ChiRhoStim

Indications and Usage for ChiRhoStim

ChiRhoStim

1.1 Stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of pancreatic exocrine dysfunction,

1.2 Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma, and

1.3 Facilitation of the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP).

ChiRhoStim Dosage and Administration

2.1 Stimulation of 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.

Gastroduodenal (Dreiling) Tube Collection Method

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 synthetic human 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, a baseline sample of duodenal fluids is collected for a 10 minute period. A test dose of ChiRhoStim

Endoscopic Collection Method: Endoscopic Pancreatic Function Test (ePFT)

After assessment of patients for sedation and analgesia, a test dose of ChiRhoStim

2.2 Stimulation of Gastrin Secretion to Aid in Diagnosis of Gastrinoma:

0.4 mcg/kg body weight by intravenous injection over 1 minute.

The patient should fast for at least 12 hours prior to beginning the test. Prior to injection of ChiRhoStim®, two blood samples are drawn for determination of fasting serum gastrin levels (baseline values). Subsequently, a test dose of ChiRhoStim

Gastrinoma is strongly indicated in patients who show an increase in serum gastrin concentrations of 110 pg/mL over basal level on any of the post injection samples.

2.3 Facilitation of the Identification of the Ampulla of Vater and Accessory Papilla During Endoscopic Retrograde Cholangiopancreatography (ERCP) to aid in cannulation of the pancreatic duct:

0.2 mcg/kg body weight by intravenous injection over 1 minute.

Administration of ChiRhoStim

2.4 ADMINISTRATION

ChiRhoStim

ChiRhoStim

For both strengths, the reconstituted drug product should be inspected visually prior to administration. If particulate matter or discoloration is seen, the product should be discarded.

3 DOSAGE FORMS AND STRENGTHS

ChiRhoStim

As a lyophilized sterile powder in 10 mL vials containing 16 mcg of human secretin.

As a lyophilized sterile powder in 10 mL vials containing 40 mcg of human secretin.

Contraindications

Patients suffering from acute pancreatitis should not receive ChiRhoStim

Warnings and Precautions

5.1 Allergic Reactions

Because of a potential allergic reaction to ChiRhoStim

5.2 Vagotomy or Inflammatory Bowel Disease

Patients who have undergone vagotomy or who have inflammatory bowel disease may be hyporesponsive to secretin stimulation. This response does not indicate pancreatic disease, and results of secretin stimulation tests in these patients should be interpreted with caution.

5.3 Alcoholic or Other Liver 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. Results of secretin stimulation tests in these patients should thus be interpreted with caution.

6 ADVERSE REACTIONS

Mild to moderate adverse reactions have been noted for synthetic human secretin in clinical studies in 533 patients and 51 healthy volunteers. Two severe adverse reactions, nausea and abdominal pain, occurred in one patient. Table 1 details the type and number of patients with adverse reactions.

Of the 584 patients and healthy volunteers treated with ChiRhoStim

Drug Interactions

The concomitant use of anticholinergic agents may make patients hyporesponsive to secretin stimulation and may produce a false result. Any results of secretin stimulation tests in these patients should thus be interpreted with caution.

USE IN SPECIAL POPULATIONS

8.1 Pregnancy

Animal reproduction studies have not been conducted with synthetic human secretin. It is also not known whether synthetic human secretin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Synthetic human secretin should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether synthetic human secretin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when synthetic human secretin is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Among the 533 patients who have received ChiRhoStim

ChiRhoStim Description

Human secretin is a gastrointestinal peptide hormone produced by cells in the duodenum in response to acidification. ChiRhoStim

Molecular Weight 3039.44

Structural Formula:

ChiRhoStim

As a 10 ml 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 per vial. 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 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.

ChiRhoStim – Clinical Pharmacology

The primary action of ChiRhoStim

12.1 Mechanism of Action

Secretin is a hormone that is normally released from the duodenum upon exposure of the proximal intestinal lumen to gastric acid, fatty acids and amino acids. Secretin is released from enterochromaffin cells in the intestinal mucosa. Secretin receptors have been identified in the pancreas, stomach, liver, colon and other tissues. When secretin binds to secretin receptors on pancreatic duct cells it opens cystic fibrosis transmembrane conductance regulator (CFTR) channels, leading to secretion of bicarbonate-rich-pancreatic fluid. Secretin may also work through vagal-vagal neural pathways since stimulation of the efferent vagus nerve stimulates bicarbonate secretion and atropine blocks secretin-stimulated pancreatic secretion. See references 6 and 7 for additional details on mechanism of action of secretin and feedback controls.

12.3 Pharmacokinetics

The PK profile for synthetic human secretin was evaluated in 12 normal subjects. After intravenous bolus administration of 0.4 mcg/kg, synthetic human secretin concentration rapidly declines to baseline secretin levels 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 L.

Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of synthetic human secretin. Studies to evaluate the potential for impairment of fertility or mutagenicity of synthetic human secretin have not been performed.

13.2 Animal Toxicology and/or Pharmacology

A single intravenous dose of synthetic human secretin at 20 mcg/kg was not lethal to mice or rabbits.

Clinical Studies

14.1 Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of Exocrine Pancreas Dysfunction:

ChiRhoStim

In two crossover studies (CRC98-2 and CRC99-9), a total of 18 patients with a documented history of chronic pancreatitis were given sHS, sPS and bPS. The results appear in Figures 1 and 2. In another study, 35 normal volunteers were given sHS. The results appear in Figures 1 and 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 (>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 (CRC 98-1, CRC 98-2, and CRC 99-9) evaluating 21 different patients with a documented history of chronic pancreatitis, synthetic human secretin (sHS) was compared to synthetic porcine secretin (sPS) and biologically derived secretin (bPS). All of the patients treated with these drugs had peak bicarbonate concentrations of < 80 mEq/L.

Pancreatic secretory response to intravenous synthetic human secretin in 35 normal 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 ≥ 80 mEq/L.

14.2 Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma

ChiRhoStim

In a three way crossover study of 6 patients with tissue diagnosed gastrinoma, there was agreement among synthetic human secretin (ChiRhoStim

14.3 Facilitation of identification of the ampulla of Vater and the accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP) to assist in cannulation of the pancreatic ducts

In a randomized, placebo controlled crossover study in 24 patients with pancreas divisum undergoing ERCP, synthetic human secretin administration 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.

15 REFERENCES

How Supplied/Storage and Handling

16.1 Supplied

ChiRhoStim

As a lyophilized sterile powder in vials containing 16 mcg of human secretin.

As a lyophilized sterile powder in vials containing 40 mcg of human secretin.

16.2 Storage

The unreconstituted product should be stored at -20°C (freezer). Expiration date is marked on the label. Protect from light.

PATIENT COUNSELING INFORMATION

Since there is no data on pregnant or nursing mothers, physicians should discuss these matters with the patient before using this product.

ChiRhoStim

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Manufactured by:

005PI504

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