Baclofen (Intrathecal) 2000 ug/mL Injection — NDC 70511-124-10 (Billing 70511-0124-10)

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 volum… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Spasticity of Spinal Cord Origin Clinical Studies: Commonly Observed in Patients with Spasticity of Spinal Origin - In pre- and post- marketing clinical trials, the most commonly observed adverse events associated with use of Baclofen Injection (Intrathecal) 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 Baclofen Injection (Intrathecal) in pre- and post- marketing clinical studies in the U.S. discontinued treatment due to adverse events.

These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations. Fatalities - See Warnings .

Incidence in Controlled Trials - Experience with Baclofen Injection (Intrathecal) obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse events because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving Baclofen Injection (Intrathecal) 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 Baclofen Injection (Intrathecal) - Adverse events associated with the use of Baclofen Injection (Intrathecal) reflect experience gained with 576 patients followed prospectively in the United States. They received Baclofen Injection (Intrathecal) for periods of one day (screening) (N = 576) to over eight years (maintenance) (N = 10).

The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of Baclofen Injection (Intrathecal) cannot be reliably assessed in many cases and many of the adverse events reported are known to occur in association with the underlying conditions being treated.

Nonetheless, many of the more commonly reported reactions hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache appear clearly drug-related. Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in the following table. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long-term treatment in the pre- and post-marketing studies.

INCIDENCE OF MOST FREQUENT (≥1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS Percent of Patients Reporting Events N = 576 N = 474 N = 430 Screening a Titration b Maintenance c Adverse Event Percent Percent Percent Hypotonia 5.4 13.5

25.3Somnolence 5.7 5.9

20.9Dizziness 1.7 1.9

7.9Paresthesia 2.4 2.1

6.7Nausea and Vomiting 1.6 2.3

5.6Headache 1.6 2.5

5.1Constipation 0.2 1.5

5.1Convulsion 0.5 1.3

4.7Urinary Retention 0.7 1.7

1.9Dry Mouth 0.2 0.4

3.3Accidental Injury 0.0 0.2

3.5Asthenia 0.7 1.3

1.4Confusion 0.5 0.6

2.3Death 0.2 0.4

3.0Pain 0.0 0.6

3.0Speech Disorder 0.0 0.2

3.5Hypotension 1.0 0.2

1.9Ambylopia 0.5 0.2

2.3Diarrhea 0.0 0.8

2.3Hypoventilation 0.2 0.8

2.1Coma 0.0 1.5

0.9Impotence 0.2 0.4

1.6Peripheral Edema 0.0 0.0

2.3Urinary Incontinence 0.0 0.8

1.4Insomnia 0.0 0.4

1.6Anxiety 0.2 0.4 0… [Excerpted — this section continues on DailyMed.]

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 dosage 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 baclofen injection (intrathecal).

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 careful… [Excerpted — this section continues on DailyMed.]