GLIADEL Wafer is indicated for the treatment of patients with:

{ "type": "p", "children": [], "text": "GLIADEL Wafer is indicated for the treatment of patients with:" }

{ "type": "ul", "children": [ "newly-diagnosed high-grade glioma as an adjunct to surgery and radiation, and", "recurrent glioblastoma as an adjunct to surgery." ], "text": "" }

The recommended dose of GLIADEL Wafer is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied.

Following maximal tumor resection, confirmation of tumor pathology and establishment of hemostasis, place up to a maximum of eight GLIADEL Wafers to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel ®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion.

GLIADEL Wafers contain a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile.

Deliver GLIADEL Wafers to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted .GLIADEL Wafers in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period.

Exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use double gloves when handling GLIADEL Wafers. Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents.

Instructions for Opening Pouch Containing GLIADEL Wafer

Read all steps of the instructions prior to opening the pouch.

Instructions for opening the pouch containing GLIADEL Wafer can be viewed at the following website: http://gliadel.com/hcp/pouch-opening-instructions. Illustrations are also pictured below.

Figure 1:To remove the sterile inner pouch from the outer pouch, locate the folded corner and slowly pull in an outward motion.

Figure 2:Do NOT pull in a downward motion rolling knuckles over the pouch. This may exert pressure on the wafer and cause it to break.

Figure 3:The inner pouch is a multi-layered, silver colored, foil laminate. Remove the inner pouch by grabbing hold of the crimped edge of the inner pouch using a sterile instrument and pulling upward.

Figure 4:To open the inner pouch, gently hold the crimped edge and cut in an arc-like fashion around the wafer.

Figure 5:To remove the GLIADEL Wafer, gently grasp the wafer with the aid of forceps and place it onto a designated sterile field.

GLIADEL Wafer is an off-white to pale yellow round wafer. Each GLIADEL Wafer contains 7.7 mg of carmustine.

{ "type": "p", "children": [], "text": "GLIADEL Wafer is an off-white to pale yellow round wafer. Each GLIADEL Wafer contains 7.7 mg of carmustine." }

None.

{ "type": "p", "children": [], "text": "None." }

Seizures occurred in 37% of patients treated with GLIADEL Wafers for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent seizures occurred within the first 5 post-operative days [see Adverse Reactions (6.1)]. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to surgery. Monitor patients for seizures postoperatively.

Brain edema occurred in 23% of patients with newly diagnosed glioma treated with GLIADEL Wafers in Study 1. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation [see Adverse Reactions (6.1)] . Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of GLIADEL Wafers or Wafer remnants.

Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgaleal, or wound effusions occur with GLIADEL Wafer treatment. In Study 1, 16% of GLIADEL Wafer-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of GLIADEL Wafer-treated patients with recurrent high-grade glioma experienced wound healing abnormalities [see Adverse Reactions (6.1)]. Monitor patients post-operatively for impaired neurosurgical wound healing.

Meningitis occurred in 4% of patients with recurrent glioma receiving GLIADEL Wafers in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection.

GLIADEL Wafer migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus.

GLIADEL Wafers can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose based on body surface area (BSA) and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose based on BSA.

Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception for 6 months after implantation of GLIADEL Wafer. Advise males with female partners of reproductive potential to use effective contraception for 3 months following implantation of GLIADEL Wafers [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly-Diagnosed High-Grade Glioma

The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1).

The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy.

Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving GLIADEL Wafers compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1).

The incidence of common adverse reactions in GLIADEL Wafer-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1. Per-Patient Incidence of Adverse Reactions Occurring in Gliadel Wafer-Treated Patients with Newly-Diagnosed High-Grade Glioma (Study 1) (Between Arm Difference of ≥ 4%)</span> </caption> <col align="left" valign="top" width="64%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">Adverse Reaction</th><th align="center" class="Rrule">GLIADEL Wafer <br/> N=120 </th><th align="center" class="Rrule">Placebo <br/> N=120 </th> </tr> <tr class="Last"> <th align="center" class="Rrule">%</th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3">GASTROINTESTINAL</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">17</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">16</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Constipation</td><td align="center" class="Rrule">19</td><td align="center" class="Rrule">12</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Abdominal pain</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule">GENERAL AND ADMINISTRATION SITE CONDITION</td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asthenia</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">15</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chest pain</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule">INJURY, POISONING AND PROCEDURAL COMPLICATIONS</td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Wound healing abnormalities <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">12</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule">MUSCULOSKELETAL AND CONNECTIVE TISSUE</td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Back pain</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3">PSYCHIATRIC</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Depression</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">10</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2. Incidence of Local Adverse Reactions, Study 1 <a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></span> </caption> <col align="left" valign="top" width="64%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">Local Adverse Reactions</th><th align="center" class="Rrule">GLIADEL Wafer <br/> N=120 </th><th align="center" class="Rrule">Placebo <br/> N=120 </th> </tr> <tr class="Last"> <th align="center" class="Rrule">%</th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Not seen at baseline or worsened if present at baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Cerebral edema</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">19</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Intracranial hypertension</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cerebral hemorrhage</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Brain abscess</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Brain cyst</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td> </tr> </tbody> </table></div>

Recurrent High-Grade Glioma

The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 222 patients with recurrent high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 2). Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery.

The population in Study 2 was 64% male, 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers.

Sixty-four severe adverse reactions were reported in 43(39%) patients receiving GLIADEL Wafers. Adverse reactions in GLIADEL Wafer-treated patients are shown in Table 3. Meningitis occurred in four patients receiving GLIADEL Wafers and in no patients receiving placebo. Bacterial meningitis was confirmed in two patients: the first with onset four days following GLIADEL Wafer implantation; the second following resection for tumor recurrence 155 days following GLIADEL Wafer implantation. One case, attributed to chemical meningitis resolved following steroid treatment. The cause of the fourth case was undetermined but resolved following antibiotic treatment.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3. Per-Patient Incidence of Adverse Reactions in Gliadel Wafer-Treated Patients with Recurrent High-Grade Glioma (Study 2) (Between Arm Difference of ≥ 4%)</span> </caption> <col align="left" valign="top" width="64%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">Adverse Reaction</th><th align="center" class="Rrule">GLIADEL Wafer <br/> N=110 </th><th align="center" class="Rrule">Placebo <br/> N=112 </th> </tr> <tr class="Last"> <th align="center" class="Rrule">%</th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3">GENERAL</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Fever</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3">INFECTIOUS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Urinary tract infections</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">17</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule">INJURY, POISONING AND PROCEDURAL COMPLICATIONS</td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Wound healing abnormalities <a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">5</td> </tr> </tbody> </table></div>

The incidence of seizures is shown in Table 4. The incidence of hydrocephalus, cerebral edema and intracranial hypertension is shown in Table 5.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4. Incidence of Seizures, Study 2</span> </caption> <col align="left" valign="top" width="64%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="Botrule First Last"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">Adverse Reaction</th><th align="center" class="Rrule">GLIADEL Wafer <br/> N=110 </th><th align="center" class="Rrule">Placebo <br/> N=112 </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Days from implantation to onset of first new or worsening seizure.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Patients with seizures (%)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Any seizures after wafer implantation</td><td align="center" class="Rrule">37</td><td align="center" class="Rrule">29</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">New or worsening seizures</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">20</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Time to new or worsening seizures (days) <a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean (SD)</td><td align="center" class="Rrule">26.09 (0.75)</td><td align="center" class="Rrule">62.36 (48.66)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Median</td><td align="center" class="Rrule">3.5</td><td align="center" class="Rrule">61.0</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5. Hydrocephalus and Cerebral Edema, Study 2 <a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></span> </caption> <col align="left" valign="top" width="64%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">Adverse Reaction</th><th align="center" class="Rrule">GLIADEL Wafer <br/> N=110 </th><th align="center" class="Rrule">Placebo <br/> N=112 </th> </tr> <tr class="Last"> <th align="center" class="Rrule">%</th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Not seen at baseline or worsened if present at baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Hydrocephalus</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Cerebral edema</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> </tbody> </table></div>

Risk Summary

GLIADEL Wafer can cause fetal harm when administered to a pregnant woman. There are no available data on GLIADEL use in pregnant women. There have been no animal reproductive studies with GLIADEL Wafer; however, carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose based on body surface area (BSA) and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose based on BSA (see Data) . Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

There are no studies assessing the reproductive toxicity of GLIADEL Wafer; however, carmustine, the active component of GLIADEL Wafer, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5 mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1 mg/kg/day (about 0.12 times the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, based on BSA). Carmustine was embryotoxic in rabbits at intravenous doses of 4 mg/kg/day (about 1.2 times the recommended human dose based on BSA). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

Risk Summary

No data are available regarding the presence of carmustine, the active component of GLIADEL Wafer, or its metabolites in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from GLIADEL Wafers, advise women not to breastfeed following implantation with GLIADEL Wafers and for at least 7 days after implantation.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to implantation with GLIADEL Wafer [see Use in Specific Populations (8.1)].

Contraception

GLIADEL Wafer can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] .

Females Advise females of reproductive potential to use effective contraception for 6 months after implantation of GLIADEL Wafer.

Males

Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception for 3 months following implantation of GLIADEL Wafer [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

Infertility

Males

Carmustine caused testicular degeneration in animals. Advise male patients of the potential risk of infertility [see Nonclinical Toxicology (13.1)] .

The safety and effectiveness of GLIADEL Wafer in pediatric patients have not been established.

Clinical trials of GLIADEL Wafer did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

GLIADEL Wafer is an implant for intracranial use, containing carmustine, a nitrosourea alkylating agent, and polifeprosan, a biodegradable copolymer used to control the release of carmustine. It is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 7.7 mg of carmustine [1, 3-bis (2-chloroethyl)-1-nitrosourea, or BCNU] and 192.3 mg of a biodegradable polyanhydride copolymer. The copolymer, polifeprosan 20, consists of poly [bis (p-carboxyphenoxy)] propane and sebacic acid in a 20:80 molar ratio. Carmustine is homogeneously distributed in the copolymer matrix.

