Prescription Drugs

CLINICAL PHARMACOLOGY The precise mechanisms of action of LIORESAL (baclofen) as an antispastic agent are not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflex transmission at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals. Actions at supraspinal sites may also contribute to its clinical effect. Baclofen is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype. Baclofen has been shown to have general Central Nervous System (CNS) depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia and respiratory and cardiovascular depression. In neurological diseases associated with spasm of the skeletal muscles, LIORESAL Intrathecal may have beneficial action on reflex muscle contractions, painful spasm, automatism, hyperreflexia, trismus and clonus. Neuromuscular transmission is not affected by baclofen. Baclofen may also reduce pain associated with spasticity. Pharmacodynamics of LIORESAL Intrathecal Intrathecal Bolus The onset of action is generally half an hour to one hour after administration of an intrathecal bolus dose. Peak antispastic effect is seen at approximately 4 hours after dosing and effects may last 4 to 8 hours. Onset, peak response, and duration of action vary with individual patients depending on the dose and severity of symptoms. Continuous Intrathecal Infusion The antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed in 24 to 48 hours. Pharmacokinetics of LIORESAL Intrathecal After LIORESAL Intrathecal administration, the concentration of baclofen in the Cerebrospinal Fluid (CSF) is approximately 100 times higher than what is found following oral administration. Because of slow CSF circulation and a baclofen concentration gradient from the lumbar to the cisternal CSF, the pharmacokinetic parameters as described below should be interpreted considering a high inter- and intra-patient variability. The clearance of intrathecal baclofen, calculated from intrathecal bolus or continuous infusion studies, approximate its CSF turnover, suggesting elimination via bulk-flow removal of CSF. Direct infusion into the spinal subarachnoid space bypasses absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord. Intrathecal bolus After a bolus lumbar injection of 50 or 100 μg LIORESAL Intrathecal in 7 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. After single intrathecal bolus injection/short-term infusion, the volume of distribution in intrathecal compartment, calculated from CSF levels, ranges from 22 to 157 mL. Continuous infusion A study, conducted in 10 patients, suggests that the mean CSF clearance for continuous intrathecal infusion of LIORESAL is approximately 30 mL/hour. Continuous intrathecal infusion daily doses of 50 to 1200 μg result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/mL at steady state. According to the half-life measured in the CSF, CSF steady state concentrations will be reached within 1-2 days. During Intrathecal infusion the plasma concentrations do not exceed 5 ng/mL. Limited pharmacokinetic data suggest that a lumbar-cisternal baclofen concentration gradient of about 4:1 is established during continuous baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap during continuous baclofen infusion at the lumbar level in doses associated with therapeutic efficacy. The interpatient variability was considerable. This gradient suggests that spasticity in the lower extremities may be relieved with little effect on the upper limbs and with fewer cerebral adverse reactions due to diminished effects on the brain. Special populations Geriatrics No pharmacokinetic data is available in elderly patients after administration of LIORESAL Intrathecal. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower rate of absorption and elimination, a slightly prolonged elimination half-life, but a similar systemic exposure to baclofen compared to young adults. Hepatic impairment No pharmacokinetic data is available in patients with hepatic impairment after administration of LIORESAL Intrathecal. However, as the liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patient with hepatic impairment. Renal impairment No pharmacokinetic data is available in patients with renal impairment after administration of LIORESAL Intrathecal. Since baclofen is primarily eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded. Severe neurological outcomes have been reported in patients with renal impairment after oral administration, thus LIORESAL Intrathecal should be given with special care and caution in these patients (see PRECAUTIONS, Renal Impairment). Pharmacology Primary Pharmacological Activity Baclofen depresses monosynaptic and polysynaptic reflex transmission in the spinal cord. The antispastic activity is derived primarily from its action at the spinal level to reduce spasms in voluntary muscles (see also LIORESAL Product Monograph). Secondary Pharmacological Activity Intrathecal baclofen exerts an antinociceptive effect in rats and cats. These effects are independent of any debilitation of voluntary motor function. In addition, intrathecal baclofen affects lower urinary tract dynamics of the anesthetized dog. Vesical and urethral pressure was significantly decreased. Within 30 minutes of injection, relaxation of the bladder and a reduction in urethral resistance occurred. Toxicology Acute Toxicity LD50 values following intrathecal dosing are not available. Long-Term Toxicity The oral toxicity of LIORESAL has been thoroughly investigated. LIORESAL Intrathecal requires the use of much smaller doses to achieve a therapeutic effect, with consequential lower systemic exposure. Repeated dose toxicity Repeated intrathecal administration of baclofen to rats and dogs was not associated with irritation or inflammation of the spinal cord and surrounding tissues. Inflammation of the spinal cord was observed in one rabbit in a study that administered intrathecal baclofen to 3 rabbits weekly over a period of 3 to 6 months. Local tolerance Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent. Teratology and Reproduction studies Oral baclofen showed no significant adverse effects on fertility or postnatal development at non-maternally toxic dose levels in rats (approximately 2.1-times the maximum oral mg/kg dose in adults). At maternally toxic dose levels (8.3-times the maximum oral mg/kg dose in adults), baclofen increased the the incidence of omphalocoeles (ventral hernias) in rats, an effect not seen in mice or rabbits. Delayed fetal growth (ossification of bones) in the fetuses of rats and rabbits was also observed at maternotoxic doses. Rat: Doses of 4.4-5 and 17.7-21.3 mg/kg/day were administered orally to two groups of female rats during pre-mating, mating, gestation and lactation. The only significant effect was a reduction in litter size and survivability of offspring (possibly due to agalactia) in the high dose group. In another rat study, doses of 5 and 10 mg/kg/day were administered by gavage during the last trimester of pregnancy and throughout the lactation period. Five of 31 dams in the high dose group showed severe weight loss from days 15-21 of gestation as well as agalactia and the entire litter of each of these dams died by day 2 postpartum. In a third study, baclofen doses of 30 mg/kg/day produces symptoms of ataxia and drowsiness in dams and the death of 4 of 24 dams dosed from gestation Days 1 to 12. At this high dose level, there was a slight increase in the resorption rate; however, the number and size of the fetuses remained normal and no malformations were reported. Rat and Mouse: Doses of 5 and 20 mg/kg/day were administered by gavage to two groups of pregnant rats on days 6-15 of gestation. The only significant finding was the presence of abdominal hernias in 4/160 fetuses in the high dose group. In a second similar study, 1/229 control fetuses and 2/293 fetuses from dams receiving 20 mg/kg/day had abdominal hernias (See also WARNINGS). Comparable lesions did not occur in a similar mouse study. The average number of stillbirths or viable newborns did not differ significantly between control and medicated groups. The average weight of neonates from the high dose group was significantly reduced. Rabbit: Doses of 1, 5 and 10 mg/kg/day were administered by gavage to groups of rabbits from the 6th to 18th day of gestation. There was an increased incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in the fetuses from the high dose group. In another study, a slight increase in resorption rates was observed in rabbits receiving 10 and 15 mg/kg/day of oral baclofen. Baclofen did not cause teratogenic effects in mice, rats, and rabbits at doses up to125-times the maximum intrathecal mg/kg dose. LIORESAL given orally increased the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. LIORESAL dosed orally caused delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits, and when given intraperitoneally, baclofen at high doses caused widening of the vertebral arch in rat fetuses. Carcinogenicity studies A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or hemorrhagic adrenal glands was observed. Mutagenicity Studies Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. References DELHAAS EM, and BROUWERS JRBJ. Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991; 29: 274-280 LAZORTHES Y, SALLERIN-CAUTE B, VERDIE J-C, BASTIDE R, and CARILLO J-P. Chronic intrathecal baclofen administration for control of severe spasticity. J Neurosurg 1990; 72: 393-402 McLEAN BN. Intrathecal baclofen in severe spasticity. Br J Hosp Med 1993; 49 (4): 262-267 MÜLLER H, ZIERSKI J, DRALLE D, KRAUSS D, and MUTSCHLER E. Pharmacokinetics of intrathecal baclofen. IN: Müller H, Zierski J, and Penn RD (eds). Local-spinal therapy of spasticity. Springer-Verlag, Berlin etc., 1988; pp 223-226 MÜLLER H, ZIERSKI J, DRALLE D, HOFFMANN O, and MICHAELIS G. Intrathecal baclofen in spasticity. IN: Müller H, Zierski J, and Penn RD (eds). Local-spinal therapy of spasticity. Springer-Verlag, Berlin, etc.,1988; pp 155-214 OCHS G. Intrathecal baclofen for long-term treatment of spasticity: a multi-centre study. J Neurol Neurosurg Psychiatry 1989; 52: 933-939 PARKE B, PENN RD, SAVOY SM and CORCOS D. Functional outcome after delivery of intrathecal baclofen. Arch Phys Med Rehabil 1989; 70: 30-32 PENN RD. Intrathecal baclofen for severe spasticity. Ann NY Acad Sci 1988; 531: 157-166 PENN RD, SAVOY SM, CORCOS D, LATASH M, GOTTLIER G, PARKE B, and KROIN JS. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989; 320: 1517-1521 PENN RD, and KROIN JS. Long-term intrathecal baclofen infusion for treatment of spasticity. J Neurosurg 1987; 66: 181-185

CLINICAL PHARMACOLOGY Mechanism Of Action 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. Baclofen 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 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 are similar to those seen in adult patients. Continuous Infusion Adult Patients Intrathecal baclofen’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. Pediatric Patients No additional information on continuous infusions is available for pediatric patients. Pharmacokinetics The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF. Intrathecal Bolus After a bolus lumbar injection of 50 mcg or 100 mcg intrathecal baclofen 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 intrathecal baclofen 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 to 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 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL. Clinical Studies Spasticity Of Spinal Cord Origin Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen 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 intrathecal baclofen 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; intrathecal baclofen 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.

