Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Extra hepatic effects of glucagon include relaxation of the smooth muscle of the stomach, small bowel, and colon. Pharmacodynamics Table 3 displays the pharmacodynamics properties of Glucagon for Injection as a diagnostic aid during radiologic examination. Table 3: Pharmacodynamic Properties of Glucagon for Injection as a Diagnostic Aid Route of Administration Dosea Time of Onset of Action for GI Smooth Muscle Relaxation Duration of Smooth Muscle Relaxation Intravenous 0.25 to 0.5 mg 45 seconds 9 to 17 minutes Intramuscular 1 mg 8 to 10 minutes 12 to 27 minutes 2 mg 4 to 7 minutes 21 to 32 minutes a Select from these doses based on type of diagnostic procedure, route of administration and procedure duration. Pharmacokinetics Absorption Following intramuscular administration of 1 mg dose, the maximum plasma glucagon concentrations of 3391 pg/mL were attained approximately 10 minutes after dosing. Metabolism The mean apparent half-life of glucagon was 26 minutes after intramuscular administration. Glucagon is degraded in the liver, kidney, and plasma.

GLUCAGON DESCRIPTION Glucagon for Injection, for intravenous or intramuscular use, is a gastrointestinal motility inhibitor that is produced by solid phase peptide synthesis. Glucagon is a single-chain polypeptide containing 29 amino acid residues. The chemical structure of the glucagon polypeptide is identical to human glucagon and to glucagon extracted from beef and pork pancreas. The structure of glucagon is: Glucagon for Injection is a sterile, lyophilized white powder in a 3 mL vial. The reconstituted solution contains 1 mg of glucagon as hydrochloride per mL and lactose monohydrate (107 mg). Glucagon for Injection is supplied at pH 2.5 to 3.5 and is soluble in water.

INDICATIONS Glucagon for Injection is indicated for use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. Limitations of Use Glucagon for Injection is not indicated for the emergency treatment of hypoglycemia because it is not packaged with a syringe and diluent necessary for rapid preparation and administration during an emergency outside of a healthcare facility. DOSAGE AND ADMINISTRATION Recommended Dose Determine the dose based on the type of diagnostic procedure, the route of administration and expected procedure duration [see CLINICAL PHARMACOLOGY]. The usual dose to inhibit movement of the: Stomach and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. Colon is 0.5 mg to 0.75 mg given intravenously or 1 mg to 2 mg given intramuscularly. Bolus doses above 1 mg administered intravenously have caused nausea and vomiting and are not recommended [see ADVERSE REACTIONS]. Reconstitution Of The Lyophilized Powder Glucagon for Injection is a lyophilized powder, which requires reconstitution with Sterile Water for Injection prior to intravenous or intramuscular use. Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial containing Glucagon for Injection lyophilized powder. Shake the vial gently until the powder is completely dissolved and no particles remain in the reconstituted solution. Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and of water-like consistency. Discard the reconstituted solution if there are signs of gel formation or particles. The reconstituted solution has a concentration of approximately 1 mg of glucagon per mL. Use the reconstituted glucagon immediately after reconstitution. Important Administration Instructions Glucagon for Injection must be administered by medical personnel. The timing of administration of Glucagon for Injection depends upon the organ under examination and route of administration [see CLINICAL PHARMACOLOGY]. If given intravenously, administer Glucagon for Injection as a bolus over a time period of 1 minute. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure. HOW SUPPLIED Dosage Forms And Strengths For injection: 1 mg of lyophilized powder in single dose vial for reconstitution. Storage And Handling Glucagon for Injection is supplied as a sterile, lyophilized white powder in a vial. Product # NDC # 509613 63323-596-13 Glucagon for Injection, 1 mg per vial, in packages of 10. Glucagon for Injection is also availableas a Diagnostic Kit, it is supplied as follows: Product # NDC # 509603 63323-596-03 One carton containing one 1 mg of Glucagon for Injection, and one 1 mL of Sterile Water for Injection, USP for reconstitution. The container closure is not made with natural rubber latex. Recommended Storage Before Reconstitution The package containing Glucagon for Injection vials may be stored up to 24 months at 20° to 25° C (68° to 77° F) [see USP Controlled Room Temperature] prior to reconstitution. Do not freeze. Keep in the original package to protect from light. After Reconstitution The Glucagon for Injection must be reconstituted with Sterile Water for Injection prior to use. Use reconstituted glucagon solution immediately. Discard any unused portion [see DOSAGE AND ADMINISTRATION]. Fresnius Kabi, Lake Zurich, IL 60047. Revised: Dec 2015