{ "type": "p", "children": [], "text": "GLIADEL Wafer is an implant for intracranial use, containing carmustine, a nitrosourea alkylating agent, and polifeprosan, a biodegradable copolymer used to control the release of carmustine. It is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 7.7 mg of carmustine [1, 3-bis (2-chloroethyl)-1-nitrosourea, or BCNU] and 192.3 mg of a biodegradable polyanhydride copolymer. The copolymer, polifeprosan 20, consists of poly [bis (p-carboxyphenoxy)] propane and sebacic acid in a 20:80 molar ratio. Carmustine is homogeneously distributed in the copolymer matrix." }

The structural formula for polifeprosan 20 is:

{ "type": "p", "children": [], "text": "The structural formula for polifeprosan 20 is:" }

The structural formula for carmustine is:

{ "type": "p", "children": [], "text": "The structural formula for carmustine is:" }

The activity of GLIADEL Wafer is due to release of cytotoxic concentrations of carmustine, a DNA and RNA alkylating agent, into the tumor resection cavity. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid into the surrounding brain tissue.

Carmustine concentrations delivered by GLIADEL Wafer in human brain tissue have not been determined. Following wafer insertion, the mean whole blood C max(± SD) is 10.2 ng/mL ± 4.8 ng/mL.

Absorption

Systemic absorption of carmustine is measurable for approximately 24 hours after wafer insertion. Carmustine C maxwas reached approximately 3 hours after wafer insertion.

Elimination

Metabolism

Carmustine degrades both spontaneously and metabolically.

GLIADEL Wafers are biodegradable when implanted into the human brain. Wafer remnants were visible on CT scans obtained 49 days after implantation of GLIADEL Wafer. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 7.8 months after GLIADEL Wafer implantation and consisted mostly of water and monomeric components with minimal detectable carmustine present.

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with GLIADEL Wafer. Carcinogenicity, mutagenicity, and impairment of fertility studies have been conducted with carmustine, the active component of GLIADEL Wafer. Carmustine was carcinogenic in rats and mice when delivered by intraperitoneal injection at doses lower than those delivered by GLIADEL Wafer at the recommended dose. There were increases in tumor incidence in all treated animals. 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).

In male rats carmustine caused testicular degeneration at intraperitoneal doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose based on body surface area).

Study 1 was a multicenter, double-blind, placebo-controlled, clinical trial in adult patients with newly-diagnosed high-grade glioma. A total of 240 patients were randomized (1:1) to receive up to eight GLIADEL Wafers or matched placebo wafers following maximal tumor resection. Patients received post-operative radiation therapy (55-60 Gy delivered in 28 to 30 fractions over six weeks) starting three weeks after surgery. Patients with anaplastic oligodendroglioma also received systemic chemotherapy (6 cycles of PCV- lomustine 110 mg/m 2day 1, procarbazine 60 mg/m 2days 8-21, vincristine 1.4 mg/m 2days 8 and 29).

The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70% and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. Patients were followed for at least three years or until death.

Efficacy results for patients randomized in Study 1 are summarized in Table 6 and Figure 6. Overall survival among all patients with newly diagnosed high-grade glioma, the primary outcome measure, was prolonged in the GLIADEL arm. Overall survival in the subset of patients with glioblastoma, a secondary outcome measure, was not significantly prolonged.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6. Overall Survival in Patients with Newly-Diagnosed High-Grade Glioma, Study 1.</span> </caption> <col align="left" valign="top" width="38%"/> <col align="center" valign="top" width="31%"/> <col align="center" valign="top" width="31%"/> <thead> <tr class="First Last"> <th align="center" valign="bottom">Overall Survival – ITT <a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center">Gliadel Wafer <br/> (n=120) </th><th align="center">Placebo Wafer <br/> (n=120) </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Based on a post-final analysis, protocol specified non-stratified log-rank test.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>p-value not adjusted for multiple comparisons</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Number of deaths, n (%)</td><td align="center">111 (93%)</td><td align="center">117(98%)</td> </tr> <tr> <td align="left">Median overall survival, months (95% CI)</td><td align="center">13.9 (12.1, 15.1)</td><td align="center">11.6 (10.2, 12.7)</td> </tr> <tr> <td align="left">Hazard ratio (95% CI)</td><td align="center" colspan="2">0.73 (0.56, 0.95)</td> </tr> <tr class="Last"> <td align="left">Log-Rank test p-value</td><td align="center" colspan="2">&lt;0.02 <a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a></td> </tr> </tbody> </table></div>

Figure 6: Kaplan-Meier Curves of Overall Survival in Patients with Newly Diagnosed High-Grade Glioma, Study 1. 1

Study 2 was a multicenter, double-blind, placebo controlled, clinical trial in adult patients with recurrent high-grade glioma. Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. Following maximal tumor resection and confirmation of high-grade glioma, a total of 222 patients were randomized (1:1) to receive a maximum of eight GLIADEL Wafers (n=110) or matched placebo wafers (n=112) positioned to cover the entire resection surface. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery. Patients were followed for up to 71 months.

The population in Study 2 was 64% male and 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers.

Survival and 6-month mortality rate in the subgroup of patients with recurrent glioblastoma, were exploratory outcome measures and are summarized in Table 7 and Figures 7 and 8. No survival prolongation was observed in patients with pathologic diagnoses other than glioblastoma.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 7. Main Efficacy Outcome Measures in Patients with Recurrent Glioblastoma, Study 2.</span> </caption> <col align="left" valign="top" width="60%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="center">GLIADEL Wafer</th><th align="center">Placebo Wafer</th> </tr> <tr class="Last"> <th align="left">GLIOBLASTOMA</th><th align="center">n=72</th><th align="center">n=73</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>p-value not adjusted for multiple comparisons</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">6-Month Survival</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Number of deaths, n (%)</td><td align="center">32</td><td align="center">47</td> </tr> <tr> <td align="left">6-month survival rate (%)</td><td align="center">56%</td><td align="center">36%</td> </tr> <tr> <td align="left">Log-Rank test p-value <br/> Gehan's generalized Wilcoxon Test p-value </td><td align="center" colspan="2">0.013 <a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a> <br/> 0.015 <a class="Sup" href="#footnote-9">*</a></td> </tr> <tr> <td align="left"><span class="Bold">Overall Survival</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Number of deaths, n (%)</td><td align="center">71 (99%)</td><td align="center">72 (99%)</td> </tr> <tr> <td align="left">Median overall survival (95% CI (months)</td><td align="center">6.51 (5.32, 7.49)</td><td align="center">4.63 (3.78, 5.52)</td> </tr> <tr class="Last"> <td align="left">Log-Rank test p-value <br/> Gehan's generalized Wilcoxon Test p-value </td><td align="center" colspan="2">0.181 <a class="Sup" href="#footnote-9">*</a> <br/> 0.021 <a class="Sup" href="#footnote-9">*</a></td> </tr> </tbody> </table></div>

Figure 7: Kaplan-Meier Curves of 6-Month Survival for Patients with Recurrent Glioblastoma, Study 2.

Figure 8: Kaplan-Meier Curves of Overall Survival for Patients with Recurrent Glioblastoma, Study 2.

{ "type": "", "children": [], "text": "" }

Store GLIADEL Wafer at or below -20ºC (-4ºF).

Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period.

GLIADEL Wafer is a cytotoxic drug and special handling and disposal procedures should be considered. 1

Seizures

Advise patients to report any new or change in their seizure activity [see Warnings and Precautions (5.1)] .

Intracranial Hypertension

Advise patients to report severe headaches, nausea, vomiting or new onset visual disturbances [see Warnings and Precautions (5.2)] .

Impaired Neurosurgical Wound Healing

Advise patients to report any evidence of wound dehiscence, fever or cerebrospinal fluid leak [see Warnings and Precautions (5.3)].

Meningitis

Advise patients to report symptoms of meningitis such as fever or stiff neck [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Advise patients of the potential risk to a fetus. Advise women to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)] .

Advise females of reproductive potential to use effective contraception for at least 6 months after implantation of GLIADEL Wafer [see Use in Specific Populations (8.3)] .

Advise males with female partners of reproductive potential to use effective contraception for 3 months following implantation of GLIADEL Wafer [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] .

Lactation

Advise women not to breastfeed following implantation with GLIADEL Wafers and for at least 7 days after implantation [see Use in Specific Populations (8.2)] .

Infertility

Advise males of reproductive potential that GLIADEL Wafer may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] .

Manufactured by Eisai Inc. Nutley, NJ 07110

{ "type": "p", "children": [], "text": "Manufactured by \n Eisai Inc. \n Nutley, NJ 07110\n " }

Distributed by Azurity Pharmaceuticals, Inc. Woburn, MA 01801

{ "type": "p", "children": [], "text": "Distributed by \n Azurity Pharmaceuticals, Inc. \n Woburn, MA 01801\n " }

Patent: https://azurity.com/patents

{ "type": "p", "children": [], "text": "Patent: https://azurity.com/patents" }

GLIADEL ®is a registered trademark of Eisai Inc.

{ "type": "p", "children": [], "text": "GLIADEL\n \n ®is a registered trademark of Eisai Inc.\n\n " }

GL-PI-05

{ "type": "p", "children": [], "text": "GL-PI-05" }

NDC 24338-050-08

{ "type": "p", "children": [], "text": "NDC 24338-050-08" }

GLIADEL ®WAFER (carmustine implant)

{ "type": "p", "children": [], "text": "\nGLIADEL\n \n ®WAFER\n \n \n\n(carmustine implant)\n" }

7.7 mg carmustine/wafer

{ "type": "p", "children": [], "text": "\n7.7 mg carmustine/wafer\n" }

For intracranial use.

{ "type": "p", "children": [], "text": "For intracranial use." }

Each sterile wafer contains 192.3 mg polifeprosan 20 and 7.7 mg carmustine.

{ "type": "p", "children": [], "text": "Each sterile wafer contains \n 192.3 mg polifeprosan 20 and \n 7.7 mg carmustine.\n " }

Contents: 8 wafers, individually packaged

{ "type": "p", "children": [], "text": "\nContents: \n 8 wafers, individually packaged\n \n" }

Store at or below -20°C (-4°F). Rx only

{ "type": "p", "children": [], "text": "\nStore at or below -20°C (-4°F).\n Rx only\n\n " }

Warning:Cytotoxic agent See package insert for full prescribing information. Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWarning:Cytotoxic agent \n See package insert for full prescribing information. \n \nKeep out of the reach of children.\n" }

Azurity PHARMACEUTICALS, Inc.

