БиКНУ

БиКНУ Wafer is indicated for the treatment of patients with:

• newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and
• recurrent glioblastoma multiforme as an adjunct to surgery.

Recommended Dose

The recommended dose of БиКНУ 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.

Insertion Instructions

Following maximal tumor resection, confirmation of tumor pathology and establishment of hemostasis, place up to a maximum of eight БиКНУ 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.

Preparation and Safe Handling

БиКНУ 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 БиКНУ 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. БиКНУ 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 БиКНУ 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 БиКНУ Wafer

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

Instructions for opening the pouch containing БиКНУ Wafer can be viewed at the following website: http://БиКНУ.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 1

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 2

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 3

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

Figure 4

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

Figure 5

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Seizures

Fifty-four percent (54%) of patients treated with БиКНУ Wafers for recurrent glioma in Study 2 experienced new or worsened seizures within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 4 days. Optimize anti-seizure therapy prior to surgery. Monitor patients for seizures postoperatively.

Intracranial Hypertension

Brain edema occurred in 23% of patients with newly diagnosed glioma treated with БиКНУ Wafers in Study 1. Additionally, one БиКНУ-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation (see ADVERSE REACTIONS). 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 БиКНУ Wafers or Wafer remnants.

Impaired Neurosurgical Wound Healing

Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgleal, or wound effusions occur with БиКНУ Wafer treatment. In Study 1, 16% of БиКНУ Wafer-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of БиКНУ Wafer-treated patients with recurrent glioma experienced wound healing abnormalities. Monitor patients post-operatively for impaired neurosurgical wound healing.

Meningitis

Meningitis occurred in 4% of patients with recurrent glioma receiving БиКНУ 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.

Wafer Migration

БиКНУ 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.

Embryo-Fetal Toxicity

БиКНУ Wafers can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of БиКНУ Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m² basis and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose on a mg/m² basis. Advise females of reproductive potential to avoid pregnancy after implantation of БиКНУ Wafers. If the patient becomes pregnant after БиКНУ Wafer implantation, warn the patient about the potential hazard to the fetus.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with БиКНУ Wafer. Carcinogenicity, mutagenicity, and impairment of fertility studies have been conducted with carmustine, the active component of БиКНУ Wafer. Carmustine was carcinogenic in rats and mice when delivered by intraperitoneal injection at doses lower than those delivered by БиКНУ 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 on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

БиКНУ Wafer can cause fetal harm when administered to a pregnant woman. There have been no studies with БиКНУ Wafer; however, carmustine, the active component of БиКНУ Wafer, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m² basis and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose on a mg/m² basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data

There are no studies assessing the reproductive toxicity of БиКНУ Wafer; however, carmustine, the active component of БиКНУ Wafer, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 0.12 the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, on a mg/m² basis). Carmustine was embryotoxic in rabbits at intravenous doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

Nursing Mothers

It is not known if carmustine, the active component of БиКНУ Wafer, is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

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

Females and Males of Reproductive Potential

Contraception

Females

БиКНУ Wafer can cause fetal harm when administered during pregnancy (see Use In Specific Populations). Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use effective contraception after implantation of БиКНУ Wafer. Advise patients to inform their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking БиКНУ.

Infertility

Males

Carmustine caused testicular degeneration in animals. Advise male patients of the potential risk of infertility, and to seek counseling on fertility and family planning options prior to implantation of БиКНУ Wafer. (see Nonclinical Toxicology)

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

The following serious adverse reactions are discussed elsewhere in the label:

• Seizures
• Intracranial Hypertension
• Impaired Neurosurgical Wound Healing
• Meningitis

Clinical Trials Experience

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 Malignant Glioma

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

The population in Study 1 was 67% male, 97% white, the median age was 53 years (range: 2172). 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 multiforme 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, 24% received systemic chemotherapy.

Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving БиКНУ Wafers compared to 2 (2%) of patients receiving placebo. Deaths on the БиКНУ 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 БиКНУ Wafer-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2.

Table 1: Per-Patient Incidence of Adverse Reactions Occurring in БиКНУ Wafer-Treated Patients with Newly-Diagnosed High Grade Malignant Glioma (Study 1) (Between Arm Difference of ≥ 4%)

Table 2: Incidence of Local Adverse Reactions, Study 1*

Recurrent Glioblastoma Multiforme

The safety of БиКНУ Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 222 patients with recurrent high-grade malignant glioma who received up to eight БиКНУ 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 had a median age of 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma multiforme, 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 БиКНУ Wafers. Adverse reactions in БиКНУ Wafer-treated patients are shown in Table 3. Meningitis occurred in four patients receiving БиКНУ Wafers and in no patients receiving placebo. Bacterial meningitis was confirmed in two patients: the first with onset four days following БиКНУ Wafer implantation; the second following resection for tumor recurrence 155 days following БиКНУ 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.

Table 3: Per-Patient Incidence of Adverse Reactions in БиКНУ Wafer-Treated Patients with Glioblastoma Multiforme (Study 2) (Between Arm Difference of ≥ 4%)

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

Table 4: Incidence of Seizures, Study 2

Table 5: Hydrocephalus and Cerebral Edema, Study 2*

No information provided.

Carmustine concentrations delivered by БиКНУ Wafer in human brain tissue have not been determined.

Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m², the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m² dose of ¹⁴C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown.

БиКНУ Wafers are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of БиКНУ Wafer. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after БиКНУ Wafer implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain