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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use CHIRHOSTIM safely and effectively. See full prescribing infrmatin fr CHIRHOSTIM. CHIRHOSTIM (human secretin) fr injectin, fr intravenus use Initial U.S. Apprval: RECENT MAJOR CHANGES Dsage and Administratin (2.1) 07/2017 Cntraindicatins, remved (4) 07/2017 Warnings and Precautins (5.1, 5.2) 07/ INDICATIONS AND USAGE ChiRhStim is a secretin class hrmne indicated fr stimulatin f: pancreatic secretins, including bicarbnate, t aid in the diagnsis f excrine pancreas dysfunctin (1) gastrin secretin t aid in the diagnsis f gastrinma (1) pancreatic secretins t facilitate the identificatin f the ampulla f Vater and the accessry papilla during endscpic retrgrade chlangipancreatgraphy (ERCP) (1) DOSAGE AND ADMINISTRATION T avid an incrrect stimulatin test result, discntinue the fllwing drugs fr the recmmended amunt f time prir t administratin f ChiRhStim : antichlinergic drugs: at least 5 half-lives. (2.1, 5.1, 7.1) H 2-receptr antagnists: at least 2 days. (2.1, 5.2, 7.2) prtn pump inhibitrs (PPIs): cnsult the prescribing infrmatin fr specific PPIs. (2.1, 5.2, 7.2) The recmmended dsage by indicatin is shwn in the table: Determine the number f vials t be recnstituted based n the patient s weight and prescribed dse (2.2) ChiRhStim must be recnstituted with 0.9% Sdium Chlride Injectin prir t administratin (2.2) See full prescribing infrmatin fr cmplete infrmatin n excrine test methds (2.3) DOSAGE FORMS AND STRENGTHS Fr injectin: 16 mcg r 40 mcg f human secretin as a lyphilized pwder in single-dse vial fr recnstitutin (3) CONTRAINDICATIONS Nne (4) WARNINGS AND PRECAUTIONS Hyprespnse t Secretin Stimulatin Testing in Patients with Vagtmy, Inflammatry Bwel Disease r Receiving Antichlinergics: Discntinue antichlinergic drugs at least 5 half-lives prir t stimulatin testing; cnsider additinal testing and clinical assessments fr aid in diagnsis. (2.1, 5.1, 7.1) Hyperrespnse t Secretin Stimulatin Testing: Increased gastrin secretin in patients receiving H 2-receptr antagnists r PPIs falsely suggesting gastrinma; discntinue c-administered drug prir t stimulatin testing. Increased pancreatic secretins in patients with alchlic r ther liver disease masking cexisting pancreatic disease; cnsider additinal testing and clinical assessments fr aid in diagnsis. (2.1, 5.2, 7.2) ADVERSE REACTIONS Mst cmmn adverse reactins ( 2 patients) are nausea, vmiting, flushing, and upset stmach. (6.1) Indicatin Stimulatin f pancreatic secretins, including bicarbnate, t aid in the diagnsis f excrine pancreas dysfunctin Stimulatin f gastrin secretin t aid in diagnsis f gastrinma Stimulatin f pancreatic secretins t facilitate the identificatin f the ampulla f Vater and accessry papilla during endscpic retrgrade chlangipancreatgraphy (ERCP) Recmmended Dsage Regimen (2.2) 0.2 mcg/kg by intravenus injectin ver 1 minute 0.4 mcg/kg by intravenus injectin ver 1 minute 0.2 mcg/kg by intravenus injectin ver 1 minute T reprt SUSPECTED ADVERSE REACTIONS, cntact ChiRhClin, Inc. at r FDA at FDA-1088 r See 17 fr PATIENT COUNSELING INFORMATION. Revised: 07/2017 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparatin Prir t Secretin Stimulatin Testing 2.2 Preparatin and Dsage Regimen 2.3 Administratin and Test Methds 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hyprespnse t Secretin Stimulatin Testing 5.2 Hyperrespnse t Secretin Stimulatin Testing 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Hyprespnse with Antichlinergics 7.2 Hyperrespnse f Gastrin Secretin with H 2-Receptr Antagnists and PPIs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactatin 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.3 Pharmackinetics 14 CLINICAL STUDIES 14.1 Stimulatin f Pancreatic Secretins, Including Bicarbnate t Aid in the Diagnsis f Excrine Pancreas Dysfunctin 14.2 Stimulatin f Gastrin Secretin t Aid in the Diagnsis f Gastrinma 14.3 Stimulatin f Pancreatic Secretins t Facilitate the Identificatin f the Ampulla f Vater and the Accessry Papilla During Endscpic Retrgrade Chlangipancreatgraphy (ERCP) 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed.