{ "type": "p", "children": [], "text": "Azurity PHARMACEUTICALS, Inc." }

Carmustine for Injection is indicated as palliative therapy as a single agent or in established combination therapy in the following:

{ "type": "p", "children": [], "text": "Carmustine for Injection is indicated as palliative therapy as a single agent or in established combination therapy in the following:\n" }

{ "type": "", "children": [], "text": "" }

The recommended dose of carmustine for injection as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days. Lower the dose when carmustine for injection is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. Administer carmustine for injection for the duration according to the established regimen. Premedicate each dose with anti-emetics.

Adjust doses subsequent to the initial dose according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" width="32.233%"/> <col align="left" width="34.433%"/> <col align="left" width="33.333%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">Nadir After Prior Dose</td><td align="center" class="Botrule Rrule Toprule" valign="top">Percentage of Prior Dose to<br/>be Given</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">Leukocytes/mm<span class="Sup">3</span></td><td align="center" class="Botrule Rrule" valign="top">Platelets/mm<span class="Sup">3</span></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">&gt;4000</td><td align="center" class="Botrule Rrule" valign="top">&gt;100,000</td><td align="center" class="Botrule Rrule" valign="top">100%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">3000-3999</td><td align="center" class="Botrule Rrule" valign="top">75,000-99,999</td><td align="center" class="Botrule Rrule" valign="top">100%</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top">2000-2999</td><td align="center" class="Botrule Rrule" valign="top">25,000-74,999</td><td align="center" class="Botrule Rrule" valign="top">70%</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">&lt;2000</td><td align="center" class="Botrule Rrule" valign="top">&lt;25,000</td><td align="center" class="Botrule Rrule" valign="top">50%</td> </tr> </tbody> </table></div>

The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of carmustine for injection until circulating blood elements have returned to acceptable levels (platelets above 100 Gi/L, leukocytes above 4 Gi/L and absolute neutrophil count above 1 Gi/L). The usual interval between courses is 6 weeks.

Evaluate renal function prior to administration and periodically during treatment. For patients with compromised renal function, monitor for toxicity more frequently. Discontinue carmustine for injection if the creatinine clearance is less than 10 mL/min. Do not administer carmustine for injection to patients with compromised renal function. Monitor transaminases and bilirubin periodically during treatment [see Adverse Reactions (6)].

Accidental contact of reconstituted carmustine for injection with the skin has caused transient hyperpigmentation of the affected areas. Wear impervious gloves to minimize the risk of dermal exposure impervious gloves when handling vials containing carmustine for injection. Immediately wash the skin or mucosa thoroughly with soap and water if carmustine for injection lyophilized material or solution contacts the skin or mucosa.1

For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).

{ "type": "p", "children": [], "text": "For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).\n" }

Carmustine is contraindicated in patients with previous hypersensitivity to carmustine or its components.

{ "type": "p", "children": [], "text": "Carmustine is contraindicated in patients with previous hypersensitivity to carmustine or its components.\n" }

Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine occurring 4 to 6 weeks after drug administration (thrombocytopenia occurs at about 4 weeks post-administration persisting for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks after a dose of carmustine persisting for 1 to 2 weeks; thrombocytopenia is generally more severe than leukopenia; anemia is less frequent and less severe compared to thrombocytopenia and/or leukopenia). Complete blood count should therefore be monitored weekly for at least six weeks after a dose. Repeat doses of carmustine should not be given more frequently than every six weeks. The bone marrow toxicity of carmustine is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior dose [see Adverse Reactions (6)]. Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine [see Drug Interactions (7)].

Cases of fatal pulmonary toxicity with carmustine have been reported. Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to occur from 9 days to 43 months after treatment with carmustine and related nitrosoureas. Pulmonary toxicity from carmustine is dose-related. Patients receiving greater than 1,400 mg/m2 cumulative dose are at significantly higher risk than those receiving less. However, there have been reports of pulmonary fibrosis in patients receiving lower total doses. Interstitial fibrosis (with lower doses) occurred rarely. Additionally, delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received carmustine (in cumulative doses ranging from 770 to 1,800 mg/m2 combined with cranial radiotherapy for intracranial tumors) in childhood and early adolescence. Other risk factors include past history of lung disease and duration of treatment. Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk.

Injection site reactions may occur during the administration of carmustine. Rapid intravenous infusion of carmustine may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. It is also associated with burning at the site of injection although true thrombosis is rare. Given the possibility of extravasation, close monitoring of the infusion site for possible infiltration during drug administration is recommended. A specific treatment for extravasation reactions is unknown at this time.

Long-term use of nitrosoureas, such as carmustine, has been reported to be associated with the development of secondary malignancies. Carmustine was carcinogenic when administered to laboratory animals [see Nonclinical Toxicity (13.1)]. Nitrosourea therapy, such as carmustine, has carcinogenic potential in humans. Patients treated with carmustine should be monitored long-term for development of second malignancies.

