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warnings and cautions
5 WARNINGS AND PRECAUTIONS Substantial Increase in Blood Pressure in Patients with Pheochromocytoma: Contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor. ( 5.1 ) Hypoglycemia in Patients with Insulinoma: In patients with insulinoma, administration may produce an initial increase in blood glucose; however, glucagon may stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously. ( 5.2 ) Serious Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties, and hypotension.( 5.3 ) Lack of Efficacy with Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen: Patients with insufficient hepatic stores of glycogen may not respond to GVOKE for subcutaneous use for the treatment of severe hypoglycemia. Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia. ( 5.4 ) Necrolytic Migratory Erythema (NME): a skin rash, has been reported postmarketing following continuous glucagon infusion and resolved with discontinuation of the glucagon. GVOKE and GVOKE VialDx are not approved for continuous infusion. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. ( 5.5 ) Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus: GVOKE VialDx in patients with diabetes mellitus may cause hyperglycemia. Monitor patients with diabetes for changes in blood glucose levels during treatment and treat hyperglycemia if indicated. ( 5.6 ) Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease: GVOKE VialDx may increase myocardial oxygen demand, blood pressure, and pulse rate. Cardiac monitoring is recommended in patients with cardiac disease during use of GVOKE VialDx as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy. ( 5.7 ) Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid: GVOKE VialDx administered to patients with glucagonoma 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. ( 5.8 ) 5.1 Substantial Increase in Blood Pressure in Patients with Pheochromocytoma GVOKE and GVOKE VialDx are contraindicated in patients with pheochromocytoma because glucagon may stimulate the release of catecholamines from the tumor [see Contraindications ( 4 )] . If the patient develops a substantial increase in blood pressure and a previously undiagnosed pheochromocytoma is suspected, 5 to 10 mg of phentolamine mesylate, administered intravenously, has been shown to be effective in lowering blood pressure. 5.2 Hypoglycemia in Patients with Insulinoma In patients with insulinoma, administration of glucagon may produce an initial increase in blood glucose; however, glucagon administration may directly or indirectly (through an initial rise in blood glucose) stimulate exaggerated insulin release from an insulinoma and cause hypoglycemia. GVOKE and GVOKE VialDx are contraindicated in patients with insulinoma [see Contraindications ( 4 )] . If a patient develops symptoms of hypoglycemia after a dose of GVOKE or GVOKE VialDx, give glucose orally or intravenously. 5.3 Serious Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with glucagon products, including generalized rash, and in some cases anaphylactic shock with breathing difficulties and hypotension. Discontinue GVOKE or GVOKE VialDx if symptoms of serious hypersensitivity reactions occur. Advise patients and/or caregivers to seek immediate medical attention if the patient experiences any symptoms of serious hypersensitivity reactions.GVOKE and GVOKE VialDx are contraindicated in patients with a prior hypersensitivity reaction to glucagon, or any of the excipients in GVOKE and GVOKE VialDx [see Contraindications ( 4 )] . 5.4 Lack of Efficacy with Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen Patients with insufficient hepatic stores of glycogen may not respond to GVOKE for the treatment of severe hypoglycemia [see Clinical Pharmacology (12.2)] . Insufficient hepatic stores of glycogen may be present in conditions such as states of starvation, or in patients with adrenal insufficiency or chronic hypoglycemia. 5.5 Necrolytic Migratory Erythema Necrolytic migratory erythema (NME), a skin rash commonly associated with glucagonomas (glucagon-producing tumors) and characterized by scaly, pruritic erythematous plaques, bullae, and erosions, has been reported postmarketing following continuous glucagon infusion.GVOKE and GVOKE VialDx are not approved for continuous infusion. NME lesions may affect the face, groin, perineum and legs or be more widespread. In the reported cases NME resolved with discontinuation of the glucagon, and treatment with corticosteroids was not effective. Should NME occur, consider whether the benefits of continuous glucagon infusion outweigh the risks. 5.6 Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus GVOKE VialDx in patients with diabetes mellitus may cause hyperglycemia. Monitor patients with diabetes for changes in blood glucose levels during treatment with GVOKE VialDx and treat hyperglycemia, if indicated. 5.7 Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease GVOKE VialDx 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 use of GVOKE VialDx as a diagnostic aid, and an increase in blood pressure and pulse rate may require therapy. 5.8 Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid Use of GVOKE VialDx in patients with glucagonoma may cause secondary hypoglycemia. GVOKE VialDx is contraindicated in patients with glucagonoma when used as a diagnostic aid [see Contraindications ( 4 )]. Test patients suspected of having glucagonoma for blood levels of glucagon prior to administration of GVOKE VialDx, and monitor for changes in blood glucose levels during treatment. If a patient develops symptoms of hypoglycemia after administration of GVOKE VialDx, administer glucose orally or intravenously.