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ChiRhStim is indicated fr the stimulatin f: pancreatic secretins, including bicarbnate, t aid in the diagnsis f pancreatic excrine dysfunctin. gastrin secretin t aid in the diagnsis f gastrinma, and pancreatic secretins t facilitate the identificatin f the ampulla f Vater and accessry papilla during endscpic retrgrade chlangipancreatgraphy (ERCP). 2 DOSAGE AND ADMINISTRATION 2.1 Preparatin Prir t Secretin Stimulatin Testing Discntinue Interacting Drugs T avid an incrrect stimulatin test result, discntinue the fllwing drugs prir t administratin f ChiRhStim : antichlinergic drugs: at least 5 half-lives prir t testing [see Warnings and Precautins (5.1), Drug Interactins (7.1)]. H 2 -receptr antagnists: at least 2 days prir t testing [see Warnings and Precautins (5.2), Drug Interactins (7.2)]. prtn pump inhibitrs (PPIs): Cnsult the prescribing infrmatin fr specific PPIs [see Warnings and Precautins (5.2), Drug Interactins (7.2)]. 2.2 Preparatin and Dsage Regimen The recmmended dsage regimen f ChiRhStim by indicatin is shwn belw in Table 1. TABLE 1: Dsage by Indicatin Indicatin Recmmended Dsage Regimen Stimulatin f pancreatic secretins, including 0.2 mcg/kg by intravenus injectin ver 1 minute bicarbnate, t aid in the diagnsis f excrine pancreas dysfunctin Stimulatin f gastrin secretin t aid in diagnsis f 0.4 mcg/kg by intravenus injectin ver 1 minute gastrinma Stimulatin f pancreatic secretins t facilitate the 0.2 mcg/kg by intravenus injectin ver 1 minute identificatin f the ampulla f Vater and accessry papilla during endscpic retrgrade chlangipancreatgraphy (ERCP) Preparatin f Recmmended Dsage ChiRhStim is a lyphilized pwder, which requires recnstitutin prir t intravenus administratin. Determine the number f vials needed fr the prescribed dsage based n the patient s weight and recmmended dsage. Fllw these steps t determine the patient dse: Ttal dse (mcg) = patient s weight (kg) x prescribed dse (mcg/kg). Ttal injectin vlume (ml) = ttal dse (mcg) divided by the cncentratin f the recnstituted slutin (2 mcg/ml). Rund the ttal injectin vlume t the nearest tenth f a ml. Ttal number f vials = ttal injectin vlume divided by the vial vlume (8 ml).

3 T recnstitute ne 16 mcg vial: Disslve the cntents f the ChiRhStim 16 mcg vial in 8 ml f 0.9% Sdium Chlride Injectin, USP, t yield a cncentratin f 2 mcg/ml. Shake vigrusly t ensure disslutin. Inspect the recnstituted slutin visually fr particulate matter and disclratin prir t administratin. If particulate matter r disclratin is seen, discard the recnstituted slutin. T recnstitute ne 40 mcg vial: Disslve the cntents f the ChiRhStim 40 mcg vial in 10 ml f 0.9% Sdium Chlride Injectin, USP, t yield a cncentratin f 4 mcg/ml. Shake vigrusly t ensure disslutin. Inspect the recnstituted slutin visually fr particulate matter and disclratin prir t administratin. If particulate matter r disclratin is seen, discard the recnstituted slutin. Repeat steps abve t recnstitute additinal vials, as needed, t administer the ttal dse. Use immediately after recnstitutin and discard any unused prtin. 2.3 Administratin and Test Methds Stimulatin testing with ChiRhStim shuld nly be perfrmed by physicians with sufficient expertise. Ensure that the institutin has established nrmative ranges fr pancreatic excrine respnse. Stimulatin f Pancreatic Secretins, including Bicarbnate, t Aid in the Diagnsis f Excrine Pancreas Dysfunctin: Preparatin: Instruct patients t fast fr at least 12 t 15 hurs prir t beginning the test. Sample Cllectin: [perfrmed using either the gastrdudenal/dreiling tube (flurscpic) r endscpic cllectin methd] Gastrdudenal (Dreiling) Tube Cllectin