FDA label 824b1807-be48-4239-bfdc-2d1d15b42c71

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 ).

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 caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site. Overdose: Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction, inadvertent subcutaneous injection, 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. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. 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 or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose. Withdrawal: Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures (see PRECAUTIONS ). 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. Priapism may develop or recur if treatment with intrathecal baclofen is interrupted. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal. Seizures have been reported during overdose and with withdrawal from 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.

Warnings Withdrawal - Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death. Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to 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. User instructions - Comply with all product instructions for initial preparation and filling, implantation, programming, refilling, and accessing the catheter access port (if present) 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, drug withdrawal symptoms, or a clinically significant or fatal drug underdose or overdose. Implantation and system management - Implantation and ongoing system management must be performed by individuals trained in the operation and handling of the infusion system and must be in compliance with procedures described in the appropriate technical instructions. Inadequate training or failure to follow instructions can require surgical revision or replacement, and result in a clinically significant or fatal drug underdose or overdose. Calculating catheter volume - Use the catheter length recorded at implant or catheter revision when calculating catheter volume. The actual implanted catheter length and catheter model number are required to accurately calculate catheter volume. A universal value does not exist that can be used as a substitute for this knowledge. An inaccurate catheter volume calculation can result in a clinically significant or fatal drug underdose or overdose. Contrast medium (pumps with a catheter access port) - Do not inject any contrast medium into the pump reservoir. Injecting contrast medium into the pump reservoir can impair pump operation. Refill - Patients must return to the clinic for refills at the prescribed times. Failure to return to the clinic for refills at the prescribed times can result in the actual flow rate of the pump being less than expected, resulting in a loss of or change in therapy, which may lead to a return of underlying symptoms, drug withdrawal symptoms, or a clinically significant or fatal drug underdose. Failure to return at the prescribed times can also damage the pump, requiring surgical replacement. Refill kit components – Use the appropriate Medtronic refill kit during all refill procedures for Medtronic implantable infusion pumps. Using components other than Medtronic components or a kit other than the appropriate refill kit can damage Medtronic components, requiring surgical revision or replacement, and allow drug leakage into surrounding tissue, resulting in loss of or change in therapy, which may lead to a return of underlying symptoms, drug withdrawal symptoms, or a clinically significant or fatal drug underdose or overdose. Injection error during a pump refill procedure - Be certain you are accessing the reservoir fill port when injecting fluids into an implanted pump. ALWAYS: identify the pump model and reservoir volume. identify the location of the reservoir fill port. Avoid pocket fill , i.e. improper injection of medication into the subcutaneous tissue (see below) Avoid inadvertent injection into the catheter access port (see below) use the instructions, noncoring needles, appropriate template edge, and other accessories provided in the appropriate kit. verify the location of the reservoir fill port during needle insertion according to the instructions provided AND using other medical procedures as appropriate. refer to the drug labeling for indications, contraindications, warnings, precautions, adverse events, and dosage and administration information. Pocket fill is the improper injection of refill medication into the subcutaneous tissue, which includes the pump pocket. The injection of drug into the subcutaneous tissue can lead to an acute systemic overdose, which can be fatal. After a pocket fill, the pump reservoir will become empty sooner than anticipated, and this may cause underdose symptoms and/or baclofen withdrawal syndrome, which can be fatal. If it is suspected or known that all or part of the drug was injected into the pocket during the refill procedure, monitor the patient closely for signs and symptoms of overdose in an appropriate facility for a sufficient amount of time or until the symptoms have resolved. Refer to the refill kit manual or the Indications, Drug Stability, and Emergency Procedures for SynchroMed and IsoMed Implantable Infusion Systems Reference Manual for emergency procedures associated with drug underdose and overdose. Refer to the drug product information label for specific drug underdose and overdose symptoms and methods of management. Inadvertent injection into