Cytalux

CYTALUX is indicated as an adjunct for intraoperative identification of:

• Malignant lesions in adult patients with ovarian cancer.
• Malignant and non-malignant pulmonary lesions in adult patients with known or suspected cancer in the lung.

Imaging

• Clinical data demonstrate that near infrared (NIR) imaging devices that excite at 760 nm to 785 nm and detect emission at 790 nm to 815 nm are suitable for use with CYTALUX.
• CYTALUX is to be used with an NIR imaging system cleared by the FDA for specific use with pafolacianine.
• CYTALUX should only be used by surgeons who have completed a training program on the use of NIR imaging systems for fluorescence imaging during surgery. Training is provided by the device manufacturer.

Injection: 3.2 mg/1.6 mL (2 mg/mL) pafolacianine (equivalent to 3.4 mg/1.6 mL pafolacianine sodium)
supplied as a dark bluish green, clear aqueous solution in a single-dose vial.

Geriatric Use

Of the total number of patients in clinical studies of CYTALUX, 221 patients (54%) were 65 years of
age and older: 153 (38%) were 65 to 74 years of age, 66 (16%) were 75 to 84 years of age, and 2
(0.5%) were 85 years of age and older. No overall differences in safety, effectiveness, or
pharmacokinetics were observed between patients 65 years of age and older and younger adult
patients.

Risk of Pafolacianine Aggregation and Infusion Reactions

Use of the incorrect diluent to prepare the CYTALUX infusion solution can cause the aggregation of
pafolacianine; aggregation may induce infusion reactions, such as nausea, vomiting, abdominal pain
or rash. Use only 5% Dextrose Injection to prepare the CYTALUX infusion solution. Do not use other
diluents. [see Dosage and Administration ( 2.3)].

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 CYTALUX was evaluated in four open label clinical studies, two studies (N = 44 and N = 150) in patients with ovarian cancer and two studies (N = 100 and N = 112) in patients with known or suspected cancer in the lung. A total of 406 patients received 0.025 mg/kg of CYTALUX via intravenous administration.

The demographic characteristics of the study population were 82% female (66% female in lung studies), mean age 64 years (range 26 to 89 years), 85% White, 6% Black or African American, 5% Asian, and 4% other race, 5% Hispanic or Latino, 92% Not Hispanic or Latino, and 3% unreported ethnicity.

Adverse reactions that occurred in > 1% of patients are presented in Table 1.

Table 1. Adverse Reactions from Clinical Studies Reported in ≥ 1% of CYTALUX Treated Patients with Ovarian Cancer or Known or Suspected Cancer in the Lung

Adverse reactions occurred during the administration of CYTALUX in 17% of patients.

Overall, the safety profile observed in patients treated with CYTALUX 0.025 mg/kg was similar between patients with ovarian cancer and patients with known or suspected cancer in the lung.

Use of folate, folic acid, or folate-containing supplements may reduce binding of pafolacianine to
folate receptors and could reduce the detection of lesions with CYTALUX. Avoid administration of
folate, folic acid, or folate-containing supplements within 48 hours before administration of CYTALUX [see Dosage and Administration (2.1) and Clinical Pharmacology (12.1)].

CYTALUX contains pafolacianine, an optical imaging agent, as a tetrasodium salt referred to as
pafolacianine sodium. Chemically, pafolacianine sodium is (S)-2-(4-(((2-amino-4-oxo-3,4-
dihydropteridin-6-yl)methyl)amino)benzamido)-3-(4-(((E)-2-((E)-2-(3,3-dimethyl-5-sulfonato-1-(4-
sulfonatobutyl)-3H-indol-1-ium-2-yl)vinyl)-6-((E)-2-(3,3-dimethyl-5-sulfonato-1-(4-
sulfonatobutyl)indolin-2-ylidene)ethylidene)cyclohex-1-en-1-yl)oxy)phenyl)propanoate hydrate
tetrasodium. Pafolacianine sodium has a molecular formula of C 61H 63N 9Na 4O 17S 4, a molecular mass
of 1414.42 g/mol and has the following structure:

CYTALUX (pafolacianine) injection is a sterile, non-pyrogenic, dark bluish green, clear aqueous
solution for intravenous use. Each vial contains 3.2 mg (2 mg/mL) pafolacianine (equivalent to 3.4 mg
pafolacianine sodium),14.4 mg sodium chloride, 0.23 mg potassium phosphate monobasic, 1.27 mg
sodium phosphate dibasic heptahydrate in 1.6 mL volume. The pH is adjusted with sodium hydroxide
and/or hydrochloric acid and is between 7.1 to 7.8.

