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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 C61H63N9Na4O17S4, a molecular mass of 1414.42 g/mol and has the following structure:
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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.
CYTALUX is indicated as an adjunct for intraoperative identification of:
Obtain a pregnancy test in females of reproductive potential and verify the absence of pregnancy prior to administration of CYTALUX [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Discontinue folate, folic acid, or folate containing supplements 48 hours before administration of CYTALUX [see DRUG INTERACTIONS].
Consider administering antihistamines and/or anti-nausea medication for prophylaxis against infusion-related reactions [see WARNINGS AND PRECAUTIONS].
The recommended dose of CYTALUX is a single intravenous infusion of 0.025 mg/kg diluted in 250 mL of 5% Dextrose Injection, administered over 60 minutes using a dedicated infusion line, 1 hour to 9 hours prior to surgery.
The recommended dose of CYTALUX is a single intravenous infusion of 0.025 mg/kg diluted in 250 mL of 5% Dextrose Injection, administered over 60 minutes using a dedicated infusion line, 1 hour to 24 hours prior to surgery.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
If the patient develops an infusion reaction during administration, interrupt the infusion and treat with antihistamines and/or anti-nausea medication as necessary, based on clinical decision. Complete the infusion within 3 hours of the start of the initial administration [see WARNINGS AND PRECAUTIONS].
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.
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.
Store frozen between -25° to -15°C (-13° to 5°F). Store in original carton to protect from light.
Manufactured by: Grand River Aseptic Manufacturing 140 Front Ave SW Grand Rapids, MI 49506. Distributed by: Patheon Logistics 100 Berkeley Dr. Swedesboro, NJ 08085. Revised: Dec 2022
The following clinically significant adverse reaction is also described elsewhere in the labeling:
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 Reaction | CYTALUX 0.025 mg/kg (N = 406) % |
| Nausea | 13 |
| Vomiting | 5 |
| Abdominal pain | 2 |
| Flushing | 2 |
| Other infusion-related reactions | 2 |
| Hypersensitivity | 2 |
| Elevation in blood pressure | 1 |
| Dyspepsia | 1 |
| Chest discomfort | 1 |
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 and CLINICAL PHARMACOLOGY].
Included as part of the PRECAUTIONS section.
Adverse reactions including nausea, vomiting, abdominal pain, flushing, hypersensitivity, elevation in blood pressure, dyspepsia, and chest discomfort were reported in patients receiving CYTALUX in clinical studies. A total of 17% of patients experienced reactions during the administration of CYTALUX [see ADVERSE REACTIONS]. Reactions typically occurred within 15 minutes of the start of infusion. CYTALUX infusion interruption or discontinuation due to adverse reactions occurred in 11% of all patients. Treatment with antihistamines and/or anti-nausea medication may be used. If an adverse reaction occurs during administration, the infusion can be interrupted and resumed after treatment of the reaction [see DOSAGE AND ADMINISTRATION].
Errors may occur with the use of CYTALUX during intraoperative fluorescence imaging to detect ovarian cancer and lesions in the lung, including false negatives and false positives. Non-fluorescing tissue in the surgical field does not rule out the presence of ovarian cancer or lesions in the lung [see Clinical Studies]. Fluorescence may be seen in normal tissues including bowel, kidneys, lymph nodes, and lungs as well as in inflamed tissues.
Based on its mechanism of action, CYTALUX may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to a fetus. Verify pregnancy status of females of reproductive potential prior to initiating CYTALUX treatment. [see Use In Specific Populations, CLINICAL PHARMACOLOGY].
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].
No carcinogenicity studies of pafolacianine have been conducted.
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.
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.
Based on its mechanism of action, pafolacianine may cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There are no available human data to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
No adverse developmental effects were observed in rats and rabbits with intravenous administration of pafolacianine during organogenesis (embryofetal development) at doses up to 158-fold (rat) and 570-fold (rabbit) the recommended human dose of 0.025 mg/kg based on AUC, otherwise 9.6 and 38.4-fold based on human equivalent dose (HED) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defects, 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.
Animal Data
In the definitive embryo-fetal development (EFD) studies, pafolacianine was intravenously administered during the period of organogenesis as follows: 0.015, 0.15, and 1.5 mg/kg/day from gestational day (GD) 6 to GD17 in rats (HEDs of 0.002, 0.024 and 0.242 mg/kg/day), and 0.3, 1, and 3 mg/kg/day from GD7 to GD20 in rabbits (HEDs of 0.097, 0.323 and 0.968 mg/kg/day). No significant drug-related maternal toxicity and embryo-fetal development toxicity were observed. NOAELs were 1.5 mg/kg/day in rats and 3 mg/kg/day in rabbits. Estimated systemic exposures were 158 times (rat) and 570 times (rabbit) the human exposure at a human dose of 0.025 mg/kg based on plasma AUC comparison.
There are no data on the presence of pafolacianine 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 CYTALUX and any potential adverse effects on the breastfed infant from CYTALUX or from the underlying maternal condition.
CYTALUX may cause fetal harm if administered to a pregnant woman [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Obtain a pregnancy test in females of reproductive potential and verify the absence of pregnancy prior to administration of CYTALUX [see DOSAGE AND ADMINISTRATION].
Safety and effectiveness of CYTALUX in pediatric patients have not been established.
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.
No Information provided
None.
CYTALUX is a fluorescent drug that targets folate receptor (FR) which may be overexpressed in ovarian cancer. Pafolacianine binds to FR-expressing cancer cells with ~1 nM affinity, internalizes via receptor mediated endocytosis, and concentrates in FR-positive cancer tissues. Pafolacianine absorbs light in the near-infrared (NIR) region within a range of 760 nm to 785 nm with peak absorption of 776 nm and emits fluorescence within a range of 790 nm to 815 nm with a peak emission of 796 nm.
