Sincalide

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions [see Warnings and Precautions (5.1)] • Evacuation of gallstones [see Warnings and Precautions (5.2)] • Adverse reactions with intravenous injection [see Warnings and Precautions (5.3)] • Preterm labor or spontaneous abortion [see Warnings and Precautions (5.4)] The following adverse reactions associated with the use of sincalide were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure. The most frequent adverse reactions (20% or greater) are gastrointestinal: abdominal discomfort or pain, and nausea; these may not necessarily indicate an abnormality of the biliary tract unless there is other clinical or radiologic evidence of disease. Less common adverse reactions include: Hypersensitivity reactions : anaphylaxis and anaphylactic shock, hypotension, throat tightness, bradycardia, shortness of breath, nausea, abdominal cramping, diaphoresis, hives, rash, itching; and numbness of face, lips and eyes [see Contraindications (4)] . Neurological reactions : seizures, headache. Vasovagal reactions : dizziness, loss of consciousness, nausea, diaphoresis, syncope and hypotension (generally self-limiting). Other : nausea, vomiting, flushing, hypertension, urge to defecate, diarrhea, sneezing. Most common adverse reactions (≥20%) are: abdominal discomfort or pain, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact MAIA Pharmaceuticals at 1-888-877-9064 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Sincalide for Injection is contraindicated in patients with: a history of a hypersensitivity reaction to sulfites or sincalide. Serious hypersensitivity reactions have included anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1), Adverse Reactions (6)]. intestinal obstruction. History of hypersensitivity to sulfites or sincalide. (4, 5.1) Intestinal obstruction. (4)

11 DESCRIPTION Sincalide for Injection is a cholecystopancreatic-gastrointestinal hormone for parenteral administration. The agent is a synthetically-prepared C-terminal octapeptide of cholecystokinin. Each single-dose vial of sincalide provides a sterile nonpyrogenic lyophilized white to off-white cake or powder consisting of 5 mcg sincalide with 30 mg arginine hydrochloride, 15 mg lysine hydrochloride,170 mg mannitol, 4 mg methionine, 2 mg pentetic acid, and 0.04 mg sodium metabisulfite. The pH is adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide prior to lyophilization. Sincalide is designated chemically as L-α-aspartyl-O- sulfo-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl- L-α-aspartyl-L-phenylalaninamide. Graphic formula: sincalide-structure