the catheter access port may result in a clinically significant or fatal drug overdose. If it is suspected or known that all or part of the drug was injected into the catheter access port during the refill procedure, monitor the patient closely for signs and symptoms of overdose in an appropriate facility for a sufficient amount of time or until the symptoms have resolved. Refer to the catheter access port kit manual or the Indications, Drug Stability, and Emergency Procedures for SynchroMed and IsoMed Implantable Infusion Systems Reference Manual for emergency procedures associated with drug overdose. Refer to the drug labeling for specific drug overdose symptoms and methods of management. Changing drug or decreasing drug concentrations - Rinse the reservoir twice between solutions when changing drug or decreasing drug concentrations in the pump reservoir. A significant amount of drug may be present in the pump reservoir after emptying the pump. This residual volume cannot be removed by emptying the pump. Rinsing the reservoir between solutions minimizes the amount of drug in this residual volume but does not eliminate it. Failure to account for residual drug in the pump reservoir can result in a concentration that is different than intended and a clinically significant or fatal drug underdose or overdose. Program a bridge bolus after rinsing the reservoir twice. The bridge bolus advances the remaining old drug (the drug left in the pump tubing, catheter access port, and catheter after emptying and refilling the pump) to the catheter tip at the prior flow rate. Refer to "Performing a reservoir rinse" on page 18 of this manual. Refer to the programming guide for bridge bolus procedures. Connections - Firmly secure all connections. Failure to secure connections can allow drug to leak onto the surrounding skin and may result in inadequate therapy or infection. Reservoir fill port injections - Do not use excessive force when accessing the reservoir fill port. Excessive force can result in damage to the needle or pump requiring surgical revision or replacement, and leakage into surrounding tissue, resulting in loss of or change in therapy, which may lead to a return of underlying symptoms, drug withdrawal symptoms, or a clinically significant or fatal drug underdose or overdose. Intrathecal therapy - For intrathecal therapy, use ONLY a preservative-free sterile solution indicated for intrathecal use. Nonindicated fluids containing preservatives or endotoxins can be neurotoxic in intrathecal applications. Using nonindicated fluids can result in adverse events including, but not limited to, extreme pain, cramps, seizures, and death. Drug information - Refer to the drug labeling for indications, contraindications, warnings, precautions, dosage and administration information, and screening procedures. Refer to the drug labeling for specific drug underdose or overdose symptoms and methods of management. Failure to refer to the drug labeling can result in inappropriate patient selection and management, inadequate therapy, intolerable side effects, or a clinically significant or fatal drug underdose or overdose. Consider the possibility of a drug error if the patient experiences unusual side effects. Failure to do so can result in misdiagnosis of patient symptoms. Mixing drugs - The effects that drug mixtures have on pump operation are unknown. Drugs can precipitate when mixed. These precipitates can inhibit pump flow or block the catheter, resulting in loss of therapy or a clinically significant or fatal drug underdose. Drug interaction and side effects - Inform patients of the appropriate warnings and precautions regarding drug interactions, potential side effects, and signs and symptoms that require medical attention, including prodromal signs and symptoms of inflammatory mass. Failure to recognize the signs and symptoms and to seek appropriate medical intervention can result in serious patient injury or death. Drug overdose symptoms and management - Refer to the emergency procedures included at the end of this manual and the drug labeling for specific drug overdose symptoms and methods of management. Drug underdose/overdose - Inform patients and caregivers of the signs and symptoms of a drug underdose and overdose. Inform patients and caregivers: to be aware and report any unusual signs or symptoms at anytime during or after a refill or catheter access port procedure. to be alert for any burning sensations in the area of the pump pocket during their refill or catheter access port procedure. to especially watch for signs of underdose and overdose. to stay alert for signs or symptoms that may indicate changes to their prescribed drug concentration or programmed dose. to seek emergency assistance as necessary. Refer to the refill kit or catheter access port kit manual or the Indications, Drug Stability and Emergency Procedures for SynchroMed and IsoMed Implantable Infusion Systems Reference Manual for emergency procedures associated with drug underdose and overdose. Failure to recognize these signs and symptoms and to seek appropriate medical intervention can result in serious patient injury or death. Patient travel - Patients should notify their clinicians of any travel plans. Clinicians need this information to coordinate patient care and pump refills and help prevent a loss of or change in therapy, which may lead to a return of underlying symptoms, drug withdrawal symptoms, or a clinically significant or fatal drug underdose.