Tumor to background ratios changed with different mass doses studied. High tumor to background ratio was observed with 0.025 mg/kg dose. CYTALUX exposure-response relationships and the time course of pharmacodynamic responses are unknown.
The mean Cmax of pafolacianine was 59.1 ± 5.94 ng/mL and AUCinf was 63.6 ± 12.6 ng.hr/mL.
The mean volume of distribution (Vz) 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.
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.
No clinically significant differences in pharmacokinetics of pafolacianine were identified based on age 18 – 89 years, weight 41.6 – 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.
No clinical studies evaluating the drug interaction potential of pafolacianine have been conducted.
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
The safety and efficacy of CYTALUX was evaluated in a randomized, multicenter, open-label study (NCT03180307). The study enrolled 178 women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery. One hundred and fifty women highly suspicious for or with confirmed ovarian cancer received CYTALUX (dosed at 0.025 mg/kg at least 1 hour before initiation of fluorescence imaging). Among them, 134 women with mean age 60 (range 33 to 81) years received both normal light imaging evaluation and fluorescence imaging evaluation (the Intent to Image set).
The study assessed the proportion of patients with at least one evaluable ovarian cancer lesion confirmed by central pathology that was detected with CYTALUX under fluorescent light but not under normal light or palpation and not otherwise identified for resection prior to surgery. The detection proportion was estimated in women who underwent both normal light and fluorescent light (Intent-to- Image Set), see Table 1. The detection performance for the Intent to Image set met the pre-specified success threshold.
Table 1: Detection Proportion with CYTALUX Under Fluorescent Light but Not Under Normal Light or Palpation In the Intent-To-Image Set
| (N=134) | |
| Patients with at least one confirmed ovarian cancer evaluable lesion | |
| Number (n) | 36 |
| Proportion (%) | 0.269 (26.9%) |
| 95% CI (proportion) | (0.196*, 0.352) |
| *The lower bound of the 95% confidence interval based on exact binomial exceeds the prespecified proportion of 0.10. | |
Patient-level false positive rate of CYTALUX with NIR fluorescent light with respect to the detection of ovarian cancer lesions confirmed by central pathology was 20.2% with 95% confidence interval (13.7%, 28.0%).
Pafolacianine binds to folate receptor (FR)-expressing cells with ~1 nM affinity, internalizes via receptor-mediated endocytosis, and accumulates intracellularly. Pafolacianine absorbs light in the near-infrared (NIR) region within a range of 760 nm to 785 nm with peak absorption of 776 nm and emits fluorescence within a range of 790 nm to 815 nm with a peak emission of 796 nm.
CYTALUX is a fluorescent drug that targets FR, which are overexpressed in ovarian cancer. The mechanism of CYTALUX detection of lung lesions is not well understood. The density of FR in malignant lesions in the lung is generally similar to that of normal lung tissue.
Tumor to background ratios of fluorescence intensity changed with different mass doses studied in patients with ovarian cancer. High tumor to background ratio was observed with 0.025 mg/kg dose.
CYTALUX exposure-response relationships and the time course of pharmacodynamic responses are unknown.
The mean Cmax of pafolacianine was 59.1 ± 5.94 ng/mL and AUCinf was 63.6 ± 12.6 ng.hr/mL.
The mean volume of distribution (Vz) 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.
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.
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.
No clinical studies evaluating the drug interaction potential of pafolacianine have been conducted.
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
The safety and efficacy of CYTALUX were evaluated in a randomized, multicenter, open-label study (NCT03180307). The study enrolled 178 women with a diagnosis or high clinical suspicion of ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery. One hundred and fifty women received CYTALUX (dosed at 0.025 mg/kg at least 1 hour before initiation of fluorescence imaging). Among them, 134 women underwent both normal light and CYTALUX evaluation (Intent-to-Image Set). The demographic characteristics were mean age 60 (range 33 to 81) years, 85% White, 4% Asian, 5% Black or African American, 3% American Indian or Alaska native, 3% other races, 11% Hispanic or Latino, and 2% unreported ethnicity.
Table 2 shows the proportion of patients with at least one evaluable ovarian cancer lesion confirmed by central histopathology that was detected with CYTALUX but not with normal light or palpation and not otherwise identified for resection prior to surgery. The detection performance met the preÂspecified success threshold.
Table 2: Detection Proportion with CYTALUX but Not with Normal Light or Palpation in the Intent-To-Image Set
| N=134 patients | Patients with at least one confirmed ovarian cancer evaluable lesion |
| Number (n) | 36 |
| Proportion (%) 95% CI | 0.269 (26.9%) (0.196*, 0.352) |
| *The pre-specified lower bound of the 95% confidence interval (CI) was 0.10. | |
In 20.2% (95% CI: 13.7%, 28.0%) of patients, all lesions detected by CYTALUX alone were negative by central histopathology (false positive).
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
| N=100 patients | Primary Lung Lesion (CSE A) | Synchronous Malignant Lung Lesion (CSE B) | Patients with CSE A and/or CSE B |
| Number (n) | 19* | 8 | 24** |
| Proportion (%) 95% CI | 0.19 (19%) (0.118, 0.281) | 0.08 (8%) (0.035, 0.152) | 0.24 (24%) (0.160***, 0.336) |
| * 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. |
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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).
Advise females of reproductive potential of the potential risk to a fetus and to contact their healthcare provider with a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Inform patients that folic acid may reduce the detection of cancer tissue with CYTALUX. Advise the patient to stop taking folate, folic acid, or folate-containing supplements 48 hours before administration of CYTALUX [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
