdose, 2)procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.Overdose: Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severeforms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostralprogression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to ahospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction ordosing error. (See Drug Overdose Symptoms and Treatment.)Extreme caution must be used when filling an FDA approved implantable pump. Such pumps should only be refilled through the reservoir refill sep-tum. However, some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection intothis 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 sta-tus, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. Inthe first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; sixpatients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Commonreasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in thepump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Prevention of abruptdiscontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and proce-dures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated onthe 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 ofbaseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndromemay resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associatedwith 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 with-drawal 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 mayprevent 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 LIORESAL INTRATHECAL as well as in patients maintained on therapeuticdoses of LIORESAL INTRATHECAL.Fatalities:Spasticity of Spinal Cord Origin: There were 16 deaths reported among the 576 U.S. patients treated with LIORESAL INTRATHECAL (baclofen injec-tion) in pre- and post-marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, itis impossible to determine definitively what role, if any, LIORESAL INTRATHECAL 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 spas-ticity 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 anyunique signs, symptoms, or laboratory results that would suggest that treatment with LIORESAL INTRATHECAL 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 MS, died in hospital on the second day following pump implantation. An autopsy demonstrated severe fibrosisof the coronary conduction system. A second patient, a 52 year-old woman with MS and a history of an inferior wall myocardial infarction, was founddead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestionand bilateral pleural effusions. It is impossible to determine whether LIORESAL INTRATHECAL contributed to these deaths. The third patient under-went three baclofen screening trials. His medical history included SCI, 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 statusepilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pur-sued and the patient died.Spasticity of Cerebral Origin: There were three deaths occurring among the 211 patients treated with LIORESAL INTRATHECAL in pre-marketingstudies as of March 1996. These deaths were not attributed to the therapy.PRECAUTIONSChildren should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manualfor specific recommendations.Safety and effectiveness in pediatric patients below the age of 4 have not been established.ScreeningPatients should be infection-free prior to the screening trial with LIORESAL INTRATHECAL (baclofen injection) because the presence of a systemicinfection may interfere with an assessment of the patient’s response to bolus LIORESAL INTRATHECAL.Pump ImplantationPatients should be infection-free prior to pump implantation because the presence of infection may increase the risk of surgical complications.Moreover, a systemic infection may complicate dosing.Pump Dose Adjustment and TitrationIn most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial doseescalation typically indicates a catheter complication (i.e., catheter kink or dislodgement).Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Refillintervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possiblysymptoms of withdrawal.Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinicalsituation should follow each refill or manipulation of the drug reservoir.Extreme caution must be used when filling an FDA approved implantable pump equipped with an injection port that allows direct access to theintrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose.Additional considerations pertaining to dosage adjustment: It may be important to titrate the dose to maintain some degree of muscle tone andallow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities ofdaily living and ease of care.Except in overdose related emergencies, the dose of LIORESAL INTRATHECAL should ordinarily be reduced slowly if the drug is discontinued for anyreason.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 LIORESAL INTRATHECAL 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 antispasticsshould be avoided.Drowsiness: Drowsiness has been reported in patients on LIORESAL INTRATHECAL. Patients should be cautioned regarding the operation of automo-biles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervoussystem depressant effects of LIORESAL INTRATHECAL (baclofen injection) may be additive to those of alcohol and other CNS depressants.Precautions in special patient populations: Careful dose titration of LIORESAL INTRATHECAL is needed when spasticity is necessary to sustainupright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care.Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with LIORESAL INTRATHECAL andkept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.LIORESAL INTRATHECAL should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli orabrupt withdrawal of LIORESAL INTRATHECAL (baclofen injection) may cause an autonomic dysreflexic episode.Because LIORESAL is primarily excreted unchanged by the kidneys, it should be given with caution in patients with impaired renal function and itmay be necessary to reduce the dosage.LABORATORY TESTSNo specific laboratory tests are deemed essential for the management of patients on LIORESAL INTRATHECAL.



