2.1 Recommended Dose 

The recommended dose of LUMISIGHT is 1 mg/kg actual body weight by intravenous injection over 3 minutes administered 2 hours to 6 hours prior to imaging.

2.2 Preparation of LUMISIGHT

Important Preparation Information

• Prior to reconstitution, store vials in the freezer at -25°C to -15°C (-13°F to 5°F). Protect from light.
• Use aseptic technique for the preparation of LUMISIGHT.
• The recommended dose depends on the individual patient’s weight. Multiple vials of LUMISIGHT may need to be reconstituted to achieve the individual patient dose.
• Only use 0.45% Sodium Chloride Injection, USP for reconstitution of LUMISIGHT to prevent high osmolality.

Preparation Instructions

1. Calculate the dose (1 mg/kg) and the total volume (mL) of LUMISIGHT based on the individual patient’s weight.
2. Obtain the number of vials required to administer the patient dose.
3. Allow the vials to acclimate to room temperature between 20°C to 25°C (68°F to 77°F) for approximately 5 minutes.
4. Reconstitute each vial of LUMISIGHT with 4 mL of 0.45% Sodium Chloride Injection, USP to permit withdrawal of 3.9 mL of LUMISIGHT 10 mg/mL.
5. Visually inspect the reconstituted solution. It should be a clear, dark blue-colored solution free of particulate matter. Discard if there is any discoloration or particulate matter.
6. If not immediately used, store the reconstituted LUMISIGHT vial at room temperature at 20°C to 25°C (68°F to 77°F) and use within 4 hours, or store the reconstituted LUMISIGHT vial in the refrigerator at 2°C to 8°C (35°F to 46°F) and use within 24 hours. Protect from light.
7. Each vial of LUMISIGHT is for a single dose. Discard unused portion.

2.3 Administration

• Withdraw the calculated volume from the appropriate number of vials into one syringe for administration of one single dose of 1 mg/kg. Verify that the syringe contains the intended volume.
• Prior to administration of LUMISIGHT, flush the peripheral intravenous (IV) line with 10 mL to 20 mL of 0.9% Sodium Chloride Injection, USP.
• Administer LUMISIGHT as an IV injection over 3 minutes beginning 2 hours to 6 hours prior to imaging with the Lumicell DVS.
• After administration of LUMISIGHT, flush the IV line with 10 mL to 20 mL of 0.9% Sodium Chloride Injection, USP.

2.4 Imaging 

LUMISIGHT is used with the Lumicell Direct Visualization System (DVS) or other fluorescence imaging device that is FDA-approved for specific use with pegulicianine in the indicated population. The device provides illumination to excite the fluorescent components of pegulicianine and collects images showing pegulicianine’s fluorescence emission. Regions suspected to contain cancerous tissue are highlighted as positive signals on the Lumicell DVS display [see Clinical Studies (14)].

Training on the use of the device is essential prior to employing the system in a lumpectomy procedure. Please refer to the device labeling for details on how to use the device and for training information.

5.1 Anaphylaxis and Other Serious Hypersensitivity Reactions

Prepare for the possibility of drug hypersensitivity reactions (including anaphylaxis), which can occur during or following administration, and take the necessary precautions.

In clinical studies, 4 of 726 (0.6%) patients treated with LUMISIGHT experienced signs and symptoms consistent with anaphylaxis. The onset was during administration in three patients. Signs and symptoms associated with other hypersensitivity reactions included pruritus, urticaria, hypotension, lip swelling, erythema, anxiety, chest pain, cyanosis, dizziness, dyspnea, headache, hypoesthesia, hyperventilation, maculopapular rash, nausea, paresthesia, visual changes, and vomiting [see Adverse Reactions (6.1)].

Before LUMISIGHT administration, assess all patients for any history of hypersensitivity reaction to contrast media or products containing polyethylene glycol (PEG), as these patients may have an increased risk for hypersensitivity reaction to LUMISIGHT. In clinical studies, three out of four patients that experienced anaphylaxis did not have a history of hypersensitivity reaction to contrast media or products containing PEG.

Always have emergency resuscitation drugs, equipment, and trained personnel available. Monitor all patients for hypersensitivity reactions through symptom reporting, direct observation, and vital sign measurements. If a hypersensitivity reaction is suspected, immediately discontinue the injection and initiate appropriate therapy. LUMISIGHT is contraindicated in patients with a history of hypersensitivity reaction to pegulicianine [see Contraindications (4)].