SIDE EFFECTS The following serious adverse reactions are described below and elsewhere in the labeling: Hypertension in patients with Pheochromocytoma [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Hypoglycemia in Patients with Insulinoma and Glucagonoma [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Hyperglycemia in Patients with Diabetes Mellitus [see WARNINGS AND PRECAUTIONS] Hypersensitivity and Allergic Reactions; generalized allergic reactions including generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension [see WARNINGS AND PRECAUTIONS] Adverse Reactions from Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in clinical trials of another drug and may not reflect the rates observed in practice. In an open-label clinical study of Glucagon for Injection, 29 healthy volunteers received a single dose of 1 mg Glucagon for Injection intramuscularly. Table 1 shows the most common adverse reactions that were not present at baseline and occurred in at least 5% of patients. Table 1: Adverse Reactions in Healthy Volunteers Who Received Glucagon for Injection, 1 mg Administered Intramuscularly (N=29) % of Patients Vomiting 17 Nausea 7 Adverse Reactions from the Literature and Other Clinical Studies The following adverse reactions have been identified from the literature and clinical studies with the use of glucagon. Therefore, it is not possible to reliably estimate their frequency. Nausea and vomiting occurred with doses above 1 mg administered by rapid intravenous injection (within 1 to 2 seconds). Doses above 1 mg are not recommended for intravenous use [see DOSAGE AND ADMINISTRATION]. Hypotension was reported up to 2 hours after administration in patients receiving glucagon as premedication for upper GI endoscopy procedures. A temporary increase in both blood pressure and pulse rate occurred following the administration of glucagon. Patients taking beta-blockers experienced a temporary increase in both pulse and blood pressure that was greater than normal [see DRUG INTERACTIONS]. Other adverse reactions included hypoglycemia and hypoglycemic coma, as described in postmarketing reports. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see DRUG INTERACTIONS]. DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with Glucagon for Injection. Table 2: Clinically Significant Drug Interactions with Glucagon for Injection Beta-Blockers Clinical Impact: The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure. Intervention: The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease. Insulin Clinical Impact: Insulin reacts antagonistically towards glucagon. Intervention: Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients. Indomethacin Clinical Impact: The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia. Intervention: Monitor blood glucose levels during glucagon treatment of patients taking indomethacin. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Intervention: Concomitant use is not recommended. Warfarin Clinical Impact: Glucagon may increase the anticoagulant effect of warfarin. Intervention: Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypertension In Patients With Pheochromocytoma Glucagon for Injection is contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor, which may result in a sudden and marked increase in blood pressure. Hypoglycemia In Patients With Insulinoma Or Glucagonoma Glucagon for Injection is contraindicated in patients with insulinoma or glucagonoma as it may cause secondary hypoglycemia. Test patients suspected of having glucagonoma for blood levels of glucagon prior to treatment, and monitor for changes in blood glucose levels during treatment. If a patient develops symptoms of hypoglycemia after a dose of Glucagon for Injection, administer glucose orally or intravenously. Hyperglycemia In Patients With Diabetes Mellitus Treatment with Glucagon for Injection in patients with diabetes mellitus may cause hyperglycemia. Monitor diabetic patients for changes in blood glucose levels during treatment. If patients develop symptoms of hyperglycemia after a dose of Glucagon for Injection, administer insulin. Blood Pressure And Heart Rate Increase In Patients With Cardiac Disease Glucagon for Injection may increase myocardial oxygen demand, blood pressure, and pulse rate which may be life-threatening in patients with cardiac disease. Cardiac monitoring is recommended in patients with cardiac disease during glucagon treatment, and an increase in blood pressure and pulse rate may require therapy. Hypersensitivity And Allergic Reactions Generalized allergic reactions and hypersensitivity, including generalized rash, and anaphylactic shock with breathing difficulties, and hypotension, have been reported with glucagon treatment or lactose. Discontinue Glucagon for Injection and administer standard treatment for anaphylaxis if needed. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long term studies in animals to evaluate carcinogenic potential have not been performed. Mutagenesis Synthetic glucagon was negative in the bacterial reverse mutation assay (Ames test). The clastogenic potential of synthetic glucagon in the Chinese Hamster Ovary (CHO) assay was positive in the absence of metabolic activation. Doses of 100 and 200 mg/kg of glucagon of both pancreatic and recombinant origins gave slightly higher incidences of micronucleus formation in male mice but there was no effect in females. The weight of evidence indicates that synthetic and recombinant glucagon are not different and do not pose a genotoxic risk to humans. Impairment of Fertility Glucagon (rDNA and synthetic origin) was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility. Use In Specific Populations Pregnancy Pregnancy Category B Reproduction studies were performed in rats and rabbits with another glucagon product at doses of 0.4, 2, and 10 mg per kg. These doses represent exposures of up to 100 and 200 times the human dose based on mg/m² for rats and rabbits, respectively, and revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Glucagon does not cross the human placental barrier. Nursing Mothers It is not known whether glucagon is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when glucagon is administered to a nursing woman. No clinical studies have been performed in nursing mothers, however, glucagon is a peptide and intact glucagon is not absorbed from the GI tract. Therefore, even if the infant ingested glucagon it would be unlikely to have any effect on the infant. Additionally, glucagon has a short plasma half-life thus limiting amounts available to the child. Pediatric Use Safety and effectiveness of Glucagon for Injection have not been established in pediatric patients for use as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract.