Baclofen

1 INDICATIONS AND USAGE Baclofen injection 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 baclofen injection 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 is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only with the Medtronic SynchroMed ® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection [see Clinical Studies ( 14 )] . Prior to implantation of a device for chronic intrathecal infusion of baclofen injection, patients must show a response to baclofen injection in a screening trial [see Dosage and Administration ( 2.2 )] . Baclofen injection is a gamma-aminobutyric acid (GABA) ergic agonist indicated for use in the management of severe spasticity of cerebral or spinal origin in adult and pediatric patients age 4 years and above ( 1 ) Baclofen injection should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable central nervous system side effects at effective doses ( 1 ) Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. ( 1 ) Spasticity due to traumatic brain injury: wait at least one year after injury before considering baclofen injection therapy ( 1 )

2 DOSAGE AND ADMINISTRATION Baclofen injection is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use in the Medtronic SynchroMed ® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection; Refer to the pump manufacturer's manual and follow the specific instructions and precautions for programming the pump and/or refilling the reservoir ( 2.1 ) Screening : Patients who do not respond to a 100 mcg intrathecal bolus should not be considered for an implanted pump for chronic infusion ( 2.2 ) Dose Titration : Spasticity may be necessary to sustain upright posture and balance in locomotion or may be useful to obtain optimal function and care ( 2.5 ) Maintenance Therapy : Titrate patients individually; Lowest dose with an optimal response should be used, generally 300 mcg/day to 800 mcg/day for spasticity of spinal cord origin and 90 mcg/day to 700 mcg/day for spasticity of cerebral origin; Titrate baclofen injection to maintain some degree of muscle tone and allow occasional spasms. ( 2.6 ) 2.1 Use Only in Medtronic SynchroMed ® II Programmable Pump (or other pumps labeled for intrathecal administration of baclofen injection) Baclofen injection is approved only for use with the Medtronic SynchroMed ® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection. 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 baclofen injection. Baclofen injection is not to be compounded with other medications. 2.2 Screening Phase Prior to pump implantation and initiation of chronic infusion of baclofen injection, patients must demonstrate a positive clinical response to a baclofen injection bolus dose administered intrathecally in a screening trial. The screening trial employs baclofen injection at a concentration of 50 mcg per mL. A 1 mL syringe (50 mcg per 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. 2.3 Preparation Information Screening Use the 1 mL screening syringe only (50 mcg per 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 per mL baclofen injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg per 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 per mL, 1,000 mcg per mL, or 2,000 mcg per mL, baclofen injection must be diluted with sterile preservative free Sodium Chloride for Injection, USP. 2.4 A…

5 WARNINGS AND PRECAUTIONS Do not directly inject baclofen injection into the pump catheter access port, as this may cause a life-threatening overdose ( 5.1 ) Potential for contamination due to non-sterile external surface of prefilled syringe ( 5.2 ) Potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure; Resuscitative equipment and trained staff must be available during screening, dose titration, and refills ( 5.3 ) Overdose may cause drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma ( 5.4 ) Possible exacerbation of psychotic disorders, schizophrenia or confusional states ( 5.6 ) 5.1 Risk of Life-Threatening Overdose During Pump Refills Use extreme caution when filling the Medtronic SynchroMed ® II Programmable Pump which is 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. 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. 5.2 Potential for Contamination due to Non-sterile External Surface of Prefilled Syringe Although the drug solution and pathway in the baclofen injection 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 baclofen injection 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. Baclofen injection 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 baclofen injection prefilled syringe. 5.3 Prescriber, Caregiver and Patient Training and Screening Procedure/Post-Implantation Environment Baclofen injection is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in the implantable Medtronic SynchroMed ® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection. 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 is adequately evaluated. Evaluation (consisting of a screening procedure) requires that baclofen injection be administered into the intrathecal space via a catheter or lumbar puncture [see Dosage and Administration ( 2.2 )] . 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 ( 2.2 and 2.5 )] . Resuscitative equipment should be available. Following surgical…

4 CONTRAINDICATIONS Baclofen injection is contraindicated in patients with a hypersensitivity to baclofen. Do not use baclofen injection for intravenous, intramuscular, subcutaneous or epidural administration. Hypersensitivity to baclofen ( 4 ) Do not use baclofen injection for intravenous, intramuscular, subcutaneous or epidural administration. ( 4 )

7 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 baclofen injection and epidural morphine include hypotension and dyspnea. Combined use with morphine: hypotension and dyspnea ( 7 )

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of baclofen injection in pregnant women. In animal studies, oral administration of baclofen to pregnant rats produced an increase in fetal malformations (see Data ) . There are no animal data on developmental risk associated with baclofen administered via continuous intrathecal infusion. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Baclofen given orally to pregnant rats has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at a dose associated with maternal toxicity. This abnormality was not seen in mice or rabbits.

6 ADVERSE REACTIONS The most common adverse reactions in patients with spasticity of spinal origin were somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia ( 6.1 ) The most common adverse reactions in patients with spasticity of cerebral origin were agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 ( 5.6 )] . 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 * 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 Adverse Reactions Percent N=576 Screening * Percent N=474 Titration † Percent N=430 Maintenance ‡ Hypotonia 5.4 13.5 25.3 Somnolence…