DRUG INTERACTIONSThere is inadequate systematic experience with the use of LIORESAL INTRATHECAL in combination with other medications to predict specificdrug-drug interactions. Interactions attributed to the combined use of LIORESAL INTRATHECAL and epidural morphine include hypotension anddyspnea.CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITYNo increase in tumors was seen in rats receiving LIORESAL (baclofen USP) orally for two years at approximately 30-60 times on a mg/kg basis, or 10-20 times on a mg/m2 basis, the maximum oral dose recommended for human use. Mutagenicity assays with LIORESAL have not been performed.PREGNANCY CATEGORY CLIORESAL (baclofen USP) given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approxi-mately 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 causedreductions in food intake and weight gain in the dams.This abnormality was not seen in mice or rabbits. There are no adequate and well-controlled studies in pregnant women. LIORESAL should be usedduring pregnancy only if the potential benefit justifies the potential risk to the fetus.NURSING MOTHERSIn mothers treated with oral LIORESAL (baclofen USP) in therapeutic doses, the active substance passes into the breast milk. It is not knownwhether detectable levels of drug are present in breast milk of nursing mothers receiving LIORESAL INTRATHECAL. As a general rule, nursingshould be undertaken while a patient is receiving LIORESAL INTRATHECAL only if the potential benefit justifiesthe potential risks to the infant.PEDIATRIC USEChildren should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manualfor specific recommendations.Safety and effectiveness in pediatric patients below the age of 4 have not been established.Considerations based on experience with oral LIORESAL (baclofen USP)A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral LIORESAL. Ovarian cysts have beenfound by palpation in about 4% of the multiple sclerosis patients who were treated with oral LIORESAL for up to one year. In most cases these cystsdisappeared 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.ADVERSE DRUG EVENTSSpasticity of Spinal Cord Origin:Commonly Observed in Patients with Spasticity of Spinal Origin — In pre- and post-marketing clinical trials, the most commonly observed adverseevents associated with use of LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebotreatedpatients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia.Associated with Discontinuation of Treatment — 8/474 patients with spasticity of spinal cord origin receiving long term infusion of LIORESALINTRATHECAL in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse events. These include: pump pocketinfections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Elevenpatients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and werenot, therefore, considered to be true discontinuations.Fatalities — See Warnings.Spasticity of Spinal Cord Origin:Incidence in Controlled Trials — Experience with LIORESAL INTRATHECAL (baclofen injection) obtained in parallel, placebo-controlled, randomizedstudies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three daysof infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving LIORESAL INTRATHECAL(baclofen injection) in two randomized, placebocontrolled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse events werereported among the 32 patients receiving placebo in these studies.Events Observed during the Pre- and Post-marketing Evaluation of LIORESAL INTRATHECAL — Adverse events associated with the use of LIORESALINTRATHECAL reflect experience gained with 576 patients followed prospectively in the United States. They received LIORESAL INTRATHECAL forperiods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10). The usual screening bolus dose administered prior to pumpimplantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncon-trolled nature of the experience, a causal linkage between events observed and the administration of LIORESAL INTRATHECAL cannot be reliablyassessed in many cases and many of the adverse events 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 the following table. Eight of 474 patients whoreceived chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post-marketing studies.



INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITOREDCLINICAL TRIALS

Percent of Patients Reporting EventsN = 576 N = 474 N = 430Screeninga Titrationb Maintenancec

Adverse Event Percent Percent PercentHypotonia 5.4 13.5 25.3Somnolence 5.7 5.9 20.9Dizziness 1.7 1.9 7.9Paresthesia 2.4 2.1 6.7Nausea and Vomiting 1.6 2.3 5.6Headache 1.6 2.5 5.1Constipation 0.2 1.5 5.1Convulsion 0.5 1.3 4.7Urinary Retention 0.7 1.7 1.9Dry Mouth 0.2 0.4 3.3Accidental Injury 0.0 0.2 3.5Asthenia 0.7 1.3 1.4Confusion 0.5 0.6 2.3Death 0.2 0.4 3.0Pain 0.0 0.6 3.0Speech Disorder 0.0 0.2 3.5Hypotension 1.0 0.2 1.9Ambylopia 0.5 0.2 2.3Diarrhea 0.0 0.8 2.3Hypoventilation 0.2 0.8 2.1Coma 0.0 1.5 0.9Impotence 0.2 0.4 1.6Peripheral Edema 0.0 0.0 2.3Urinary Incontinence 0.0 0.8 1.4Insomnia 0.0 0.4 1.6Anxiety 0.2 0.4 0.9Depression 0.0 0.0 1.6Dyspnea 0.3 0.0 1.2Fever 0.5 0.2 0.7Pneumonia 0.2 0.2 1.2Urinary Frequency 0.0 0.6 0.9Urticaria 0.2 0.2 1.2Anorexia 0.0 0.4 0.9Diplopia 0.0 0.4 0.9Dysautonomia 0.2 0.2 0.9Hallucinations 0.3 0.4 0.5Hypertension 0.2 0.6 0.5a Following administration of test bolusb Two month period following implantc Beyond two months following implantN=total number of patients entering each period%=% of patients evaluated



In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post-mar-keting studies, experience from an additional 194 patients exposed to LIORESAL INTRATHECAL (baclofen injection) from foreign studies has beenreported. The following adverse events, 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, vasodilitation, cerebrovascular accident, nystagmus, personalitydisorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reactionand 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:Commonly Observed — In pre-marketing clinical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHE-CAL (baclofen injection) which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somno-lence, leukocytosis, chills, urinary retention and hypotonia.Associated with Discontinuation of Treatment — Nine of 211 patients receiving LIORESAL INTRATHECAL in pre-marketing clinical studies in the U.S.discontinued long term infusion due to adverse events associated with intrathecal therapy.The nine adverse events 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 LIORESAL INTRATHECAL, were reported in patients in clinical trials involving patientswith spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients.Incidence in Controlled Trials — Experience with LIORESAL INTRATHECAL (baclofen injection) obtained in parallel, placebo-controlled, randomizedstudies provides only a limited basis for estimating the incidence of adverse events because the studies involved a total of 62 patients exposed to asingle 50 mcg intrathecal bolus. The following events occurred among the 62 patients receiving LIORESAL INTRATHECAL in two randomized, place-bo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomit-ing, nystagmus, chills, urinary retention, and hypotonia.Events Observed during the Pre-marketing Evaluation of LIORESAL INTRATHECAL — Adverse events associated with the use of LIORESALINTRATHECAL 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 LIORESAL INTRATHECAL 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 50-75 mcg. The maintenance dose ranged from 22mcg to 1400 mcg per day. Doses used in this patient population for long term infusion are generally lower than those required for patients withspasticity of spinal cord origin.Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of LIORESALINTRATHECAL 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 events reported during all clinical trials are shown in the following table. Nine patients discontinued long termtreatment due to adverse events.



INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITOREDCLINICAL TRIALS

Percent of Patients Reporting EventsN = 211 N = 153 N = 150Screeninga Titrationb Maintenancec