Methd Pass a radipaque, duble-lumen gastrdudenal tube thrugh the muth using a guidewire. Under flurscpic guidance, place the pening f the prximal lumen in the gastric antrum and the pening f the distal lumen beynd the ampulla f Vater. Cnfirm the tube psitining and secure the tube. Cnnect bth the prximal (gastric) and distal (dudenal) lumens t lw intermittent suctin, and apply negative pressure f 25 t 40 mmhg t bth lumens. Cllect a sample f the dudenal cntents and check the ph f the aspirate t verify tube psitin. Prceed t next step if the dudenal aspirate has a ph f 6 r higher. If the ph is less than 6, repsitin the tube. Cllect a baseline sample f dudenal fluid fr a 15-minute perid. Administer ChiRhStim at a dse f 0.2 mcg/kg bdy weight intravenusly ver 1 minute [see Dsage and Administratin (2.2)]. Fr the 60-minute perid fllwing the injectin, cllect fur cnsecutive 15-minute samples f dudenal fluid. Clear the dudenal lumen f the tube with an injectin f air after each 15-minute sample cllectin. Nte that wide variatin in aspirate vlumes is indicative f incmplete aspiratin between samples. Endscpic Cllectin Methd: Endscpic Pancreatic Functin Test (epft) Administer a tpical anesthetic spray t the psterir pharynx and place a bite blck in the muth.

4 Perfrm a standard upper endscpy by passing the endscpe int the stmach with the patient in the left lateral decubitus psitin. After gastric insufflatin, aspirate all gastric fluid thrugh the endscpe and discard. Pass the endscpe thrugh the pylrus int small intestine and psitin the tip f the endscpe at the junctin f the secnd and third prtin f the dudenum. Aspirate dudenal fluid fr several secnds t clear the residual gastric acid frm the tube. Cllect a baseline aspirate f dudenal fluid (3 t 5 ml) frm the pst-bulbar dudenum. Administer ChiRhStim at a dse f 0.2 mcg/kg f bdy weight intravenusly ver 1 minute [see Dsage and Administratin (2.2)]. Starting 15 minutes after administratin f ChiRhStim, cllect 4 timed dudenal fluid aspirates (each 3 t 5 ml) at 15-minute intervals. Keep the patient in the left lateral decubitus psitin thrughut the prcedure. Sample Handling and Interpretatin: Place fluid specimens n ice fr immediate measurement f bicarbnate cncentratin. If samples will nt be analyzed immediately, stre fluid at 80 C. Peak bicarbnate cncentratins f 80 t 130 meq/l after administratin indicate nrmal pancreatic excrine functin. Stimulatin f Gastrin Secretin t Aid in the Diagnsis f Gastrinma: Preparatin: Instruct patients t fast fr at least 12 hurs prir t beginning the test. Sample Cllectin: Befre administering ChiRhStim, draw tw bld samples fr determinatin f fasting serum gastrin levels (baseline values). Administer ChiRhStim at a dse f 0.4 mcg/kg f bdy weight intravenusly ver 1 minute [see Dsage and Administratin (2.2)]. Cllect pst-injectin bld samples after 1, 2, 5, 10, and 30 minutes fr determinatin f serum gastrin cncentratins. Sample Interpretatin: Gastrinma is strngly suspected in patients wh shw an increase in serum gastrin cncentratin f mre than 110 picgrams (pg) per ml ver baseline levels n any f the pst injectin samples. Stimulatin f Pancreatic Secretins t Facilitate the Identificatin f the Ampulla f Vater and Accessry Papilla During Endscpic Retrgrade Chlangipancreatgraphy (ERCP): When difficulty is encuntered by the endscpist in identifying the ampulla f Vater r in identifying the accessry papilla in patients with pancreas divisum: Administer ChiRhStim at a dse f 0.2 mcg/kg f bdy weight intravenusly ver 1 minute [see Dsage and Administratin (2.2)]. Visible excretin f pancreatic fluid frm the rifices f these papillae will enable their identificatin and facilitate cannulatin.

