Spasticity management CRG

SYNCHROMED II 速

Programmable Infusion System Clinical Reference Guide

Intrathecal Baclofen for the Management of Severe Spasticity April, 2004

Key Contacts MEDTRONIC REPRESENTATIVES

Name:________________________________________________________________ Phone: _____________________________ Pager: _____________________________ Name:________________________________________________________________ Phone: _____________________________ Pager: _____________________________ Other Contacts: Name:________________________________________________________________ Phone: _____________________________ Pager: _____________________________ Name:________________________________________________________________ Phone: _____________________________ Pager: _____________________________ IN THE U.S. Medtronic offices are open from 8:00 a.m. to 5 p.m. Central Standard Time Monday through 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 each country. Contact information for country offices is provided on the back of this module.

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Table of Contents Spasticity: Assessment and Overall Management.................................................................................................................1 Spasticity Defined .......................................................................................................................................................................1 Pathophysiology ............................................................................................................................................................................1 Manifestations and Impact of Spasticity..................................................................................................................2 Assessment of Spasticity.......................................................................................................................................................2 Spasticity Management..........................................................................................................................................................3 Lioresal速 Intrathecal ...........................................................................................................................................................4 Description.......................................................................................................................................................................................4 Indications........................................................................................................................................................................................4 Pharmacodynamics...................................................................................................................................................................4 Pharmacokinetics........................................................................................................................................................................5 Available Concentrations.......................................................................................................................................................6 Storage Requirements .............................................................................................................................................................6 Stability/Compatibility in Pump ....................................................................................................................................6 Demonstrated Safety and Efficacy ................................................................................................................................7 Patient Selection and Screening...................................................................................................................................7 Goal ........................................................................................................................................................................................................7 Review Patient Selection Criteria ...................................................................................................................................7 Select the Patient........................................................................................................................................................................11 Establish Objectives for Treatment..............................................................................................................................11 Provide Patient and Caregiver Education ...............................................................................................................12 Prepare for Screening Test ................................................................................................................................................12 Conduct Screening Test.......................................................................................................................................................14 Measurement Tools .................................................................................................................................................................16 Ongoing Patient Management.....................................................................................................................................19 Dosing and Titration Guidelines...................................................................................................................................19 Tolerance.........................................................................................................................................................................................22 Potential Adverse Effects .............................................................................................................................................22 Adverse Reaction to Lioresal Intrathecal ...............................................................................................................22 Withdrawal Symptoms and Treatment ..................................................................................................................23 Overdose Symptoms and Treatment.........................................................................................................................25 Potential Adverse Events .............................................................................................................................................28 System-Related ..........................................................................................................................................................................28 Catheter-Related........................................................................................................................................................................28 Procedure-Related....................................................................................................................................................................29 Other ..................................................................................................................................................................................................29 Drug-Related................................................................................................................................................................................29 References...........................................................................................................................................................................30 Appendix..............................................................................................................................................................................32 Spinal 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 Brief Disclosure .................................................................................................................................................................47 Index ..................................................................................................................................................................................48

Clinical Reference Guide

i

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Spasticity: Assessment and Overall Management Spasticity Defined

Although the pathophysiology of spasticity is not completely understood, it 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 the stretch reflex, as one component of the upper motor neuron syndrome.”1 The velocity-dependent nature of spasticity distinguishes it from other forms 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 develops when 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 (gammaaminobutyric acid) from interneurons, and thus inhibitory impulses.

GABA is an inhibitory neurotransmitter that modulates excitatory input at the alpha motor neuron.4 For a comparison of spinal-origin and cerebral-origin spasticity, please see the Spinal-Origin vs. Cerebral-Origin Spasticity Comparison Chart in the Appendix of this module.

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

Clinical Reference Guide

Infection (including urinary-tract infections) Pain (e.g., from kidney stones) Other noxious stimuli (e.g., from ingrown nails or overly-restrictive clothing) 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 1

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Manifestations and Impact of Spasticity

Intrathecal Baclofen for the Management of Severe Spasticity

Symptoms and physiologic impairments associated with spasticity can include the following: ■ Increased muscle tone ■ Reduced range of motion about a joint, which can lead to fixed contractures ■ ■ ■ ■ ■

Poor motor control Muscle weakness Fatigue Pain (typically through increased muscle spasms) Excessive metabolic requirements

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

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

In some circumstances the increased muscle tone of spasticity may provide some benefits to individual patients. For example, patients with long-standing spasticity may have learned to rely on their excess tone when transferring. Other benefits may include: ■ ■ ■

Assessment of Spasticity

Maintenance of muscle mass Maintenance of posture Increased venous blood return, which may help prevent the formation of deep vein thromboses

Details on the assessment of spasticity and associated symptoms (e.g., 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 ■ ■ ■ ■ ■ ■

Clinical Reference Guide

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)

2

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

Spasticity Management

Functional Independence Measure (FIM) Canadian Occupational Performance Measure (COPM) SF-36 and SF-12 Sickness Impact Profile (SIP)

Management of spasticity is most successful when it is based on goals that are: ■ Specific ■ Realistic ■ Reflective of the spasticity’s impact on function, comfort, and caregiving ■

Set jointly by the patient, family, other caregivers, and multidisciplinary health care team

■

Documented prior to the initiation of treatment For more on goal setting, refer to the Establish Objectives for Treatment section in this module. As shown in Figure 1, effective management of spasticity 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 1 Spectrum of Care for Management of Spasticity

Clinical Reference Guide

3

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Lioresal® Intrathecal Description

Baclofen is a drug that acts as a GABA agonist. GABAB receptors, located in the superficial layers of the spinal cord, are sensitive to baclofen.

“Therefore administration of baclofen into the intrathecal space requires that 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 and antispastic solution free of antioxidants, preservatives or other potentially neurotoxic additives, and is indicated only for intrathecal administration.8 Lioresal Intrathecal is the only commercially available baclofen product with clinical studies demonstrating its safe use for intrathecal administration. In addition, it is the only baclofen injection product approved for use in the SynchroMed II Infusion System.

While the precise mechanism of action is not fully understood, it is known that baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level. This is thought to decrease excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal 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 10 times higher than that achieved with oral baclofen.4 Although oral baclofen acts at the spinal level, the amount of drug that penetrates the blood-brain barrier is often not sufficient to provide adequate effect and the side effects may be intolerable.

Indications

Lioresal Intrathecal is indicated for use in the management of severe spasticity. Its intended use is by either a single bolus test dose (via spinal catheter or lumbar puncture) or continuous infusion via an implantable pump approved by the U.S. Food and Drug Administration (FDA) specifically for the administration of Lioresal Intrathecal into the intrathecal space.8

Pharmacodynamics

Refer to Table 1 for a pharmacodynamics overview of Lioresal Intrathecal.

For additional information on Lioresal Intrathecal, see the Drug Package Insert in the Appendix of this module.

Clinical Reference Guide

4

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Table 1 Pharmacodynamics of Lioresal Intrathecal 8

Delivery Method Intrathecal Bolus

Intrathecal Baclofen for the Management of Severe Spasticity

Onset, Peak Response and Duration of Action ■

■

■

Continuous Infusion

■

■ ■

Pharmacokinetics

Table 2 Lioresal Intrathecal Clearance Data 8

The onset of action is generally 30 to 60 minutes after an intrathecal bolus.

Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours.

Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms.

Antispastic action is first seen at six to eight hours after initiation of continuous infusion.

Maximum activity is observed in 24 to 48 hours.

The onset, peak response, and duration of action are similar for pediatric and adult patients.¸

CSF clearance of Lioresal Intrathecal calculated from the intrathecal bolus or continuous infusion studies approximates CSF turnover. This suggests that elimination is by bulk-flow removal of CSF.8 Refer to Table 2 for a summary of Lioresal Intrathecal clearance data.

Method Intrathecal Bolus

Onset, Peak Response and Duration of Action ■

■

Continuous Infusion

■

■

After bolus lumbar injection of 50 to 100 micrograms of baclofen injection in seven patients, the average CSF elimination half-life was approximately 1.5 hours over the first four hours.