ADVERSE REACTIONS Spasticity of Spinal Cord Origin – Clinical Studies: 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 placebo-treated 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. 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, placebo-controlled 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. INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS a Following administration of test bolus b Two month period following implant c Beyond two months following implant N= total number of patients entering each period %=% of patients evaluated Percent of Patients Reporting Events N = 576 N = 474 N = 430 Screening a Titration b Maintenance c 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 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 – Clinical Studies: 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. INCIDENCE OF MOST FREQUENT (≥ 1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF CEREBRAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS a Following administration of test bolus b Two month period following implant c Beyond two months following implant N= Total number of patients entering each period. 211 patients received drug; (1 of 212) received placebo only. Percent of Patients Reporting Events N = 211 N = 153 N = 150 Screening a Titration b Maintenance c 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 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. Postmarketing Experience: The following adverse events have been reported during post-approval use of LIORESAL INTRATHECAL. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. Musculoskeletal: The onset of scoliosis or worsening of a pre-existing scoliosis has been reported. Urogenital: Sexual dysfunction in men and women, including decreased libido and orgasm dysfunction, have been reported. Erectile dysfunction in men has also been reported. Priapism has been reported following baclofen withdrawal.

Adverse events The adverse events associated with the use of this device may include, but may not be limited to, the following: Meningitis Infection Reservoir contamination Overpressurization of the reservoir Injection into pocket or subcutaneous tissue Activation of reservoir valve

<table width="70%" ID="b091930d-fa54-41b7-99dd-3d512b45fa8e"> <colgroup> <col width="42%"/> <col width="17%"/> <col width="21%"/> <col width="19%"/> </colgroup> <thead> <tr styleCode="First Last"> <th colspan="4">INCIDENCE OF MOST FREQUENT (&#x2265;1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS</th> </tr> </thead> <tfoot> <tr styleCode="First Last"> <td colspan="100%"> <paragraph> ^a Following administration of test bolus</paragraph> <paragraph> ^b Two month period following implant</paragraph> <paragraph> ^c Beyond two months following implant</paragraph> <paragraph>N= total number of patients <content styleCode="underline">entering</content> each period</paragraph> <paragraph>%=% of patients evaluated</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td/> <td align="center" colspan="3"> <content styleCode="bold">Percent of Patients Reporting Events</content> </td> </tr> <tr> <td align="center"/> <td align="center"> <content styleCode="bold">N = 576</content> </td> <td align="center"> <content styleCode="bold">N = 474</content> </td> <td align="center"> <content styleCode="bold">N = 430</content> </td> </tr> <tr> <td align="center"/> <td align="center">Screening^a </td> <td align="center">Titration^b </td> <td align="center">Maintenance^c </td> </tr> <tr> <td> <content styleCode="bold">Adverse Event</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> </tr> <tr> <td>Hypotonia</td> <td align="center">5.4</td> <td align="center">13.5</td> <td align="center">25.3</td> </tr> <tr> <td>Somnolence</td> <td align="center">5.7</td> <td align="center">5.9</td> <td align="center">20.9</td> </tr> <tr> <td>Dizziness</td> <td align="center">1.7</td> <td align="center">1.9</td> <td align="center">7.9</td> </tr> <tr> <td>Paresthesia</td> <td align="center">2.4</td> <td align="center">2.1</td> <td align="center">6.7</td> </tr> <tr> <td>Nausea and Vomiting</td> <td align="center">1.6</td> <td align="center">2.3</td> <td align="center">5.6</td> </tr> <tr> <td>Headache</td> <td align="center">1.6</td> <td align="center">2.5</td> <td