Adverse Event Percent Percent PercentHypotonia 2.4 14.4 34.7Somnolence 7.6 10.5 18.7Headache 6.6 7.8 10.7Nausea and Vomiting 6.6 10.5 4.0Vomiting 6.2 8.5 4.0Urinary Retention 0.9 6.5 8.0Convulsion 0.9 3.3 10.0Dizziness 2.4 2.6 8.0Nausea 1.4 3.3 7.3Hypoventilation 1.4 1.3 4.0Hypertonia 0.0 0.7 6.0Paresthesia 1.9 0.7 3.3Hypotension 1.9 0.7 2.0Increased Salivation 0.0 2.6 2.7Back Pain 0.9 0.7 2.0Constipation 0.5 1.3 2.0Pain 0.0 0.0 4.0Pruritus 0.0 0.0 4.0Diarrhea 0.5 0.7 2.0Peripheral Edema 0.0 0.0 3.3Thinking Abnormal 0.5 1.3 0.7Agitation 0.5 0.0 1.3Asthenia 0.0 0.0 2.0Chills 0.5 0.0 1.3Coma 0.5 0.0 1.3Dry Mouth 0.5 0.0 1.3Pneumonia 0.0 0.0 2.0Speech Disorder 0.5 0.7 0.7Tremor 0.5 0.0 1.3Urinary Incontinence 0.0 0.0 2.0Urination Impaired 0.0 0.0 2.0

a Following administration of test bolusb Two month period following implantc Beyond two months following implantN=Total number of patients entering each period. 211 patients received drug; (1 of 212) received placebo only.The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to LIORESAL INTRATHECAL (baclofeninjection) have been reported. In the total cohort, the following adverse events, not described in the table, and arranged in decreasing order offrequency, and classified by body system, were reported:Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personalitydisorder, 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.



DRUG OVERDOSESpecial attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titrationphase of treatment, but also during re-introduction of LIORESAL INTRATHECAL after a period of interruption in therapy.Symptoms of LIORESAL INTRATHECAL Overdose: Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral pro-gression of hypotonia and loss of consciousness progressing to coma of up to 72 hr. duration. In most cases reported, coma was reversible withoutsequelae after drug was discontinued.Symptoms of LIORESAL INTRATHECAL 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 LIORESAL INTRATHECAL (baclofen injection); however, the following steps should ordinarilybe undertaken:1) Residual LIORESAL INTRATHECAL 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. Cautionin 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 morethan 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 mgper 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 30-40 ml of CSF to reduce CSF baclofen concentration.DOSAGE AND ADMINISTRATIONRefer to the manufacturer’s manual for the implantable pump approved for intrathecal infusion for specific instructions and precautions for pro-gramming the pump and/or refilling the reservoir.Screening Phase: Prior to pump implantation and initiation of chronic infusion of LIORESAL INTRATHECAL (baclofen injection), patients mustdemonstrate a positive clinical response to a LIORESAL INTRATHECAL bolus dose administered intrathecally in a screening trial. The screening trialemploys LIORESAL INTRATHECAL at a concentration of 50 mcg/ml. A 1 ml ampule (50 mcg/ml) is available for use in the screening trial. Thescreening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space bybarbotage 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 signifi-cant decrease in muscle tone and/or frequency and/or severity of spasms. If the initial response is less than desired, a second bolus injection maybe administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should beobserved 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 beadministered 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, ascreening 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.Post-Implant Dose Titration Period: To determine the initial total daily dose of LIORESAL INTRATHECAL following implant, the screening dose thatgave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for morethan 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 givenin the first 24 hours (i.e., until the steady state is achieved).Adult Patients with Spasticity of Spinal Cord Origin: After the first 24 hours, for adult patients, the daily dosage should be increased slowly by10-30% 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 5-15% only once every 24hours, until the desired clinical effect is achieved.Pediatric Patients: After the first 24 hours, the daily dose should be increased slowly by 5-15% only once every 24 hours, until the desired clinicaleffect is achieved.If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency.Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediatelyfollowing implant. Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable side effects.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 frequencyand severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjustedduring the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of thepump, the daily dose may be increased by 10-40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reducedby 10-20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronictherapy. 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 LIORESAL INTRATHECAL (baclofen injection) has ranged from 12 mcg/day to 2,003mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily dosesgreater than 1000 mcg/day. Determination of the optimal LIORESAL INTRATHECAL dose requires individual titration. The lowest dose with an opti-mal 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 andseverity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone foroptimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes inlife style due to the alleviation of spasticity.During periodic refills of the pump, the daily dose may be increased by 5 - 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10-20% if patients experience side effects. Many patients require gradual increases in dose over time to maintainoptimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink ordislodgement).