The average CSF clearance was approximately 30 mL/hr.

In a study involving ten patients on intrathecal baclofen, the mean CSF clearance for baclofen injection was approximately 30 mL/hour. Concurrent plasma concentrations of baclofen during intrathecal administration were low (0–5 nanograms/mL).

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

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

Clinical Reference Guide

5

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Available Concentrations

Intrathecal Baclofen for the Management of Severe Spasticity

FOR SCREENING TEST Lioresal Intrathecal is available in the United States in a single use 1 mL ampule for screening tests in the concentration of 50 micrograms/mL. FOR REFILL In the United States, refill kits containing Lioresal Intrathecal are available in single-use ampules in concentrations of 500 and 2000 micrograms/mL. If dilution is required, use sterile, preservative-free 0.9% pharmacy-grade sodium chloride for injection. The refill kits also contain sterile supplies for drug preparation and pump refill. Customers outside the United States may be able to purchase Lioresal Intrathecal from Novartis. When purchased from Novartis, the refill kit components are not included.

Storage Requirements

Lioresal Intrathecal does not require refrigeration.

■ 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/ Compatibility in Pump

The Medtronic drug stability and material compatibility testing conducted with Lioresal Intrathecal and the SynchroMed II Infusion 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 implantable SynchroMed II Infusion System. Stability is defined as ≥90% of initial concentration.

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 demonstrated to be safe and effective for use in the SynchroMed II Infusion System. The use of pharmaceutical products that are not specifically labeled for intrathecal administration via continuous infusion may cause damage to components of the infusion system. This could potentially lead to diminished device performance, reduced therapy efficacy, or could jeopardize patient safety. Seemingly similar products may contain preservatives, antimicrobials or antioxidants or exhibit chemical properties that are not compatible with the SynchroMed II Infusion System.

Clinical Reference Guide

6

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Demonstrated Safety and Efficacy

Intrathecal Baclofen for the Management of Severe Spasticity

Since early reports of clinical efficacy with Lioresal Intrathecal, multiple clinical studies have been conducted. Collectively, they have demonstrated: ■

Clinically significant reductions in severe spasticity of cerebral origin and spinal origin.9,10

■

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

■

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

Patient Selection and Screening Goal

The overall goal for patient selection is to choose those patients most likely 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

Clinical Reference Guide

■

Review patient selection criteria.

■

Select the patient.

■

Establish objectives for treatment.

■

Provide patient and caregiver education.

■

Prepare for screening test.

■

Conduct screening test.

The first key task involves reviewing indications and contraindications for inclusion.

Candidates for ITB Therapy (Figure 2) are patients who have: ■

A diagnosis of severe spasticity

■

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

■

Demonstrated positive response to a single bolus dose of Lioresal Intrathecal during the screening test

■

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

7

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Figure 2 Patient Selection Algorithm

Intrathecal Baclofen for the Management of Severe Spasticity

Patient Selection Algorithm: ITBTM Therapy for the Management of Severe Spasticity of Cerebral and Spinal Origin See the accompanying Lioresal® Intrathecal (baclofen injection) drug package insert for full prescribing information.

Step 1: INCLUSION CRITERIA FOR ITB THERAPY (INTRATHECAL BACLOFEN THERAPY) 1. Spasticity due to spinal cord injury, multiple sclerosis, cerebral palsy, stroke or brain injury (1 year post trauma).

Step 2: EXCLUSION CRITERIA FOR ITB THERAPY 1. Infection is present at time of screening or implant.

No 2. Patient has a history of allergy (hypersensitivity) to oral baclofen.

Yes

No

2. Spasticity is severe.

CONTINUE TO STEP 3

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

Step 3: GENERAL CLINICAL CONSIDERATIONS

Yes

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

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

Case-related considerations do not support decision to proceed with screening test.

Yes 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.

STOP

Step 4: TEST SCREENING FLOW CHART

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

Day 1 No response Bolus: 50mcg + response

Implant

Yes

Day 2 No response Bolus: 75mcg + response

CONTINUE TO STEP 2 Implant

Day 3 No response Bolus: 100mcg + response Implant

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

Clinical Reference Guide

8

Patient ineligible for implant.

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Figure 2 (cont.)

Patient Selection Algorithm

Intrathecal Baclofen for the Management of Severe Spasticity

Step 3: GENERAL CLINICAL CONSIDERATIONS 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.

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.

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.

Return to Step 3 (reverse side) 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.

Clinical Reference Guide

9

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

PRECAUTIONS IN SPECIAL POPULATIONS Lioresal Intrathecal should be used with caution in patients who need spasticity to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain increased function and care. Refer to Table 3 for other precautions in special patient populations. Refer to the Drug Package Insert in the Appendix of this module for additional prescribing information.

Table 3 Precautions in Special Patient Populations 8

Condition Autonomic Dysreflexia

Precautions ■

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

■

The presence of nociceptive stimuli or abrupt baclofen withdrawal may cause an autonomic dysreflexic episode.

Impaired Renal Function

■

Because oral baclofen is primarily excreted unchanged by the kidneys, Lioresal Intrathecal should be given with caution in patients with impaired renal function and it may be necessary to reduce the dosage.

Psychotic Disorders, Schizophrenia, or Confusional States

■

Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with Lioresal 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 no adequate and well-controlled studies in pregnant women for intrathecal baclofen. Lioresal Intrathecal should be used during pregnancy only if the potential benefit justifies the potential 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 not known whether detectable levels of drug are present in breast milk of nursing mothers receiving Lioresal Intrathecal; therefore, use only if the potential benefit justifies the potential risks to the infant.

Pediatric Use

■

Children should be of sufficient body mass to accommodate an implantable programmable pump.

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

Clinical Reference Guide

10

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Select the Patient

Intrathecal Baclofen for the Management of Severe Spasticity

Patient assessment is an essential step prior to selecting candidates for 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 may diagnose severe spasticity, and the physical therapist may determine that some spasticity is beneficial for transfers. Reducing tone completely may make the patient less functional. A team that works together provides optimal 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 assessment as 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 Objectives for Treatment

Clinical Reference Guide

■

Establish realistic goals with patient, family, caregivers, and an interdisciplinary spasticity management team.

■

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

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

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

11

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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 and Caregiver Education

Patient education is critical to managing patient expectations and the long-term success of ITB Therapy. Education begins at the initial assessment and continues throughout all phases of the therapy. The Patient Education Checklist for Screening in the Appendix of this module provides a detailed checklist of key patient education topics. The patient and caregiver need to understand their commitment to ITB Therapy. For example, they must keep scheduled refill appointments, report unusual or unexpected symptoms, etc.

Prepare for Screening Test

OBJECTIVE

Clinical Reference Guide

The objective of the screening test is to assess patient response to a bolus test dose of Lioresal Intrathecal and determine eligibility for long-term therapy. A bolus dose of Lioresal Intrathecal is delivered by lumbar puncture or spinal catheter, and the patient’s response to the bolus dose is evaluated. Patients with a positive clinical response may be considered candidates for receiving an implant. Patients who do not respond to a 100 microgram bolus or less are not considered candidates for ITB Therapy.

An acceptable response should be determined for each patient in advance of the screening test.

12

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

KEY CONSIDERATIONS FOR THE SCREENING TEST The screening test must be conducted in a medically supervised and adequately equipped environment with immediate access to resuscitative equipment. 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 screening test, refer to the Patient Education Checklist for Screening in the Appendix 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 antispasmodic medications. Some physicians only hold the daily dose on the day of screening. Refer to the section on Withdrawal from Oral Antispasmodics 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 as a result of the bolus injection. Following implant, the dose will be continuously administered over a 24-hour period and titrated to meet individual 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 be made to discontinue concomitant oral antispasmodic medications. This should be done to avoid the risk of overdose or adverse drug interactions with Lioresal Intrathecal.

