Gablofen (Page 4 of 6)

6.2 Spasticity of Cerebral Origin

Most Common Adverse Reactions

In pre-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.

Adverse Reactions Associated with Discontinuation of Treatment

Nine of 211 patients receiving intrathecal baclofen in pre-marketing clinical studies in the U.S. discontinued long-term infusion due to adverse reactions associated with intrathecal therapy.

The nine adverse reactions 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 intrathecal baclofen, 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 intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following adverse reactions occurred among the 62 patients receiving intrathecal baclofen 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 Intrathecal Baclofen

Adverse events associated with the use of intrathecal baclofen 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 intrathecal baclofen 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 mcg 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 intrathecal baclofen 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 reactions reported during all clinical trials are shown in Table 2. Nine patients discontinued long term treatment due to adverse reactions.

Table 2: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Cerebral Origin

Adverse Reaction

Percent N=211 Screening*

Percent N=153 Titration

Percent N=150 Maintenance

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

* Following administration of test bolus
Two month period following implant
Beyond two months following implantN=Total number of patients entering each period. 211 patients received drug; (1 of 212) received placebo only

The more common (1% or more) adverse reactions reported in the prospectively followed 211 patients exposed to intrathecal baclofen have been reported. In the total cohort, the following adverse reactions, not described in Table 2, 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.

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