Prescription Drugs

CLINICAL PHARMACOLOGY The primary action of SecreFlo™ (secretin) is to increase the volume and bicarbonate content of secreted pancreatic juices. The standard unit of activity used for SecreFlo™ (secretin) is the clinical unit defined by Jorpes & Mutt in 1966.(1) In the validated cat bioassay, which was used to define and quantitate the biological activity of secretin and as the release test for the biologically derived porcine secretin product, SecreFlo™ (secretin) demonstrates a potency of approximately 5000 clinical units (CU) per milligram of peptide as opposed to 3000 CU per mg for biologically derived porcine secretin. As a pure peptide drug product, SecreFlo™ (secretin) dosing is expressed by weight in micrograms. The relationship of micrograms of secretin to biological activity is 0.2 mcg = 1 CU. Pharmacokinetics: The PK profile for SecreFlo™ (secretin) was evaluated in 12 normal subjects. After intravenous bolus administration of 0.4 mcg/kg, SecreFlo™ (secretin) concentration rapidly declines to baseline secretin levels within 60 to 90 minutes in most of the normal volunteers studied. The elimination half-life of SecreFlo™ (secretin) is 27 minutes. The clearance of SecreFlo™ (secretin) is 487 ±136 mL/minute and the volume of distribution is about 2 liters. Clinical Studies To stimulate pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction: SecreFlo™ (secretin) administered intravenously stimulates the exocrine pancreas to secrete pancreatic juice, which can assist in the diagnosis of exocrine pancreas dysfunction. Normal ranges for pancreatic secretory response to intravenous secretin in patients with defined pancreatic diseases have been shown to vary. One source of variation is related to the inter-investigator differences in operative technique. Two small studies (CRC 97-1 and CRC 98-1) examined the relationship of peak bicarbonate concentration observed in three groups of patients: normal healthy subjects; patients with chronic pancreatitis; patients with a past medical history of chronic pancreatitis and abnormal secretin stimulation test results but with sufficient recovery of exocrine pancreas function to have currently normal test results (Figure 1). SecreFlo (secretin) ™ was compared to biologically derived porcine secretin (bPS). All 12 normal subjects had peak bicarbonate concentrations > 80 mEq/L while all patients with chronic pancreatitis had peak bicarbonate concentrations < 80 mEq/L. Figure 1 The values obtained for Figure 1 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 2.0 mL/kg/hr, bicarbonate concentration of less than 80 mEq/L, and 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 for diagnosis of pancreatic disease should begin by assessing enough normal subjects ( > 5) to develop proficiency in proper techniques and to generate normal response ranges for the commonly assessed parameters of pancreatic exocrine response to SecreFlo™ (secretin) . In three crossover studies (CRC 98-1, CRC 98-2, and CRC 99-9) evaluating 21 different patients with a documented history of chronic pancreatitis, SecreFlo™ was compared to biologically derived secretin (bPS). All of the patients, treated with either drug, had peak concentrations of < 80 mEq/L. Proper technique for carrying out secretin stimulation testing is described in DOSAGE AND ADMINISTRATION. Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma: SecreFlo™ (secretin) administered intravenously stimulates gastrin release in patients with gastrinoma whereas only small changes in serum gastrin concentrations occur in normal subjects and patients with peptic ulcer disease. Deveney et al.,1977(2) established secretin stimulation testing as an aid in the diagnosis of gastrinoma by using discriminant analysis. An increase from basal levels of ≥ 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 two crossover studies, eight patients with tissue confirmed gastrinoma received SecreFlo™ (secretin) . Results of serum gastrin concentrations were compared with those for biologically derived porcine secretin. Serum gastrin concentrations exceeded 110 pg/mL from basal levels in all patients for both drugs tested. Correlation with clinical data and additional diagnostic modalities should be utilized when considering the diagnosis of gastrinoma. Proper technique for carrying out secretin stimulation testing is described in DOSAGE AND ADMINISTRATION. Faciliation of identification of the ampulla of Vater and the accessory papilla during ERCP to assist in cannulation of the pancreatic ducts: In a randomized, placebo controlled crossover study in 31 patients with pancreas divisum undergoing ERCP, SecreFlo™ (secretin) administration at a dose of 0.2 mcg/kg resulted in 25 of 28 successful cannulations of the minor duct compared to 1 of 16 for placebo. References 1. Jorpes, E. and Mutt V. On the biological assay of secretin. The reference standard. Acta Physiol Scand 66 (1966) 316-325. 2. Deveney, C.W., et al. Use of calcium and secretin in the diagnosis of gastrinoma (Zollinger-Ellison Syndrome). Annals of Internal Medicine 87 (1977) 680-686.