Reduction and discontinuation of oral antispasmodics should be done slowly and with careful monitoring by the physician. Abrupt or largescale reductions in dose should be avoided.

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

Clinical Reference Guide

13

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

If possible, develop a plan with a clinical pharmacist to slowly wean patients off oral antispasmodics. The plan should include consideration of the 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 hallucinations. 8 Carefully consider the withdrawal symptoms of other oral medications, including combined effects. Consult the prescribing information for all current medications.

If, for safety reasons or patient comfort, the oral medications cannot be withdrawn prior to screening, gradually taper the medications postimplant, while increasing Lioresal Intrathecal to a therapeutic dose.

Conduct Screening Test

Patients should be closely monitored in a fully equipped and staffed environment throughout the entire screening test procedure. An apnea monitor or a pulse oximeter may be used. Resuscitative equipment should be readily available.

NOTE: Special attention must be given to recognizing the signs and symptoms of overdose, especially during the Screening Test. For specific information on management of overdose, see the Overdose Symptoms and Treatment section of this module.

Figure 2 contains an algorithm, which outlines the screening test procedure.

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

Clinical Reference Guide

14

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Table 4 Screening Test Dose and Drug Volume

Intrathecal Baclofen for the Management of Severe Spasticity

Screening Dose

50 micrograms/mL Amplue/s

25 micrograms

0.5 mL

50 micrograms

1.0 mL

75 micrograms

1.5 mL

100 micrograms

2.0 mL

NOTE: The recommended concentration for the screening test is 50 micrograms/mL. If a lower concentration of Lioresal Intrathecal is used at 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 with multiple sclerosis), adjust subsequent doses accordingly. Screening doses greater than 50 micrograms will require the use of 2 ampules.

2. Evaluate patient’s spasticity and/or spasms prior to administering a bolus dose of Lioresal Intrathecal. Ideally, the same evaluator should be used to assess patient response before, during, and after the screening test to eliminate consistency issues between evaluators.

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

■

The onset of action of Lioresal Intrathecal is 30 to 60 minutes after delivery of the intrathecal bolus.

■

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

■

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

■

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

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

Clinical Reference Guide

15

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

5. If the clinical response is less than desired, a second bolus injection of 75 micrograms (1.5 mL of the 50 micrograms/mL solution) may be administered NO LESS THAN 24 hours after the first bolus. If the initial dose was 25 micrograms, adjust the second dose accordingly.

■

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

6. If the clinical response is again less than desired, a third bolus injection 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 not respond to a 100 micrograms bolus of Lioresal Intrathecal should not be considered candidates for ITB Therapy.

■

Monitor the patient for an interval of 4–8 hours and observe for response. Continue to monitor until patient’s spasticity begins to return 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 Procedures module of this guide for information related to pump implant including Pre-operative Patient Education.

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

Measurement Tools

Spasticity and related symptoms can be measured in several ways, 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 various muscle groups. These scales provide a means for measuring resistance to passive involuntary movement that the examiner objectively rates when moving a limb. For a sample evaluation form, refer to the Lioresal Intrathecal Screening Test Assessment Form in the Appendix of this module.

Clinical Reference Guide

16

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

The Ashworth Scale was used in Lioresal Intrathecal clinical trials to assess patient response. In clinical trials, a positive response to the screening test was defined as a 2-point drop in the average lower extremity Ashworth scores in spasticity of spinal origin and a 1-point drop in spasticity of cerebral origin. An excessive loss of tone during the screening test is not considered 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, knee flexion and extension, and ankle dorsiflexion. An average score for only the lower extremities should be calculated. The upper extremities should also be assessed but are not included in the average score. There is not always a reduction in upper extremity spasticity during the screening test, but there may be an effect once the patient receives ITB Therapy with an implanted pump, depending on the catheter tip location.20 Table 5 Ashworth Scale and Modified Ashworth Scale21

Clinical Reference Guide

S

Ashworth Scale

Score

Criteria

Modified Ashworth Scale Score

Criteria

1

No increase in tone.

0

No increase in tone.

2

Slight increase in tone, giving a “catch” when moved in flexion or extension.

1

Slight increase in muscle tone, manifested by a catch and release, or by minimal resistance at the end of the range of motion (ROM) when the affected parts(s) is moved into flexion or extension.

3

More marked increase in tone but affected parts(s) easily flexed.

1+

Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM.

4

Considerable increase in tone; passive movement difficult.

2

More marked increase in muscle tone through most of the ROM, but the affected part(s) is easily moved.

5

Affected parts(s) rigid in flexion or extension.

3

Considerable increase in muscle tone, passive movement is difficult.

4

Affected part(s) is rigid in flexion or extension.

17

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

Table 6 Spasm Scale6

Spasm Scale 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

PASSIVE QUANTITATIVE TESTS The clinician manually or mechanically manipulates the patient’s limbs to assess 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 if spasticity is interfering with voluntary movement. Gait analysis and ergometers can measure direct interference with movement. Indirect interference with movement is measured by observing everyday movements and how they affect the spasticity or spasms in other muscle groups.

Clinical Reference Guide

18

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Ongoing Patient Management Dosing and Titration Guidelines

INITIAL DOSE The initial dosing recommendations are the same for patients with cerebral and spinal origin spasticity. A concentration of 500 micrograms/mL is recommended for use at initial implant to allow for delivering a dose as low as 24 micrograms/day. No dose increases should be given in the first 24 hours (i.e., until a steady state is achieved). Table 7 describes how the starting dose is determined based on the duration of effect obtained from the screening test dose.

Table 7 Starting Drug Dose at Implant

Screen Dose Duration of Effect

Initial Dose At Implant

Duration of Delivery

Less than 8 hrs

Double the amount of the effective Continuous over 24 hrs screening dose

Greater than 8 hrs

Same as the effective screening dose

Continuous over 24 hrs

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

■

Clinical Reference Guide

Monitor patient for side effects, signs of overdose, and underdose/withdrawal.

19

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Table 8 Post-Implant Dosing Guidelines8

Intrathecal Baclofen for the Management of Severe Spasticity

Spinal Origin

Cerebral Origin

Pediatric (under 12)

TITRATION Increase slowly by 10-30% increments no more than once every 24 hours until desired clinical effect is achieved.

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

Maximum effect seen in 24-48 hours.

Increase slowly by 5-15% no more than once every 24 hours until desired clinical effect is achieved.

Increase slowly by 5-15% no more than once every 24 hours until desired effect is achieved.

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

Maximum effect seen in 24-48 hours.

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

Increase slowly by 5-20% no more than once every 24 hours.

Dosing ranges in clinical studies: Range: 22-1400 micrograms/day Range for most patients: 90-703 micrograms/day

Increase slowly by 5-20% no more than once every 24 hours.

Dosing ranges in clinical studies: Range: 24-1199 micrograms/day Pediatric patients over 12 years: same as adults.

Maximum effect seen in 24-48 hours.

MAINTENANCE Increase slowly by 10-40% increments no more than once every 24 hours.

Dosing ranges in clinical studies: Range: 12-2003 micrograms/day Range for most patients: 300-800 micrograms/day

Note: Additional clinical studies have shown that dosage requirements for children and adolescents do not seem to be different from that of adult patients. Average daily doses at 3 months after pump implantation were 153.1, 179.6, and 142.8 micrograms/day for ages <12, 12-15, and â&#x2030;Ľ 16, respectively.12

MAINTENANCE PERIOD The maintenance period begins 60 days after implantation. The goal of the maintenance period dosing is to maintain muscle tone as close to normal as possible, and to reduce the frequency and severity of spasms without inducing intolerable side effects. Depending on the individual response and goals of each patient, dose adjustments may continue for 6 months or more. See Table 8 for a comparison of dosing guidelines.

Clinical Reference Guide

20

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Titrate the dose for each patient based on the patient’s specific goals and needs, but always use the lowest dose required to achieve an optimal response. During the maintenance period, it is important to continue education for the patient and caregiver to ensure understanding of all patient 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 side effects, reduce the drug dose by 10–20% each day until the side effects are diminished or gone. Reduce the dose slowly to minimize the possibility of baclofen withdrawal.