Pharmacokinetics

The mean C max of pafolacianine was 59.1 ± 5.94 ng/mL and AUC inf was 63.6 ± 12.6 ng.hr/mL.
Distribution
The mean volume of distribution (V z) is 17.1 ± 5.99 L, indicating distribution into tissues.
Plasma protein binding of pafolacianine is 93.7%. No notable partitioning into red blood cells has
been observed.
Elimination
The elimination half-life of pafolacianine is 0.44 ± 0.23 hours and mean plasma clearance is 28.6 ±
4.97 L/hr.
Metabolism
Pafolacianine sodium is not metabolized by cytochrome P450 (CYP) enzymes.
Excretion
Following a single IV infusion of radiolabeled pafolacianine sodium, approximately 35% of the dose
was recovered in urine (19.1%) and in feces (15.8%) after approximately 3-5 weeks.
Specific Populations
No clinically significant differences in pharmacokinetics of pafolacianine were identified based on age
18 to 89 years, weight 41.6 to 133.6 kg, mild to moderate renal impairment (CLcr 30 to 89 mL/min),
mild to moderate hepatic impairment (total bilirubin < 3 ULN and AST > ULN). The effect of severe
renal impairment (CLcr < 30 mL/min) and severe hepatic impairment (total bilirubin > 3 ULN and any
AST value) on the pharmacokinetics of pafolacianine have not been studied.
Drug Interaction Studies
No clinical studies evaluating the drug interaction potential of pafolacianine have been conducted.
In Vitro Studies
CYP Enzymes: Pafolacianine is not an inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19 2D6, 3A4/5.
UDP-glucuronosyltransferase (UGT) Enzymes: Pafolacianine is not an inhibitor of UGT1A1.
Transporter Systems: Pafolacianine is a substrate for OATP1B1, OATP1B3, and OAT1. Pafolacianine
is not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, or BCRP

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
No carcinogenicity studies of pafolacianine have been conducted.
Mutagenesis
No genotoxic hazards were identified when pafolacianine was evaluated in a standard testing battery
consisting of a bacterial reverse mutation assay, an in vitro micronucleus study conducted in Chinese
Hamster Ovary (CHO) cells, and a rat bone marrow micronucleus study.
Impairment of Fertility
Reproductive and developmental toxicity (fertility and embryonic development, pre- and postnatal
development) studies in animals have not been performed to evaluate the effects of pafolacianine on
fertility.

Patients with Known or Suspected Cancer in the Lung

The safety and efficacy of CYTALUX were evaluated in a randomized, multicenter, open-label study (NCT04241315). The study enrolled 140 patients scheduled to undergo thoracoscopic or open segmental or subsegmental resection for primary lung lesions that were either confirmed or suspected to be cancer. One hundred and twelve patients received CYTALUX (dosed at 0.025 mg/kg between 1 and 24 hours before initiation of fluorescence imaging). Among them, 100 patients underwent both normal light and CYTALUX evaluation (Intent-to-Image Set). The demographic characteristics were 61% female, mean age 66 (range 26 to 83) years, 88% White, 8% Black or African American, 2% Asian, 2% other races, 99% Not Hispanic or Latino, and 1% unreported ethnicity. Histopathology of the primary lung lesions in these 100 patients showed primary lung cancer in 65%, metastasis to the lung in 21%, benign lung lesions in 11%, and other/unknown cancer in 3%. Among the primary lung cancers, 86% were adenocarcinoma, 8% were squamous cell carcinoma, 3% were adeno-squamous carcinoma, and 3% were atypical carcinoid.

Table 3 shows the proportion of patients in whom at least one of the following clinically significant events (CSE) occurred with CYTALUX but not with normal light or palpation: localization of the primary lung lesion, whether benign or malignant (CSE A), and detection of one or more synchronous malignant lung lesions (CSE B). Synchronous lesions were not identified prior to surgery. The combined CSE A and CSE B detection performance met the pre-specified success threshold.

Table 3: Proportion of Clinically Significant Events Occurring with CYTALUX but Not with Normal Light or Palpation in the Intent-To-Image Set

* Including two subjects with benign primary lesions.

** Three patients had both primary lesion localization and synchronous malignant lesion detection, resulting in 27 events in 24 unique patients.

*** The pre-specified lower bound of the 95% confidence interval (CI) was 0.10.

CYTALUX did not identify the primary lung lesion in 23% (95% CI:15%, 32%) of patients. Among the 20 patients who had synchronous lesions detected only by CYTALUX, 12 patients had only benign synchronous lesions.

The depth of primary lung lesions detected by CYTALUX ranged from 0 to 38 mm from the lung surface (mean depth 6 mm).

How Supplied
CYTALUX (pafolacianine) injection, 3.2 mg /1.6 mL (2 mg/mL), is a dark bluish green, clear aqueous
solution packaged in a sealed amber glass single-dose vial. It is supplied in a carton containing 10
vials (NDC 81052-138-10), individually packaged.

Storage and Handling
Store vials in their original cartons to protect from light.

CYTALUX may be stored according to the table below. If CYTALUX vial is not used within the maximum single period at either room temperature or under refrigerated conditions the vial may be refrozen up to one time.​

Do not use the product past the expiration date.