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, possiblyby 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 GABA receptor subtype. Baclofen Injection (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 Baclofen Injection (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: Intrathecal baclofen'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. No additional information is available for pediatric patients. Pharmacokinetics Of Baclofen Injection (Intrathecal) The pharmacokinetics of CSF clearance of intrathecal baclofen calculated from intrathecal bolus orcontinuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF. Intrathecal Bolus : After a bolus lumbar injection of 50 or 100 mcg intrathecal baclofen 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 intrathecal baclofen 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 to 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 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL.

Find Lowest Prices on LIORESAL® Intrathecal (baclofen) Injection  0.05 mg/mL, 0.5 mg/mL and 2 mg/mL For intrathecal injection and infusion only DESCRIPTION Drug Substance Baclofen Chemical Name: 4-amino-3-(p-chlorophenyl) butyric acid Molecular Formula: C10H12ClNO2 Molecular Weight: 213.67 Description: White to off-white, odorless or practically odorless crystalline powder. Solubility: Slightly soluble in water, very slightly soluble in methanol and insoluble in chloroform.   pKa: pKa, 1 = 3.87 (carboxyl group) and pKa, 2 = 9.62 (amino group) in water at 20OC. Composition The contents of each sterile ampoule are described in the following table. Dosage mg/mL Total Volume mL Medicinal ingredient Non-medicinal ingredients Baclofen/mg Sodium chloride/mg Water for injection 0.05 1 0.05 9 up to 1 mL 0.5 20 10 180 up to 20 mL 2 5 10 45 up to 5 mL

Find Lowest Prices on GABLOFEN (baclofen) Injection, for Intrathecal Use WARNING DO NOT DISCONTINUE ABRUPTLY 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 sheduling 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 post-implant clinician and patient information [see WARNINGS AND PRECAUTIONS]. DESCRIPTION GABLOFEN (baclofen injection) is a muscle relaxant and antispastic. Baclofen's pharmacological class is a gamma-aminobutyric acid (GABA) ergic agonist. Baclofen's chemical name is 4-amino- 3-(4- chlorophenyl) butanoic acid, and its structural formula is: Baclofen 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.

Baclofen (Intrathecal) 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 Baclofen Injection (Intrathecal) is a muscle relaxant and antispastic. Its chemical name is 4- amino- 3-(4- chlorophenyl) butanoic acid, and its structural formula is: Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform. Baclofen Injection (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 Baclofen Injection (Intrathecal) contains baclofen 50 mcg, 500 mcg or 2000 mcg and sodium chloride 8.8 mg in Water for Injection; pH range is 5.5-6.8. Each ampule is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT AUTOCLAVE.

INDICATIONS LIORESAL Intrathecal (baclofen injection) is indicated for the management of patients with severe spasticity due to spinal cord injury or multiple sclerosis who are unresponsive to oral baclofen or who experience unacceptable side effects at effective oral doses. LIORESAL Intrathecal therapy may be considered as an alternative to destructive neurosurgical procedures. Prior to implantation of a device for chronic intrathecal infusion, patients must demonstrate a positive clinical response to a LIORESAL Intrathecal screening trial (see DOSAGE AND ADMINISTRATION). LIORESAL Intrathecal has been used in patients with other spasticity of cerebral origin, e.g. spasticity following hypoxic encephalopathy, head injury, or stroke; however, clinical experience is limited. DOSAGE AND ADMINISTRATION Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. This is due to the great variability in the effective individual therapeutic dose. General The first dose should be performed with resuscitative equipment on stand-by. 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 available for immediate use in case of life threatening or intolerable adverse reactions. Implantation of pumps should only be performed in experienced centres in order to minimize the risks in the perioperative phase. Screening Phase Prior to initiation of chronic infusion of intrathecal baclofen, patients must demonstrate a response to intrathecal baclofen bolus in a screening trial. A test bolus dose of LIORESAL is usually administered via a lumbar puncture or an intrathecal catheter to elicit a response. For this purpose, low concentration ampoules of 0.05 mg/mL are available. The usual initial test dose is 25 μg or 50 μg and is stepped up by 25 μg increments at least 24 hours apart, until an approximately 4- to 8-hour response is observed; the dose should be given by barbotage over at least one minute. If an adverse reaction occurs at a dose of 25 μg, a lower dose, such as 10 μg may be tested. Patients should demonstrate a positive clinical response in order to be considered responders to treatment. A positive clinical response is characterized by a significant decrease in muscle tone and/or frequency and/or severity of spasms. There is great variability in sensitivity to intrathecal baclofen. Patients who do not respond to a 100 μg test dose should not be given further increases of dose or be considered for continuous intrathecal infusion. However, in rare instances some patients, particularly those with spasticity of cerebral origin, have received higher test bolus doses. Dose Titration Phase After confirmation that the patient is responsive to LIORESAL Intrathecal (baclofen injection) by means of test bolus doses, intrathecal infusion is established using a suitable delivery system. (See Drug delivery devices) To determine the initial total daily dose of LIORESAL Intrathecal following implant, the screening dose which 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 12 hours. In this case, the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be administered in the first 24 hours. After the first 24 hours, the dosage should be adjusted slowly on a daily basis to achieve the desired effect, with dosage increments limited to 10 to 30% to avoid possible overdosing. With programmable pumps, the dose should be increased only once every 24 hours. For non-programmable pumps with a 76 cm catheter delivering 1 mL/day, intervals of 48 hours are suggested for evaluation of response. If the daily dose has been significantly increased and no clinical effect is achieved, check for proper pump function and catheter patency. The clinical goal is to maintain as normal a muscle tone as possible, and to minimize the frequency and severity of spasms without inducing intolerable side effects. There is limited experience with doses greater than 1000 μg/day. Maintenance Therapy The lowest dose producing an adequate response should be used. Most patients require gradual increases in dose over time to maintain optimum response during chronic therapy due to decreased responsiveness to therapy or to progress of the disease. The daily dose may be gradually increased by 10 to 30% to maintain adequate symptom control by adjusting the dosing rate of the pump and/or the concentration of LIORESAL Intrathecal in the reservoir. The daily dose may also be reduced by 10 to 20% if patients experience side effects. A sudden requirement for substantial dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement) or pump malfunction. Maintenance dosage for long-term continuous infusion of intrathecal baclofen ranges from 10 μg/day to 1200 μg/day, most patients being adequately maintained on 300 μg/day to 800 μg/day. The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. Please consult pump manufacturer's manual for specific recommendations. During long-term treatment approximately 10% of patients become refractory to increasing doses. This 'tolerance' may be treated by gradually reducing LIORESAL Intrathecal dose over a 2 to 4 week period and switching to alternative methods of spasticity management (e.g. intrathecal preservative-free morphine sulfate). After a few days the sensitivity to baclofen may be restored and treatment should be resumed at the initial continuous infusion dose and followed by a titration phase to avoid overdose accidents. This must be performed in a hospital unit. Caution should be exercised when switching from LIORESAL Intrathecal to morphine and vice versa (see PRECAUTIONS: DRUG INTERACTIONS). Regular clinical review remains a necessity throughout to assess dosage requirements, functioning of the delivery system, and monitoring for possible adverse drug reactions or evidence of infection. Special Populations Renal impairment No studies have been performed in patients with renal impairment with LIORESAL Intrathecal therapy. Since baclofen is primarily eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded (see CLINICAL PHARMACOLOGY). LIORESAL Intrathecal should only be administered to end stage renal failure patients when benefit outweighs risk. These patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (see PRECAUTIONS, Renal Impairment). Since unwanted effects are more likely to occur in elderly patients or in patients with spastic states of cerebral origin, it is recommended that a very cautious dosage schedule be adopted in such cases and that the patient should be kept under appropriate surveillance. Patients should be monitored for signs of overdose, central nervous system depression and toxic encephalopathy such as drowsiness, impairment of consciousness, coma, respiratory depression, hallucinations, agitation, and convulsions (see Symptoms And Treatment Of Overdosage). Hepatic impairment No studies have been performed in patients with hepatic impairment receiving LIORESAL Intrathecal therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of LIORESAL. Therefore, hepatic impairment is not expected to impact the drug systemic exposure (see CLINICAL PHARMACOLOGY). However, patients with severe hepatic impairment should be treated with caution, as they are in general more sensitive to therapeutic effects/adverse effects of drugs. Geriatrics Several patients over the age of 65 years have been treated with LIORESAL Intrathecal during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated (see WARNINGS, PRECAUTIONS and CLINICAL PHARMACOLOGY). Delivery Regimen LIORESAL Intrathecal is most often administered in a continuous infusion mode immediately following implant. After the patient has stabilized with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimize control of spasticity at different times of the day. For example, patients who have increased spasm at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect. Drug Delivery Devices Intrathecal administration of LIORESAL through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to. Consult pump manufacturer's literature for information on the appropriate use and care of these devices. Evidence demonstrating the efficacy of LIORESAL Intrathecal was obtained using the Medtronic SynchroMed Programmable Infusion System. Other pumps proven to be suitable for intrathecal baclofen administration may be used. The Medtronic SynchroMed Programmable Infusion System is an implantable drug delivery system with refillable reservoirs which, after general or local anesthesia, is implanted in a subcutaneous pocket usually on the abdominal wall. This device is connected to an intrathecal catheter that passes subcutaneously to the subarachnoid space. The Medtronic SynchroMed Programmable Infusion System has an 18 mL drug reservoir and may be programmed to different flow rates such as single bolus, periodic boluses, continuous and complex continuous. However, the lithium battery of the pump has a life span of 3 to 4 years and therefore requires replacement. LIORESAL Intrathecal proved to be stable in the implanted SynchroMed Programmable Infusion System for 11 weeks. Details regarding the availability and use of this drug delivery device can be obtained from the manufacturer. Medtronic of Canada Ltd. 6733 Kitimat Road Mississauga, Ontario L5N 1W3 1 (800) 268 5346 Fax: 1 (416) 826 6620 General guidelines regarding the use of all implantable systems are located under PRECAUTIONS. Before using other systems, it must be confirmed that the technical specifications, including chemical stability of baclofen in the reservoir fulfil the requirements for safe and effective use of LIORESAL Intrathecal. Please consult pump manufacturer's manual for this information. HOW SUPPLIED Availability Of Dosage Forms PrLIORESAL Intrathecal (baclofen injection) 0.05 mg/mL: Each 1 mL ampoule of clear, colorless solution contains 0.05 mg baclofen for intrathecal administration. PrLIORESAL Intrathecal (baclofen injection) 0.5 mg/mL: Each 20 mL ampoule of clear, colorless solution contains 10 mg baclofen for intrathecal administration. PrLIORESAL Intrathecal (baclofen injection) 2 mg/mL: Each 5 mL ampoule of clear, colourless solution contains 10 mg baclofen for intrathecal administration. PrLIORESAL Intrathecal 0.05 mg/ml and 2 mg/ml are provided in cartons of 5 ampoules. PrLIORESAL Intrathecal 0.5 mg/ml is provided in cartons of 1 ampoule. Stability And Storage Recommendations Protect from heat (store at 15-30°C). Do not freeze. Do not heat sterilize. LIORESAL Intrathecal must be kept out of the reach and sight of children. Parenteral Products Instructions for use/handling: LIORESAL Intrathecal is intended for intrathecal injection and continuous intrathecal infusion as indicated by the delivery specifications of the infusion system. Each ampoule is intended for single use only. Discard any unused portion. Parenteral drug products should be inspected for particulate matter and discoloration prior to administration whenever solution and container permit. The concentration to be used depends upon the total daily dose required as well as the delivery rate of the pump. Please consult manufacturer's manual for specific recommendations. For patients who require concentrations other than 0.05 mg/mL, 0.5 mg/mL or 2.0 mg/mL, LIORESAL Intrathecal must be diluted, under aseptic conditions, with sterile preservative-free sodium chloride injection and used immediately. As a rule LIORESAL ampoules for intrathecal administration should not be mixed with other infusion or injection solutions. Dextrose proved to be incompatible due to a chemical reaction with baclofen. This leaflet was prepared by Novartis Pharmaceuticals Canada Inc., 385 Bouchard, Dorval, Quebec, H9S 1A9. Last Revised: September 18, 2013

