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EXENATIDE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Exenatide is a synthetic form of exendin-4, an amino acid peptide isolated from the venom of the Gila monster, and is a glucagon-like peptide-1 agonist.
    B) Albiglutide, liraglutide, lixisenatide, and dulaglutide are glucagon-like peptide-1 (GLP-1) receptor agonists that lower blood glucose by stimulating insulin secretion. Liraglutide and lixisenatide also lower glucagon secretion. They act similarly to exenatide.

Specific Substances

    A) ALBIGLUTIDE (SYNONYM)
    1) CAS 782500-75-8
    DULAGLUTIDE (SYNONYM)
    1) CAS 923950-08-7
    EXENATIDE (SYNONYM)
    1) Synthetic Exendin-4
    2) AC-2993
    3) AC-002993
    4) AC-2993A
    5) LY-2148568
    6) CAS 141732-76-5 (exendin-4)
    7) AC 2993 LAR
    8) EXENDIN - 4 (SYNTHETIC)
    LIRAGLUTIDE (SYNONYM)
    1) Liraglutida
    2) Liraglutidum
    3) CAS 204656-20-2
    4) NN-2211
    5) NNC-901170
    LIXISENATIDE (SYNONYM)
    1) CAS 320367-13-3

    1.2.1) MOLECULAR FORMULA
    1) EXENATIDE: C184H282N50O60S
    2) LIRAGLUTIDE: C172H265N43O51
    3) LIXISENATIDE: C215H347N61O65S

Available Forms Sources

    A) FORMS
    1) ALBIGLUTIDE
    a) Albiglutide is available as 30 mg and 50 mg in single dose pens for subcutaneous injection (Prod Info TANZEUM subcutaneous injection powder, 2014).
    2) DULAGLUTIDE
    a) Dulaglutide is available as 0.75 mg/0,5 mL and 1.5 mg/0.5 mL solution in single-dose pens, and 0.75 mg/0.5 mL and 1.5 mg/0.5 mL solution in single-dose prefilled syringes (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    3) EXENATIDE
    a) Exenatide is available as 250 mcg/mL in a sterile solution for subcutaneous injection (Prod Info BYETTA(TM) injection, 2005). It is also available for 2 mg extended-release powder for suspension for subcutaneous injection (Prod Info BYDUREON(R) subcutaneous extended release injection suspension, 2014).
    4) LIRAGLUTIDE
    a) Liraglutide is available in a pre-filled, multi-dose pen that delivers doses of 0.6 mg , 1.2 mg or 1.8 mg (6 mg/mL, 3 mL) for subcutaneous injection (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    5) LIXISENATIDE
    a) Lixisenatide is available as 50 mcg/mL and 100 mcg/mL in prefilled pens for subcutaneous injection (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).
    B) USES
    1) ALBIGLUTIDE
    a) Albiglutide is indicated as an adjunctive therapy to diet and exercise for improvement of glycemic control in adult patients with type 2 diabetes mellitus (Prod Info TANZEUM subcutaneous injection powder, 2014).
    2) DULAGLUTIDE
    a) Dulaglutide is used as an adjunctive therapy to diet and exercise for improvement of glycemic control in adult patients with type 2 diabetes mellitus (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    3) EXENATIDE
    a) Exenatide is indicated as adjunctive therapy in type 2 diabetic patients who are taking metformin and/or a sulfonylurea and are not achieving adequate glycemic control (Prod Info BYETTA(TM) injection, 2005).
    4) LIRAGLUTIDE
    a) Liraglutide is used as adjunct therapy along with diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; it is not a first-line therapy. Its use is not intended for type 1 diabetes or diabetic ketoacidosis (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    5) LIXISENATIDE
    a) Lixisenatide is used as adjunctive therapy along with diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is not intended to be used to treat type 1 diabetes or diabetic ketoacidosis (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist and is used as adjunctive therapy to treat type 2 diabetes mellitus. Other GLP-1 receptor agonists include the following agents: albiglutide, dulaglutide, liraglutide, and lixisenatide.
    B) PHARMACOLOGY: GLP-1 receptor agonists activate the GLP-1 receptor, resulting in an increase in glucose-dependent insulin secretion by the beta-cells of the pancreas and a decrease in glucagon secretion. Gastric emptying is also delayed.
    C) EPIDEMIOLOGY: Overdose is rarely reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: Albiglutide (10% or greater incidence): nausea, diarrhea, injection site reaction, and upper respiratory tract infection. Dulaglutide (5% or greater incidence): nausea, vomiting, diarrhea, abdominal pain, and decreased appetite. Exenatide (5% or greater incidence): nausea, vomiting, diarrhea, constipation, feeling jittery, dizziness, headache, dyspepsia, and asthenia. Liraglutide (5% or greater incidence): nausea, diarrhea, and headache.
    2) LESS COMMON: Other adverse effects that may occur less frequently include hypersensitivity reactions (rash, pruritus, dyspnea) acute pancreatitis, and hypoglycemia. The risk of hypoglycemia may be increased with concomitant administration of a GLP-1 receptor agonist and insulin or an insulin secretagogue (eg sulfonylurea). Tachycardia and ECG abnormalities (increased PR intervals and first degree AV block) were infrequently reported with dulaglutide therapy.
    E) WITH POISONING/EXPOSURE
    1) Exposure information is limited for these agents. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. EXENATIDE: Three patients with type 2 diabetes experienced severe nausea, vomiting, and hypoglycemia following subcutaneous administration of 100 mcg exenatide (10 times the maximum recommended dose). Another patient developed vomiting, diarrhea, and weakness with normal blood glucose after 90 mcg exenatide. LIRAGLUTIDE: Two adults developed severe nausea and vomiting following liraglutide subcutaneous injections of 17.4 mg (10 times the maximum recommended dose) and 72 mg; hypoglycemia did not develop.
    0.2.20) REPRODUCTIVE
    A) The brand name of liraglutide called Saxenda(R), which is indicated as an adjunct to diet and exercise for chronic weight management in overweight or obese patients, has a pregnancy category of X. Exenatide, albiglutide, dulaglutide, and another brand of liraglutide, Victoza(R), are classified as FDA pregnancy category C. There are no human data available on the effects of exenatide, albiglutide, or liraglutide during pregnancy, lactation, or fertility. Exenatide and liraglutide animal studies have demonstrated reduced fetal and neonatal growth, skeletal abnormalities, and an increased incidence of neonatal deaths. Reproductive toxicity was reported in mice administered albiglutide up to 39 times the maximum recommended human dose during nonclinical studies; however, there were no reports of teratogenicity. In lactating mice, a low concentration of exenatide was present in milk. In studies of lactating rats, liraglutide was excreted in the milk of lactating rats at concentrations approximately 50% of maternal plasma concentrations.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of exenatide in humans. Liraglutide and dulaglutide cause thyroid C-cell tumors in rodents, and the relevance of this to humans could not be determined. Therefore, both drugs are contraindicated when the patient has a personal or family history of medullary thyroid carcinoma or has multiple endocrine neoplasia syndrome type 2 (MEN 2).

