SIDE EFFECTS
Tablets
The most common is transient drowsiness (10-63%). In one
controlled study of 175 patients, transient drowsiness
was observed in 63% of those receiving baclofen compared
to 36% of those in the placebo group. Other common adverse
reactions are dizziness (5-15%), weakness (5-15%) and
fatigue (2-4%). Others reported:
Neuropsychiatric: Confusion (1-11%),
headache (4-8%), insomnia (2-7%); and rarely, euphoria,
excitement, depression, hallucinations, paresthesia, muscle
pain, tinnitus, slurred speech, coordination disorder,
tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus,
strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic
seizure.
Cardiovascular: Hypotension (0.9%).
Rare instances of dyspnea, palpitation, chest pain, syncope.
Gastrointestinal: Nausea (4-12%), constipation
(2-6%); and rarely, dry mouth, anorexia, taste disorder,
abdominal pain, vomiting, diarrhea, and positive test
for occult blood in stool.
Genitourinary: Urinary frequency (2-6%);
and rarely, enuresis, urinary retention, dysuria, impotence,
inability to ejaculate, nocturia, hematuria.
Other: Instances of rash, pruritus,
ankle edema, excessive perspiration, weight gain, nasal
congestion.
Some of the CNS and genitourinary symptoms may be related
to the underlying disease rather than to the drug therapy.
The following laboratory tests have been found to be
abnormal in a few patients receiving baclofen: increased
SGOT, elevated alkaline phosphatase, and elevation of
blood sugar.
Injection
Commonly Observed in Patients with Spasticity
of Spinal Origin: In pre- and post-marketing
clinical trials, the most commonly observed adverse events
associated with the use of baclofen 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 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), gynocological
fibroids (1), and pump overpressurization (1) with unknown,
if any, sequela. Eleven patients who developed coma secondary
to overdose had their reatment temporarily suspended,
but all were subsequently re-started and were not, therefore,
considered to be true discontinuations.
Fatalities: see WARNINGS.
Spasticity of Spinal Cord Origin
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:
Hypertension (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--drowsiness, dizziness, headache, nausea,
hypotension, hypotonia and coma--appear clearly drug-related.
Adverse experiences reported during all domestic studies
(both controlled and uncontrolled) are shown in the following
table (TABLE 1). None of these adverse experiences led
to a discontinuation of treatment.
TABLE 1 - Incidence Of Most Frequent (³1%)
Adverse Events In Patients With Spasticity Of Spinal Origin
In Prospectively Monitored Clinical Studies
| Adverse
Event |
Number of Patients Reporting
Events |
| N
= 576 |
N
= 474 |
N
=430 |
| Screeninga |
Titrationb |
Maintenancec |
|
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/Vomiting
|
1.6 |
2.3 |
5.6 |
|
Headache
|
1.6 |
2.5 |
5.1 |
|
Constipation
|
0.2 |
1.5 |
5.1 |
|
Convulsions
|
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 |
|
Dysaulonomia
|
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
|
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
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.
Central Nervous System: Abnormal gait,
thinking abnormal, tremor, amnesia, twitching, vasodilation,
cerebrovascular accident, nystagmus, personality disorder,
psychotic depression, cerebral ischemia, emotional lability,
euphoria, hypertonia, ileus, drug dependance, 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 accomodation, 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
Commonly Observed: In pre-marketing
clinical trials, the most commonly observed adverse events
associated with the use of baclofen injection which were
not seen at an equivalent incidence among placebo-treated
patients included: agitation, constipation, somnolence,
leukocytosis, chills, fever, 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 adverseevents leading to discontinuation
were: three causes of infection, two cases of
CSF leaks, two cases of menigitis, one case of drainage,
and one case of unmanageable trunk control.
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, somnolencec, 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 50-75 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 cannot be reliably assessed in many
cases. Nonetheless, many of the more commonly reported
reactions - somnolence, dizziness, headache, nausea, hypotension,
hypotonia, and coma - appear clealy drug-related.
The most frequent (³ 1%) adverse events reported
during all clinical trials are shown in the following
table. Nine patients discontinued long term treatment
due to adverse events.
TABLE 2 - Incidence Of Most Frequent (³1%)
Adverse Events In Patients With Spasticity Of Spinal Origin
In Prospectively Monitored Clinical Studies
| Adverse
Event |
Number of Patients Reporting Events
|
| N
= 211 |
N
= 153 |
N
= 150 |
| Screeninga |
Titrationb |
Maintenancec |
|
Hypotonia
|
2.4 |
14.4 |
34.7 |
|
Somnolence
|
7.6 |
10.5 |
18.7 |
|
Headache
|
6.6 |
7.8 |
10.7 |
|
Nausea/Vomiting
|
6.6 |
10.5 |
4.0 |
|
Vomiting
|
6.2 |
8.5 |
4.0 |
|
Urinary Retention
|
0.9 |
6.5 |
8.0 |
|
Convulsions
|
0.2 |
1.5 |
5.1 |
|
Constipation
|
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 |
|
Hypotonia
|
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 |
|
Urticaria
|
0.2 |
0.2 |
1.2 |
|
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
enteringeach period. 211 patients received
drug; (1 of 212) received placebo only |
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, arranged in
decreasing order of frequency, and classified by body system,
were reported:
Nervous system: Akathisia, ataxia, confusion,
depression, opisthotonos, amnesia, anxiety, halluciantions,
hysteria, insomnia, nystagmus, personality disorder, reflexes
decreased, and vasodilation.
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,
alopecias, contact dermatitis, and skin ulcer.
Special Senses: Abnormality of accomodation.
Body as a Whole: Death, fever, pain,
abdominal pain, carcinoma, malaise, and hypothermia.
Hemic and Lymphatic System: Leukocytosis
and petechial rash.
DRUG INTERACTIONS
Injection
There is inadequate systematic experience with the use
of baclofen injection in combination with other medications
to predict specific drug-drug interactions. Interactions
attributed to the combined use of baclofen injection and
epidural morphine include hypotension and dyspnea.
| |