Flex Dosing Spasticity can often be managed more effectively by programming the pump to deliver medication at different rates throughout the day. For example:

Clinical Reference Guide

■

Some patients may want less tone early in the morning so dressing is easier, but need more tone during the day for ambulating and transferring.

■

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

21

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Tolerance

Intrathecal Baclofen for the Management of Severe Spasticity

Some patients may become refractory to increasing doses of Lioresal Intrathecal. Sufficient experience is not available to make firm recommendations for management of tolerance; however, tolerance has been treated on occasion with a “drug holiday” using the following methods.8 ■

Gradually reduce Lioresal Intrathecal over a 2–4 week period and switch to an alternative method of spasticity management.

Intrathecal baclofen reduction should be carefully managed to reduce the risk of withdrawal. See the Withdrawal Symptoms and Treatment section of this module for more information.

■

After the “drug holiday”, restart Lioresal Intrathecal at the initial continuous dose.

Potential Adverse Effects In pre- and post-market clinical trials with Lioresal Intrathecal, the following adverse effects have been reported:

!

WARNING Patients must consult their physician before engaging in activities involving pressure or temperature changes (e.g., scuba diving, saunas, hot tubs, hyperbaric chambers, airline flights, skydiving, non-pressurized aircraft, etc.). Pressure and temperature changes can cause temporary underinfusion or overinfusion and result in a clinically significant underdose or overdose. Refer to the Flow Rate Accuracy section of the System Components module of this guide for more information regarding the effects of temperature and pressure on the SynchroMed II pump.

Adverse Reaction to Lioresal Intrathecal

Patients vary in their sensitivity to Lioresal Intrathecal. The most commonly observed side effects associated with Lioresal Intrathecal are: ■ Hypotonia ■ Somnolence ■ Nausea/vomiting ■ Headache ■ Dizziness A more detailed list of side effects, cautions, and warnings associated with Lioresal Intrathecal can be found in the Drug Package Insert in the Appendix of this module.

Clinical Reference Guide

22

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Withdrawal Symptoms and Treatment

Intrathecal Baclofen for the Management of Severe Spasticity

SYMPTOMS OF WITHDRAWAL Baclofen underdose usually precedes signs of withdrawal. Early 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 may resemble 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 to the Managing Complications section of the Therapy Maintenance module of this guide.

Clinical Reference Guide

23

April, 2004

Clinical Reference Guide

•

24

City: ______________________________

UC200303503 EN NP5676EN PN221500-101

State: ____________________________

Name: ______________________________ Phone: ____________________________

ITB Therapy Physician

Contact Information

All patients receiving ITB Therapy are potentially at risk. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, or infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, and other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. A rapid and accurate diagnosis is important in an emergency room or intensive care setting before initiating treatment in order to prevent the potentially life-threatening central nervous and systemic effects of intrathecal baclofen withdrawal.

Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has, in rare cases, resulted in a life-threatening syndrome that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that progressed to rhabdomyolysis, multiple organ-system failure, and death.

Refer to the drug manufacturer’s package insert for a complete list of indications, contraindications, warnings, precautions, adverse events, and dosage and administration information.

1 Coffey RJ, Edgar TS, Francisco GE, et al. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome. Arch Phys Med Rehabil: Vol. 83. June, 2002. pp735-41 Lioresal® is a registered trademark of Novartis Pharmaceuticals Corporation.

Report incident to Medtronic, Inc. In the U.S. call 1-800-328-0810.

In other world areas contact your Medtronic representative.

• high-dose oral* or enteral baclofen • restoration of intrathecal baclofen infusion • intravenous benzodiazepines by continuous or intermittent infusion, titrating the dosage until the desired therapeutic effect is achieved *Note: Oral baclofen should not be relied upon as the sole treatment for intrathecal baclofen withdrawal syndrome.

2. If an ITB Therapy physician is unavailable, consider instituting one or more of the following options, unless otherwise contraindicated:

1. Immediately contact a physician experienced in ITB Therapy, preferably the physician managing the therapy for the patient in question; follow the recommendations of this physician. This step is important even if the patient’s signs and symptoms seem mild.

If a patient receiving ITB™ Therapy (Intrathecal Baclofen Therapy) presents with the signs and symptoms suggestive of baclofen withdrawal (above), the following approach is consistent with that suggested by a panel of therapy-experienced clinicians convened to explore this issue:1

Initiate life-sustaining measures if indicated.

Suggested Treatment for Intrathecal Baclofen Underdose/Withdrawal

Baclofen withdrawal has been identified during post-approval use of Lioresal Intrathecal.

Because this reaction is reported spontaneously from a population of uncertain size, it is not possible to reliably estimate the frequency.

surgical repair, revision, or replacement of system components

system troubleshooting procedures to determine the cause of ITB Therapy interruption

•

Medtronic SynchroMed Infusion System

The SynchroMed Infusion System consists of an implantable programmable pump, intraspinal catheter and pump programmer. The pump is implanted in the lower abdomen and dispenses medication from the pump’s reservoir through the catheter to the intrathecal or epidural space. Some pumps are equipped with a catheter access port that bypasses the pump reservoir, permitting direct catheter access to the intrathecal or epidural space.

a pump refill procedure with the appropriate concentration of baclofen

•

radiologic examination of the pump and catheter system

•

Symptoms of Intrathecal Baclofen Withdrawal

High fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases has advanced to rhabdomyolysis, multiple organ system failure and death.

The condition may resemble autonomic dysreflexia, sepsis, malignant hyperthermia, and neuroleptic-malignant syndrome.

interrogation of the pump status using the Medtronic pump programmer

•

The physician experienced with ITB Therapy should expeditiously attempt device troubleshooting.

This may include, but is not limited to:

Pruritus, hypotension, paresthesias, fever, and altered mental state.

Symptoms of Underdose

EMERGENCY PROCEDURE

In the U.S. emergency technical support is available 24 hours/day for clinicians managing patients with Medtronic SynchroMed® Infusion System implants: 800-707-0933. In other world areas contact your Medtronic representative.

Lioresal Intrathecal (baclofen injection) Underdose/Withdrawal

®

EMERGENCY PROCEDURE FOR WITHDRAWAL

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

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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 be found in the Drug Package Insert in the Appendix of this module.

Overdose Symptoms and Treatment

SYMPTOMS OF BACLOFEN OVERDOSE Clinicians must be especially alert to the signs and symptoms of overdose, especially during the screening test, post-implant dose titration, and whenever ITB Therapy has been interrupted and reintroduced. Signs and symptoms 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: ■ ■ ■ ■ ■ ■ ■

Clinical Reference Guide

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.

25

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

More information about overdose symptoms can be found in the Drug Package Insert in the Appendix of this module. For information of possible causes of overdose refer to the Managing Complications section of the Therapy Maintenance module of this guide.

Clinical Reference Guide

26

April, 2004

Clinical Reference Guide ®

27

8637-40 8637-20 8627-18, 8627L-18* 8627-10, 8627L-10* 8626-18, 8626L-18* 8626-10, 8626L-10* 8618-18, 8618L-18* 8617-18, 8617L-18* 8617-10 8616-18 8616-10

Yes, funnel-shaped Yes, funnel-shaped Yes, screened Yes, screened No No Yes, not screened Yes, screened Yes, screened No No

Catheter Access Port?

40 mL 20 mL 18 mL 10 mL 18 mL 10 mL 18 mL 18 mL 10 mL 18 mL 10 mL

Intraspinal catheter

Suture Loop

Catheter access port

Lioresal® is a registered trademark of Novartis Pharmaceuticals Corporation.

