Baclofen

Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information (see

).

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.

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.

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).

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 prefilled 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.

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.

To determine the initial total daily dose of Baclofen Injection following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved).

After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10 to 30% increments and only once every 24 hours, until the desired clinical effect is achieved.

After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved.

After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable side effects.

— 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.

— 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.

— 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.

— 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:

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.

Flatulence, dysphagia, dyspepsia and gastroenteritis.

Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.

Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis.

Hematuria and kidney failure.

Alopecia and sweating.

Weight loss, albuminuria, dehydration and hyperglycemia.

Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus.

Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose.

Anemia.

— 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.

— 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).

— 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.

— 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.

— 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:

Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, halluci­nations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.

Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.

Bradycardia.

Apnea, dyspnea and hyperventilation.

Abnormal ejaculation, kidney calculus, oliguria and vaginitis.

Rash, sweating, alopecia, contact dermatitis and skin ulcer.

Abnormality of accommodation.

Death, fever, abdominal pain, carcinoma, malaise and hypothermia.

Leukocytosis and petechial rash.

The following adverse events have been reported during post-approval use of Baclofen Injection. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

The onset of scoliosis or worsening of a pre-existing scoliosis has been reported.

Sexual dysfunction in men and women, including decreased libido and orgasm dysfunction, have been reported. Erectile dysfunction in men has also been reported. Priapism has been reported following baclofen withdrawal.