INDICATIONS GABLOFEN is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of GABLOFEN via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. GABLOFEN is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in pumps labeled for intrathecal administration of GABLOFEN[see Clinical Studies]. Prior to implantation of a device for chronic intrathecal infusion of GABLOFEN, patients must show a response to GABLOFEN in a screening trial [see DOSAGE AND ADMINISTRATION]. DOSAGE AND ADMINISTRATION Use Only In Pumps Labeled For Intrathecal Administration Of GABLOFEN GABLOFEN is approved only for use in implantable pumps labeled for intrathecal administration of GABLOFEN. Refer to the manufacturer’s manual for specific instructions and precautions for programming the pump and/or refilling the reservoir. It is important to select the appropriate refill kit for the pump used to administer GABLOFEN. GABLOFEN is not to be compounded with other medications. Screening Phase Prior to pump implantation and initiation of chronic infusion of GABLOFEN, patients must demonstrate a positive clinical response to a GABLOFEN bolus dose administered intrathecally in a screening trial. The screening trial employs GABLOFEN at a concentration of 50 mcg/mL. A 1 mL syringe (50 mcg/mL) is available for use in the screening trial. The screening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space by barbotage over a period of not less than one minute. The patient is observed over the ensuing 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should be observed for an interval of 4 to 8 hours. If the response is still inadequate, a final bolus screening dose of 100 micrograms in 2 milliliters may be administered 24 hours later. Pediatric Patients The starting screening dose for pediatric patients is the same as in adult patients, i.e., 50 mcg. However, for very small patients, a screening dose of 25 mcg may be tried first. Patients who do not respond to a 100 mcg intrathecal bolus should not be considered candidates for an implanted pump for chronic infusion. Preparation Information Screening Use the 1 mL screening syringe only (50 mcg/mL) for bolus injection into the subarachnoid space. For a 50 mcg bolus dose, use 1 mL of the screening syringe. Use 1.5 mL of 50 mcg/mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/mL baclofen injection (2 screening syringes). Maintenance The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. For patients who require concentrations other than 500 mcg/mL, 1,000 mcg/mL, 2,000 mcg/mL, or 3,000 mcg/mL, GABLOFEN must be diluted with sterile preservative free Sodium Chloride for Injection, USP. Administration Information Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. The external surface of GABLOFEN prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. The use of GABLOFEN prefilled syringe in an aseptic setting (i.e., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended. For outpatient use, modify aseptic procedures to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the GABLOFEN prefilled syringe when filling the pump reservoir [see WARNINGS AND PRECAUTIONS]. Delivery Regimen GABLOFEN is most often administered in a continuous infusion mode immediately following implant. For those patients implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of GABLOFEN delivery. For example, patients who have increased spasms at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect. Dose Titration Post-Implant Dose Titration Period To determine the initial total daily dose of GABLOFEN following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved). In most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial dose escalation typically indicates a catheter complication (i.e., catheter kink or dislodgement). Adult Patients With Spasticity Of Spinal Cord Origin After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10% to 30% increments and only once every 24 hours, until the desired clinical effect is achieved. Adult Patients With Spasticity Of Cerebral Origin After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours, until the desired clinical effect is achieved. Pediatric Patients After the first 24 hours, the daily dose should be increased slowly by 5% to 15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dosetitration period immediately following implant. Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable side effects. Additional Considerations Pertaining To Dosage Adjustment Careful dose titration of GABLOFEN is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care. It may be important to titrate the dose to maintain some degree of muscle tone and allow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities of daily living and ease of care. Except in overdose related emergencies, the dose of GABLOFEN should ordinarily be reduced slowly if the drug is discontinued for any reason. An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic GABLOFEN infusion. Reduction and discontinuation of oral anti-spasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided. Maintenance Therapy Spasticity Of Spinal Cord Origin Patients The clinical goal is to maintain muscle tone as close to normal as possible, and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in lifestyle due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 10% to 40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10% to 20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of intrathecal baclofen has ranged from 12 mcg/day to 2,003 mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1,000 mcg/day. Determination of the optimal GABLOFEN dose requires individual titration. The lowest dose with an optimal response should be used. Spasticity Of Cerebral Origin Patients The clinical goal is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in lifestyle due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 5% to 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10% to 20% if patients experience side effects. Many patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of intrathecal baclofen has ranged from 22 mcg/day to 1,400 mcg/day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients required daily doses greater than 1,000 mcg/day. Pediatric Patients Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed to require a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/day, with a range of 24 mcg/day to 1,199 mcg/day. Dosage requirement for pediatric patients over 12 years does not seem to be different from that of adult patients. Determination of the optimal GABLOFEN dose requires individual titration. The lowest dose with an optimal response should be used. Potential Need For Dose Adjustments In Chronic Use During long term treatment, approximately 5% (28/627) of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this “tolerance” has been treated on occasion, in hospital, by a “drug holiday” consisting of the gradual reduction of intrathecal baclofen over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” intrathecal baclofen may be restarted at the initial continuous infusion dose. HOW SUPPLIED Dosage Forms And Strengths GABLOFEN 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 GABLOFEN contains baclofen USP 50 mcg, 500 mcg, 1,000 mcg or 2,000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.5 to 7.5. Each vial or syringe is intended for single use only. Discard any unused portion. Do not autoclave. Storage And Handling GABLOFEN (baclofen injection) is available in single use syringes and vials for intrathecal administration only. 50 mcg Per mL NDC 66794-151-01: 1 mL Syringe – 50 mcg per 1 mL 500 mcg Per mL NDC 66794-155-01: 20 mL Syringe – 10,000 mcg per 20 mL NDC 66794-155-02: 20 mL Vial – 10,000 mcg per 20 mL 1,000 mcg Per mL NDC 66794-156-01: 20 mL Syringe – 20,000 mcg per 20 mL NDC 66794-156-02: 20 mL Vial – 20,000 mcg per 20 mL 2,000 mcg Per mL NDC 66794-157-01: 20 mL Syringe – 40,000 mcg per 20 mL NDC 66794-157-02: 20 mL Vial – 40,000 mcg per 20 mL Does not require refrigeration. Do not store above 86°F (30°C). Do not freeze. Do not heat sterilize. Distributed By: Piramal Critical Care, Inc. 3950 Schelden Circle ,Bethlehem, PA 18017. Revised: Mar 2017

