Sincalide Injection, Powder, Lyophilized, For Solution
FDA Label NDC 70511-131

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.

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).

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

For injection: 5 mcg of sincalide as a lyophilized white to off-white cake or powder for reconstitution in a single-dose vial.

Sincalide for Injection is contraindicated in patients with:

• a history of a hypersensitivity reaction to sincalide. Serious hypersensitivity reactions have included anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1), Adverse Reactions (6)].
• intestinal obstruction.

In postmarketing experience, anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported during and within one hour following administration of sincalide [see Adverse Reactions (6)].

Due to the potential for anaphylaxis, appropriate medical support should be readily available when Sincalide for Injection is administered.  If anaphylaxis or other hypersensitivity reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment.  Observe patients closely during and after the infusion.  Do not reinitiate Sincalide for Injection in patients who have experienced symptoms of hypersensitivity [see Contraindications (4)].

Stimulation of gallbladder contraction in patients with small gallbladder stones could lead to the evacuation of the stones from the gallbladder, resulting in their lodging in the cystic duct or in the common bile duct.

Administration of Sincalide for Injection as an intravenous injection may cause adverse reactions such as nausea, vomiting, abdominal pain or cramping, dizziness, and flushing [see Adverse Reactions (6)]. These reactions are generally transient. To reduce the risk of adverse reactions with intravenous injection when used to simulate contraction of the gallbladder or accelerate transit of a barium meal through the small intestine, administer Sincalide for Injection as an intravenous infusion over 50 or 30 minutes, respectively [see Dosage and Administration (2.1)].

Based on limited human data and mechanism of action, advise pregnant patients that Sincalide for Injection may cause preterm labor or spontaneous abortion [see Use in Specific Populations (8.1)].

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:

Hypersensitivityreactions: 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.

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.

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.

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.

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).

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

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.

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 (Sincalide Structure)

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.

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.

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

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].

Anaphylaxis, Anaphylactic Shock and Other Hypersensitivity Reactions

Inform patients that 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

Vial Label (Vial)

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.