Maintenance dosage for long term continuous infusion of LIORESAL INTRATHECAL (baclofen injection) has ranged from 22 mcg/day to 1400mcg/day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients requireddaily doses greater than 1000 mcg/day.Pediatric Patients: Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed torequire a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/day, with a range of 24 to 1199 mcg/day.Dosage requirement for pediatric patients over 12 years does not seem to be different from that of adult patients. Determination of the optimalLIORESAL INTRATHECAL 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 toincreasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this “tolerance” has beentreated on occasion, in hospital, by a “drug holiday” consisting of the gradual reduction of LIORESAL INTRATHECAL over a 2 to 4 week period andswitching to alternative methods of spasticity management. After the “drug holiday,” LIORESAL INTRATHECAL may be restarted at the initialcontinuous infusion dose.StabilityParenteral drug products should be inspected for particulate matter and discoloration prior toadministration, whenever solution and container permit.Delivery SpecificationsThe specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. LIORESALINTRATHECAL may require dilution when used with certain implantable pumps. Please consult manufacturer’s manual for specific recommendations.Preparation Instruction:ScreeningUse the 1 ml screening ampule only (50mcg/ml) for bolus injection into the subarachnoid space.For a 50mcg bolus dose, use 1 ml of the screening ampule. Use 1.5 ml of 50mcg/ml baclofeninjection for a 75mcg bolus dose. For the maximum screening dose of 100mcg, use 2 ml of 50mcg/ml baclofen injection (2 screening ampules).MaintenanceFor patients who require concentrations other than 500 mcg/ml or 2000 mcg/ml, LIORESAL INTRATHECAL must be diluted.LIORESAL INTRATHECAL must be diluted with sterile preservative free Sodium Chloride forInjection, U.S.P.Delivery Regimen:LIORESAL INTRATHECAL is most often administered in a continuous infusion mode immediately following implant. For those patients implantedwith programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using morecomplex schedules of LIORESAL INTRATHECAL delivery. For example, patients who have increased spasms at night may require a 20% increase intheir hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect.HOW SUPPLIEDLIORESAL INTRATHECAL (baclofen injection) is available in single use ampules of 10 mg/20 ml (500 mcg/ml) or 10 mg/5 ml (2000 mcg/ml)packaged in a Refill Kit for intrathecal administration.For screening, LIORESAL INTRATHECAL is available in a single use ampule of 0.05 mg/1 ml. Model 8561 LIORESAL INTRATHECAL Refill Kit containsone ampule of 10 mg/20 ml (500 mcg/ml) (NDC 58281-560-01).Model 8562 LIORESAL INTRATHECAL Refill Kit contains two ampules of 10 mg/5 ml (2000 mcg/ml) (NDC 58281-561-02).Model 8564 LIORESAL INTRATHECAL Refill Kit contains four ampules of 10 mg/5 ml (2000 mcg/ml) (NDC 58281-561-04).Model 8563s LIORESAL INTRATHECAL contains one ampule of 0.05 mg/1 ml (NDC 58281-562-01).STORAGEDoes not require refrigeration.Do not store above 86°F (30°C).Do not freeze.Do not heat sterilize.Manufactured by Novartis Pharma AG, Basle, Switzerland, for Medtronic, Inc., Minneapolis, Minnesota 55432-5604 USA.



Brief DisclosureSynchroMed® II Drug Infusion System Brief Summary:

Product technical manual and the appropriate drug labeling must be reviewed prior to use for detailed disclosure.