Carmustine has been administered through an intraarterial intracarotid route; this procedure is investigational and has been associated with ocular toxicity. Safety and effectiveness of the intra-arterial route have not been established.

Carmustine was embryotoxic in rats and rabbits and teratogenic in rats when given in doses lower than the maximum cumulative human dose based on body surface area. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use highly effective contraception during and after treatment with carmustine for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with carmustine for at least 3 months after therapy [see Use in Specific Populations (8.1, 8.3)].

The following serious adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described elsewhere in the labeling:\n" }

{ "type": "ul", "children": [ "Myelosuppression [see Warnings and Precautions (5.1)]\n", "Pulmonary toxicity [see Warnings and Precautions (5.2)]\n", "Administration Reactions [see Warnings and Precautions (5.3)]\n", "Carcinogenicity [see Warnings and Precautions (5.4)]\n", "Ocular Toxicity [see Warnings and Precautions (5.5)]\n" ], "text": "" }

The following adverse reactions associated with the use of carmustine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of carmustine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n" }

Cardiac Disorders

{ "type": "p", "children": [], "text": "\nCardiac Disorders\n" }

Tachycardia and chest pain

{ "type": "p", "children": [], "text": "Tachycardia and chest pain\n" }

Eye Disorders

{ "type": "p", "children": [], "text": "\nEye Disorders\n" }

Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perception

{ "type": "p", "children": [], "text": "Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perception\n" }

Gastrointestinal Toxicity

{ "type": "p", "children": [], "text": "\nGastrointestinal Toxicity\n" }

Nausea, vomiting, anorexia, and diarrhea

{ "type": "p", "children": [], "text": "Nausea, vomiting, anorexia, and diarrhea\n" }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Increased transaminase, increased alkaline phosphatase, increased bilirubin levels

{ "type": "p", "children": [], "text": "Increased transaminase, increased alkaline phosphatase, increased bilirubin levels\n" }

Infections and Infestations

{ "type": "p", "children": [], "text": "\nInfections and Infestations\n" }

Opportunistic infection (including with fatal outcome)

{ "type": "p", "children": [], "text": "Opportunistic infection (including with fatal outcome)\n" }

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

{ "type": "p", "children": [], "text": "\nNeoplasms Benign, Malignant and Unspecified (including cysts and polyps)\n" }

Acute leukemia, bone marrow dysplasias

{ "type": "p", "children": [], "text": "Acute leukemia, bone marrow dysplasias\n" }

Nephrotoxicity

{ "type": "p", "children": [], "text": "\nNephrotoxicity\n" }

Progressive azotemia, decrease in kidney size, renal failure

{ "type": "p", "children": [], "text": "Progressive azotemia, decrease in kidney size, renal failure\n" }

Nervous System Disorders

{ "type": "p", "children": [], "text": "\nNervous System Disorders\n" }

Headaches, encephalopathy, and seizures

{ "type": "p", "children": [], "text": "Headaches, encephalopathy, and seizures\n" }

Pulmonary Toxicity

{ "type": "p", "children": [], "text": "\nPulmonary Toxicity\n" }

Pneumonitis, interstitial lung disease

{ "type": "p", "children": [], "text": "Pneumonitis, interstitial lung disease\n" }

Reproductive System and Breast Disorders

{ "type": "p", "children": [], "text": "\nReproductive System and Breast Disorders\n" }

Gynecomastia

{ "type": "p", "children": [], "text": "Gynecomastia\n" }

Skin and Subcutaneous Tissue Disorders

{ "type": "p", "children": [], "text": "\nSkin and Subcutaneous Tissue Disorders\n" }

Burning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic reaction

{ "type": "p", "children": [], "text": "Burning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic reaction\n" }

Vascular Disorders

{ "type": "p", "children": [], "text": "\nVascular Disorders\n" }

Veno-occlusive disease

{ "type": "p", "children": [], "text": "Veno-occlusive disease\n" }

Cimetidine: Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported when oral cimetidine has been coadministered with carmustine. Consider alternative drugs to cimetidine.

Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine. Consider alternative drugs to phenobarbital.

Phenytoin: Carmustine when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

Risk Summary

Carmustine for injection can cause fetal harm when administered to a pregnant woman based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals [see Data]. Limited available data with carmustine use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Carmustine was embryotoxic in rats and rabbits and teratogenic in rats (thoracoabdominal closure, neural tube, and eye defects and malformations of the skeletal system of the fetus) when given in doses lower than the maximum cumulative human dose based on body surface area. Consider the benefits and risks of carmustine for the mother and possible risks to the fetus when prescribing carmustine to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Intraperitoneal (IP) administration of carmustine to pregnant rats 14 days prior to mating and during the period of organogenesis at cumulative doses ≥ 26 mg/kg (158 mg/m2), approximately 0.1 times the maximum cumulative human dose of 1,400 mg/m2, resulted in pre-implantation loss, increased resorptions (including completely resorbed litters), and reduced the number of live births in the presence of maternal toxicity.