5 3 DOSAGE FORMS AND STRENGTHS Fr injectin: 16 mcg r 40 mcg f human secretin as a white lyphilized pwder in single-dse vial fr recnstitutin. 4 CONTRAINDICATIONS Nne. 5 WARNINGS AND PRECAUTIONS 5.1 Hyprespnse t Secretin Stimulatin Testing Patients wh have undergne vagtmy, have inflammatry bwel disease r are receiving antichlinergic drugs at the time f ChiRhStim stimulatin testing, may be hyprespnsive t ChiRhStim stimulatin falsely suggesting pancreatic disease. Discntinue antichlinergic drugs at least 5 half-lives prir t stimulatin testing [see Dsage and Administratin (2.1)]. Cnsider additinal testing and clinical assessments fr aid in diagnsis. 5.2 Hyperrespnse t Secretin Stimulatin Testing Gastrin Secretin Patients receiving H 2 -receptr antagnists r PPIs at the time f stimulatin testing with ChiRhStim t aid in the diagnsis f gastrinma may be hyperrespnsive t secretin stimulatin, falsely suggesting gastrinma. Discntinue H 2 -receptr antagnists at least 2 days prir t stimulatin testing. Cnsult the prescribing infrmatin f each specific PPI befre administering ChiRhStim [see Dsage and Administratin (2.1)]. Pancreatic Secretins Patients with alchlic r ther liver disease may be hyperrespnsive t stimulatin with ChiRhStim, masking the presence f cexisting pancreatic disease. Cnsider additinal testing and clinical assessments fr aid in diagnsis. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are cnducted under varying cnditins, adverse reactin rates bserved during the clinical trials f a drug cannt always be directly cmpared t the rates bserved during the clinical trials f anther drug and may nt reflect the adverse reactin rates bserved in practice. The data described belw reflect expsure t ChiRhStim in 531 patients frm an pen-label clinical trial. The ppulatin cnsisted f patients aged 1 t 91 years, 185 males, 346 females, 480 Caucasians, 31 Blacks, 12 American Indians, 6 Hispanics, and 2 Asians with knwn r suspected diseases f the excrine pancreas including chrnic pancreatitis and pancreatic cancer. Mst patients received a single dse f ChiRhStim in a dse range f 0.2 mcg/kg t 0.4 mcg/kg. The mst cmmn adverse reactins (reprted in at least 2 patients in the trial) are listed in Table 2. TABLE 2 Adverse Reactins in at Least 2 Patients Treated with a Single-Dse f ChiRhStim in a Clinical Trial Adverse Reactin ChiRhStim Number f Patients N = 531 Nausea 9 Vmiting 3 Flushing 2 Upset stmach 2

6 7 DRUG INTERACTIONS 7.1 Hyprespnse with Antichlinergics The cncmitant use antichlinergic drugs may cause a hyprespnse t stimulatin testing with ChiRhStim. Discntinue antichlinergic drugs at least 5 half-lives befre administering ChiRhStim [see Dsage and Administratin (2.1)]. 7.2 Hyperrespnse f Gastrin Secretin with H 2 -Receptr Antagnists and PPIs The cncmitant use f H 2 -receptr antagnists r PPIs may cause a hyperrespnse in gastrin secretin in respnse t stimulatin testing with ChiRhStim, falsely suggesting gastrinma. Discntinue H 2 -receptr antagnists at least 2 days befre administering ChiRhStim t aid in the diagnsis f gastrinma. The time it takes fr serum gastrin cncentratins t return t baseline fllwing discntinuatin f PPIs is specific t the individual drug. Cnsult the prescribing infrmatin f each specific PPI befre administering ChiRhStim t aid in the diagnsis f gastrinma. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are n available data (either clinical studies r pstmarketing reprts) f use f synthetic human secretin in pregnant wmen. Animal reprductin studies have nt been cnducted with synthetic human secretin. The estimated backgrund risk f majr birth defects and miscarriage fr the indicated ppulatins are unknwn. All pregnancies have a backgrund risk f birth defect, lss, r ther adverse utcmes. In the U.S. general ppulatin, the estimated backgrund risk f majr birth defects and miscarriage in clinically recgnized pregnancies is 2% t 4% and 15% t 20%, respectively. 8.2 Lactatin Risk Summary There are n data n the presence f synthetic human secretin in human r animal milk, the effects f synthetic human secretin n the breastfed infant, r the effects f synthetic human secretin n milk prductin. The develpmental and health benefits f breastfeeding shuld be cnsidered alng with the mther s clinical need fr ChiRhStim and any ptential adverse effects n the breastfed infant frm ChiRhStim r frm the underlying maternal cnditin. 8.4 Pediatric Use The safety and effectiveness f ChiRhStim in pediatric patients have nt been established.