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Substantial Increase in Blood Pressure in Patients with Pheochromocytoma [see Warnings and Precautions ( 5.1 )] . Hypoglycemia in Patients with Insulinoma [see Warnings and Precautions ( 5.2 )] . Serious Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Lack of Efficacy With Subcutaneous Use for Severe Hypoglycemia in Patients with Decreased Hepatic Glycogen [see Warnings and Precautions ( 5.4 )] Necrolytic Migratory Erythema [see Warnings and Precautions ( 5.5 )] . Hyperglycemia with Intravenous Use as a Diagnostic Aid in Patients with Diabetes Mellitus [see Warnings and Precautions ( 5.6 )] Blood Pressure and Heart Rate Increases with Intravenous Use as a Diagnostic Aid in Patients with Cardiac Disease [see Warnings and Precautions ( 5.7 )] Hypoglycemia in Patients with Glucagonoma with Intravenous Use as a Diagnostic Aid [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence 2% or greater) reported for GVOKE were: Adults—nausea, vomiting, injection site edema raised 1 mm or greater, and headache ( 6.1 ) Pediatric Patients—nausea, hypoglycemia, vomiting, headache, abdominal pain, hyperglycemia, injection site discomfort and reaction, and urticaria ( 6.1 ) Most common adverse reactions (incidence 5 % or greater) reported for GVOKE VialDx were nausea, dysgeusia, headache, dizziness and hot flush ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at toll-free 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of GVOKE and GVOKE VialDx cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. GVOKE for Subcutaneous Use for the Treatment of Severe Hypoglycemia in Adult and Pediatric Patients 2 Aged Years and Older with Type 1 Diabetes Mellitus Adverse Reactions in Adult Patients The safety of GVOKE for subcutaneous use for the treatment of severe hypoglycemia in adults with diabetes was evaluated in two randomized, blinded, 2-way crossover studies conducted in adults with type 1 diabetes mellitus. In total, 154 patients received a subcutaneous injection of GVOKE [see Clinical Studies ( 14.1 )] . The most common adverse reactions that occurred in 2% or more of adults treated with GVOKE during these two clinical trials are listed in Table 1. Table 1: Adverse Reactions that occurred ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus Treated with GVOKE a a Adverse Reactions that occurred within 12 hours. GVOKE 1 mg dose (N = 154) Nausea 30% Vomiting 16% Injection site edema raised 1 mm or greater 7% Headache 5% Injection site pain was reported by 1% of GVOKE-treated patients. Hypertension and tachycardia have occurred with glucagon treatment. Adverse Reactions in Pediatric Patients Aged 2 Years and Older The safety of GVOKE for the treatment of severe hypoglycemia in patients with diabetes was evaluated in one single-arm, open-label, study in 31 pediatric patients with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] . The data in Table 2 reflect the exposure of 31 pediatric patients to 0.5 mg or 1 mg of GVOKE given subcutaneously. The most common adverse reactions that occurred in ≥2% of GVOKE-treated pediatric patients aged 2 years and older are listed in Table 2. Table 2: Adverse Reactions That Occurred ≥ 2% in GVOKE-treated Pediatric Patients Aged 2 Years and Older with Type 1 Diabetes Mellitus a a Adverse Reactions that occurred within 12 hours. 2 to 6 years of age (0.5 mg dose) N =7 6 to 12 years of age (0.5 mg dose) N = 13 12 to 18 years of age (1 mg dose) N = 11 Total N = 31 Nausea 43% 54% 36% 45% Hypoglycemia 29% 54% 27% 39% Vomiting 14% 23% 18% 19% Headache 0% 15% 0% 7% Abdominal pain 0% 8% 0% 3% Hyperglycemia 14% 8% 0% 7% Injection site discomfort 0% 8% 0% 3% Injection site reaction 0% 0% 9% 3% Urticaria 0% 8% 0% 3% GVOKE VialDx for Intravenous Use As a Diagnostic Aid in Adults The safety of GVOKE VialDx for intravenous use as a diagnostic aid in adults was evaluated in an open-label single-dose study in 83 adult healthy volunteers. Table 3 displays the most common adverse reactions that occurred in 5% or greater in healthy volunteers who received 0.75 mg of GVOKE VialDx intravenously. Table 3: Adverse Reactions that Occurred ≥ 5 % in Adult Healthy Volunteers Who Received 0.75 mg of GVOKE VialDx for Intravenous Use as a Diagnostic Aid N=83 Nausea 37.3% Dysgeusia 18.1% Headache 10.8% Hot Flush 9.6% Dizziness 8.4% 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of glucagon. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Necrolytic migratory erythema (NME) cases have been reported postmarketing in patients receiving continuous infusion of glucagon. Hypoglycemia and hypoglycemic coma. Patients taking indomethacin may be more likely to experience hypoglycemia following glucagon administration [see Drug Interactions ( 7 )] .
adverse reactions table
<table><caption>Table 1: Adverse Reactions that occurred ≥ 2% in Adult Patients with Type 1 Diabetes Mellitus Treated with GVOKE<sup>a</sup></caption><col width="50%"/><col width="50%"/><tfoot><tr><td valign="top" colspan="2"><sup>a</sup>Adverse Reactions that occurred within 12 hours.</td></tr></tfoot><tbody><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>GVOKE 1 mg dose</paragraph><paragraph>(N = 154)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Injection site edema raised 1 mm or greater</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7%</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5%</paragraph></td></tr></tbody></table>