align="center">5.1</td> </tr> <tr> <td>Constipation</td> <td align="center">0.2</td> <td align="center">1.5</td> <td align="center">5.1</td> </tr> <tr> <td>Convulsion</td> <td align="center">0.5</td> <td align="center">1.3</td> <td align="center">4.7</td> </tr> <tr> <td>Urinary Retention</td> <td align="center">0.7</td> <td align="center">1.7</td> <td align="center">1.9</td> </tr> <tr> <td>Dry Mouth</td> <td align="center">0.2</td> <td align="center">0.4</td> <td align="center">3.3</td> </tr> <tr> <td>Accidental Injury</td> <td align="center">0.0</td> <td align="center">0.2</td> <td align="center">3.5</td> </tr> <tr> <td>Asthenia</td> <td align="center">0.7</td> <td align="center">1.3</td> <td align="center">1.4</td> </tr> <tr> <td>Confusion</td> <td align="center">0.5</td> <td align="center">0.6</td> <td align="center">2.3</td> </tr> <tr> <td>Death </td> <td align="center">0.2</td> <td align="center">0.4</td> <td align="center">3.0</td> </tr> <tr> <td>Pain</td> <td align="center">0.0</td> <td align="center">0.6</td> <td align="center">3.0</td> </tr> <tr> <td>Speech Disorder</td> <td align="center">0.0</td> <td align="center">0.2</td> <td align="center">3.5</td> </tr> <tr> <td>Hypotension</td> <td align="center">1.0</td> <td align="center">0.2</td> <td align="center">1.9</td> </tr> <tr> <td>Ambylopia</td> <td align="center">0.5</td> <td align="center">0.2</td> <td align="center">2.3</td> </tr> <tr> <td>Diarrhea</td> <td align="center">0.0</td> <td align="center">0.8</td> <td align="center">2.3</td> </tr> <tr> <td>Hypoventilation</td> <td align="center">0.2</td> <td align="center">0.8</td> <td align="center">2.1</td> </tr> <tr> <td>Coma</td> <td align="center">0.0</td> <td align="center">1.5</td> <td align="center">0.9</td> </tr> <tr> <td>Impotence</td> <td align="center">0.2</td> <td align="center">0.4</td> <td align="center">1.6</td> </tr> <tr> <td>Peripheral Edema</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">2.3</td> </tr> <tr> <td>Urinary Incontinence</td> <td align="center">0.0</td> <td align="center">0.8</td> <td align="center">1.4</td> </tr> <tr> <td>Insomnia</td> <td align="center">0.0</td> <td align="center">0.4</td> <td align="center">1.6</td> </tr> <tr> <td>Anxiety</td> <td align="center">0.2</td> <td align="center">0.4</td> <td align="center">0.9</td> </tr> <tr> <td>Depression</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">1.6</td> </tr> <tr> <td>Dyspnea</td> <td align="center">0.3</td> <td align="center">0.0</td> <td align="center">1.2</td> </tr> <tr> <td>Fever</td> <td align="center">0.5</td> <td align="center">0.2</td> <td align="center">0.7</td> </tr> <tr> <td>Pneumonia</td> <td align="center">0.2</td> <td align="center">0.2</td> <td align="center">1.2</td> </tr> <tr> <td>Urinary Frequency</td> <td align="center">0.0</td> <td align="center">0.6</td> <td align="center">0.9</td> </tr> <tr> <td>Urticaria</td> <td align="center">0.2</td> <td align="center">0.2</td> <td align="center">1.2</td> </tr> <tr> <td>Anorexia</td> <td align="center">0.0</td> <td align="center">0.4</td> <td align="center">0.9</td> </tr> <tr> <td>Diplopia</td> <td align="center">0.0</td> <td align="center">0.4</td> <td align="center">0.9</td> </tr> <tr> <td>Dysautonomia</td> <td align="center">0.2</td> <td align="center">0.2</td> <td align="center">0.9</td> </tr> <tr> <td>Hallucinations</td> <td align="center">0.3</td> <td align="center">0.4</td> <td align="center">0.5</td> </tr> <tr> <td>Hypertension</td> <td align="center">0.2</td> <td align="center">0.6</td> <td align="center">0.5</td> </tr> </tbody> </table>

<table width="70%" ID="table1"> <colgroup> <col width="42%"/> <col width="19%"/> <col width="19%"/> <col width="20%"/> </colgroup> <thead> <tr styleCode="First Last"> <th colspan="4">INCIDENCE OF MOST FREQUENT (&#x2265; 1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF CEREBRAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS</th> </tr> </thead> <tfoot> <tr styleCode="First Last"> <td colspan="100%"> <paragraph> ^a Following administration of test bolus</paragraph> <paragraph> ^b Two month period following implant</paragraph> <paragraph> ^c Beyond two months following implant</paragraph> <paragraph>N= Total number of patients <content styleCode="underline">entering</content> each period. 