7 8.5 Geriatric Use Amng the 531 patients wh have received ChiRhStim in a clinical trial, 11% were 65 years f age r lder and 5% were 75 years f age r lder. N verall differences in safety, pharmaclgic respnse, r diagnstic effectiveness were bserved between these subjects and yunger subjects, and ther reprted clinical experience has nt identified differences in respnses between the elderly and the yunger patients, but greater sensitivity f sme lder individuals cannt be ruled ut. 11 DESCRIPTION ChiRhStim is a pure sterile, nnpyrgenic, lyphilized white cake pwder acetate salt f secretin, a peptide hrmne. ChiRhStim has an amin acid sequence identical t the naturally ccurring hrmne cnsisting f 27 amin acids. Synthetic human secretin is chemically defined as fllws: Mlecular Weight Empirical Frmula: C 130 H 220 N 44 O 39 CAS # Structural Frmula: 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 f bilgical activity fr ChiRhStim is the clinical unit (CU). (3) One (1) CU f secretin bilgical activity is equal t 0.2 micrgrams (mcg) f human secretin. ChiRhStim is available in tw strengths: As a 10 ml single-dse vial which cntains 16 mcg f purified synthetic human secretin, 1.5 mg f L- cysteine hydrchlride, 20 mg f mannitl, and 9 mg f sdium chlride. When recnstituted in 8 ml f Sdium Chlride Injectin USP, each ml f slutin cntains 2 mcg synthetic human secretin fr intravenus use. The ph f the recnstituted slutin has a range f 3 t 6.5. As a 10 ml single-dse vial which cntains 40 mcg f purified synthetic human secretin, 3.75 mg f L- cysteine hydrchlride, 50 mg f mannitl, and 22.5 mg f sdium chlride per vial. When recnstituted in 10 ml f Sdium Chlride Injectin USP, each ml f slutin cntains 4 mcg synthetic human secretin fr intravenus use. The ph f the recnstituted slutin has a range f 3 t CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin The primary actin f ChiRhStim is t stimulate pancreatic ductal cells t secrete pancreas fluid in large vlumes that cntain bicarbnate. Secretin is a hrmne that is nrmally released frm the dudenum upn expsure f the prximal intestinal lumen t gastric acid, fatty acids and amin acids. Secretin is released frm enterchrmaffin cells in the intestinal mucsa. Secretin receptrs have been identified in the pancreas, stmach, liver, cln and ther tissues. When secretin binds t secretin receptrs n pancreatic duct cells it pens cystic fibrsis transmembrane cnductance regulatr (CFTR) channels, leading t secretin f bicarbnate-rich-pancreatic fluid. Secretin may als wrk thrugh vagal-vagal neural pathways since stimulatin f the efferent vagus nerve stimulates bicarbnate secretin and atrpine blcks secretin-stimulated pancreatic secretin Pharmackinetics The pharmackinetic prfile fr synthetic human secretin was evaluated in 12 healthy subjects fllwing a single-dse f human secretin administered as a 0.4 mcg/kg intravenus blus. The plasma cncentratins f human secretin declined t baseline cncentratins within 90 t 120 minutes. The eliminatin half-life f synthetic human secretin is 45 minutes. The clearance f synthetic human secretin is ± 51.3 ml/min and the vlume f distributin is 2.7 liters.