SecreFlo™ (secretin) for Injection DESCRIPTION SecreFlo™ (secretin) is a pure sterile, nonpyrogenic, lyophilized white cake powder acetate salt of secretin, a peptide hormone. Secretin has an amino acid sequence identical to the naturally occurring porcine secretin consisting of 27 amino acids. Secretin is chemically defined as follows: Molecular Weight: 3055.5 Empirical Formula: C130H220N44O41 Structural Formula: H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser- Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2 SecreFlo™ contains 16 mcg of purified secretin, 15 mg of L-cysteine hydrochloride, and 20 mg of mannitol per vial. When reconstituted in 8 mL of Sodium Chloride Injection USP, each mL of solution contains 2 mcg secretin for intravenous use. The pH of the reconstituted solution has a range of 3-6.5.

INDICATIONS SecreFlo™ (secretin) is indicated for use in secretin stimulation testing for: Stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of pancreatic exocrine dysfunction. Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma. Stimulation of pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP). DOSAGE AND ADMINISTRATION Dissolve the contents of the vial of SecreFlo™ (secretin) in 8 mL of Sodium Chloride Injection USP, to yield a concentration of 2 mcg/mL. Shake vigorously to ensure dissolution. Use immediately after reconstitution. Discard any unused portion after reconstitution. The reconstituted drug product should be inspected visually prior to administration. If particulate matter or discoloration is seen, the product should be discarded. Dosage: SECRETIN STIMULATION TESTING: TO STIMULATE PANCREATIC SECRETIONS, INCLUDING BICARBONATE, TO AID IN THE DIAGNOSIS OF EXOCRINE PANCREAS DYSFUNCTION: 0.2 mcg/kg body weight by intravenous injection over 1 minute. STIMULATION OF GASTRIN SECRETION TO AID IN THE DIAGNOSIS OF GASTRINOMA: 0.4 mcg/kg body weight by intravenous injection over 1 minute. FACILITATION OF THE IDENTIFICATION OF THE AMPULLA OF VATER AND ACCESSORY PAPILLA DURING ERCP to aid in the cannulation of the pancreatic ducts: 0.2 mcg/kg body weight by intravenous injection over 1 minute. Administration: SECRETIN STIMULATION TESTING: TO STIMULATE PANCREATIC SECRETIONS, INCLUDING BICARBONATE, TO AID IN THE DIAGNOSIS OF EXOCRINE PANCREAS DYSFUNCTION: A radiopaque, double-lumen tube is passed through the mouth following a 12-15 hour fast. Under fluoroscopic control, the opening of the proximal lumen of the tube is placed in the gastric antrum and the opening of the distal lumen just beyond the papilla of Vater. The positioning of the tube must be confirmed and the tube secured prior to secretin testing. Intermittent negative pressure of 25-40 mmHg is applied to both lumens and maintained throughout the test. When duodenal contents have a pH of ≥ 6.0, a baseline sample of duodenal fluids is collected for a 10 minute period. A test dose of SecreFlo™ (secretin) 0.2 mcg (0.1 mL) is injected intravenously to test of possible allergies. After one minute, if there are no untoward reactions, SecreFlo™ (secretin) at a dose of 0.2 mcg/kg of body weight is injected intravenously over 1 minute. Duodenal fluid is collected for 60 minutes thereafter. The aspirate is divided into four collection periods of fifteen minutes each. The duodenal lumen of the tube is cleared with an injection of air after collection of each sample. Wide variation in volume of the aspirate is indicative of incomplete aspiration. Each sample of duodenal fluid is to be chilled and subsequently analyzed for volume and bicarbonate concentration. Exocrine pancreas dysfunction typically associated with chronic pancreatitis is indicated if the peak bicarbonate concentration for any sample is < 80 mEq/L. STIMULATON OF GASTRIN TO AID IN THE DIAGNOSIS OF GASTRINOMA: The patient should have fasted for at least 12 hours prior to beginning the test. Before injecting SecreFlo™ (secretin) , two blood samples are drawn for determination of fasting serum gastrin levels (baseline values). Subsequently, a test dose of SecreFlo™ (secretin) 0.2 mcg (0.1 mL) is injected intravenously, to test for possible allergies. If no untoward reactions, 0.4 mcg/kg of SecreFlo™ (secretin) is administered intravenously over 1 minute; post-injection blood samples are collected after 1, 2, 5, 10, and 30 minutes for determination of serum gastrin concentrations. Gastrinoma is strongly suspected in patients who show an increase in serum gastrin concentration of more than 110 pg per mL over basal levels on any of the post injection samples. FACILITATION OF THE IDENTIFICATION OF THE AMPULLA OF VATER AND ACCESSORY PAPILLA DURING 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, administration of secretin at a does of 0.2 mcg/kg of body weight intravenously over 1 minute will result in visible excretion of pancreatic fluids from the orifices of these papillae enabling their identification and facilitating cannulation. HOW SUPPLIED SecreFlo™ (secretin) is supplied as a lyophilized sterile powder in vials containing 16 mcg secretin. Storage The unreconstituted product should be stored at -20ºC (freezer). Manufactured for: ChiRhoClin, Inc. Silver Spring, MD 20905. Manufactured by: Chesapeake Biological Laboratories, Baltimore, MD 21230. November 2002. FDA Rev date: 4/4/2002

