Secretin

DESCRIPTION ChiRhoStim ® is a pure sterile, nonpyrogenic, lyophilized white cake powder acetate salt of secretin, a peptide hormone. ChiRhoStim ® has an amino acid sequence identical to the naturally occurring hormone consisting of 27 amino acids. Synthetic human secretin is chemically defined as follows: Molecular Weight 3039.44 Empirical Formula: C 130 H 220 N 44 O 39 CAS # 108153-74-8 Structural Formula: His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH 2 The standard unit of biological activity for ChiRhoStim ® is the clinical unit (CU). (2) One (1) CU of secretin biological activity is equal to 0.2 micrograms (mcg) of human secretin. ChiRhoStim ® is available in two strengths: As a 10 mL single-dose vial which contains 16 mcg of purified synthetic human secretin, 1.5 mg of L-cysteine hydrochloride, 20 mg of mannitol, and 9 mg of sodium chloride. When reconstituted in 8 mL of Sodium Chloride Injection USP, each mL of solution contains 2 mcg synthetic human secretin for intravenous use. The pH of the reconstituted solution has a range of 3 to 6.5. As a 10 mL single-dose vial which contains 40 mcg of purified synthetic human secretin, 3.75 mg of L-cysteine hydrochloride, 50 mg of mannitol, and 22.5 mg of sodium chloride per vial. When reconstituted in 10 mL of Sodium Chloride Injection USP, each mL of solution contains 4 mcg synthetic human secretin for intravenous use. The pH of the reconstituted solution has a range of 3 to 6.5.

INDICATIONS AND USAGE ChiRhoStim ® is indicated for the stimulation of: pancreatic secretions, including bicarbonate, to aid in the diagnosis of pancreatic exocrine dysfunction. gastrin secretion to aid in the diagnosis of gastrinoma, and pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP). ChiRhoStim® is a secretin class hormone indicated for stimulation of: pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction (1) gastrin secretion to aid in the diagnosis of gastrinoma (1) pancreatic secretions to facilitate the identification of the ampulla of Vater and the accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP) (1)

HOW SUPPLIED/STORAGE AND HANDLING ChiRhoStim ® (human secretin), for injection is supplied as a white lyophilized sterile powder in a single-dose vial for reconstitution: NDC # 67066-005-01 16 mcg NDC # 67066-007-01 40 mcg Store at -20°C (freezer). Protect from light.

DOSAGE AND ADMINISTRATION 2.2 Preparation and Dosage Regimen The recommended dosage regimen of ChiRhoStim® by indication is shown below in Table 1. TABLE 1: Dosage by Indication Indication Recommended Dosage Regimen 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 Preparation of Recommended Dosage ChiRhoStim ® is a lyophilized powder, which requires reconstitution prior to intravenous administration. Determine the number of vials needed for the prescribed dosage based on the patient’s weight and recommended dosage. Follow 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)

CONTRAINDICATIONS None. None (4)

WARNINGS AND PRECAUTIONS Patients with alcoholic or other liver disease may be hyperresponsive to stimulation with ChiRhoStim®, masking the presence of coexisting pancreatic disease. Consider additional testing and clinical assessments for aid in diagnosis. ​​ Hyporesponse to Secretin Stimulation Testing in Patients with Vagotomy, Inflammatory Bowel Disease or Receiving Anticholinergics : Discontinue anticholinergic drugs at least 5 half-lives prior to stimulation testing; consider additional testing and clinical assessments for aid in diagnosis. (2.1, 5.1, 7.1) Hyperresponse to Secretin Stimulation Testing : Increased gastrin secretion in patients receiving H 2 -receptor antagonists or PPIs falsely suggesting gastrinoma; discontinue co-administered drug prior to stimulation testing. Increased pancreatic secretions in patients with alcoholic or other liver disease masking coexisting pancreatic disease; consider additional testing and clinical assessments for aid in diagnosis. (2.1, 5.2, 7.2)

DRUG INTERACTIONS 7.1 Hyporesponse with Anticholinergics The concomitant use anticholinergic drugs may cause a hyporesponse to stimulation testing with ChiRhoStim ® . Discontinue anticholinergic drugs at least 5 half-lives before administering ChiRhoStim ® [see Dosage and Administration (2.1)] . 7.2 Hyperresponse of Gastrin Secretion with H 2 -Receptor Antagonists and PPIs The concomitant use of H 2 -receptor antagonists or PPIs may cause a hyperresponse in gastrin secretion in response to stimulation testing with ChiRhoStim ® , falsely suggesting gastrinoma. Discontinue H 2 -receptor antagonists at least 2 days before administering ChiRhoStim ® to aid in the diagnosis of gastrinoma. The time it takes for serum gastrin concentrations to return to baseline following discontinuation of PPIs is specific to the individual drug. Consult the prescribing information of each specific PPI before administering ChiRhoStim ® to aid in the diagnosis of gastrinoma.

Risk Summary There are no available data (either clinical studies or postmarketing reports) of use of synthetic human secretin in pregnant women. Animal reproduction studies have not been conducted with synthetic human secretin. The estimated background risk of major birth defects and miscarriage for the indicated populations are 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.

The safety and effectiveness of ChiRhoStim ® in pediatric patients have not been established.

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.

ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials of a drug cannot always be directly compared to the rates observed during the clinical trials of another drug and may not reflect the adverse reaction rates observed in practice. The data described below reflect exposure to ChiRhoStim® in 531 patients from an open-label clinical trial. The population consisted of patients aged 1 to 91 years, 185 males, 346 females, 480 Caucasians, 31 Blacks, 12 American Indians, 6 Hispanics, and 2 Asians with known or suspected diseases of the exocrine pancreas including chronic pancreatitis and pancreatic cancer. Most patients received a single dose of ChiRhoStim® in a dose range of 0.2 mcg/kg to 0.4 mcg/kg. The most common adverse reactions (reported in at least 2 patients in the trial) are listed in Table 2. TABLE 2 Adverse Reactions in at Least 2 Patients Treated with a Single-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