INDICATIONS Baclofen Injection (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 Baclofen Injection (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. Baclofen Injection (Intrathecal) 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 Baclofen Injection (Intrathecal) into the intrathecal space. Spasticity of Spinal Cord Origin Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen 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 intrathecal baclofen 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; intrathecal baclofen 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. Baclofen Injection (Intrathecal) therapy may be considered an alternative to destructive neurosurgical procedures. Prior to implantation of a device for chronic intrathecal infusion of Baclofen Injection (Intrathecal), patients must show a response to Baclofen Injection (Intrathecal) in a screening trial (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Refer to the manufacturer's manual for the implantable pump approved for intrathecal infusion for specific instructions and precautions for programming the pump and/ or refilling the reservoir. There are various pumps with varying reservoir volumes and there are various refill kits available. It is important to be familiar with all of these products in order to select the appropriate refill kit for the particular pump in use. Screening Phase Prior to pump implantation and initiation of chronic infusion of Baclofen Injection (Intrathecal), patients must demonstrate a positive clinical response to a Baclofen Injection (Intrathecal) bolus dose administered intrathecally in a screening trial. The screening trial employs Baclofen Injection (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 res pond 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 Baclofen Injection (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 to 30% increments and only once every 24 hours, until the desired clinical effect is achieved. Adult Patients With Spasticity Of Cerebral Origin After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved. Pediatric Patients After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and 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 to 40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10 to 20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of Baclofen Injection (Intrathecal) has ranged from 12 mcg/day to 2003 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 Baclofen Injection (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 to 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10 to 20% if patients experience side effects. Many patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of Baclofen Injection (Intrathecal) 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 Baclofen Injection (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 Baclofen Injection (Intrathecal) over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday”, Baclofen Injection (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. Baclofen Injection (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 (50 mcg/mL) for bolus injection into the subarachnoid space. For a 50 mcg bolus dose, use 1 mL of the screening ampule. Use 1.5 mL of 50 mcg/mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/mL baclofen injection (2 screening ampules). Maintenance For patients who require concentrations other than 500 mcg/mL or 2000 mcg/mL, Baclofen Injection (Intrathecal) must be diluted. Baclofen Injection (Intrathecal) must be diluted with sterile preservative free Sodium Chloride for Injection, U.S.P. Delivery Regimen Baclofen Injection (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 Baclofen Injection (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 Baclofen Injection (Intrathecal) is packaged in single use ampules of 0.05 mg/mL (50 mcg/mL), 10 mg/20 mL (500 mcg/mL) or 40 mg/20 mL (2000 mcg/mL) supplied as follow: Screening dose: Baclofen Injection (Intrathecal) 0.05 mg/mL (50 mcg/mL) in shelf carton of 10 ampules Baclofen Injection (Intrathecal) 10 mg/20 mL (500 mcg/mL) in individual packaging of 1 ampule Baclofen Injection (Intrathecal) 40 mg/20 mL (2000 mcg/mL) in individual packaging of 1 ampule Storage Does not require refrigeration. Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature]. Do not freeze. Do not heat sterilize. Manufactured by Sintetica SA, Mendrisio, Switzerland. Revised: May 2016

PATIENT INFORMATION PrLIORESAL Intrathecal (baclofen) Injection 0.05 mg/mL, 0.5 mg/mL and 2 mg/mL For intrathecal injection and infusion only This leaflet is part III of a three-part “Product Monograph” published when LIORESAL IT was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about LIORESAL IT. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS MEDICATION What the medication is used for: LIORESAL Intrathecal belongs to a group of medicines called muscle relaxants. It is used to reduce and relieve the excessive stiffness and/or spasms occurring in various illnesses such as, for example, multiple sclerosis, diseases or injuries of the spinal cord, and certain brain disorders. What it does: The solution is injected or infused into the fluid space around the spinal cord by use of a special pump which is implanted under the skin of your abdomen. From the pump a constant amount of the solution is delivered into the fluid space around the spinal cord through a tiny tube. Due to the beneficial effect on muscle contractions and the consequent relief from pain, LIORESAL Intrathecal improves your mobility and your ability to manage your daily activities without aid. LIORESAL also helps you to benefit more from physiotherapy. When it should not be used: You should not be treated with LIORESALIT if you: are allergic (hypersensitivity) to LIORESAL Intrathecal or any of the other ingredients of LIORESAL Intrathecal listed below. What the medicinal ingredient is: baclofen. What the nonmedicinal ingredients are: LIORESAL IT contains: sodium chloride and water for injection What dosage forms it comes in: LIORESAL Intrathecal (baclofen injection) 0.05 mg/mL: Each 1 mL ampoule contains 0.05 mg baclofen for intrathecal administration. LIORESAL Intrathecal (baclofen injection) 0.5 mg/mL: Each 20 mL ampoule contains 10 mg baclofen for intrathecal administration. LIORESAL Intrathecal (baclofen injection) 2 mg/mL: Each 5 mL ampoule contains 10 mg baclofen for intrathecal administration. WARNINGS AND PRECAUTIONS LIORESAL Intrathecal is suitable for many, but not all, patients with muscle spasms. BEFORE you use LIORESALIT talk to your doctor or pharmacist if you: have any kind of infection have Parkinson's disease or certain mental illnesses accompanied by confusion have epilepsy (seizures) have diabetes ever had heart problems ever had kidney problems have breathing problems have acute pain in your stomach or intestine have disturbed blood circulation in your brain have ever experienced sudden episodes of high blood pressure, anxiety, excessive sweating, “goose flesh”, pounding headache, and unusually slow heartbeat due to an overreaction of your nervous system to stimuli such as distension of the bladder and intestine, skin irritation and pain If any of these apply to you, your doctor may not want to give you this medicine or may want to take special precautions. If you have not told your doctor about any of these things, tell him/her before you start LIORESAL Intrathecal treatment. If you think you may be allergic, ask your doctor for advice. Driving and using machines: LIORESAL Intrathecal may make you feel sleepy or dizzy. Be careful when driving a car or using a machine or doing things that need careful attention until you are feeling normal again. INTERACTIONS WITH THIS MEDICATION Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including herbal and non- prescription medicines (over the counter). Some other medicines may interact with LIORESALIT. Your doctor may change the dosage or sometimes stop one of the medicines. This is particularly important for the following medicines: other medicines for your spastic condition medicines for Parkinson' disease medicines for epilepsy medicines used to treat mood disorders such as antidepressants and lithium medicines for high blood pressure other drugs which affect the kidney, e.g. ibuprofen opiates for pain relief medicines used to help you sleep or calm you down medicines which slow down the central nervous system, e.g. anti-histamines and sedatives (some of these can be bought over the counter) Always tell your doctor or nurse about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor. Be careful if you drink alcoholic beverages during treatment with LIORESAL Intrathecal as you may feel more sleepy or dizzy than usual. PROPER USE OF THIS MEDICATION Usual dose LIORESAL Intrathecal can only be given by experienced doctors using special medical equipment. You will need to stay in hospital, at least at the beginning of treatment. Your doctor will inject a small amount of LIORESAL Intrathecal into your spinal cord to see if it improves your muscle spasms. If it does, then a special pump will be implanted under your skin. The pump will give you a small amount of medicine all the time. It may take several days to find out the amount of medicine that suits you best, your doctor will keep a close watch on you during this time. After that, your doctor will still want to see you regularly to check your progress and make sure your pump is working well. IT IS OF UTMOST IMPORTANCE THAT APPOINTMENTS TO REFILL THE PUMP ARE KEPT, OTHERWISE SPASMS MAY RECUR BECAUSE YOU ARE NOT GETTING A HIGH ENOUGH DOSE OF LIORESAL INTRATHECAL. MUSCLE SPASTICITY MAY NOT IMPROVE OR MAY WORSEN AS A RESULT. If muscle spasticity is not improving or if you start having spasms again, either gradually or suddenly, contact your doctor immediately. Please consult the pump manufacturer's literature for information regarding proper home care of the pump and the insertion site. Monitoring during treatment with LIORESAL Intrathecal You will be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediately following pump implant. You will regularly be assessed for your dosage requirements, for possible side effects or evidence of infection. The functioning of the delivery system will also be checked. Pregnancy and breast-feeding You should tell your doctor if you are pregnant, or planning to become pregnant as LIORESAL Intrathecal should not be used during pregnancy, or if you are breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine. Your doctor will discuss with you the potential risk of taking LIORESAL Intrathecal during pregnancy. The doctor will decide if you may receive LIORESAL Intrathecal in these special situations. Only very small quantities of LIORESAL pass into the breast milk. Ask your doctor if you want to breast-feed. Overdose In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms. Signs of overdose may appear suddenly or insidiously e.g. by a malfunctioning of the pump. It is very important that you and those caring for you recognize signs of overdosage. If you experience any one or a combination of the following symptoms, tell your doctor without delay as the amount of drug you receive may be too high: unusual muscular weakness (too little muscle tone) sleepiness lightheadedness or dizziness excessive salivation nausea or vomiting difficulties in breathing, seizures or loss of consciousness abnormal low body temperature Missed Dose Abruptly stopping LIORESAL Intrathecal can result in serious medical problems and in rare cases has been fatal. Signs that your pump is not functioning properly or that it is not delivering the right amount of medication include an increase or return in spasticity, itching, low blood pressure, lightheadedness, tingling sensation, high fever, altered mental status, and muscle rigidity or new muscle weakness or paralysis. It is important to tell your doctor right away if you experience any of the above symptoms. SIDE EFFECTS AND WHAT TO DO ABOUT THEM As with all medicines, patients treated with LIORESAL Intrathecal, may experience some side effects, although not everybody gets them. These occur more often at the start of treatment during your hospital stay but they may also occur later and should be checked with your doctor. Very common: Drowsiness, muscle weakness Common: Feeling of anxiety, sedation and weariness (exhaustion), weakness in the legs, stiffness in the muscles, dizziness/light-headedness, headache, sleepiness, feeling sick and/or vomiting, tingling in hands and feet, insomnia, slurred speech, pneumonia, weakness, chills, fatigue, pain, dry mouth, skin rash and/or itching, swelling of the ankles, feet, or lower legs, puffy face, unusual nervousness or restlessness, confusion/disorientation, constipation, diarrhea, decreased appetite, excessive salivation, fever/shivering, urinary problems, sexual difficulties. Uncommon: Mood or mental changes, paranoia, feeling extreme happiness (euphoria), loss of muscle coordination (ataxia), abnormally low body temperature, memory loss, continuous uncontrollable eye movements, decreased sense of taste, difficulty in swallowing, abdominal pain, hair loss, excessive sweating. Rare: Restlessness, abnormally slow breathing rate. Tell your doctor if you notice any other effect. Some side effects could be associated with the delivery system. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom / effect Talk with your doctor or pharmacist Stop taking drug and immediately seek assistance Only if severe In all cases Common Low Blood Pressure √ Shortness of breath or unusually slow or troubled breathing √ Uncommon Unusually slow heartbeat √ Feeling of depression √ Suicidal ideas and suicide attempt √ Hallucina-tions: seeing or hearing things that are not there √ Visual Disturbance: blurred vision, double vision √ This is not a complete list of side effects. For any unexpected effects while taking LIORESAL IT contact your doctor or pharmacist. HOW TO STORE IT Store LIORESAL IT ampoules between 15-30°C (protect from heat). Do not freeze. Do not heat sterilize. Keep all medicines out of the reach and sight of children. This medicine is prescribed for your specific medical problem and for your own use only. Do not give to other people. Do not use outdated medicines. Discard them safely out of the reach of children or take them to your pharmacist who will dispose of them for you. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: Report online at www.healthcanada.gc.ca/medeffect Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: Fax toll-free to 1-866-678-6789, or Mail to: Canada Vigilance Program, Health Canada, Postal Locator 0701E, Ottawa, Ontario, K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect. NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice. MORE INFORMATION This document plus the full product monograph, prepared for health professionals can be found at: http://www.novartis.ca or by contacting the sponsor, Novartis Pharmaceuticals Canada Inc, at: 1-800-363-8883