5.2 Risk of Misdiagnosis

False positive and false negative findings may occur during use of LUMISIGHT to detect residual cancer. Absence of signal in the lumpectomy cavity does not rule out the presence of residual cancer. Additionally, positive signal has been observed in some non-cancerous tissue [see Clinical Studies (14)].

5.3 Interference from Dyes Used for Sentinel Lymph Node Mapping

Blue dyes used for sentinel lymph node (SLN) mapping procedures interfere with LUMISIGHT imaging. The potential of other dyes to interfere with LUMISIGHT imaging has not been evaluated. Avoid administration of dyes used for SLN mapping procedures before imaging the lumpectomy cavity in patients receiving LUMISIGHT [see Drug Interactions (7)].

6.1 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.

The safety of LUMISIGHT was evaluated in 726 patients who received a single dose of 1 mg/kg of LUMISIGHT. Among these 726 patients, 703 (97%) had breast cancer and 23 (3%) had other types of cancer. The mean age of the patients was 62 years (range: 36 years to 95 years), and 98% of them were female. Distribution by race was 82% White, 7% Black or African American, 6% Asian, and 5% other or unreported. Distribution by ethnicity was 3% Hispanic/Latino, 93% non-Hispanic/Latino, and 4% unknown or unreported.

Adverse reactions occurring in ≥ 1% of patients receiving LUMISIGHT were hypersensitivity (1.4%, including anaphylaxis [4 out of 726]) and chromaturia (85%). Chromaturia resolved within 48 hours after administration in 93% of patients, with the longest time to resolution of 15 days.

Adverse reactions occurring in use < 1% of patients were skin discoloration after extravasation, nausea, dyspnea, pyrexia, and vomiting.

8.1 Pregnancy

Risk Summary

There are no available data on pegulicianine use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction studies were not conducted with pegulicianine.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

8.2 Lactation

Risk Summary

There are no data on the presence of pegulicianine or its metabolites in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUMISIGHT and any potential adverse effects on the breastfed infant from LUMISIGHT or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of LUMISIGHT in pediatric patients have not been established.

8.5 Geriatric Use

Of 703 patients in clinical studies of LUMISIGHT for breast cancer who received the recommended dose of 1 mg/kg, 44% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or effectiveness have been observed between these patients and younger adult patients.

12.1 Mechanism of Action

Pegulicianine is a prodrug that is optically inactive when intact and produces a fluorescent signal after its peptide chain is cleaved by cathepsins and matrix metalloproteases (MMPs). The levels of these enzymes are higher in and around tumor and tumor-associated cells than normal cells.

This enzymatic cleavage results in “fragment 2” and “fragment 3”, which are optically active metabolites that emit fluorescence, as well as “fragment 1” containing the fluorescence quencher that keeps the intact molecule optically inactive. “Fragment 2” and “fragment 3” absorb light in the visible light region with a peak absorption at 650 nm and fluoresce with a peak emission at 675 nm.

12.2 Pharmacodynamics

The relationships between the plasma concentrations of the optically active metabolites and the time course of pharmacodynamic response have not been fully characterized.

12.3 Pharmacokinetics

Elimination

Metabolism

Pegulicianine is cleaved by cathepsins and matrix metalloproteases to the active metabolites “fragment 2” and “fragment 3.” Pegulicianine undergoes minimal hepatic metabolism in vitro.

Excretion

Pegulicianine excretion pathway in humans is unknown. Observed blue/green discoloration of urine (chromaturia) in subjects receiving pegulicianine suggests that pegulicianine and/or its metabolites may be excreted renally.

Specific Populations

Patients with Renal Impairment

Mild renal impairment (RI) does not appear to have a clinically meaningful effect on the pharmacokinetics, safety, and efficacy of pegulicianine and fragment 3; fragment 2 data are not available. The effect of moderate or severe RI on the pharmacokinetics, safety, and efficacy of pegulicianine, fragment 2, and fragment 3 has not been evaluated.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies in animals have been conducted to evaluate the carcinogenic potential of pegulicianine.

The nonfluorescent major metabolite of pegulicianine was not mutagenic in nonclinical tests, i.e., in vitro reverse mutation test in bacteria (Ames test), in vitro chromosomal aberration test in human peripheral blood lymphocytes, and in vivo (mice) micronucleus test after intravenous doses up to 11.24 mg/kg (225 times the pegulicianine clinical dose of 1 mg/kg).

No reproductive and developmental toxicity studies in animals have been performed to evaluate the effects of pegulicianine on fertility.