Indications: Chronic intraspinal (epidural and intrathecal) infusion of preservative-free morphine sulfate sterile solution (and preservative-free morphinehydrochloride outside of the United States) in the treatment of chronic intractable pain, and chronic intrathecal infusion of Lioresal® Intrathecal (baclofeninjection) for the management of severe spasticity; chronic intravascular infusion of floxuridine (FUDR) or methotrexate for the treatment of primary ormetastatic cancer.

Contraindications: When infection is present; when the pump cannot be implanted 2.5 cm or less from the surface of the skin; when body size is not suf-ficient to accept pump bulk and weight; when contraindications exist relating to the drug.

Warnings: Comply with all product instructions for initial preparation and filling, implantation, programming, refilling, and injecting into the catheteraccess port (CAP) of the pump. Failure to comply with all instructions can lead to technical errors or improper use of implanted infusion pumps and resultin additional surgical procedures, a return of underlying symptoms, or a clinically significant or fatal drug under- or overdose. Refer to the appropriatedrug labeling for specific under- or overdose symptoms and methods of management. Avoid using short wave (RF) diathermy within 30 cm of the pumpor catheter. Diathermy may produce significant temperature rises in the area of the pump and continue to heat the tissue in a localized area. If overheat-ed, the pump may over infuse the drug, potentially causing a drug overdose. Effects of other types of diathermy (microwave, ultrasonic, etc.) on the pumpare unknown. An inflammatory mass that can result in serious neurological impairment, including paralysis, may occur at the tip of the implanted catheter.Clinicians should monitor patients on intraspinal opioid therapy carefully for any new neurological signs or symptoms. For intraspinal therapy, use only pre-servative-free sterile solution indicated for intraspinal use. Use only Medtronic components indicated for use with this system. Failure to firmly secure con-nections can allow drug or cerebrospinal fluid (CSF) leakage into tissue and result in tissue damage or inadequate therapy. A postoperative priming bolusshould not be programmed if the pump is a replacement and the catheter has not been aspirated.

Refer to appropriate drug labeling for indications, contraindications, warnings, precautions, dosage and administration information, and screeningprocedures. Physicians must be familiar with the drug stability information in the technical manual and must understand the dose relationship todrug concentration and pump flow rate before prescribing pump infusion. Implantation and ongoing system management must be performed byindividuals trained in the operation and handling of the infusion system.

Inform patients of the signs and symptoms of drug under- or overdose, appropriate drug warnings and precautions regarding drug interactions, potentialside effects, and signs and symptoms that require medical attention. Instruct patients to notify their clinician of travel plans, to return for refills at pre-scribed times, avoid activities such as strenuous exercise or contact sports that jar, impact, twist, or stretch the body, to always carry their Medtronicdevice identification card, to avoid manipulating the pump through the skin, and to notify healthcare professionals of the implanted pump before medicaltests/procedures. Patients must consult their physician before engaging in activities involving pressure or temperature changes (e.g., scuba diving, saunas,hot tubs, hyperbaric chambers, flights, skydiving, etc.) Inform patients that pump has an Elective Replacement Indicator (ERI) that sounds when the pumpis nearing its end of service. When the alarm sounds, patients must contact their doctor to schedule pump replacement.

Precautions: The pump is ethylene oxide sterilized. Do not use if the product or package is damaged, the sterile seal is broken, or the “Use By” date hasexpired. Do not reuse or resterilize the pump; it is intended for “single use only.” Do not expose the pump to temperatures above 43°C or below 5°C.Consider use of peri- and post-operative antibiotics for pump implantation, for any subsequent surgical procedure, or if infection is present. For patientsprone to CSF leaks, clinicians should consider special procedures, such as a blood patch. Follow instructions for emptying and filling the pump during areplacement or revisions that require removal of the pump from the pocket. Explant the pump postmortem if incineration is planned (to avoid explosion),or if local environmental regulations mandate removal. Return explanted devices to Medtronic for analysis and safe disposal. Do not implant a pumpdropped onto a hard surface or showing signs of damage. Implant the pump less than 2.5 cm from the surface of the skin. Ensure pump ports will be easyto access after implant, that the catheter is not kinked and secured well away from pump ports before suturing. Keep the implant site clean, dry, and pro-tected from pressure or irritation. If therapy is discontinued for an extended period of time, fill the reservoir with preservative-free saline in intraspinalapplications or appropriate heparinized solution (if not contraindicated) in vascular applications.