Carmustine administered IP to pregnant rats during the period of organogenesis at cumulative doses ≥ 4 mg/kg (24 mg/m2), approximately 0.02 times the maximum cumulative human dose based on a mg/m2 basis, resulted in reduced fetal weight and various malformations, which included thoracoabdominal closure defects, neural tube defects, and eye defects, including microphthalmia/anophthalmia, and skeletal anomalies in the skull, sternebra, vertebrae and ribs, and reduced skeletal ossification) in the presence of maternal toxicity. Embryo-fetal death was observed at cumulative doses ≥ 8 mg/kg (48 mg/m2), approximately 0.03 times the maximum cumulative human dose on a mg/m2 basis. Intravenous (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/m2), approximately 0.2 times the maximum cumulative human dose on a mg/m2 basis, during the last quarter of pregnancy resulted in the death of offspring within 4 months. Carmustine administered IV to rabbits during the period of organogenesis resulted in spontaneous abortions in mothers and growth defects in the fetus, mainly at cumulative doses ≥ 13 mg/kg (156 mg/m2), approximately 0.1 times the maximum cumulative human dose on a mg/m2 basis.

Risk Summary

There is no information regarding the presence of carmustine in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse events (e.g., carcinogenicity and myelosuppression) in nursing infants, nursing should be discontinued while taking carmustine.

Contraception

Advise female patients to avoid pregnancy during treatment with carmustine because of the risk of fetal harm [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use highly effective contraception during and for up to six months after completion of treatment.

Advise males with female sexual partners of reproductive potential to use effective contraception during carmustine treatment and for at least three months after the final dose of carmustine [see Nonclinical Toxicology (13.1)].

Infertility

Based on nonclinical findings, male fertility may be compromised by treatment with carmustine [see Nonclinical Toxicology (13.1)].

Safety and effectiveness in children have not been established. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study of patients who received carmustine in childhood and early adolescence (1-16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5 patients initially treated at less than 5 years of age, died of pulmonary fibrosis [see Adverse Reactions (6.1)].

Clinical studies of carmustine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Carmustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

The main result of overdose is myeloablation. No proven antidotes have been established for carmustine overdosage.

{ "type": "p", "children": [], "text": "The main result of overdose is myeloablation. No proven antidotes have been established for carmustine overdosage.\n" }

The active ingredient in Carmustine for Injection, USP is a nitrosourea with the chemical name 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.06. The drug product is supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine for Injection, USP is administered by intravenous infusion after reconstitution, as recommended.

{ "type": "p", "children": [], "text": "The active ingredient in Carmustine for Injection, USP is a nitrosourea with the chemical name 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.06. The drug product is supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine for Injection, USP is administered by intravenous infusion after reconstitution, as recommended." }

The structural formula of carmustine is:

{ "type": "p", "children": [], "text": "The structural formula of carmustine is:" }

Carmustine for Injection, USP is available in 100 mg single-dose vials of lyophilized material. Sterile diluent for constitution of Carmustine for Injection, USP is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 mL of Dehydrated Alcohol Injection, USP.

{ "type": "p", "children": [], "text": "\nCarmustine for Injection, USP is available in 100 mg single-dose vials of lyophilized material. Sterile diluent for constitution of Carmustine for Injection, USP is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 mL of Dehydrated Alcohol Injection, USP.\n" }

The mechanism of action of carmustine is not fully understood. While carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The metabolites may contribute to antitumor activity and toxicities of carmustine.

The exposure-response relationship for efficacy or safety is unknown.

Distribution

Carmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or equal to 50% of those measured concurrently in plasma.

Elimination

Following a short intravenous infusion, the reported elimination half-life ranges from 15 minutes to 75 minutes.

Metabolism

Carmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes, including NADPH and glutathione-S-transferase.

Excretion

Approximately 60% to 70% of a total dose is excreted in the urine within 96 hours. Approximately 10% is eliminated as respiratory CO2.

Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans [see Adverse Reactions (6.1)].

Carmustine was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.

Male rats treated with carmustine at cumulative doses ≥ 36 mg/kg (216 mg/m2), approximately 0.15 times the maximum cumulative human dose on a mg/m2 basis, showed decreases in reproductive potential when mated with untreated female rats (e.g., decreased implantations, increased resorption rate, and a decrease in viable fetuses).

{ "type": "", "children": [], "text": "" }

Carmustine for Injection, USP is supplied as follows:

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" width="20.267%"/> <col align="left" width="52.800%"/> <col align="left" width="26.933%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" valign="top"><span class="Bold">NDC</span></td><td align="left" valign="top"><span class="Bold">Carmustine for Injection, USP Kit</span></td><td align="left" valign="top"><span class="Bold">Package Factor</span></td> </tr> <tr> <td align="left" valign="top">71288-<span class="Bold">126</span>-90</td><td align="left" valign="top">One 100 mg Single-Dose Vial of lyophilized carmustine (NDC 71288-124-30)<br/>and<br/>One 3 mL Vial of sterile diluent (Dehydrated Alcohol Injection, USP)<br/>(NDC 71288-125-03)</td><td align="left" valign="top">1 vial per carton<br/> <br/> <br/>1 vial per carton</td> </tr> </tbody> </table></div>

Store product and diluent in a refrigerator (2°-8°C, 36°-46°F).