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosage and Administration by Indication: To Stimulate Contraction of the Gallbladder 0.02 mcg/kg as a single dose over 30 to 60 seconds via intravenous injection. If satisfactory contraction does not occur in 15 minutes, administer a dose of 0.04 mcg/kg over 30 to 60 seconds. (2.1) Alternatively consider an intravenous infusion to reduce gastrointestinal adverse reactions: 0.12 mcg/kg diluted in 100 mL of 0.9% Sodium Chloride Injection USP and infused over 50 minutes at a rate of 2 mL per minute. (2.1, 2.2, 5.3) To Stimulate Pancreatic Secretion in Combination with Secretin 30 minutes after initiation of secretin for injection, administer 0.02 mcg/kg diluted in 30 mL of 0.9% Sodium Chloride Injection USP and infused over 30 minutes at a rate of 1 mL per minute. (2.1, 2.2) To Accelerate Transit of a Barium Meal Through the Small Intestine: After the barium meal is beyond the proximal jejunum, administer 0.04 mcg/kg over 30 to 60 seconds via intravenous injection. (2.1) If satisfactory transit of the barium meal has not occurred in 30 minutes, administer a second dose of 0.04 mcg/kg over 30 to 60 seconds. (2.1) Alternatively consider an intravenous infusion to reduce gastrointestinal adverse reactions: 0.12 mcg/kg diluted in 100 mL 0.9% Sodium Chloride Injection USP and infused over 30 minutes. (2.1, 2.2, 5.3) 2.1 Recommended Dosage and Administration Instructions The recommended dosage and administration of Sincalide for Injection by indication is shown in Table 1. For preparation instructions see Dosage and Administration (2.2) . Table 1: Recommended Adult Dosage and Administration of Sincalide for Injection by Treatment Indication Indication Recommended Adult Dosage and Administration of Sincalide for Injection To stimulate contraction of the gallbladder Sincalide for Injection 0.02 mcg/kg as a single dose over 30 to 60 seconds via intravenous injection. If satisfactory contraction does not occur in 15 minutes, administer a dose of 0.04 mcg/kg over 30 to 60 seconds. Alternatively, Consider an Intravenous Infusion to Reduce Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.3)] : 0.12 mcg/kg diluted in 100 mL of 0.9% Sodium Chloride Injection USP and infused over 50 minutes at a rate of 2 mL per minute. To stimulate pancreatic secretion in combination with secretin for injection Secretin for Injection: 0.25 units/kg as intravenous infusion over 60 minutes Sincalide for Injection: 30 minutes after initiation of secretin infusion, administer Sincalide for Injection 0.02 mcg/kg diluted in 30 mL of 0.9% Sodium Chloride Injection USP and infused over 30 minutes at a rate of 1 mL per minute. To accelerate the transit of a barium meal through the small intestine After the barium meal is beyond the proximal jejunum, administer Sincalide for Injection 0.04 mcg/kg over 30 to 60 seconds via intravenous injection. If satisfactory transit of the barium meal has not occurred in 30 minutes, administer a second dose of 0.04 mcg/kg over 30 to 60 seconds. Alternatively, Consider an Intravenous Infusion to Reduce Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.3)] : 0.12 mcg/kg diluted in 100 mL 0.9% Sodium Chloride Injection USP and infused over 30 minutes. 2.2 Preparation Instructions For Intravenous Injection Reconstitute Sincalide for Injection aseptically by adding 5 mL of Sterile Water for Injection USP to the vial. Inspect the reconstituted solution visually for particulate matter and discoloration after reconstitution and prior to administration. Withdraw the prescribed dose of the reconstituted solution from the vial and administer as an intravenous injection over 30 to 60 seconds, as shown in Table 1. Discard the unused portion. Store the reconstituted solution at room temperature. Discard after 8 hours . For single use only; discard unused portion. For Intravenous Infusion Reconstitute Sincalide for Injection aseptically by adding 5 mL of Sterile Water for Injection USP to the vial. After reconstitution, withdraw the prescribed dose of the solution from the vial. Discard unused portion. Dilute the reconstituted solution in 30 mL or 100 mL of 0.9% Sodium Chloride Injection USP, depending on the indication, as described in Table 1. Inspect the Sincalide solutions visually for particulate matter and discoloration after reconstitution, dilution and prior to administration. Store the diluted solution at room temperature. Discard after 1 hour.

1 INDICATIONS AND USAGE Sincalide for Injection is indicated in adults to: stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals; stimulate pancreatic secretion in combination with secretin prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. Sincalide for Injection is a cholecystokinin (CCK) analog indicated in adults to: • stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals. (1) • stimulate pancreatic secretion in combination with secretin prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology. (1) • accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. (1)

10 OVERDOSAGE In the event of an overdose, symptoms related to vagal stimulation, such as gastrointestinal symptoms (abdominal cramps, nausea, vomiting and diarrhea), hypotension with dizziness or fainting may occur. Overdosage symptoms should be treated symptomatically and should be of short duration. A single bolus intravenous injection of 0.05 mcg/kg (approximately 2 to 3 times the human dose of 0.02 mcg/kg), sincalide caused hypotension and bradycardia in dogs. In addition, higher doses injected intravenously once or repeatedly in dogs caused syncope and ECG changes (approximately 5 times the human dose of 0.02 mcg/kg). These effects were attributed to sincalide-induced vagal stimulation in that all were prevented by pretreatment with atropine or bilateral vagotomy.