The magnetic field or telemetry signals produced by the programmer may cause sensing problems and inappropriate device responses with animplantable pacemaker and/or defibrillator. Electromagnetic interference (EMI) is an energy field generated by equipment found in the home, work, med-ical, or public environments. Most EMI normally encountered will not affect the operation of the pump. Exceptions include: injury resulting from heating ofthe pump which can damage surrounding tissue (diathermy, MRI), system damage which can require surgical replacement or result in loss/change insymptom control (defibrillation, electrocautery, high-output ultrasonics, radiation therapy), and operational changes to the pump causing the motor tostop, loss of therapy, return of underlying symptoms, and require confirmation of pump function (diathermy, high magnetic field devices,hyperbaric/hypobaric conditions, magnetic resonance imaging (MRI)). MRI will temporarily stop the pump motor’s rotor due to the magnetic field of theMRI scanner and suspend drug infusion during MRI exposure which will cause the pump alarm to sound. The pump should resume normal operation upontermination of MRI exposure. Prior to MRI, the physician should determine if the patient can safely be deprived of drug delivery. If not, alternative deliverymethods for the drug can be utilized during the MRI scan. Prior to scheduling an MRI scan and upon its completion, pump status should be confirmed.

Adverse Events: Include, but are not limited to, cessation of therapy due to end of device service life or component failure, change in flow performancedue to component failure, inability to program the device due to programmer failure, CAP component failure; inaccessible refill port due to inverted pump,pocket seroma, hematoma, erosion, infection, post-lumbar puncture (spinal headache), CSF leak, radiculitis, arachnoiditis, bleeding, spinal cord damage,meningitis (intrathecal applications), anesthesia complications, damage to the pump, catheter and catheter access system due to improper handling andfilling before, during, or after implantation; change in catheter performance due to catheter kinking, disconnection, leakage, breakage, occlusion, dislodge-ment, migration, or catheter fibrosis; body rejection phenomena, surgical replacement of pump or catheter due to complications; local and systemic drugtoxicity and related side effects, complications due to use of unapproved drugs and/or not using drugs in accordance with drug labeling, or inflammatorymass at the tip of the catheter in patients receiving intraspinal morphine or other opioid drugs.

Caution: Federal law (U.S.A.) restricts this device to sale by or on the order of a physician.



Index Adverse Effects of Lioresal Intrathecal .................................................................................22

Antispasmodics .......................................................................................................................................13

Ashworth Scale .......................................................................................................................................16

Ashworth Scale, Modified ...............................................................................................................17

Assessment (Patient) for ITB™ Therapy......................................................................................................................7, 11for Screening Test.........................................................................................................................16

Complications (Lioresal Intrathecal) ..............................................................................22, 29

Contraindications ..................................................................................................................................10Disclosure....................................................................................................................................................47

Dosing.............................................................................................................................................................19dose reductions ...............................................................................................................................21

flex dosing...........................................................................................................................................21

initial dosing.....................................................................................................................................19

maintenance dosing ...................................................................................................................20

screening test dosing ............................................................................................................8, 14

Drug – See Lioresal Intrathecal

Drug Holidays ..........................................................................................................................................22

Emergency Procedures

overdose ...............................................................................................................................................27

underdose/withdrawal.............................................................................................................24

