Gablofen

1 INDICATIONS AND USAGE 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 with the Medtronic SynchroMed ® Programmable Pump or other pumps labeled for intrathecal administration of GABLOFEN [see Clinical Studies (14)] . 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 (2.2)] . GABLOFEN 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 ) GABLOFEN 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 GABLOFEN therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION 2.1 Use Only in Medtronic SynchroMed ® Programmable Pump (or other pumps labeled for intrathecal administration of GABLOFEN) GABLOFEN is approved only for use with the Medtronic SynchroMed ® Programmable Pump or other 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. 2.2 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. 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, GABLOFEN must be diluted with sterile preservative free Sodium Chloride for Injection, USP. 2.4 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 ( 5.2 )]. 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 t …

3 DOSAGE FORMS AND STRENGTHS GABLOFEN (baclofen injection) is a clear, colourless solution available as: Single-dose syringe containing 50 mcg/mL Single-dose syringes and vials of 10,000 mcg per 20 mL (500 mcg/mL) Single-dose syringes and vials of 20,000 mcg per 20 mL (1,000 mcg/mL) Single-dose syringes and vials of 40,000 mcg per 20 mL (2,000 mcg/mL) Injection: 50 mcg/mL, 500 mcg/mL, 1,000 mcg/mL, and 2,000 mcg/mL (3)

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

6 ADVERSE REACTIONS 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 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. …

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 GABLOFEN 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) See 17 for PATIENT COUNSELING INFORMATION 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of GABLOFEN 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. 8.2 Lactation Risk Summary There is insufficient information regarding levels of baclofen in milk of nursing mothers receiving GABLOFEN. There are no adequate data on the effects of GABLOFEN 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 GABLOFEN and any potential adverse effects on the breastfed infant from GABLOFEN 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 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 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. 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 mL 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. structure

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 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: 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 GABLOFEN (baclofen injection) is a clear, colorless, sterile, pyrogenfree, isotonic solution supplied as follows: Package Type Strength (Concentration) NDC Single-dose syringe 50 mcg per mL 66794-151-01 10,000 mcg per 20 mL (500 mcg/mL) 66794-155-01 20,000 mcg per 20 mL (1,000 mcg/mL) 66794-156-01 40,000 mcg per 20 mL (2,000 mcg/mL) 66794-157-01 Single-dose vial 10,000 mcg per 20 mL (500 mcg/mL) 66794-155-02 20,000 mcg per 20 mL (1,000 mcg/mL) 66794-156-02 40,000 mcg per 20 mL (2,000 mcg/mL) 66794-157-02 Pump Refill Kits are supplied as requested by healthcare professionals in the following models: The Pump Refill Kit Model 9000 is supplied for use in combination with single-dose syringes of GABLOFEN (baclofen injection). The Pump Refill Kit Model 8500 is supplied for use in combination with single-dose vials of GABLOFEN (baclofen injection). 16.2 Storage and Handling Store between 20°C and 25°C (68°F and 77°F). Do not store above 30°C (86°F). Does not require refrigeration. Do not freeze. Do not heat sterilize. Discard any unused portion.