Gliadel Side Effects, and Drug Interactions - Polifeprosan 20 With Carmustine Implant

Gliadel Side Effects, and Drug Interactions - Polifeprosan 20 With Carmustine Implant

SIDE EFFECTS

Data in the following table are based on the experience of 222 patients with recurrent malignant glioma randomized to GLIADEL or placebo (wafer without carmustine).

The spectrum of adverse events observed in patients who received GLIADEL or placebo in clinical studies was consistent with that encountered in patients undergoing craniotomy for malignant gliomas.

GLIADEL was not reported to be the cause of death in any of the GLIADEL clinical trials.

The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL in the placebo-controlled clinical trial. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the GLIADEL group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period in the randomized trial was up to 71 months.

The following adverse events were also reported in 4-9% of GLIADEL patients but were at least as frequent in the placebo group as in GLIADEL-treated patients: infection, deep thrombophlebitis, pulmonary embolism, nausea, oral moniliasis, anemia, hyponatremia, pneumonia.

The following four categories of adverse events are possibly related to treatment with GLIADEL. The frequency with which they occurred in the randomized trial along with descriptive detail are provided below.

1. Seizures: In the randomized study, the majority of seizures in the placebo and GLIADEL groups were mild or moderate in severity. The incidence of new or worsened seizures was 19% in patients treated with GLIADEL and 19% in patients receiving placebo. Of the patients with new or worsened seizures post-operatively, 12/22 (54%) of patients treated with GLIADEL and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL and 61 days in placebo patients. The occurrence of seizures did not reduce the survival benefit of GLIADEL.

2. Brain Edema: In the randomized trial, brain edema was noted in 4% of patients treated with GLIADEL and in 1% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of wafer or its remnants.

3. Healing Abnormalities: The majority of these events were mild to moderate in severity. Healing abnormalities occurred in 14% of GLIADEL-treated patients compared to 5% of placebo recipients. These events included cerebrospinal fluid leaks, subdural fluid collections, subgaleal or wound effusions, and wound breakdown.

4. Intracranial Infection:   In the randomized trial, intracranial infection (meningitis or abscess) occurred in 4% of patients treated with GLIADEL and in 1% of patients receiving placebo. In GLIADEL-treated patients, there were two cases of bacterial meningitis, one case of chemical meningitis, and one case of meningitis which was not further specified. A brain abscess developed in one placebo-treated patient. The rate of deep wound infection (infection of subgaleal space, bone, meninges, or neural parenchyma) was 6% in both GLIADEL and placebo treated patients.

The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL in all studies (n=273). The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL caused these events cannot be determined.

Body as a Whole:   peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%)

Cardiovascular System:   hypertension (3%); hypotension (1%)

Digestive System:   diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)

Hemic and Lymphatic System:   thrombocytopenia (1%); leukocytosis (1%)

Metabolic and Nutritional Disorders:   hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)

Musculoskeletal System:   infection (1%)

Nervous System:   hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with GLIADEL.

Respiratory System:   infection (2%); aspiration pneumonia (1%)

Skin and Appendages:   rash (2%)

Special Senses:   visual field defect (2%); eye pain (1%)

Urogenital System:   urinary incontinence (2%)

Interactions of GLIADEL with other drugs or radiotherapy have not been formally evaluated. In clinical trials, few patients have received systemic chemotherapy within 30 days of GLIADEL (6) or external beam radiation therapy (36). Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. External beam radiation therapy was initiated no sooner than three weeks after GLIADEL implantation. Of the 36 patients who received GLIADEL at initial surgery for newly diagnosed, malignant glioma followed by external beam radiation therapy, 3/15 (20%) in one study and 11/21 (52%) in the other study experienced new or worsened seizures. Patients were followed for a maximum of 24 months. The short and long-term toxicity profiles of GLIADEL when given in conjunction with radiation or chemotherapy have not been fully explored.