7 DRUG INTERACTIONS Drugs that Affect Gallbladder Motility or Contractile Response : May interfere with response to sincalide. Consider discontinuing these drugs prior to administration of Sincalide for Injection, when used to stimulate contraction of the gallbladder. (7.1) 7.1 Drugs that Affect Gallbladder Motility or Contractile Response Drugs that may stimulate or inhibit gallbladder motility or contractile response, may interfere with the response to sincalide. Consider discontinuing these drugs prior to administration of Sincalide for Injection, when used to simulate contraction of the gallbladder.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action When injected intravenously, Sincalide stimulates gallbladder contraction and reduction in size. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. Sincalide also stimulates pancreatic secretion and intestinal motility causing pyloric contraction and slows gastric emptying. Concurrent administration of sincalide with secretin increases both the volume of pancreatic secretion and the output of bicarbonate and enzymes. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate. 12.2 Pharmacodynamics Following an intravenous (bolus) injection of 0.02 mcg/kg sincalide, maximal contraction of the gallbladder occurred in 5 to 15 minutes. Sincalide reduced gallbladder radiographic size by at least 40%, which is generally considered satisfactory contraction.

12.1 Mechanism of Action When injected intravenously, Sincalide stimulates gallbladder contraction and reduction in size. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. Sincalide also stimulates pancreatic secretion and intestinal motility causing pyloric contraction and slows gastric emptying. Concurrent administration of sincalide with secretin increases both the volume of pancreatic secretion and the output of bicarbonate and enzymes. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate.

12.2 Pharmacodynamics Following an intravenous (bolus) injection of 0.02 mcg/kg sincalide, maximal contraction of the gallbladder occurred in 5 to 15 minutes. Sincalide reduced gallbladder radiographic size by at least 40%, which is generally considered satisfactory contraction.

20231101

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3 DOSAGE FORMS AND STRENGTHS For injection: 5 mcg of sincalide as a lyophilized white to off-white cake or powder for reconstitution in a single-dose vial. For injection: 5 mcg of sincalide as a lyophilized cake or powder in a single-dose vial for reconstitution (3)

Sincalide Sincalide SINCALIDE SINCALIDE MANNITOL ARGININE HYDROCHLORIDE LYSINE HYDROCHLORIDE METHIONINE PENTETIC ACID SODIUM METABISULFITE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.

NDA210850

Sincalide

Sincalide

70511-131

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Principal Display Panel NDC 70511-131-05 Sincalide for Injection 5 mcg/vial For Intravenous Use Vial contains a sterile, lyophilized powder providing 5 mcg sincalide (see insert for inactive ingredients); pH adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide. Recommended Dosage: See Prescribing Information Single-Dose Vial. Discard Unused Portion. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature] Manufactured for MAIA Pharmaceuticals, Inc. vial

Contraindications (4) 10/2023 Warnings and Precautions, Anaphylaxis, Anaphylactic Shock and other Serious Hypersensitvity Reactions (5.1) 10/2023

17 PATIENT COUNSELING INFORMATION Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions Inform patients serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock have been reported during or following administration of Sincalide for Injection. Advise patients to report immediately to a healthcare provider if they experience symptoms of a hypersensitivity reaction [see Warnings and Precautions (5.1)]. Gastrointestinal Adverse Reactions Advise patients that Sincalide for Injection may cause transient gastrointestinal symptoms [see Warnings and Precautions (5.3)]. Pregnancy Advise pregnant women of the potential risk for preterm labor and spontaneous abortion [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Manufactured for: MAIA Pharmaceuticals, Inc. 707 State Road, Suite #104 Princeton, NJ 08540 USA Manufactured by: Gland Pharma Limited Hyderabad, 500 043, India Manufactured in India

8.5 Geriatric Use Clinical studies of sincalide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Animal Data Direct injection of sincalide in neonatal rats reduced milk consumption with the youngest rats exhibiting the greatest sensitivity to this effect. Although safety margins relative to maternal doses cannot be calculated since rat pups were injected directly, the safety margin in the youngest rat pups was less than 0.1 on a body surface area bases compared to the maximum adult clinical dose. At higher doses administered subcutaneously in neonatal rats, transient behavioral changes and small effects on physical developmental milestones such as ear opening, eye opening, and incisor appearance were observed (at doses 10 to 200-fold higher than the maximum recommended human dose on a body surface area basis).

