Intrathecal Bolus:

Continuous Infusion:

Baclofen Injection'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.

Pharmacokinetics of Baclofen Injection:

The pharmacokinetics of CSF clearance of Baclofen Injection calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF.

Spasticity of Spinal Cord Origin: There were 16 deaths reported among the 576 U.S. patients treated with Baclofen Injection 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, Baclofen Injection 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 Baclofen Injection 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 Baclofen Injection 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 Baclofen Injection in pre- marketing studies as of March 1996. These deaths were not attributed to the therapy.

Overinfusion: Delivery of more drug volume than the programmed rate (overinfusion) can result in unexpected overdose, or withdrawal caused by early emptying of the pump reservoir. Refer to the manufacturer's pump manual and instructions for refilling the reservoir.

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 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 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. 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 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 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 and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.

Baclofen Injection should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Baclofen Injection may cause an autonomic dysreflexic episode.

Because Baclofen Injection 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.

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 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 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 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 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 — Adverse events associated with the use of Baclofen Injection reflect experience gained with 576 patients followed prospectively in the United States. They received Baclofen Injection 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 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.

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 Baclofen Injection 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.

Commonly Observed — In pre-marketing clinical trials, the most commonly observed adverse events associated with use of Baclofen Injection 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 Baclofen Injection in pre-marketing 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 Baclofen Injection, 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 Baclofen Injection obtained in parallel, placebo-controlled, 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 Baclofen Injection 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 Baclofen Injection — Adverse events associated with the use of Baclofen Injection 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 Baclofen Injection 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 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 Baclofen Injection 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.

The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to Baclofen Injection 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.

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 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 Baclofen Injection 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 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 Baclofen Injection 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 over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” Baclofen Injection may be restarted at the initial continuous infusion dose.

Screening

The external surface of the Baclofen Injection 50 mcg per mL strength prefilled syringe is not sterile. The use of the Baclofen Injection prefilled syringe to refill an intrathecal baclofen pump, or use in an aseptic setting (i.e., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended. Modify aseptic procedures to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the Baclofen Injection prefilled syringe when performing the test dose procedure.

Use the 1 mL screening prefilled 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 prefilled 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 prefilled syringes).

Maintenance

For patients who require concentrations other than 500 mcg per mL or 2,000 mcg per mL, Baclofen Injection must be diluted.

Baclofen Injection must be diluted with sterile preservative free Sodium Chloride for Injection, USP.