8 14 CLINICAL STUDIES 14.1 Stimulatin f Pancreatic Secretins, Including Bicarbnate t Aid in the Diagnsis f Excrine Pancreas Dysfunctin ChiRhStim administered intravenusly stimulates the excrine pancreas t secrete pancreatic juice, which can assist in the diagnsis f excrine pancreas dysfunctin. Nrmal ranges fr pancreatic secretry respnse t intravenus secretin in patients with defined pancreatic disease have been shwn t vary. One surce f variatin is related t the inter-investigatr differences in perative technique. In tw studies, a ttal f 18 patients with a dcumented histry f chrnic pancreatitis were given 0.2 mcg/kg synthetic human secretin (shs), 0.2 mcg/kg synthetic prcine secretin (sps), and 1 CU/kg (equal t 0.2 mcg/kg fr bilgically derived secretin (bps)) in a crssver design. The results appear in Figures 1 and 2. In anther study, 35 healthy subjects were given shs at a dse f 0.2 mcg/kg. The results appear in Figures 1 and 2. FIGURE 1

9 FIGURE 2 The values btained fr Figures 1 and 2 were perfrmed by investigatrs skilled in perfrming secretin stimulatin testing and are t be taken nly as guidelines. These results shuld nt be generalized t results f secretin stimulatin testing cnducted in ther labratries. Hwever, a vlume respnse f less than 2 ml/kg/hr, bicarbnate cncentratin f less than 80 meq/l, and a bicarbnate utput f less than 0.2 meq/kg/hr are cnsistent with impaired pancreatic functin. A physician r institutin planning t perfrm secretin stimulatin testing as an aid t the diagnsis f pancreatic disease shuld begin by assessing enugh nrmal subjects (greater than 5) t develp prficiency in prper techniques and t generate nrmal respnse ranges fr the cmmnly assessed parameters fr pancreatic excrine respnse t ChiRhStim. In three crssver studies evaluating 21 different patients with a dcumented histry f chrnic pancreatitis, shs was cmpared t sps and bps at a dse f 0.2 mcg/kg fr each drug. All f the patients treated with these drugs had peak bicarbnate cncentratins f less than 80 meq/l. Pancreatic secretry respnse t intravenus synthetic human secretin in 35 healthy subjects demnstrated a mean peak bicarbnate cncentratin f 100 meq/l and a mean ttal vlume ver ne hur f ml. All 35 subjects had peak bicarbnate cncentratins greater than r equal t 80 meq/l Stimulatin f Gastrin Secretin t Aid in the Diagnsis f Gastrinma ChiRhStim administered intravenusly stimulates gastrin release in patients with gastrinma (Zllinger- Ellisn Syndrme), whereas n r nly small changes in serum gastrin cncentratins ccur in healthy subjects and in patients with dudenal ulcer disease. Discriminant analysis was used t establish secretin stimulatin testing as an aid in the diagnsis f gastrinma. An increase frm basal levels f greater than r equal t 110 pg/ml was the ptimal pint separating psitive and negative tests. This gastrin respnse is the basis fr the use f secretin as a prvcative test in the evaluatin f patients in whm gastrinma is a diagnstic cnsideratin. In a three way crssver study, 6 patients with tissue cnfirmed gastrinma received synthetic human secretin (ChiRhStim ), synthetic prcine secretin and bilgically derived prcine secretin at a dse f 0.4 mcg/kg fr each drug. Serum gastrin levels were reprted t be greater than 110 pg/ml fr all secretin prducts tested after stimulatin. Testing f ChiRhStim in 12 healthy subjects demnstrated cmpletely negative results fr gastrinma Stimulatin f Pancreatic Secretin t Facilitate Identificatin f the Ampulla f Vater and the Accessry Papilla During Endscpic Retrgrade Chlangipancreatgraphy (ERCP)

10 In a randmized, placeb cntrlled crssver study in 24 patients with pancreas divisum underging ERCP, ChiRhStim at a dse f 0.2 mcg/kg resulted in 16 f 24 successful cannulatins f the minr duct cmpared t 2 f 24 fr placeb. 15 REFERENCES 1 Gardner TB, Purich ED and Grdn SR. Pancreatic Duct Cmpliance After Secretin Stimulatin. A Nvel Endscpic Ultrasund Diagnstic Tl fr Chrnic Pancreatitis. Pancreas Mar;41(2): Jrpes, E. and Mutt V. On the bilgical assay f secretin. The reference standard. Acta Physil Scand Mar;66(3): HOW SUPPLIED/STORAGE AND HANDLING ChiRhStim (human secretin), fr injectin is supplied as a white lyphilized sterile pwder in a singledse vial fr recnstitutin: NDC # NDC # mcg 40 mcg Stre at -20 C (freezer). Prtect frm light. 17 PATIENT COUNSELING INFORMATION Advise the patient t tell their healthcare prvider all the medicatins they are taking, including antichlinergic drugs, H 2 -receptr antagnists r PPIs [see Warnings and Precautins (5.1, 5.2)]. Manufactured fr: ChiRhClin, Inc. Burtnsville, MD PI507

11 This is a representatin f an electrnic recrd that was signed electrnically and this page is the manifestatin f the electrnic signature /s/ JOYCE A KORVICK 07/18/2017