8.1 Pregnancy Risk Summary Based on limited human data and mechanism of action, Sincalide for Injection may cause preterm labor or spontaneous abortion [see Warnings and Precautions (5.4)]. Limited available data with Sincalide for Injection are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal embryo-fetal development studies in which sincalide was administered to hamsters and rats during the period of organogenesis, no effects were seen at doses comparable to the maximum recommended clinical dose on a mg/kg basis. However, in a prenatal development study in which rats were administered sincalide during organogenesis through parturition, decreased weight gain and developmental delays were observed at a dose 122 times higher than the maximum recommended human dose based on body surface area. The estimated 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. Data Animal Data There were no effects on embryo-fetal development in hamsters when sincalide was administered subcutaneously at 250 or 750 ng/kg during organogenesis (Gestation Days 7 to 13) at doses up to 0.8 times the maximum recommended dose of 120 ng/kg on a body surface area basis. No effects on embryo-fetal development were observed in Sprague-Dawley rats at subcutaneous doses of 250, 450, or 750 ng/kg from Gestation Days 6 to16, representing 1.0 time the maximum recommended human dose on a body surface area basis. In a separate study at a higher dose of 90 mcg/kg administered subcutaneously to CFY rats from Gestation Day 10 through parturition (representing 122 times the maximum recommended human dose on a body surface area basis), offspring showed decreased growth, behavioral changes, and developmental delays.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on limited human data and mechanism of action, Sincalide for Injection may cause preterm labor or spontaneous abortion [see Warnings and Precautions (5.4)]. Limited available data with Sincalide for Injection are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal embryo-fetal development studies in which sincalide was administered to hamsters and rats during the period of organogenesis, no effects were seen at doses comparable to the maximum recommended clinical dose on a mg/kg basis. However, in a prenatal development study in which rats were administered sincalide during organogenesis through parturition, decreased weight gain and developmental delays were observed at a dose 122 times higher than the maximum recommended human dose based on body surface area. The estimated 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. Data Animal Data There were no effects on embryo-fetal development in hamsters when sincalide was administered subcutaneously at 250 or 750 ng/kg during organogenesis (Gestation Days 7 to 13) at doses up to 0.8 times the maximum recommended dose of 120 ng/kg on a body surface area basis. No effects on embryo-fetal development were observed in Sprague-Dawley rats at subcutaneous doses of 250, 450, or 750 ng/kg from Gestation Days 6 to16, representing 1.0 time the maximum recommended human dose on a body surface area basis. In a separate study at a higher dose of 90 mcg/kg administered subcutaneously to CFY rats from Gestation Day 10 through parturition (representing 122 times the maximum recommended human dose on a body surface area basis), offspring showed decreased growth, behavioral changes, and developmental delays. 8.2 Lactation Risk Summary There are no data regarding the presence of sincalide in 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 Sincalide for Injection and any potential adverse effect on the breastfed infant from Sincalide for Injection or from the underlying condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Animal Data Direct injection of sincalide in neonatal rats reduced milk consumption with the youngest rats exhibiting the greatest sensitivity to this effect. Although safety margins relative to maternal doses cannot be calculated since rat pups were injected directly, the safety margin in the youngest rat pups was less than 0.1 on a body surface area bases compared to the maximum adult clinical dose. At higher doses administered subcutaneously in neonatal rats, transient behavioral changes and small effects on physical developmental milestones such as ear opening, eye opening, and incisor appearance were observed (at doses 10 to 200-fold higher than the maximum recommended human dose on a body surface area basis). 8.5 Geriatric Use Clinical studies of sincalide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING Sincalide for Injection is supplied as 5 mcg of sincalide as a lyophilized white to off-white cake or powder for reconstitution in a single-dose vial; in packages of 10 vials (NDC 70511-131-05). Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].