is. (2.1, 5.2, 7.2)

w these steps to determine the patient dose: total dose (mcg) = patient’s weight (kg) x prescribed dose (mcg/kg). total injection volume (ml) = total dose (mcg) divided by the concentration of the reconstituted solution (2 mcg/ml). round the total injection volume to the nearest tenth of a ml. total number of vials = total injection volume divided by the vial volume (8 ml). to reconstitute one 16 mcg vial: dissolve the contents of the chirhostim ® 16 mcg vial in 8 ml of 0.9% sodium chloride injection, usp, to yield a concentration of 2 mcg/ml. shake vigorously to ensure dissolution. inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. if particulate matter or discoloration is seen, discard the reconstituted solution. to reconstitute one 40 mcg vial: dissolve the contents of the chirhostim ® 40 mcg vial in 10 ml of 0.9% sodium chloride injection, usp, to yield a concentration of 4 mcg/ml. shake vigorously to ensure dissolution. inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. if particulate matter or discoloration is seen, discard the reconstituted solution. repeat steps above to reconstitute additional vials, as needed, to administer the total dose. use immediately after reconstitution and discard any unused portion. 2.3 administration and test methods stimulation testing with chirhostim ® should only be performed by physicians with sufficient expertise. ensure that the institution has established normative ranges for pancreatic exocrine response. stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction: preparation: instruct patients to fast for at least 12 to 15 hours prior to beginning the test. sample collection: [performed using either the gastroduodenal/dreiling tube (fluoroscopic) or endoscopic collection method] gastroduodenal (dreiling) tube collection method pass a radiopaque, double-lumen gastroduodenal tube through the mouth using a guidewire. under fluoroscopic guidance, place the opening of the proximal lumen in the gastric antrum and the opening of the distal lumen beyond the ampulla of vater. confirm the tube positioning and secure the tube. connect both the proximal (gastric) and distal (duodenal) lumens to low intermittent suction, and apply negative pressure of 25 to 40 mmhg to both lumens. collect a sample of the duodenal contents and check the ph of the aspirate to verify tube position. proceed to next step if the duodenal aspirate has a ph of 6 or higher. if the ph is less than 6, reposition the tube. collect a baseline sample of duodenal fluid for a 15-minute period. administer chirhostim ® at a dose of 0.2 mcg/kg body weight intravenously over 1 minute [see dosage and administration (2.2)] . for the 60-minute period following the injection, collect four consecutive 15-minute samples of duodenal fluid. clear the duodenal lumen of the tube with an injection of air after each 15-minute sample collection. note that wide variation in aspirate volumes is indicative of incomplete aspiration between samples. endoscopic collection method: endoscopic pancreatic function test (epft) administer a topical anesthetic spray to the posterior pharynx and place a bite block in the mouth. perform a standard upper endoscopy by passing the endoscope into the stomach with the patient in the left lateral decubitus position. after gastric insufflation, aspirate all gastric fluid through the endoscope and discard. pass the endoscope through the pylorus into small intestine and position the tip of the endoscope at the junction of the second and third portion of the duodenum. aspirate duodenal fluid for several seconds to clear the residual gastric acid from the tube. collect a baseline aspirate of duodenal fluid (3 to 5 ml) from the post-bulbar duodenum. administer chirhostim ® at a dose of 0.2 mcg/kg of body weight intravenously over 1 minute [see dosage and administration (2.2)] . starting 15 minutes after administration of chirhostim ® , collect 4 timed duodenal fluid aspirates (each 3 to 5 ml) at 15-minute intervals. keep the patient in the left lateral decubitus position throughout the procedure. sample handling and interpretation: place fluid specimens on ice for immediate measurement of bicarbonate concentration. if samples will not be analyzed immediately, store fluid at –80°c. peak bicarbonate concentrations of 80 to 130 meq/l after administration indicate normal pancreatic exocrine function. stimulation of gastrin secretion to aid in the diagnosis of gastrinoma: preparation: instruct patients to fast for at least 12 hours prior to beginning the test. sample collection: before administering chirhostim ® , draw two blood samples for determination of fasting serum gastrin levels (baseline values). administer chirhostim ® at a dose of 0.4 mcg/kg of body weight intravenously over 1 minute [see dosage and administration (2.2)] . collect post-injection blood samples after 1, 2, 5, 10, and 30 minutes for determination of serum gastrin concentrations. sample interpretation: gastrinoma is strongly suspected in patients who show an increase in serum gastrin concentration of more than 110 picograms (pg) per ml over baseline levels on any of the post injection samples. stimulation of pancreatic secretions to facilitate the identification of the ampulla of vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ercp): when difficulty is encountered by the endoscopist in identifying the ampulla of vater or in identifying the accessory papilla in patients with pancreas divisum: administer chirhostim ® at a dose of 0.2 mcg/kg of body weight intravenously over 1 minute [see dosage and administration (2.2)] . visible excretion of pancreatic fluid from the orifices of these papillae will enable their identification and facilitate cannulation. to avoid an incorrect stimulation test result, discontinue the following drugs for the recommended amount of time prior to administration of chirhostim®: anticholinergic drugs: at least 5 half-lives. (2.1, 5.1, 7.1) h2-receptor antagonists: at least 2 days. (2.1, 5.2, 7.2) proton pump inhibitors (ppis): consult the prescribing information for specific ppis. (2.1, 5.2, 7.2) the recommended dosage by indication is shown in the table: indication recommended dosage regimen (2.2) stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction 0.2 mcg/kg by intravenous injection over 1 minute stimulation of gastrin secretion to aid in diagnosis of gastrinoma 0.4 mcg/kg by intravenous injection over 1 minute stimulation of pancreatic secretions to facilitate the identification of the ampulla of vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ercp) 0.2 mcg/kg by intravenous injection over 1 minute determine the number of vials to be reconstituted based on the patient’s weight and prescribed dose (2.2) chirhostim® must be reconstituted with 0.9% sodium chloride injection prior to administration (2.2) see full prescribing information for complete information on exocrine test methods (2.3)