Catheter access port

Models with catheter access ports

Intraspinal catheter

7.4 cm

3.7 cm

3.5 cm

Pump dimensions

7.0 cm

Pump dimensions

SynchroMed EL Pumps

Reservoir fill port

Intraspinal catheter

SynchroMed II Pumps

Reservoir Fill Port

Models without catheter access ports

Reservoir Size

UC200303503 EN NP5676EN PN221500-101

Name: ______________________________ Phone: ____________________________ City: ______________________________ State: ____________________________

ITB Therapy Physician

Contact Information

Equipment: • 22-gauge or smaller needle (1.5 in./3.8 cm or 2 in./5.1 cm) • 20 mL luer-lock syringe Insert needle into drug reservoir fill port and empty • antiseptic agent 1. Locate the pump (right or left abdomen) by palpation.

Pump diameter is approximately 3 in./7 cm.

The reservoir fill port is located in the CENTER of the pump.

2. Prepare injection site by cleansing area using an antiseptic agent; allow skin to dry.

3. Locate reservoir fill port and insert needle through skin. Enter the port’s septum until the needle touches the metal needle stop. If you encounter resistance during needle insertion, reassess placement. Do not force the needle; use of excessive force may damage the needle.

4. Withdraw fluid from reservoir using negative pressure. Empty reservoir until large air bubbles are apparent in syringe.

5. Maintain negative pressure while removing needle and attached syringe together from port septum and skin.

6. Record amount of fluid emptied from reservoir in patient chart.

Emergency Procedure to Empty the Pump Reservoir

*L=pump contains suture loops

SynchroMed II SynchroMed II SynchroMed EL SynchroMed EL SynchroMed EL SynchroMed EL SynchroMed SynchroMed SynchroMed SynchroMed SynchroMed

Model

Medtronic SynchroMed Pump Descriptions Pump Name

Refer to the drug manufacturer’s package insert for a complete list of indications, contraindications, warnings, precautions, adverse events, and dosage and administration information.

2 Müller-Schwefe G., Penn R.D. Physostigmine in the treatment of intrathecal baclofen overdose: report of three cases. J Neurosurg. August, 1989; 71:273-5.

Report incident to Medtronic, Inc. In the U.S. call 1-800-328-0810.

In other world areas contact your Medtronic representative.

Continue to monitor closely for symptom recurrence.

Notify patient’s ITB™ Therapy Physician (see right).

If not contraindicated, withdraw 30-40 mL CSF by lumbar puncture or through the catheter access port to reduce baclofen concentration in the CSF. For instructions on how to withdraw CSF through the catheter access port, please contact Medtronic Technical Services. In the U.S. call 1-800-707-0933.

In other world areas contact your Medtronic representative.

Administer physostigmine if not contraindicated.

Adult Dosage: 0.5 to 1.0 mg IM or IV @ slow controlled rate of not >1mg/min.

(May repeat every 10-30 min. if desired patient response is not obtained.)

Pediatric Dosage: 0.02 mg/kg IM or IV, not >0.5 mg/min. May repeat every 5-10 min. up to 2 mg max.

Empty pump reservoir to stop drug flow (see right).

Record amount withdrawn.

Maintain Airway/Breathing/Circulation.

Intubation and respiratory support may be necessary.

Suggested Treatment for Intrathecal Baclofen Overdose

The SynchroMed Infusion System consists of an implantable programmable pump, intraspinal catheter and pump programmer. The pump is implanted in the lower abdomen and dispenses medication from the pump’s reservoir through the catheter to the intrathecal or epidural space. Some pumps are equipped with a catheter access port that bypasses the pump reservoir, permitting direct catheter access to the intrathecal or epidural space.

Medtronic SynchroMed Infusion System

There is no specific antidote for treating overdoses of Lioresal Intrathecal. However, anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression.2

Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma.

EMERGENCY PROCEDURE Symptoms of Overdose

In the U.S. emergency technical support is available 24 hours/day for clinicians managing patients with Medtronic SynchroMed® Infusion System implants: 800-707-0933. In other world areas contact your Medtronic representative.

Lioresal Intrathecal (baclofen injection) Overdose

EMERGENCY PROCEDURE FOR OVERDOSE

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

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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:

SystemRelated

■ ■ ■ ■

CatheterRelated

Clinical Reference Guide

■

Cessation of theray due to end of device service life or component 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 Changes in catheter performance due to catheter kinking, catheter disconnection, catheter leakage, catheter breakage, complete or partial catheter occlusion, catheter dislodgement or migration, or catheter fibrosis or hygroma.

28

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

ProcedureRelated

■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Other

■ ■ ■ ■

DrugRelated

■ ■ ■ ■

Intrathecal Baclofen for the Management of Severe Spasticity

Inaccessible reservoir fill port or catheter access port due to pump 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 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”) Local 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 information on other drug-related adverse effects: Adverse Reaction to Lioresal Intrathecal, Withdrawal Symptoms and Treatment, and Overdose Symptoms and Treatment.

Clinical Reference Guide

29

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

References 1. Lance JW: Synopsis. In: Feldman RG, Young RR, Koella WP, eds.

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

2. Sanger TD, Delgado MR, Gaebler-Spira, D, et al. Classification and Definition of Disorders Causing Hypertonia in Childhood. Pediatrics.

2003;111(1):89-97.

3. Meythaler JM. Concept of spastic hypertonia. Phys Med Rehabil Clin N Am. 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 Innovative Approach for Controlling Spasticity. Rehab Nurs. 1993; 18(2): 105-113.

7. Guidelines for the Rehabilitation Team. Minneapolis, MN: Medtronic, Inc., 1998, UC9502736EN. 8. LIORESAL速 INTRATHECAL (baclofen injection) [package insert].

Manufactured by Novartis Pharma AG, Basle, Switzerland, for Medtronic, Inc., Minneapolis, MN 55432-5604 USA. 2002. (Lioresal速 is a registered trademark of Novartis Pharmaceuticals Corporation.)

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

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

11. Coffey R, Cahill D, Steers W, et al. Intrathecal Baclofen for Intractable Spasticity 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 Intrathecal Baclofen Therapy for Severe Spasticity of Cerebral Origin. J Neurosurg.

2003; 98: 291-295.

13. Campbell S, Almeida G, Penn Ret al. The Effects of Intrathecally Administered Baclofen on Function in Patients with Spasticity.

Physical Therapy. 1995; 75(5); 352-362.

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

Clinical Reference Guide

30

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

16. Meythaler J, Guin-Renfroe S, Law C, et al. Continuously Infused Intrathecal Baclofen Over 12 Months for Spastic Hypertonia in Adolescents and Adults with Cerebral Palsy. Arch Phys Med Rehabil.

2001; 82: 155-161.

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

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

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

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

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

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

Clinical Reference Guide

31

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Appendix Spinal 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

Clinical Reference Guide

32

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Spinal Origin vs. Cerebral Origin Spasticity Comparison Chart Spasticity of Spinal Origin Patients Spasticity

Patient Selection

Screening Test Dosing

Initial Dosing

Clinical Reference Guide

Spasticity of Cerebral Origin Patients

■

Usually symmetrical in lower extremities.

■

Asymmetrical in muscle groups and extremities.

■

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 clonus but not usually spasms.

■

Severe spasticity.

■

SAME

■

Responds to ≤ 100 microgram bolus of Lioresal Intrathecal.

■

SAME

■

Cannot be hypersensitive to baclofen.

■

SAME

■

Free of infection.

■

SAME

■

Unresponsive to oral baclofen or intolerable side effects at effective doses.

■

Prior oral antispasmodic use is not required.

■

In traumatic brain injury, wait 1-year post injury.

■

Begin with a 50 microgram bolus; if inadequate response is seen, proceed to a 75 microgram bolus 24 hours later.

If the response is still inadequate, a 100 microgram bolus can be given 24 hours later.

■

SAME

■

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

■

In very small children, a 25 microgram bolus may be considered.

■

Onset of action 30 to 60 minutes after bolus injection. Peak spasmolytic response is 4 hours post injection.

■

SAME

■

Double the effective screening test dose if the effect lasts 8 hours or less.

■

SAME

■

If the effect lasts more than 8 hours, use same dose as the effective screening test dose.