PATIENT INFORMATION Risks Related To Sudden Withdrawal Of GABLOFEN Advise patients and caregivers that sudden withdrawal of GABLOFEN, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organsystem failure, and death. Inform patients that early symptoms of GABLOFEN withdrawal may include increased spasticity, itching, and tingling of extremities. If GABLOFEN withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment. Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug. GABLOFEN Overdose Inform patients and their caregivers that GABLOFEN overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump. Operation Of Automobiles And Other Dangerous Machinery Advise patients that GABLOFEN may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness. Increased Risk Of Drowsiness With Alcohol And Other CNS Depressants Inform patients and their caregivers that the drowsiness associated with GABLOFEN use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Symptoms And Treatment Of Overdosage For management of a suspected drug overdose, contact your regional Poison Control Centre for the most current information. Special attention must be given to recognizing the signs and symptoms of overdosage at all times, especially during the initial “screening” and “dose titration” phase of treatment and also during reintroduction of LIORESAL Intrathecal (baclofen injection) after a period of interruption of therapy. Symptoms Signs of overdose may appear suddenly or insidiously. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea and/or vomiting and cephalad progression of hypotonia. Respiratory depression, apnea, and coma result from serious overdosage. Serious overdose may occur, for example, by inadvertent delivery of catheter contents during catheter patency/position analysis. Errors in programming, excessively rapid dose increases, and concomitant treatment with oral baclofen are other possible causes of overdosage. Possible pump malfunction should also be investigated. Symptoms of severe LIORESAL Intrathecal overdose (coma) were reported in a sensitive adult patient after receiving a 25 μg intrathecal bolus dose. Treatment There is no specific antidote for treating overdoses of intrathecal baclofen, however, the following steps should generally be undertaken: Residual LIORESAL solution should be removed from the pump as soon as possible. Patients with respiratory depression should be intubated if necessary, until the drug is eliminated. If lumbar puncture is not contraindicated, consideration should be given in the early stage of the intoxication to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration. Institute measures to support cardiovascular function. In the event of convulsions, administer diazepam I.V. with caution. CONTRAINDICATIONS Known or suspected hypersensitivity to baclofen or to any of the excipients. LIORESAL Intrathecal should not be administered by intravenous, intramuscular, subcutaneous or epidural routes.

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 GABLOFEN after a period of interruption in therapy. Symptoms Of Intrathecal Baclofen Overdose Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus. Treatment Suggestions For Overdose There is no specific antidote for treating overdoses of GABLOFEN; however, the following steps should ordinarily be undertaken: Residual intrathecal baclofen solution should be removed from the pump as soon as possible. Patients with respiratory depression should be intubated if necessary, until the drug is eliminated. Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia. Physostigmine Doses For Adult Patients Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur. Physostigmine Doses For Pediatric Patients Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained. Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support. If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration. CONTRAINDICATIONS GABLOFEN is contraindicated in patients with a hypersensitivity to baclofen. Do not use GABLOFEN for intravenous, intramuscular, subcutaneous or epidural administration.

OVERDOSE Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dos e-titration phase of treatment, but also during re-introduction of Baclofen Injection (Intrathecal) after a period of interruption in therapy. Symptoms Of Baclofen Injection (Intrathecal) Overdose Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, hypothermia, seizures, rostral progression of hypotonia and loss of con-sciousness progressing to coma of up to 72 hr. duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus. Treatment Suggestions For Overdose There is no specific antidote for treating overdoses of Baclofen Injection (Intrathecal); however, the following steps should ordinarily be undertaken: Residual Baclofen Injection (Intrathecal) solution should be removed from the pump as soon as possible. Patients with respiratory depression should be intubated if necessary, until the drug is eliminated. If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration. CONTRAINDICATIONS Hypersensitivity to baclofen. Baclofen Injection (Intrathecal) is not recommended for intravenous, intramuscular, subcutaneous or epidural administration.

