Baclofen

INDICATIONS AND USAGE Baclofen Injection 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 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 in implantable pumps approved by the FDA specifically for the administration of Baclofen Injection into the intrathecal space. Spasticity of Spinal Cord Origin: Evidence supporting the efficacy of Baclofen Injection was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of Baclofen Injection to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Baclofen Injection 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 Baclofen Injection 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; Baclofen Injection 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 therapy may be considered an alternative to destructive neurosurgical procedures. 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 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/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. 2.3 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 or 2,000 mcg/mL, baclofen injection must be diluted with sterile preservative free Sodium Chloride for Injection, USP. 2.4 Administration Information Parenteral …

3 DOSAGE FORMS AND STRENGTHS Baclofen injection 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 contains baclofen USP 1,000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.5 to 7.5. Each vial is intended for single use only. Discard any unused portion. Do not autoclave.

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 )

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 Nexus Pharmaceuticals at 1-855-642-2594 or email: safety.nexuspharma@lambda-cro.com 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 Adverse Reaction 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 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 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Pediatric use: Safety and effectiveness in pediatric patients below the age of 4 years have not been established ( 8.4 ) 8.1 Pregnancy ​Risk Summary There are no adequate data on the development 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 development 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 recognize 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. 8.2 Lactation ​Risk Summary There is insufficient information regarding levels of baclofen in milk of nursing mothers receiving baclofen injection. There are no adequate data on the effects of baclofen injection on the breastfed infant or on milk production. At recommended oral doses, baclofen is present in human milk and withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped or when breastfeeding is stopped. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for baclofen injection and any potential adverse effects on the breastfed infant from baclofen injection or from the underlying maternal condition. 8.4 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.

12.1 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.

11 DESCRIPTION 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 C 10 H 12 ClNO 2 Baclofen is a white to off-white powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol and ethanol, practically insoluble in acetone and ether, soluble in 0.1N hydrochloric acid, 0.1N sodium hydroxide, and insoluble in chloroform. Baclofen injection 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 mL of baclofen injection contains baclofen USP 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. Baclofen Injection Structure

5.4 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 Overdosage ( 10 )] . Extreme caution must be used when filling the implantable pump. Medtronic SynchroMed® II Programmable Pump should only be refilled through the reservoir refill septum. The Medtronic SynchroMed® II Programmable Pump is also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose.

10 OVERDOSAGE 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 baclofen injection 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 baclofen injection; however, the following steps should ordinarily be undertaken: 1) Residual intrathecal baclofen solution should be removed from the pump as soon as possible. 2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated. Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia. Physostigmine Doses for Adult Patients Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur. Physostigmine Doses for Pediatric Patients Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained. Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support. If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.

16 HOW SUPPLIED/STORAGE AND HANDLING Baclofen injection, USP is a sterile, pyrogen-free, isotonic solution available in single-dose vials of 10,000 mcg per 20 mL (500 mcg/mL), 20,000 mcg per 20 mL (1,000 mcg/mL), and 40,000 mcg per 20 mL (2,000 mcg/mL) for intrathecal administration only. 500 mcg per mL NDC 72888-145-36: 20 mL Vial - 10,000 mcg per 20 mL 1,000 mcg per mL NDC 72888-146-36: 20 mL Vial - 20,000 mcg per 20 mL 2,000 mcg per mL NDC 72888-147-36: 20 mL Vial - 40,000 mcg per 20 mL Baclofen injection does not contain any antioxidants, preservatives or other potentially neurotoxic additives. Each single-dose vial is intended for single use only. Discard any unused portion. Does not require refrigeration. Do not store above 86°F (30°C). Do not freeze. Do not heat sterilize.