■

SAME

33

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Spinal Origin vs. Cerebral Origin Spasticity Comparison Chart - Continued Spasticity of Spinal Origin Patients Post-Implant Dose Titration

Maintenance Period Goals

■

No dosing increases during first 24 hours.

■

SAME

■

Increase 10–30% once every 24 hours until desired clinical effect is achieved.

■

Increase 5-15% once every 24 hours until desired clinical effect is achieved.

■

Response action first seen 6–8 hours after initiation of continuous infusion.

Peak response observed in 24–48 hours.

■

SAME

■

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

■

SAME

■

SAME

■

Maintenance Period Dosing

Spasticity of Cerebral Origin Patients

Minimize frequency and severity of spasms.

■

10–40% increases no more than once every 24 hours.

■

5-20% increases no more than once every 24 hours.

■

Clinical Experience: Range: 12–2003 micrograms/day Typical Range: 300–800 micrograms/day

■

In pediatric patients over 12, doses did not seem to be different than adult cerebral origin spasticity patients

■

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

■

Clinical Experience: Pediatric patients (under 12) seem to require lower daily doses.

Range: 24-1199 micrograms/day

Dose Reductions

■

10-20% reduction slowly

■

SAME

Flex Mode

■

Patients who have increased spasms at night may require up to a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect.

■

May use variable programming throughout the day (i.e., more drug during morning for dressing and less later when transferring).

Adverse Events

■

The most common drug adverse events reported were hypotonia, somnolence, nausea and vomiting, headache, and dizziness.

■

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

Clinical Reference Guide

34

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Patient Education Checklist For Screening Test

Intrathecal Baclofen for the Management of Severe Spasticity

It important to involve the patient, family members, and all caregivers in the education process. The following are key topics that should be covered prior to the actual screening test: ■ Educate patients, their families and caregivers about the benefits and 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 Situation Total Prime Phase Both pump and cather impl

■

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 effect with minimal side effects; replace pump as needed

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

■

■

Clinical Reference Guide

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 management team members, specifically: ■

■

Volume = Both pump and catheter are Goal anted or replaced

Importance of a responsible patient and/or caregiver during the maintenance phase of therapy Expectation that the patient/caregiver will schedule and keep refill appointments, monitor for and report adverse events, and be mindful of the potential interaction of intrathecal baclofen with CNS depressants

Discuss the management plan for existing medications, including withdrawal of oral antispasmodics

35

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Lioresal Intrathecal (Baclofen Injection) Screening Test Assessment Form LIORESAL速 INTRATHECAL (baclofen injection) Screening Test Assessment Form Date ___________________________ Solution given via:

Lumbar Puncture ______

Dose Given

Time of Injection

Intrathecal Catheter _____

Pre-Bolus 1/2 Hr. after bolus

1 Hr. after bolus

2 Hrs. after bolus

3 Hrs. after 4 Hrs. after 6 Hrs. after 8 Hrs. after 12 Hrs. after bolus bolus bolus bolus bolus

Time Respirations/minute

L R

L

R

Wrist Flexion Wrist Extension Elbow Flexion

Hip Adduction Hip Abduction Hip Flexion Knee Extension Knee Flexion Ankle Dorsiflexion

R

sa

Plantar Flexion

L

L

R

L

R

L

R

L

R

L

R

L

R

m

Elbow Extension

pl

Pulse/minute Blood Pressure

Heart Monitor

e

_______ mcg

Spasticity Scores

Clinician ___________________________

Circle device(s) used: Apnea Monitor Pulse Oximiter

Average Upper Extremity Average Lower Extremity Overall Spasm Score*

SCALE Used:

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

Clinical Reference Guide

(comments continued on back)

36

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

1+ 2 3 4

Modified Ashworth Scale Criteria 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.

e

Score 0 1

Ashworth Scale Criteria No increase in tone Slight increase in tone, giving a “catch” when the affected part(s) is moved in flexion or extension More marked increase in tone but affect part(s) easily flexed Considerable increase in tone-passive movement difficult Affected part(s) rigid in flexion or extension

pl

Score 1 2 3 4 5

Spasm Scale

Criteria None No spontaneous spasms; vigorous sensory and motor stimulation results in spasms Occasional spontaneous spasms and easily induced spasms Greater than one but less than ten spontaneous spasms per hour Greater than ten spontaneous spasms per hour

m

Score 0 1 2 3 4

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

Dose

Time

Medication

Dose

Time

Medication

Dose

sa

Time

COMMENTS (continued):

Clinical Reference Guide

37

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Drug Package Insert LIORESAL® INTRATHECAL (baclofen injection) Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information (see WARNINGS).

DESCRIPTION LIORESAL INTRATHECAL (baclofen injection) is a muscle relaxant and antispastic. Its chemical name is 4-amino-3-(4chlorophenyl) 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 other potentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37° C and compatible with CSF. Each milliliter of LIORESAL INTRATHECAL contains baclofen U.S.P. 50 mcg, 500 mcg or 2000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.0 - 7.0. Each ampule is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT AUTOCLAVE.

C1

H2N–CH2–CH CH2 COOH

CLINICAL PHARMACOLOGY The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory 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 with resultant 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 sedation 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 at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual 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 observed in 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 approximates 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 elimination half-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 study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected 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 during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position.

Six pediatric patients (age 8-18 years) receiving continuous intrathecal baclofen infusion at doses of 77-400 mcg/day had plasma baclofen levels near or below 10 ng/ml.

Clinical Reference Guide

38

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

INDICATIONS LIORESAL INTRATHECAL is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of LIORESAL INTRATHECAL via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. LIORESAL INTRATHECAL (baclofen injection) is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically 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 investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of LIORESAL INTRATHECAL to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. LIORESAL INTRATHECAL was superior to placebo on both principal 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 with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; LIORESAL INTRATHECAL was superior to placebo in reducing spasticity 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 last study, 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 for chronic intrathecal infusion of LIORESAL INTRATHECAL, patients must show a response to LIORESAL INTRATHECAL in a screening trial (see Dosage and Administration).

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

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

The pump system should not be implanted until the patient’s response to bolus LIORESAL INTRATHECAL injection is adequately evaluated.

Evaluation (consisting of a screening procedure: see Dosage and Administration) requires that LIORESAL INTRATHECAL be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section.

Resuscitative equipment should be available.

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

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

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

Overdose: Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction or dosing error. (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 septum. However, some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose.

Withdrawal:.Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal.

All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.

Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially lifethreatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal

Clinical Reference Guide

39

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Seizures have been reported during overdose and with withdrawal from LIORESAL INTRATHECAL as well as in patients maintained on therapeutic doses 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 injection) in pre- and post-marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, 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 spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/or had received multiple concomitant medications. A case-by-case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with 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 fibrosis of the coronary conduction system. A second patient, a 52 year-old woman with MS and a history of an inferior wall myocardial infarction, was found dead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is impossible to determine whether LIORESAL INTRATHECAL contributed to these deaths. The third patient underwent 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 status epilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pursued and the patient died.

Spasticity of Cerebral Origin: There were three deaths occurring among the 211 patients treated with LIORESAL INTRATHECAL in pre-marketing studies as of March 1996. These deaths were not attributed to the therapy.

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

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

Screening Patients should be infection-free prior to the screening trial with LIORESAL INTRATHECAL (baclofen injection) because the presence of a systemic infection may interfere with an assessment of the patientâ&#x20AC;&#x2122;s response to bolus LIORESAL INTRATHECAL. Pump Implantation Patients 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 Titration In most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial dose escalation typically indicates a catheter complication (i.e., catheter kink or dislodgement).

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

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

Extreme caution must be used when filling an FDA approved implantable pump equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose.

Additional considerations pertaining to dosage adjustment: It may be important to titrate the dose to maintain some degree of muscle tone and allow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities of daily living and ease of care.

Except in overdose related emergencies, the dose of LIORESAL INTRATHECAL should ordinarily be reduced slowly if the drug is discontinued for any reason.

An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic LIORESAL INTRATHECAL infusion. Reduction and discontinuation of oral antispasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided.