SIDE EFFECTS Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression. The most commonly reported adverse events with LIORESAL Intrathecal (baclofen injection) in clinical trials were drowsiness, weakness in the lower extremities, dizziness and seizures. Adverse drug reactions from clinical trials are listed in the table below according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common ( ≥ 1/10); common ( ≥ 1/100, < 1/10); uncommon ( ≥ 1/1,000, < 1/100); rare ( ≥ 1/10,000, < 1/1,000); very rare ( < 1/10,000), including isolated reports. Adverse events associated with the delivery system (e.g. mass at the tip of the catheter, catheter dislocation with possible complications, pocket infection, meningitis, overdose due to wrong manipulation of the device) have been reported, whereby in some cases a causal relationship with baclofen cannot be excluded (see WARNINGS). These are in addition to those listed below. In a fatal case of a child (causality with baclofen uncertain), inflammatory signs in the posterior horns and signs of arachnoiditis in proximity of the catheter tip were observed. This corresponds to observations in dogs, where chronic inflammatory reactions to the foreign body of the catheter were observed, independently of baclofen concentration. Incidence of Most Frequent Adverse Events in US Clinical Trials Adverse Event Number of patients reporting events (%) Screening (N= 244) Titration (N= 214) Maintenance (N=214) Somnolence 13 (5.3%) 11(5.1%) 18 (8.4%) Weakness, Lower Extremities 1 (0.4%) 11(5.1%) 15 (7.0%) Dizziness 6 (2.4%) 5 (2.3%) 12(5.6%) Convulsion 1 (0.4%) 4 (1.9%) 11 (5.1%) Headache 0 (0%) 3 (1.4%) 9 (4.2%) Nausea/Vomiting 3 (1.2%) 5 (2.3%) 3 (1.4%) Numbness/Itching/Tingling 2 (0.8%) 1 (0.5%) 8 (3.7%) Hypotension 3 (1.2%) 0 (0%) 5 (2.3%) Vision Blurred 0 (0%) 2 (0.9%) 5 (2.3%) Constipation 0 (0%) 2 (0.9%) 5 (2.3%) Hypotonia 2 (0.8%) 3 (1.4%) 2 (0.9%) Dysarthria 0 (0%) 1 (0.5%) 6 (2.8%) Coma (Overdose) 0 (0%) 4 (1.9%) 3 (1.4%) Lethargy 1 (0.4%) 0 (0%) 4 (1.9%) Weakness, Upper Extremities 1 (0.4%) 0 (0%) 4 (1.9%) Hypertension 1 (0.4%) 2 (0.9%) 2 (0.9%) Dyspnea 1 (0.4%) 2 (0.9%) 1 (0.5%) In addition to the more common adverse events reported above, the following adverse events were observed during clinical trials elsewhere or reported by clinicians. Metabolism and nutritional disorders Uncommon: Dehydration, weight loss, albuminuria and hyperglycemia Psychiatric disorders Common: Depression, anxiety, agitation Uncommon: Suicide ideation and suicide attempt, hallucinations, paranoia, euphoric mood Nervous system disorders Common: Confusional state, disorientation, insomnia, sedation, paresthesia, fatigue, lethargy Uncommon: nystagmus, ataxia, memory impairment. Eye disorders Common: Accommodation disorder, diplopia Cardiac disorders Uncommon: Bradycardia Rare: pulmonary embolism. Vascular disorders Uncommon: Deep vein thrombosis, flushing, pallor Gastrointestinal disorders Common: Dry mouth, diarrhea, decreased appetite, increased salivation Uncommon: Ileus, hypogeusia, dysphagia Respiratory, thoracic and mediastinal disorders Common: Respiratory depression, pneumonia, Renal and urinary disorders Common: urinary incontinence, urinary retention. Reproduction system and breast disorders Common: Sexual dysfunction Skin and subcutaneous tissue disorders Common: Urticaria, pruritus, facial and/or peripheral edema Uncommon: Alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders Common: Hypertonia General disorders and administration site conditions Common: Asthenia, pyrexia, chills, pain Uncommon: Hypothermia Adverse Drug Reactions From Spontaneous Reports And Literature Cases (frequency not known) The following adverse drug reactions have been derived from post-marketing experience with LIORESAL Intrathecal via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. Nervous system disorders: dysphoria Respiratory, thoracic and mediastinal disorders: bradypnea DRUG INTERACTIONS There is little experience with the use of LIORESAL Intrathecal in combination with systemic medications to predict specific drug-drug interactions, although it is suggested that the low baclofen systemic exposure observed after intrathecal administration could reduce the potential for pharmacokinetic interactions (see CLINICAL PHARMACOLOGY). Drug-Drug Interactions Levodopa/ Dopa Decarboxylase (DDC) inhibitor (carbidopa) Concomitant use of oral LIORESAL and levodopa (alone or in combination with a DDC inhibitor, carbidopa) resulted in increased risk of adverse events such as visual hallucinations, confusional state, headache and nausea. Worsening of the symptoms of Parkinsonism has also been reported. Thus, similar interaction can be anticipated for intrathecal LIORESAL. Anesthetics Concomitant use of intrathecal baclofen and general anesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anesthetics are administered to patients receiving intrathecal LIORESAL. Morphine The combined use of morphine and intrathecal baclofen was responsible for hypotension in one patient. The potential for this combination to cause dyspnea or other CNS symptoms cannot be excluded. The co-administration of other intrathecal agents with LIORESAL Intrathecal has not been tested and the safety of these combinations is unknown. Alcohol and other compounds affecting CNS The central nervous system depressant effects of alcohol and other compounds affecting the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) may be additive to the effects of LIORESAL Intrathecal. Increased sedation may occur when LIORESAL Intrathecal is taken concomitantly with other drugs causing CNS depression, including other muscle relaxants (such as tizanidine), synthetic opiates, hypnotics, anxiolytics or alcohol (see PRECAUTIONS - Driving and using machines). The risk of respiratory depression is also increased. Careful monitoring of respiratory and cardiovascular functions is essential, especially in patients with cardiopulmonary disease and respiratory muscle weakness. Tricyclic antidepressants When using oral baclofen, concurrent treatment with tricyclic antidepressants may potentiate the effect of LIORESAL, resulting in pronounced muscular hypotonia. In addition, concomitant use of tricyclic antidepressants can cause sedation, drowsiness and potentiate the effects of LIORESAL resulting in pronounced muscular hypotonia. Therefore, caution is advised when using LIORESAL Intrathecal in this combination. Lithium Concomitant use of oral baclofen and lithium resulted in aggravated hyperkinetic symptoms. Caution should be exercised when LIORESAL Intrathecal is used concomitantly with lithium. Antihypertensives Since concomitant treatment with oral LIORESAL and antihypertensives is likely to increase antihypertensive effects, it is recommended that blood pressure is checked and if necessary, the dosage of antihypertensive medication adjusted accordingly.

SIDE EFFECTS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In a recent clinical study, 153 adult and pediatric patients with spasticity of spinal cord or cerebral origin were treated with Gablofen 3,000 mcg/mL. The adverse reactions seen in this study were similar to that found with lower concentrations of Gablofen. Spasticity Of Spinal Cord Origin Most Common Adverse Reactions In Patients With Spasticity Of Spinal Origin In pre- and post-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia. Adverse Reactions Associated With Discontinuation Of Treatment 8/474 patients with spasticity of spinal cord origin receiving long term infusion of intrathecal baclofen in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse reactions. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations. Fatalities - [see WARNINGS AND PRECAUTIONS]. Incidence In Controlled Trials Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving intrathecal baclofen in two randomized, placebo-controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse reactions were reported among the 32 patients receiving placebo in these studies. Events Observed During The Pre- And Post-Marketing Evaluation Of Intrathecal Baclofen Adverse events associated with the use of intrathecal baclofen reflect experience gained with 576 patients followed prospectively in the United States. They received intrathecal baclofen for periods of one day (screening) (N=576) to over eight years (maintenance) (N=10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2,003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases and many of the adverse reactions reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions . hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache . appear clearly drug-related. Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in Table 1. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post-marketing studies. Table 1: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Spinal Origin in Prospectively Monitored Clinical Trials Adverse Reactions Percent N=576 Screening* Percent N=474 Titration† Percent N=430 Maintenance‡ 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 Dypsnea 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 * 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 In addition to the more common (1% or more) adverse reactions reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to intrathecal baclofen from foreign studies has been reported. The following adverse reactions, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported: Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilatation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis. Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis. Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia. Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis. Urogenital: Hematuria and kidney failure. Skin and Appendages: Alopecia and sweating. Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia. Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus. Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose. Hemic and Lymphatic System: Anemia. Spasticity Of Cerebral Origin Most Common Adverse Reactions In pre-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia. Adverse Reactions Associated with Discontinuation of Treatment Nine of 211 patients receiving intrathecal baclofen in pre-marketing clinical studies in the U.S. discontinued long-term infusion due to adverse reactions associated with intrathecal therapy. The nine adverse reactions leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1). Fatalities Three deaths, none of which were attributed to intrathecal baclofen, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients. Incidence In Controlled Trials Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following adverse reactions occurred among the 62 patients receiving intrathecal baclofen in two randomized, placebocontrolled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia. Events Observed During The Pre-Marketing Evaluation Of Intrathecal Baclofen Adverse events associated with the use of intrathecal baclofen reflect experience gained with a total of 211 U.S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received intrathecal baclofen for periods of one day (screening) (N=211) to 84 months (maintenance) (N=1). The usual screening bolus dose administered prior to pump implantation in these studies was 50 mcg to 75 mcg. The maintenance dose ranged from 22 mcg to 1,400 mcg per day. Doses used in this patient population for long-term infusion are generally lower than those required for patients with spasticity of spinal cord origin. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions . somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma . appear clearly drug-related. The most frequent (≥1%) adverse reactions reported during all clinical trials are shown in Table 2. Nine patients discontinued long term treatment due to adverse reactions. Table 2: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Cerebral Origin Adverse Reactions Percent N=211 Screening* Percent N=153 Titration† Percent N=150 Maintenance‡ 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 Impotence 0.5 0.0 1.3 Agitation 0.0 0.0 2.0 Asthenia 0.5 0.0 1.3 Chills 0.5 0.0 1.3 Coma 0.5 0.0 1.3 Dry Mouth 0.0 0.0 2.0 Pneumonia 0.5 0.7 0.7 Speech Disorder 0.5 0.0 1.3 Tremor 0.0 0.0 2.0 Urinary Incontinence 0.0 0.0 2.0 Urination Impaired 2.4 14.4 34.7 * 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 reactions reported in the prospectively followed 211 patients exposed to intrathecal baclofen have been reported. In the total cohort, the following adverse reactions, not described in Table 2, and arranged in decreasing order of frequency, and classified by body system, were reported: Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation. Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder. Cardiovascular: Bradycardia. Respiratory: Apnea, dyspnea and hyperventilation. Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis. Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer. Special Senses: Abnormality of accommodation. Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia. Hemic and Lymphatic System: Leukocytosis and petechial rash. DRUG INTERACTIONS There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of GABLOFEN and epidural morphine include hypotension and dyspnea.