Lioresal Intrathecal (Baclofen injection)

adverse effects.................................................................................................................................22

concentrations available .............................................................................................................6

contraindications...........................................................................................................................10

description............................................................................................................................................4

dilution ....................................................................................................................................................6

dosing (see Dosing as a separate topic)

indications ............................................................................................................................................4

labeling (drug package insert)............................................................................................38



overdose symptoms and treatment ................................................................................25

pharmacodynamics.......................................................................................................................4

pharmocokinetics............................................................................................................................5

safety & efficacy ...............................................................................................................................7

stability in pump.............................................................................................................................6

storage requirements ...................................................................................................................6

titration (after implant) ...........................................................................................................19

withdrawal.........................................................................................................................................23

Overdose .......................................................................................................................................................25

emergency procedure................................................................................................................27

symptoms ...........................................................................................................................................25

treatment ............................................................................................................................................27

Patient Assessment

for ITB™ Therapy......................................................................................................................7, 11

for screening test...........................................................................................................................16

Patient Education

screening test ...........................................................................................................................12, 35

Patient Management (ongoing)...................................................................................................19

dose reduction .................................................................................................................................21

flex dosing...........................................................................................................................................21

initial dose after implant.........................................................................................................19

maintenance period....................................................................................................................20

overdose ..............................................................................................................................................25

filtration period (first 60 days)...........................................................................................19

tolerance ..............................................................................................................................................22

withdrawal.........................................................................................................................................23

Patient Selection........................................................................................................................................7

algorithm...............................................................................................................................................8

assessment..............................................................................................................................7, 11, 16



contraindications...........................................................................................................................10

functional assessment ...............................................................................................................16

goal .............................................................................................................................................................7

goal setting (patient) ...................................................................................................................11

precautions in special populations..................................................................................10

Pharmacodynamics................................................................................................................................4

Pharmacokinetics.....................................................................................................................................5

Precautions in Special Populations ..........................................................................................10

References ...................................................................................................................................................30

Screening Test..........................................................................................................................................12

assessing spasticity during....................................................................................................16

dosing.....................................................................................................................................................14

key considerations ........................................................................................................................13

measurement tools.......................................................................................................................16

oral medication........................................................................................................................13, 14

patient education ..................................................................................................................12, 35

preparation for ................................................................................................................................12

procedure.............................................................................................................................................14

withdrawal from oral antispasmodics..........................................................................13

Spasm Scale................................................................................................................................................18

Spasticity.........................................................................................................................................................1

assessment ............................................................................................................................................2

definition................................................................................................................................................1

management........................................................................................................................................3

manifestation and impact ........................................................................................................2

measuring...........................................................................................................................................16

pathophysiology.................................................................................................................................1

symptoms..............................................................................................................................................2

Tolerance......................................................................................................................................................22



Trial – see Screening Test

Withdrawal

from oral antispasmodics .......................................................................................................13

from Lioresal Intrathecal ........................................................................................................23



United States of AmericaMedtronic Neurological710 Medtronic Parkway Minneapolis, MN 55432-5604USAInternet: www.medtronic.comTel. 763-505-5000Fax 763-505-1000Toll-free 1-800-328-0810

EuropeMedtronic Europe SàrlRoute du Molliau 31Case Postale1131 TolochenazSwitzerlandInternet: www.medtronic.co.ukTel. 41-21-802-7000Fax 41-21-802-7900

Asia-PacificMedtronic International, Ltd.Suite 1602 16/FManulife PlazaThe Lee Gardens, 33 Hysan AvenueCauseway BayHong KongTel. 852-2891-4456Fax 852-2891-6830

AustraliaMedtronic Australasia Pty. Ltd.Unit 4/446 Victoria RoadGladesville NSW 2111AustraliaTel. 02-9879-5999Fax 02-9879-5100Toll-free 1-800-251-760

CanadaMedtronic of Canada Ltd.6733 Kitimat RoadMississauga, Ontario L5N 1W3CanadaTel. 1-905-826-6020Fax 1-905-826-6620

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Spasticity management CRG

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