Drowsiness: Drowsiness has been reported in patients on LIORESAL INTRATHECAL. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of 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 sustain upright 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 and kept 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 or abrupt 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 it may be necessary to reduce the dosage.

LABORATORY TESTS No specific laboratory tests are deemed essential for the management of patients on LIORESAL INTRATHECAL.

Clinical Reference Guide

40

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

DRUG INTERACTIONS There is inadequate systematic experience with the use of LIORESAL INTRATHECAL in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of LIORESAL INTRATHECAL and epidural morphine include hypotension and dyspnea.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No 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 1020 times on a mg/m2 basis, the maximum oral dose recommended for human use. Mutagenicity assays with LIORESAL have not been performed.

PREGNANCY CATEGORY C LIORESAL (baclofen USP) given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams.

This abnormality was not seen in mice or rabbits. There are no adequate and well-controlled studies in pregnant women. LIORESAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NURSING MOTHERS In mothers treated with oral LIORESAL (baclofen USP) in therapeutic doses, the active substance passes into the breast milk. It is not known whether detectable levels of drug are present in breast milk of nursing mothers receiving LIORESAL INTRATHECAL. As a general rule, nursing should be undertaken while a patient is receiving LIORESAL INTRATHECAL only if the potential benefit justifies the potential risks to the infant.

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

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

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 been found 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 cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

ADVERSE DRUG EVENTS Spasticity of Spinal Cord Origin: Commonly Observed in Patients with Spasticity of Spinal Origin — In pre- and post-marketing clinical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebotreated patients 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 LIORESAL INTRATHECAL in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse events. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations.

Fatalities — See Warnings.

Spasticity of Spinal Cord Origin: Incidence in Controlled Trials — Experience with LIORESAL INTRATHECAL (baclofen injection) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving LIORESAL INTRATHECAL (baclofen injection) in two randomized, placebocontrolled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse events were reported 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 LIORESAL INTRATHECAL reflect experience gained with 576 patients followed prospectively in the United States. They received LIORESAL INTRATHECAL for periods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of LIORESAL INTRATHECAL cannot be reliably assessed 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 who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post-marketing studies.

Clinical Reference Guide

41

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS Percent of Patients Reporting Events N = 576 N = 474 N = 430 Screeninga Titrationb Maintenancec Adverse Event Percent Percent Percent Hypotonia 5.4 13.5 25.3 Somnolence 5.7 5.9 20.9 Dizziness 1.7 1.9 7.9 Paresthesia 2.4 2.1 6.7 Nausea and Vomiting 1.6 2.3 5.6 Headache 1.6 2.5 5.1 Constipation 0.2 1.5 5.1 Convulsion 0.5 1.3 4.7 Urinary Retention 0.7 1.7 1.9 Dry Mouth 0.2 0.4 3.3 Accidental Injury 0.0 0.2 3.5 Asthenia 0.7 1.3 1.4 Confusion 0.5 0.6 2.3 Death 0.2 0.4 3.0 Pain 0.0 0.6 3.0 Speech Disorder 0.0 0.2 3.5 Hypotension 1.0 0.2 1.9 Ambylopia 0.5 0.2 2.3 Diarrhea 0.0 0.8 2.3 Hypoventilation 0.2 0.8 2.1 Coma 0.0 1.5 0.9 Impotence 0.2 0.4 1.6 Peripheral Edema 0.0 0.0 2.3 Urinary Incontinence 0.0 0.8 1.4 Insomnia 0.0 0.4 1.6 Anxiety 0.2 0.4 0.9 Depression 0.0 0.0 1.6 Dyspnea 0.3 0.0 1.2 Fever 0.5 0.2 0.7 Pneumonia 0.2 0.2 1.2 Urinary Frequency 0.0 0.6 0.9 Urticaria 0.2 0.2 1.2 Anorexia 0.0 0.4 0.9 Diplopia 0.0 0.4 0.9 Dysautonomia 0.2 0.2 0.9 Hallucinations 0.3 0.4 0.5 Hypertension 0.2 0.6 0.5 a

Following administration of test bolus Two month period following implant Beyond two months following implant N=total number of patients entering each period %=% of patients evaluated b c

Clinical Reference Guide

42

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to LIORESAL INTRATHECAL (baclofen injection) from foreign studies has been reported. 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, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis.

Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis.

Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.

Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis.

Urogenital: Hematuria and kidney failure.

Skin and Appendages: Alopecia and sweating.

Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia.

Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus.

Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose.

Hemic and Lymphatic System: Anemia.

Spasticity of Cerebral Origin: Commonly Observed — In pre-marketing clinical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, 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 patients with 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, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following events occurred among the 62 patients receiving LIORESAL INTRATHECAL in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.

Events Observed during the Pre-marketing Evaluation of LIORESAL INTRATHECAL — Adverse events associated with the use of LIORESAL INTRATHECAL 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 22 mcg to 1400 mcg per day. Doses used in this patient population for long term infusion are generally lower than those required for patients with spasticity of spinal cord origin.

Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of LIORESAL INTRATHECAL 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 term treatment due to adverse events.

Clinical Reference Guide

43

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

INCIDENCE OF MOST FREQUENT (â&#x2030;Ľ1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS Percent of Patients Reporting Events N = 211 N = 153 N = 150 Screeninga Titrationb Maintenancec Adverse Event Percent Percent Percent Hypotonia 2.4 14.4 34.7 Somnolence 7.6 10.5 18.7 Headache 6.6 7.8 10.7 Nausea and Vomiting 6.6 10.5 4.0 Vomiting 6.2 8.5 4.0 Urinary Retention 0.9 6.5 8.0 Convulsion 0.9 3.3 10.0 Dizziness 2.4 2.6 8.0 Nausea 1.4 3.3 7.3 Hypoventilation 1.4 1.3 4.0 Hypertonia 0.0 0.7 6.0 Paresthesia 1.9 0.7 3.3 Hypotension 1.9 0.7 2.0 Increased Salivation 0.0 2.6 2.7 Back Pain 0.9 0.7 2.0 Constipation 0.5 1.3 2.0 Pain 0.0 0.0 4.0 Pruritus 0.0 0.0 4.0 Diarrhea 0.5 0.7 2.0 Peripheral Edema 0.0 0.0 3.3 Thinking Abnormal 0.5 1.3 0.7 Agitation 0.5 0.0 1.3 Asthenia 0.0 0.0 2.0 Chills 0.5 0.0 1.3 Coma 0.5 0.0 1.3 Dry Mouth 0.5 0.0 1.3 Pneumonia 0.0 0.0 2.0 Speech Disorder 0.5 0.7 0.7 Tremor 0.5 0.0 1.3 Urinary Incontinence 0.0 0.0 2.0 Urination Impaired 0.0 0.0 2.0 a

Following administration of test bolus Two month period following implant Beyond two months following implant N=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 (baclofen injection) have been reported. In the total cohort, 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: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.

Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.

Cardiovascular: Bradycardia.

Respiratory: Apnea, dyspnea and hyperventilation.

Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis.

Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer.

Special Senses: Abnormality of accommodation.

Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia.

Hemic and Lymphatic System: Leukocytosis and petechial rash. b c

Clinical Reference Guide

44

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

Symptoms of LIORESAL INTRATHECAL Overdose: Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hr. duration. In most cases reported, coma was reversible without sequelae 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 ordinarily be 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. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia.

Physostigmine Doses for Adult Patients: Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur.

Physostigmine Doses for Pediatric Patients: Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained.

Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.

If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30-40 ml of CSF to reduce CSF baclofen concentration.

DOSAGE AND ADMINISTRATION Refer to the manufacturerâ&#x20AC;&#x2122;s manual for the implantable pump approved for intrathecal infusion for specific instructions and precautions for programming the pump and/or refilling the reservoir.

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

Pediatric Patients: The starting screening dose for pediatric patients is the same as in adult patients, i.e., 50 mcg. However, for very small patients, a screening dose of 25 mcg may be tried first.