211 patients received drug; (1 of 212) received placebo only.</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td/> <td align="center" colspan="3"> <content styleCode="bold">Percent of Patients Reporting Events</content> </td> </tr> <tr> <td align="center"/> <td align="center"> <content styleCode="bold">N = 211</content> </td> <td align="center"> <content styleCode="bold">N = 153</content> </td> <td align="center"> <content styleCode="bold">N = 150</content> </td> </tr> <tr> <td align="center"/> <td align="center">Screening^a </td> <td align="center">Titration^b </td> <td align="center">Maintenance^c </td> </tr> <tr> <td align="center"/> </tr> <tr> <td> <content styleCode="bold">Adverse Event</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> <td align="center"> <content styleCode="bold">Percent</content> </td> </tr> <tr> <td>Hypotonia</td> <td align="center">2.4</td> <td align="center">14.4</td> <td align="center">34.7</td> </tr> <tr> <td>Somnolence</td> <td align="center">7.6</td> <td align="center">10.5</td> <td align="center">18.7</td> </tr> <tr> <td>Headache</td> <td align="center">6.6</td> <td align="center">7.8</td> <td align="center">10.7</td> </tr> <tr> <td>Nausea and Vomiting</td> <td align="center">6.6</td> <td align="center">10.5</td> <td align="center">4.0</td> </tr> <tr> <td>Vomiting</td> <td align="center">6.2</td> <td align="center">8.5</td> <td align="center">4.0</td> </tr> <tr> <td>Urinary Retention</td> <td align="center">0.9</td> <td align="center">6.5</td> <td align="center">8.0</td> </tr> <tr> <td>Convulsion</td> <td align="center">0.9</td> <td align="center">3.3</td> <td align="center">10.0</td> </tr> <tr> <td>Dizziness</td> <td align="center">2.4</td> <td align="center">2.6</td> <td align="center">8.0</td> </tr> <tr> <td>Nausea</td> <td align="center">1.4</td> <td align="center">3.3</td> <td align="center">7.3</td> </tr> <tr> <td>Hypoventilation</td> <td align="center">1.4</td> <td align="center">1.3</td> <td align="center">4.0</td> </tr> <tr> <td>Hypertonia</td> <td align="center">0.0</td> <td align="center">0.7</td> <td align="center">6.0</td> </tr> <tr> <td>Paresthesia</td> <td align="center">1.9</td> <td align="center">0.7</td> <td align="center">3.3</td> </tr> <tr> <td>Hypotension</td> <td align="center">1.9</td> <td align="center">0.7</td> <td align="center">2.0</td> </tr> <tr> <td>Increased Salivation</td> <td align="center">0.0</td> <td align="center">2.6</td> <td align="center">2.7</td> </tr> <tr> <td>Back Pain</td> <td align="center">0.9</td> <td align="center">0.7</td> <td align="center">2.0</td> </tr> <tr> <td>Constipation</td> <td align="center">0.5</td> <td align="center">1.3</td> <td align="center">2.0</td> </tr> <tr> <td>Pain</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">4.0</td> </tr> <tr> <td>Pruritus</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">4.0</td> </tr> <tr> <td>Diarrhea</td> <td align="center">0.5</td> <td align="center">0.7</td> <td align="center">2.0</td> </tr> <tr> <td>Peripheral Edema</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">3.3</td> </tr> <tr> <td>Thinking Abnormal</td> <td align="center">0.5</td> <td align="center">1.3</td> <td align="center">0.7</td> </tr> <tr> <td>Agitation</td> <td align="center">0.5</td> <td align="center">0.0</td> <td align="center">1.3</td> </tr> <tr> <td>Asthenia</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">2.0</td> </tr> <tr> <td>Chills</td> <td align="center">0.5</td> <td align="center">0.0</td> <td align="center">1.3</td> </tr> <tr> <td>Coma</td> <td align="center">0.5</td> <td align="center">0.0</td> <td align="center">1.3</td> </tr> <tr> <td>Dry Mouth</td> <td align="center">0.5</td> <td align="center">0.0</td> <td align="center">1.3</td> </tr> <tr> <td>Pneumonia</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">2.0</td> </tr> <tr> <td>Speech Disorder</td> <td align="center">0.5</td> <td align="center">0.7</td> <td align="center">0.7</td> </tr> <tr> <td>Tremor</td> <td align="center">0.5</td> <td align="center">0.0</td> <td align="center">1.3</td> </tr> <tr> <td>Urinary Incontinence</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">2.0</td> </tr> <tr> <td>Urination Impaired</td> <td align="center">0.0</td> <td align="center">0.0</td> <td align="center">2.0</td> </tr> </tbody> </table>