LIORESAL INTRATHECAL SIDE EFFECTS
- Generic Name: baclofen injection
- Brand Name: Lioresal Intrathecal
- Drug Class: Skeletal Muscle Relaxants
SIDE EFFECTS
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 LIORESAL INTRATHECAL (baclofen injection) which were not seen at an equivalent incidence among placebotreated 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 LIORESAL 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 restarted and were not, therefore, considered to be true discontinuations.
Fatalities
Incidence In Controlled Trials
Experience with LIORESAL INTRATHECAL (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 LIORESAL INTRATHECAL (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 LIORESAL INTRATHECAL
Adverse events associated with the use of LIORESAL INTRATHECAL reflect experience gained with 576 patients followed prospectively in the United States. They received LIORESAL INTRATHECAL forperiods 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 LIORESAL 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 PATIENTSWITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS
| Percent of Patients Reporting Events | |||
| N = 576 Screeninga Percent |
N = 474 Titrationb Percent |
N = 430 Maintenancec Percent |
|
| Adverse Event | |||
| 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 |
| 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 |
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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 LIORESAL INTRATHECAL (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.
Spasticity Of Cerebral Origin – Clinical Studies
Commonly Observed
In pre-marketing clinical trials, the most commonly observed adverse events associated with use of LIORESAL INTRATHECAL (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 LIORESAL 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 LIORESAL INTRATHECAL, were reported in patients in clinical trials involving patients with spasticity of cerebral origin.
Incidence In Controlled Trials
Experience with LIORESAL INTRATHECAL (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 LIORESAL 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 LIORESAL INTRATHECAL
Adverse events associated with the use of LIORESAL 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 LIORESAL 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 LIORESAL 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
| Percent of Patients Reporting Events | |||
| N = 211 Screeninga Percent |
N = 153 Titrationb Percent |
N = 150 Maintenancec Percent |
|
| Adverse Event | |||
| 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 |
| 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. |
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The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to LIORESAL INTRATHECAL (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.
Postmarketing Experience
The following adverse events have been reported during post-approval use of LIORESAL 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.
SRC: NLM .