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE A single intravenous dose of 20 mcg/kg of secretin was not lethal to mice or rabbits. CONTRAINDICATIONS Patients suffering from acute pancreatitis should not receive SecreFlo™ (secretin) until the acute episode has subsided.

SIDE EFFECTS Occasional mild adverse events have been noted in association with the use of SecreFlo™ (secretin) in clinical studies of over 957 patients and 24 volunteer subjects. TABLE 1: ADVERSE EVENTS EVENT SecreFlo™ n = 981 Incidence (Patients) Abdominal cramps 2 (2) Abdominal discomfort 7 (7) Bleeding - sphincterectomy 6 (6) Bleeding - upper GI 2º to endoscopic abrasion 2 (2) Bloating 1 (1) Bradycardia (mild) 2 (2) Burning in stomach 3 (2) Decreased blood pressure 6 (5) Diaphoresis 6 (4) Diarrhea 1 (1) Endoscopic perforation of pancreatic duct 2 (2) Fatigue 1 (1) Fever 1 (1) Flushing 6 (5) Headache 2 (2) Hot Sensation 1 (1) Hunger Pangs 1 (1) Leukocytoplastic Vasculitis 1 (1) Lightheaded 3 (2) Nausea 8 (8) Numbness/Tingling in extremeties 2 (1) Pallor 1 (1) Possible seizure 1 (1) Rash -abdominal 1 (1) Thready pulse 1 (1) Transient low O2 saturation 1 (1) Transient respiratory distress 2 (2) Urticaria 2º contrast material (prior to secretin administration) 1 (1) Vomiting 1 (1) Total Patients with AE's (%) 73 (7.4) DRUG INTERACTIONS Drug/Laboratory Test Interaction: The concomitant use of anticholinergic agents may make patients hyporesponsive, i.e. may produce a false positive result.

WARNINGS Because of a potential allergic reaction to secretin, patients should receive an intravenous test dose of 0.2 mcg (0.1 mL). If no allergic reaction is noted after one minute, the recommended dose for the specific indication (see DOSAGE AND ADMINISTRATION) may be injected slowly over 1 minute. A test dose is especially important in patients with a history of atopic allergy and/or asthma. Appropriate measures for the treatment of acute hypersensitivity reactions should be immediately available. No allergic reactions were observed after the test dose or full dose of SecreFlo™ (secretin) in over 981 patients. PRECAUTIONS General Patients who have undergone vagotomy, or are receiving anticholinergic agents at the time of secretin stimulation testing, or who have inflammatory bowel disease may be hyporesponsive to secretin stimulation. This response does not indicate pancreatic disease. A greater than normal volume response to secretin stimulation, which may mask coexisting pancreatic disease, is occasionally encountered in patients with alcoholic or other liver disease. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of secretin. Studies to evaluate its potential for impairment of fertility or its mutagenic potential have not been performed. Pregnancy Teratogenic Effects, Pregnancy Category C: Animal reproduction studies have not been conducted with secretin. It is also not known whether secretin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Secretin should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether secretin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when secretin is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Among the 981 patients who have received SecreFlo™ (secretin) in clinical trials 16% were 65 years of age or older and 11% were 75 years of age or older. Dosing was identical to the overall population of patients. No overall differences in safety, pharmacological 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.