Baclofen (Intrathecal) (Page 2 of 4)

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

baclofen injection (intrathecal) should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of baclofen injection (intrathecal) may cause an autonomic dysreflexic episode.

Because baclofen injection (intrathecal) 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.

LABORATORY TESTS

No specific laboratory tests are deemed essential for the management of patients on baclofen injection (intrathecal).

DRUG INTERACTIONS

There is inadequate systematic experience with the use of baclofen injection (intrathecal) in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of baclofen injection (intrathecal) and epidural morphine include hypotension and dyspnea.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY

No increase in tumors was seen in rats receiving baclofen orally for two years. Adequate genotoxicity assays of baclofen have not been performed.

PREGNANCY

There are no adequate and well-controlled studies in pregnant women. In animal studies, baclofen had adverse effects on embryofetal development when administered orally to pregnant rats. Baclofen injection (intrathecal) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Baclofen given orally increased the incidence of fetal structural abnormalities (omphaloceles) in rats. Reductions in food intake and body weight gain were observed in the dams. Fetal structural abnormalities were not observed in mice or rabbits.

NURSING MOTHERS

In mothers treated with oral Baclofen (baclofen USP) in therapeutic doses, the active substance passes into the milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving baclofen injection (intrathecal). As a general rule, nursing should be undertaken while a patient is receiving baclofen injection (intrathecal) only if the potential benefit justifies the potential risks to the infant.

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.

Considerations based on experience with oral Baclofen (baclofen USP)

A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral Baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral Baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

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 (Intrathetcal) 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

a Following administration of test bolus

b Two month period following implant

c Beyond two months following implant

N= total number of patients entering each period

%=% of patients evaluated

Percent of Patients Reporting Events
N = 576 N = 474 N = 430
Screeninga Titrationb Maintenancec
Adverse Event Percent Percent Percent
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
Dyspnea 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 0.9
Urticaria 0.2 0.2 1.2
Anorexia 0.0 0.4 0.9
Diplopia 0.0 0.4 0.9
Dysautonomia 0.2 0.2 0.9
Hallucinations 0.3 0.4 0.5
Hypertension 0.2 0.6 0.5

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 (Intrathecal) 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.

Spasticity of Cerebral Origin – Clinical Studies:

Commonly Observed — In pre-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 included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.

Associated with Discontinuation of Treatment — Nine of 211 patients receiving Baclofen Injection (Intrathecal) 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 (Intrathecal), 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 (Intrathecal) 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 (Intrathecal) 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 (Intrathecal) — Adverse events associated with the use of Baclofen Injection (Intrathecal) 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 (Intrathecal) 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 50-75 mcg. The maintenance dose ranged from 22 mcg to 1400 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 (Intrathecal) 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.

INCIDENCE OF MOST FREQUENT (≥ 1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF CEREBRAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS

a Following administration of test bolus

b Two month period following implant

c Beyond two months following implant

N= Total number of patients entering each period. 211 patients received drug; (1 of 212) received placebo only.

Percent of Patients Reporting Events
N = 211 N = 153 N = 150
Screeninga Titrationb Maintenancec
Adverse Event Percent Percent Percent
Hypotonia 2.4 14.4 34.7
Somnolence 7.6 10.5 18.7
Headache 6.6 7.8 10.7
Nausea and Vomiting 6.6 10.5 4.0
Vomiting 6.2 8.5 4.0
Urinary Retention 0.9 6.5 8.0
Convulsion 0.9 3.3 10.0
Dizziness 2.4 2.6 8.0
Nausea 1.4 3.3 7.3
Hypoventilation 1.4 1.3 4.0
Hypertonia 0.0 0.7 6.0
Paresthesia 1.9 0.7 3.3
Hypotension 1.9 0.7 2.0
Increased Salivation 0.0 2.6 2.7
Back Pain 0.9 0.7 2.0
Constipation 0.5 1.3 2.0
Pain 0.0 0.0 4.0
Pruritus 0.0 0.0 4.0
Diarrhea 0.5 0.7 2.0
Peripheral Edema 0.0 0.0 3.3
Thinking Abnormal 0.5 1.3 0.7
Agitation 0.5 0.0 1.3
Asthenia 0.0 0.0 2.0
Chills 0.5 0.0 1.3
Coma 0.5 0.0 1.3
Dry Mouth 0.5 0.0 1.3
Pneumonia 0.0 0.0 2.0
Speech Disorder 0.5 0.7 0.7
Tremor 0.5 0.0 1.3
Urinary Incontinence 0.0 0.0 2.0
Urination Impaired 0.0 0.0 2.0

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

Postmarketing Experience:

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

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

Urogenital: 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.

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