Patients who do not respond to a 100 mcg intrathecal bolus should not be considered candidates for an implanted pump for chronic infusion.

Post-Implant Dose Titration Period: To determine the initial total daily dose of LIORESAL INTRATHECAL following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved).

Adult Patients with Spasticity of Spinal Cord Origin: After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10-30% 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 24 hours, until the desired clinical effect is achieved.

Pediatric Patients: After the first 24 hours, the daily dose should be increased slowly by 5-15% only once every 24 hours, until the desired clinical effect is achieved.

If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency.

Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediately following 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 frequency and severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 10-40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10-20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement).

Maintenance dosage for long term continuous infusion of LIORESAL INTRATHECAL (baclofen injection) has ranged from 12 mcg/day to 2,003 mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1000 mcg/day. Determination of the optimal LIORESAL INTRATHECAL dose requires individual titration. The lowest dose with an optimal response should be used.

Spasticity of Cerebral Origin Patients: The clinical goal is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life 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 maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement).

Clinical Reference Guide

45

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Maintenance dosage for long term continuous infusion of LIORESAL INTRATHECAL (baclofen injection) has ranged from 22 mcg/day to 1400 mcg/day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients required daily doses greater than 1000 mcg/day.

Pediatric Patients: Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed to require a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/day, with a range of 24 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 optimal LIORESAL 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 to increasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this “tolerance” has been treated on occasion, in hospital, by a “drug holiday” consisting of the gradual reduction of LIORESAL INTRATHECAL over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” LIORESAL INTRATHECAL may be restarted at the initial continuous infusion dose.

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

Delivery Specifications The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. LIORESAL INTRATHECAL may require dilution when used with certain implantable pumps. Please consult manufacturer’s manual for specific recommendations.

Preparation Instruction: Screening Use 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 baclofen injection for a 75mcg bolus dose. For the maximum screening dose of 100mcg, use 2 ml of 50mcg/ml baclofen injection (2 screening ampules).

Maintenance For 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 implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of LIORESAL INTRATHECAL delivery. For example, patients who have increased spasms at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect.

HOW SUPPLIED LIORESAL 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 contains one 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).

STORAGE Does 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.

Clinical Reference Guide

46

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Brief Disclosure SynchroMed® 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 morphine hydrochloride outside of the United States) in the treatment of chronic intractable pain, and chronic intrathecal infusion of Lioresal® Intrathecal (baclofen injection) for the management of severe spasticity; chronic intravascular infusion of floxuridine (FUDR) or methotrexate for the treatment of primary or metastatic 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 sufficient 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 catheter access port (CAP) of the pump. Failure to comply with all instructions can lead to technical errors or improper use of implanted infusion pumps and result in additional surgical procedures, a return of underlying symptoms, or a clinically significant or fatal drug under- or overdose. Refer to the appropriate drug labeling for specific under- or overdose symptoms and methods of management. Avoid using short wave (RF) diathermy within 30 cm of the pump or catheter. Diathermy may produce significant temperature rises in the area of the pump and continue to heat the tissue in a localized area. If overheated, the pump may over infuse the drug, potentially causing a drug overdose. Effects of other types of diathermy (microwave, ultrasonic, etc.) on the pump are 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 preservative-free sterile solution indicated for intraspinal use. Use only Medtronic components indicated for use with this system. Failure to firmly secure connections can allow drug or cerebrospinal fluid (CSF) leakage into tissue and result in tissue damage or inadequate therapy. A postoperative priming bolus should 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 screening procedures. Physicians must be familiar with the drug stability information in the technical manual and must understand the dose relationship to drug concentration and pump flow rate before prescribing pump infusion. Implantation and ongoing system management must be performed by individuals 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, potential side effects, and signs and symptoms that require medical attention. Instruct patients to notify their clinician of travel plans, to return for refills at prescribed times, avoid activities such as strenuous exercise or contact sports that jar, impact, twist, or stretch the body, to always carry their Medtronic device identification card, to avoid manipulating the pump through the skin, and to notify healthcare professionals of the implanted pump before medical tests/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 pump is 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 has expired. 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 patients prone to CSF leaks, clinicians should consider special procedures, such as a blood patch. Follow instructions for emptying and filling the pump during a replacement 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 pump dropped 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 easy to 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 protected from pressure or irritation. If therapy is discontinued for an extended period of time, fill the reservoir with preservative-free saline in intraspinal applications 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 an implantable pacemaker and/or defibrillator. Electromagnetic interference (EMI) is an energy field generated by equipment found in the home, work, medical, or public environments. Most EMI normally encountered will not affect the operation of the pump. Exceptions include: injury resulting from heating of the pump which can damage surrounding tissue (diathermy, MRI), system damage which can require surgical replacement or result in loss/change in symptom control (defibrillation, electrocautery, high-output ultrasonics, radiation therapy), and operational changes to the pump causing the motor to stop, 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 the MRI scanner and suspend drug infusion during MRI exposure which will cause the pump alarm to sound. The pump should resume normal operation upon termination of MRI exposure. Prior to MRI, the physician should determine if the patient can safely be deprived of drug delivery. If not, alternative delivery methods 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 performance due 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 and filling before, during, or after implantation; change in catheter performance due to catheter kinking, disconnection, leakage, breakage, occlusion, dislodgement, migration, or catheter fibrosis; body rejection phenomena, surgical replacement of pump or catheter due to complications; local and systemic drug toxicity and related side effects, complications due to use of unapproved drugs and/or not using drugs in accordance with drug labeling, or inflammatory mass 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.

Clinical Reference Guide

47

April, 2004

Medtronic SynchroMed® II Programmable Infusion System

Index

Intrathecal Baclofen for the Management of Severe Spasticity

Adverse Effects of Lioresal Intrathecal.................................................................................22 Antispasmodics .......................................................................................................................................13 Ashworth Scale .......................................................................................................................................16 Ashworth Scale, Modified ...............................................................................................................17 Assessment (Patient) for ITB™ Therapy......................................................................................................................7, 11 for Screening Test.........................................................................................................................16 Complications (Lioresal Intrathecal) ..............................................................................22, 29 Contraindications ..................................................................................................................................10 Disclosure....................................................................................................................................................47 Dosing.............................................................................................................................................................19 dose 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

Clinical Reference Guide

48

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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 ITBâ&#x201E;˘ 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

Clinical Reference Guide

49

April, 2004

Medtronic SynchroMed速 II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

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

Clinical Reference Guide

50

April, 2004

Medtronic SynchroMedÂŽ II Programmable Infusion System

Intrathecal Baclofen for the Management of Severe Spasticity

Trial â&#x20AC;&#x201C; see Screening Test Withdrawal from oral antispasmodics .......................................................................................................13 from Lioresal Intrathecal ........................................................................................................23

Clinical Reference Guide

51

April, 2004

United States of America Medtronic Neurological 710 Medtronic Parkway Minneapolis, MN 55432-5604 USA Internet: www.medtronic.com Tel. 763-505-5000 Fax 763-505-1000 Toll-free 1-800-328-0810

Asia-Pacific Medtronic International, Ltd. Suite 1602 16/F Manulife Plaza The Lee Gardens, 33 Hysan Avenue Causeway Bay Hong Kong Tel. 852-2891-4456 Fax 852-2891-6830

Europe Medtronic Europe SĂ rl Route du Molliau 31 Case Postale 1131 Tolochenaz Switzerland Internet: www.medtronic.co.uk Tel. 41-21-802-7000 Fax 41-21-802-7900

Australia Medtronic Australasia Pty. Ltd. Unit 4/446 Victoria Road Gladesville NSW 2111 Australia Tel. 02-9879-5999 Fax 02-9879-5100 Toll-free 1-800-251-760

Canada Medtronic of Canada Ltd. 6733 Kitimat Road Mississauga, Ontario L5N 1W3 Canada Tel. 1-905-826-6020 Fax 1-905-826-6620

UC200300010 EN NP5255EN PN 182942-101 Š Medtronic, Inc. 2004 All Rights Reserved Printed in USA