gle-dose of chirhostim® in a clinical trial adverse reaction chirhostim® number of patients n = 531 nausea 9 vomiting 3 flushing 2 upset stomach 2 most common adverse reactions (≥2 patients) are nausea, vomiting, flushing, and upset stomach. (6.1) to report suspected adverse reactions, contact chirhoclin, inc. at 1-877-272-4888 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. see 17 for patient counseling information. revised: 07/2017

® and any potential adverse effects on the breastfed infant from chirhostim ® or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of chirhostim ® in pediatric patients have not been established. 8.5 geriatric use among the 531 patients who have received chirhostim ® in a clinical trial, 11% were 65 years of age or older and 5% were 75 years of age or older. no overall differences in safety, pharmacologic response, or diagnostic effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and the younger patients, but greater sensitivity of some older individuals cannot be ruled out.

okinetic profile for synthetic human secretin was evaluated in 12 healthy subjects following a single-dose of human secretin administered as a 0.4 mcg/kg intravenous bolus. the plasma concentrations of human secretin declined to baseline concentrations within 90 to 120 minutes. the elimination half-life of synthetic human secretin is 45 minutes. the clearance of synthetic human secretin is 580.9 ± 51.3 ml/min and the volume of distribution is 2.7 liters.

igure 2 the values obtained for figures 1 and 2 were performed by investigators skilled in performing secretin stimulation testing and are to be taken only as guidelines. these results should not be generalized to results of secretin stimulation testing conducted in other laboratories. however, a volume response of less than 2 ml/kg/hr, bicarbonate concentration of less than 80 meq/l, and a bicarbonate output of less than 0.2 meq/kg/hr are consistent with impaired pancreatic function. a physician or institution planning to perform secretin stimulation testing as an aid to the diagnosis of pancreatic disease should begin by assessing enough normal subjects (greater than 5) to develop proficiency in proper techniques and to generate normal response ranges for the commonly assessed parameters for pancreatic exocrine response to chirhostim®. in three crossover studies evaluating 21 different patients with a documented history of chronic pancreatitis, shs was compared to sps and bps at a dose of 0.2 mcg/kg for each drug. all of the patients treated with these drugs had peak bicarbonate concentrations of less than 80 meq/l. pancreatic secretory response to intravenous synthetic human secretin in 35 healthy subjects demonstrated a mean peak bicarbonate concentration of 100 meq/l and a mean total volume over one hour of 260.7 ml. all 35 subjects had peak bicarbonate concentrations greater than or equal to 80 meq/l. 14.2 stimulation of gastrin secretion to aid in the diagnosis of gastrinoma chirhostim® administered intravenously stimulates gastrin release in patients with gastrinoma (zollinger-ellison syndrome), whereas no or only small changes in serum gastrin concentrations occur in healthy subjects and in patients with duodenal ulcer disease. discriminant analysis was used to establish secretin stimulation testing as an aid in the diagnosis of gastrinoma. an increase from basal levels of greater than or equal to 110 pg/ml was the optimal point separating positive and negative tests. this gastrin response is the basis for the use of secretin as a provocative test in the evaluation of patients in whom gastrinoma is a diagnostic consideration. in a three way crossover study, 6 patients with tissue confirmed gastrinoma received synthetic human secretin (chirhostim®), synthetic porcine secretin and biologically derived porcine secretin at a dose of 0.4 mcg/kg for each drug. serum gastrin levels were reported to be greater than 110 pg/ml for all secretin products tested after stimulation. testing of chirhostim® in 12 healthy subjects demonstrated completely negative results for gastrinoma. 14.3 stimulation of pancreatic secretion to facilitate identification of the ampulla of vater and the accessory papilla during endoscopic retrograde cholangiopancreatography (ercp) in a randomized, placebo controlled crossover study in 24 patients with pancreas divisum undergoing ercp, chirhostim® at a dose of 0.2 mcg/kg resulted in 16 of 24 successful cannulations of the minor duct compared to 2 of 24 for placebo. figure 1 figure 2