SIDE EFFECTS 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 intrathecal baclofen 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 intrathecal baclofen 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 intrathecal baclofen obtained in parallel, placebocontrolled, 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 intrathecal baclofen 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 Intrathecal Baclofen: Adverse events associated with the use of intrathecal baclofen reflect experience gained with 576 patients followed prospectively in the United States. They received intrathecal baclofen for periods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases and many of the adverse 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 drugrelated.  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 postmarketing studies. 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 Screeninga N = 474 Titrationb N = 430 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 aFollowing administration of test bolus bTwo month period following implant cBeyond two months following implant N = total number of patients entering each period % = % of patients evaluated In addition to the more common (1% or more) adverse events reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to intrathecal baclofen 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 intrathecal baclofen 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 intrathecal baclofen in premarketing 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 intrathecal baclofen, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See WARNINGS on other deaths reported in spinal spasticity patients. Incidence in Controlled Trials: Experience with intrathecal baclofen obtained in parallel, placebocontrolled, 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 intrathecal baclofen 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 Intrathecal Baclofen: Adverse events associated with the use of intrathecal baclofen reflect experience gained with a total of 211 U.S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received intrathecal baclofen for periods of one day (screening) (N= 211) to 84 months (maintenance) (N= 1). The usual screening bolus dose administered prior to pump implantation in these studies was 50 to 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 intrathecal baclofen cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions - somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma - appear clearly drug-related. The most frequent (≥1%) adverse 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 Percent of Patients Reporting Events N = 211 Screening a N = 153 Titration b N = 150 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 Diarrea 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 aFollowing administration of test bolus bTwo month period following implant cBeyond two months following implant N = total number of patients entering each period. 211 patients received drug; 1 of 212 received placebo only. % = % of patients evaluated The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to intrathecal baclofen 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. DRUG INTERACTIONS There is inadequate systematic experience with the use of Baclofen Injection (Intrathecal) in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of Baclofen Injection (Intrathecal) and epidural morphine include hypotension and dyspnea.