Stability

Store the unopened vial of the dry drug in a refrigerator (2° to 8°C, 36° to 46°F). Store the diluent vials in a refrigerator (2° to 8°C, 36° to 46°F). The recommended storage of unopened Carmustine for Injection, USP vials provides a stable product for up to 3 years.

Compatibility/Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride containers. DO NOT USE PVC CONTAINERS.

Administer Carmustine for Injection, USP solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC-free and DEHP-free.

Important Note

Carmustine for Injection, USP has a low melting point (30.5° to 32.0°C or 86.9° to 89.6°F). Exposure of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This is a sign of decomposition and vials should be discarded. If there is a question of adequate refrigeration upon receipt of this product, immediately inspect the vial in each individual carton. Hold the vial to a bright light for inspection. Carmustine for Injection, USP will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, Carmustine for Injection, USP is suitable for use and should be refrigerated immediately.

The container closure is not made with natural rubber latex.

Myelosuppression [see Warnings and Precautions (5.1)]

A serious and frequent toxicity of carmustine is delayed myelosuppression and usually occurs 4 to 6 weeks after drug administration. Hence, patients should be advised to get blood counts monitored weekly for at least 6 weeks. The bone marrow toxicity of carmustine is cumulative.

Pulmonary Toxicity [see Warnings and Precautions (5.2)]

Advise patients to contact a health care professional immediately for any of the following: shortness of breath, particularly during exercise, dry, hacking cough, fast, shallow breathing, gradual unintended weight loss, tiredness, aching joints and muscles, clubbing (widening and rounding) of the tips of the fingers or toes.

Seizures [see Adverse Reactions (6)]

Inform the patient that they may suffer from fits and advise them to get medical attention immediately in such cases.

Pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1 and 8.3)]

Advise pregnant women and females of reproductive potential that carmustine exposure during pregnancy can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Advise women of reproductive potential to avoid becoming pregnant. Advise females of reproductive potential to use effective contraception during treatment.

Lactation [see Use in Specific Populations (8.2)]

Advise the female patient to discontinue nursing while taking carmustine.

meitheal® Mfd. for Meitheal PharmaceuticalsChicago, IL 60631 (USA)©2023 Meitheal Pharmaceuticals Inc.

Mfd. by Kindos Pharmaceuticals Co., Ltd.Chengdu, China 611731

Revised: September 2023

LB-287-V4

PRINCIPAL DISPLAY PANEL – Carmustine for Injection, USP 100 mg Vial Label

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL – Carmustine for Injection, USP 100 mg Vial Label\n" }

NDC 71288-124-30

{ "type": "p", "children": [], "text": "NDC 71288-124-30" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Carmustine for Injection, USP

{ "type": "p", "children": [], "text": "\nCarmustine for Injection, USP\n" }

100 mg per vial

{ "type": "p", "children": [], "text": "\n100 mg per vial\n" }

For Intravenous Infusion After Reconstitution

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion After Reconstitution\n" }

REFRIGERATE IMMEDIATELY

{ "type": "p", "children": [], "text": "\nREFRIGERATE IMMEDIATELY\n" }

Single-Dose Vial

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial\n" }

Discard Unused Portion

{ "type": "p", "children": [], "text": "\nDiscard Unused Portion\n" }

PRINCIPAL DISPLAY PANEL – Dehydrated Alcohol Injection, USP 3 mL Vial Label

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL – Dehydrated Alcohol Injection, USP 3 mL Vial Label\n" }

NDC 71288-125-03

{ "type": "p", "children": [], "text": "NDC 71288-125-03" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Dehydrated Alcohol Injection, USP

{ "type": "p", "children": [], "text": "\nDehydrated Alcohol Injection, USP\n" }

3 mL

{ "type": "p", "children": [], "text": "\n3 mL\n" }

Sterile Diluent for Carmustine for Injection, USP

{ "type": "p", "children": [], "text": "\nSterile Diluent for Carmustine for Injection, USP\n" }

PRINCIPAL DISPLAY PANEL – Carmustine for Injection, USP Kit Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL – Carmustine for Injection, USP Kit Carton\n" }

NDC 71288-126-90

{ "type": "p", "children": [], "text": "NDC 71288-126-90" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Carmustine for Injection, USP

{ "type": "p", "children": [], "text": "\nCarmustine for Injection, USP\n" }

100 mg per vial

{ "type": "p", "children": [], "text": "\n100 mg per vial\n" }

Each carton contains: 1 vial Carmustine for Injection, USP 100 mg and 1 vial Sterile Diluent for Carmustine for Injection, USP 3 mL

{ "type": "p", "children": [], "text": "\nEach carton contains: 1 vial Carmustine for Injection, USP 100 mg and 1 vial Sterile Diluent for Carmustine for Injection, USP 3 mL\n" }

For Intravenous Infusion After Reconstitution

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion After Reconstitution\n" }

REFRIGERATE IMMEDIATELY

{ "type": "p", "children": [], "text": "\nREFRIGERATE IMMEDIATELY\n" }

Single-Dose Vial

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial\n" }

Discard Unused Portion

{ "type": "p", "children": [], "text": "\nDiscard Unused Portion\n" }