Gliadel Warnings, Precautions, Pregnancy, Nursing, Abuse - Polifeprosan 20 With Carmustine Implant

Gliadel Warnings, Precautions, Pregnancy, Nursing, Abuse - Polifeprosan 20 With Carmustine Implant

WARNINGS

Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL, including one case leading to brain herniation.

Pregnancy:   There are no studies assessing the reproductive toxicity of GLIADEL. Carmustine, the active component of GLIADEL, can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m ²  basis). Carmustine was embryotoxic in rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m ² basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

There are no studies of GLIADEL in pregnant women. If GLIADEL is used during pregnancy, or if the patient becomes pregnant after GLIADEL implantation, the patient must be warned of the potential hazard to the fetus.

General:   Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication exists, it should be closed prior to wafer implantation.

Imaging Studies:   Computed tomography and magnetic resonance imaging of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of GLIADEL wafers. This enhancement may represent edema and inflammation caused by GLIADEL or tumor progression.

Therapeutic Interactions:   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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:   No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with GLIADEL. Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL. Carmustine was given three times a week for six months, followed by 12 months observation, to Swiss mice at i.p. doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m ² basis) and to SD rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on a mg/m ² basis.) There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: Carmustine was mutagenic in vitro (Ames assay, human lymphoblast HGPRT assay) and clastogenic both in vitro (V79 hamster cell micronucleus assay) and in vivo (SCE assay in rodent brain tumors, mouse bone marrow micronucleus assay). Impairment of Fertility: Carmustine caused testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m ² basis) in male rats.

Pregnancy:   Pregnancy Category D: see

WARNINGS

Nursing Mothers:   It is not known if either carmustine, carboxyphenoxypropane, or sebacic acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from carmustine in nursing infants, it is recommended that patients receiving GLIADEL discontinue nursing.

Pediatric Use:   The safety and effectiveness of GLIADEL in pediatric patients have not been established.