WARNINGS Because of the possibility of potential life-threatening CNS depression, cardiovascular collapse and/or respiratory failure, physicians must be adequately trained in intrathecal infusion therapy. Specific instructions for programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to. Consult pump manufacturer's literature for information on the appropriate use and care of these devices. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these procedures must be conducted in a medically supervised and adequately equipped environment (see DOSAGE AND ADMINISTRATION). Resuscitative equipment should be available. The pump system should not be implanted until the patient's response to bolus intrathecal injection of LIORESAL Intrathecal (baclofen injection) has been properly evaluated and found to be clinically safe and effective. Following surgical implantation of the pump, particularly during the initial phase 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. Whenever the dosing rate of the pump and/or the concentration of LIORESAL Intrathecal 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 and all those involved in the care of the patient receive adequate information regarding the risks of LIORESAL Intrathecal 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. Inflammatory mass at the tip of implanted catheter with LIORESAL Intrathecal Cases of inflammatory mass at the tip of the implanted catheter, have been reported in patients receiving LIORESAL Intrathecal monotherapy. The most frequent symptom associated with these masses is decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases). It is known that inflammatory mass at intrathecal tip can result in pain and serious neurological impairment. Clinicians should monitor patients on LIORESAL Intrathecal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an inflammatory mass, consider a neurosurgical consultation since many of the symptoms of inflammatory mass are similar to the symptoms experienced by patients with severe spasticity from their disease. A diagnostic imaging procedure may be appropriate to confirm or rule-out inflammatory mass. Inflammatory masses have also been reported in patients receiving pharmacy compounded drugs or admixtures, including opioids. Diagnosis and management of inflammatory mass in these patients should take into consideration the pharmacology of the drugs in addition to LIORESAL. Abrupt Drug Withdrawal Abrupt discontinuation of LIORESAL Intrathecal, 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 LIORESAL Intrathecal requires careful attention to proper programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of LIORESAL 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 LIORESAL Intrathecal). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information. (see WARNINGS). In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of LIORESAL Intrathecal therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of LIORESAL Intrathecal therapy. Common reasons for abrupt interruption of LIORESAL Intrathecal 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. All patients receiving LIORESAL Intrathecal 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 LIORESAL Intrathecal 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 LIORESAL Intrathecal withdrawal. The suggested treatment for LIORESAL Intrathecal withdrawal is the restoration of LIORESAL Intrathecal 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 baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral baclofen alone should not be relied upon to halt the progression of the effects of LIORESAL Intrathecal 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. Therefore, except for serious adverse reactions and overdose related emergencies, the dose should always be reduced slowly when the drug is discontinued (over a period of approximately 1-2 weeks). Neonatal Withdrawal Convulsions have been reported in neonates after intrauterine exposure to oral baclofen (See PRECAUTIONS, Pregnant Women). PRECAUTIONS 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 patient's response to bolus intrathecal baclofen. Careful monitoring of respiratory and cardiovascular functions is essential during initial test dose administration (screening phase), especially in patients with cardiopulmonary disease and respiratory muscle weakness as well as those being treated concomitantly with benzodiazepine-type preparations or opiates who are at higher risk of respiratory depression. 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 attempts to adjust the dose. Patient Monitoring Following surgical implantation of the pump, particularly during the initial phases of pump use, and on each occasion that the dosing rate of the pump and/or the concentration of baclofen in the reservoir is adjusted, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and stable. Pump 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 Filling 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. Depending on individual daily dose requirements and the flow rate of the pump, refill intervals generally vary between one and three months. Strictly aseptic filling is required to avoid microbial 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 implantable pump equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the access port may cause a life-threatening overdose. In order to prevent excessive weakness and falling, LIORESAL Intrathecal should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion or whenever spasticity is used to maintain function. It may be important to maintain some degree of muscle tone and allow occasional spasms to help support circulatory function and possibly prevent the formation of deep vein thrombosis. An attempt should be made to discontinue concomitant oral antispastic medication to avoid possible overdose or adverse drug interactions, preferably before initiating baclofen infusion, with careful monitoring by the physician. However, abrupt reduction or discontinuation of concomitant antispastics during chronic intrathecal therapy with baclofen should be avoided. Driving And Using Machines Central nervous systems (CNS) depressant effects, such as somnolence and sedation have been reported in some patients on intrathecal baclofen. Other listed events include ataxia, hallucinations, diplopia and withdrawal symptoms (see ADVERSE REACTIONS). Patients should be cautioned regarding the operation of automobiles or dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system effects of baclofen may be additive to those of alcohol and other CNS depressants. Geriatrics Elderly patients may be more susceptible to the side effects of oral baclofen in the titration stage and this may also apply to intrathecal baclofen. Pediatrics The safety and efficacy of LIORESAL Intrathecal has not been studied in patients under 18 years of age. Its use in pediatric patients is not recommended unless the benefits outweigh the risk. Pregnant Women There are no adequate and well-controlled studies of LIORESAL Intrathecal in pregnant women. LIORESAL Intrathecal has been detected in maternal plasma (see CLINICAL PHARMACOLOGY) and is known to cross the placental barrier (see Toxicology). Post-marketing reports on mothers who used LIORESAL Intrathecal during pregnancy suggest a higher than expected rate of preterm delivery and delivery by caesarian section. Further, these preterm births have resulted in low birth weights according to what would be expected for gestational age. Therefore, LIORESAL Intrathecal should not be used during pregnancy unless the potential benefits to the mother outweigh the potential risk to the fetus. Infants exposed to LIORESAL through maternal oral dosing during pregnancy are at risk of experiencing baclofen withdrawal at birth; identification of this condition may be confounded due to delayed appearance of withdrawal symptoms in this population. One case of suspected withdrawal reaction (generalized convulsions) has been reported in a week-old infant whose mother had taken oral baclofen during pregnancy. The convulsions, which were refractory to different anticonvulsants, ceased within 30 minutes of giving baclofen to the infant. Nursing Women Oral baclofen at therapeutic doses passes into breast milk. LIORESAL Intrathecal should not be used in nursing women unless the potential the benefit outweigh the risk. Patients With Special Diseases And Conditions In patients with abnormal CSF flow, the spread of the drug and therefore, the distribution of antispastic activity may be inadequate. Patients suffering from psychotic disorders, schizophrenia, confusional states, or Parkinson's disease should be treated cautiously with LIORESAL Intrathecal and kept under careful surveillance as exacerbations of these conditions have been observed with oral baclofen administration. Special attention should be given to patients known to suffer from epilepsy as seizures have been reported during overdose with, and withdrawal from, LIORESAL Intrathecal, as well as in patients maintained on therapeutic doses of LIORESAL Intrathecal. 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 may cause an autonomic dysreflexic episode. LIORESAL should be used with caution in patients with cerebrovascular or respiratory insufficiency, as these conditions may be exacerbated by baclofen. Interaction of intrathecal baclofen with underlying, non-CNS related diseases is unlikely because the systemic availability of the drug after intrathecal administration is substantially lower than after oral administration. Nevertheless, observations after oral baclofen therapy suggest that caution should be exercised in the following situations: history of peptic ulcers, pre-existing sphincter hypertonia, and impaired hepatic function. Renal impairment No studies have been performed in patients with renal impairment receiving LIORESAL Intrathecal therapy. After oral LIORESAL dosing, severe neurological outcomes including clinical manifestations of toxic encephalopathy (e.g. somnolence, depressed level of consciousness and coma) have been reported in patients with renal impairment. Caution should be exercised while administering LIORESAL Intrathecal in patients with renal impairment because baclofen is primarily excreted unchanged through the kidneys. Patients with severe renal impairment should be treated with extra caution, as they are in general more sensitive to therapeutic effects/adverse effects of drugs. Severely renal impaired patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (see Symptoms And Treatment Of Overdosage). Hepatic Impairment No studies have been performed in patients with hepatic impairment receiving LIORESAL Intrathecal therapy. As baclofen does not undergo predominant hepatic metabolism, its pharmacokinetics is unlikely to be altered to a clinically significant level in patients with hepatic impairment. However, the patients with severe hepatic impairment should be treated with caution, as they are in general more sensitive to therapeutic effects/adverse effects of drugs. In rare instances, elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral baclofen.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Risk Of Life-Threatening Overdose During Pump Refills Use extreme caution when filling pumps equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a lifethreatening overdose. Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Carefully calculate refill intervals to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal. Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir. Potential For Contamination Due To Non-Sterile External Surface Of Prefilled Syringe Although the drug solution and pathway in the GABLOFEN prefilled syringes are sterile, the external surface of the prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. This has the potential to lead to contamination and consequent adverse reactions. The use of GABLOFEN prefilled syringe in an aseptic setting (e.g., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended, unless the external surface of the prefilled syringe is treated to ensure sterility. GABLOFEN supplied in vials may be used with conventional aseptic technique to fill intrathecal pumps prior to implantation. Procedures should also be put in place while refilling implantable intrathecal pumps in an outpatient setting to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the GABLOFEN prefilled syringe. Prescriber, Caregiver And Patient Training And Screening Procedure/Post-Implantation Environment GABLOFEN is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps labeled for intrathecal administration of GABLOFEN. Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy. The pump system should not be implanted until the patient's response to bolus GABLOFEN injection is adequately evaluated. Evaluation (consisting of a screening procedure) requires that GABLOFEN be administered into the intrathecal space via a catheter or lumbar puncture [see DOSAGE AND ADMINISTRATION ]. 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 [see DOSAGE AND ADMINISTRATION]. Resuscitative equipment should be available. Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable. On each occasion that the dosing rate of the pump and/or the concentration of GABLOFEN in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient’s response to the infusion is acceptable and reasonably stable. It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site. Overdose Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma. Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction or dosing error [see OVERDOSE] Extreme caution must be used when filling the implantable pump. Pumps should only be refilled through the reservoir refill septum. Use extreme caution when filling a pump which is equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose. Withdrawal Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures [see Drowsiness]. Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal. Seizures have been reported during overdose and with withdrawal from intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen. Possible Exacerbation Of Psychotic Disorders, Schizophrenia, Or Confusional States Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with GABLOFEN and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration. Fatalities Spasticity Of Spinal Cord Origin There were 16 deaths reported among the 576 U.S. patients treated with intrathecal baclofen in pre- and post-marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, intrathecal baclofen played in their deaths. As a group, the patients who died were relatively young (mean age was 47 with a range from 25 to 63), but the majority suffered from severe spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/or had received multiple concomitant medications. A case-by-case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with intrathecal baclofen caused their deaths. Two patients, however, did suffer sudden and unexpected death within 2 weeks of pump implantation and one patient died unexpectedly after screening. One patient, a 44 year-old male with Multiple Sclerosis, died in hospital on the second day following pump implantation. An autopsy demonstrated severe fibrosis of the coronary conduction system. A second patient, a 52 year-old woman with MS and a history of an inferior wall myocardial infarction, was found dead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is impossible to determine whether intrathecal baclofen contributed to these deaths. The third patient underwent three baclofen screening trials. His medical history included spinal cord injury, aspiration pneumonia, septic shock, disseminated intravascular coagulopathy, severe metabolic acidosis, hepatic toxicity, and status epilepticus. Twelve days after screening (he was not implanted), he again experienced status epilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pursued and the patient died. Spasticity Of Cerebral Origin There were three deaths occurring among the 211 patients treated with intrathecal baclofen in premarketing studies as of March 1996. These deaths were not attributed to the therapy. Use With Caution In Patients With A History Of Autonomic Dysreflexia GABLOFEN should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of GABLOFEN may cause an autonomic dysreflexic episode. Infections Patients should be infection-free prior to the screening trial with GABLOFEN because the presence of a systemic infection may interfere with an assessment of the patient’s response to bolus GABLOFEN. Patients should be infection-free prior to implantation of the pump because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing. Drowsiness Drowsiness has been reported in patients on intrathecal baclofen. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of intrathecal baclofen may be additive to those of alcohol and other CNS depressants. Intrathecal Mass Formation Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass. Ovarian Cysts A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population. Nonclinical Toxicology Carcinogenesis & Mutagenesis & Impairment Of Fertility No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m2 basis, the maximum oral dose recommended for human use. Mutagenicity assays with baclofen have not been performed. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. GABLOFEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits. Labor & Delivery The effect of baclofen on labor and delivery is unknown. Nursing Mothers At therapeutic oral doses, baclofen is excreted in human milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving GABLOFEN. Because of the potential for serious adverse reactions in nursing infants from GABLOFEN, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer’s manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established.

WARNINGS Baclofen Injection (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 Baclofen Injection (Intrathecal) is adequately evaluated. Evaluation (consisting of a screening procedure: see DOSAGE AND ADMINISTRATION) requires that Baclofen Injection (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 Baclofen Injection (Intrathecal) 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. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neurolepticmalignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Rapid, accurate diagnosis and treatment in an emergency-room or intensive- care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal. Seizures have been reported during overdose and with withdrawal from intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen. Fatalities Spasticity Of Spinal Cord Origin There were 16 deaths reported among the 576 U.S. patients treated with intrathecal baclofen in pre- and post- marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, intrathecal baclofen played in their deaths. As a group, the patients who died were relatively young (mean age was 47 with a range from 25 to 63), but the majority suffered from severe spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/ or had received multiple concomitant medications. A case- by- case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with intrathecal baclofen caused their deaths. Two patients, however, did suffer sudden and unexpected death within 2 weeks of pump implantation and one patient died unexpectedly after screening. One patient, a 44 year-old male with 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 intrathecal baclofen 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 intrathecal baclofen 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 Baclofen Injection (Intrathecal) because the presence of a systemic infection may interfere with an assessment of the patient's response to bolus Baclofen Injection (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. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Subcutaneous injection may result in symptoms of a systemic overdose or early depletion of the reservoir. 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 Dos Age 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 Baclofen Injection (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 Baclofen Injection (Intrathecal) infusion. Reduction and discontinuation of oral anti-spasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided. Drowsiness Drowsiness has been reported in patients on intrathecal baclofen. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of Baclofen Injection (Intrathecal) may be additive to those of alcohol and other CNS depressants. Intrathecal Mass Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. In patients with new neurological signs or symptoms suggestive of an intrathecal mass, consider a neurosurgical consultation, since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an intrathecal mass. Precautions In Special Patient Populations Careful dose titration of Baclofen Injection (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 Baclofen Injection (Intrathecal) and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration. Baclofen Injection (Intrathecal) should be used with caution in patients with a history of autonomic dys- reflexia. The presence of nociceptive stimuli or abrupt withdrawal of Baclofen Injection (Intrathecal) may cause an autonomic dysreflexic episode. Because baclofen 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 Baclofen Injection (Intrathecal). Carcinogenesis, Mutagenesis, And Impairment Of Fertility No increase in tumors was seen in rats receiving baclofen (baclofen USP) orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m² basis, the maximum oral dose recommended for human use. Mutagenicity assays with baclofen have not been performed. Pregnancy Category C Baclofen (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. Baclofen 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 (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 intrathecal baclofen. As a general rule, nursing should be undertaken while a patient is receiving intrathecal baclofen 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. Cons iderations bas ed on experience with oral baclofen (baclofen USP) A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.