Sincalide

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 out-put 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.

1 INDICATIONS AND USAGE Kinevac is indicated in adults to: 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; to stimulate pancreatic secretion in combination with secretin prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; to 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. Kinevac 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 )

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 Kinevac by indication is shown in Table 1. For preparation instructions see Dosage and Administration ( 2.2 ) . Table 1: Recommended Adult Dosage and Administration of Kinevac by Treatment Indication Indication Recommended Adult Dosage and Administration of KINEVAC To stimulate contraction of the gallbladder Kinevac 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 Kinevac: 30 minutes after initiation of secretin infusion, administer Kinevac 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 Kinevac 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 Kinevac 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 Kinevac 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 Kinevac 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 .

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 Kinevac 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 ), ( 5.1 )] . 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 Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 Kinevac, 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 Kinevac, when used to stimulate contraction of the gallbladder.