Laboratory Monitoring

    A) Monitor electrolytes and fluid status as indicated in patients with significant gastrointestinal symptoms following exposure.
    B) Monitor serum lipase in patients showing signs and symptoms consistent with pancreatitis.
    C) Hypoglycemic effects are enhanced in patients with concurrent administration of insulin or insulin secretagogues; obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    D) Monitor dermal injection sites for irritation or hypersensitivity reactions.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. HYPOGLYCEMIA: Hypoglycemic effects are enhanced in patients with concurrent administration of insulin or insulin secretagogues; obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. DIET: If the patient is awake and alert, offer carbohydrates. If hypoglycemia persists or becomes severe, treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia. NOT RECOMMENDED: Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPOGLYCEMIA: Hypoglycemic effects are enhanced in patients with concurrent administration of insulin or insulin secretagogues; obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. Treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia. ACUTE ALLERGIC REACTION: Oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) These agents are administered subcutaneously; ingestion is unlikely.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) HYPOGLYCEMIA
    1) DEXTROSE: Give dextrose if symptomatic or BS less than 60 mg/dL. DOSE: ADULT: 0.5 to 1 g/kg of D50W (50% dextrose) IV push; ADOLESCENT: 0.5 to 1 g/kg (1 to 2 mL/kg) of 50% dextrose IV push; INFANT and CHILD: 0.5 to 1 g/kg (2 to 4 mL/kg) of 25% dextrose IV push. Follow with an infusion of 10% dextrose; titrate to a BS of 100 mg/dL. DIET: When the patient is awake and alert, supplement IV glucose with carbohydrate intake.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: All children with inadvertent injections should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent injection of an extra dose who are asymptomatic can be monitored at home. Asymptomatic nondiabetic adults with an inadvertent injection of an extra dose can be monitored at home.
    2) OBSERVATION CRITERIA: There is no information on the onset or duration of hypoglycemia after overdose of these patients; however, due to the prolonged half-lives of these agents, patients may need to be monitored for a minimum of 8 to 12 hours if they are also taking insulin or an insulin secretagogue.
    3) ADMISSION CRITERIA: Patients who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    4) CONSULT CRITERIA: Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    I) PITFALLS
    1) There is no information on the onset and duration of hypoglycemia after overdose of these agents in patients who take insulin or an insulin secretagogue. Patients who develop hypoglycemia should not be discharged until they have been able to maintain euglycemia for at least 8 hours without supplemental dextrose.
    J) PHARMACOKINETICS
    1) ALBIGLUTIDE: Volume of distribution is 11 L; elimination half-life is 5 days. DULAGLUTIDE: Absolute bioavailability was 47% and 65% following subQ administration of 1.5 mg and 0.75 mg doses, respectively; mean volume of distribution was 17.4 L (range: 9.3 to 33 L) at the 1.5 mg dose, and 19.2 L (range: 14.3 to 26.4 L) at the 0.75 mg dose; elimination half-life is 5 days at the 0.75 mg dose and at the 1.5 mg dose. EXENATIDE: Volume of distribution is 28.3 L; elimination half-life is 3.3 to 4 hours following administration of immediate-release formulation. LIRAGLUTIDE: Absolute bioavailability is approximately 55%; greater than 98% bound to plasma proteins; volume of distribution following a 0.6 mg subQ dose is approximately 13 L and 0.07 L/kg following an intravenous dose; elimination half-life is approximately 13 hours. LIXISENATIDE: Volume of distribution is approximately 100 L; elimination half-life is approximately 3 hours following multiple-dose administration.
    K) DIFFERENTIAL DIAGNOSIS
    1) Exposure to other hypoglycemic agents such as insulin or sulfonylureas. The differential diagnosis of hypoglycemia is otherwise very broad and includes sepsis, liver failure, malnutrition, neoplasm, adrenal insufficiency, insulinoma and others.

Range Of Toxicity

    A) TOXICITY: Specific toxic doses for these agents have not been established. EXENATIDE: Severe nausea, vomiting, and hypoglycemia occurred in three patients with type 2 diabetes following subcutaneous administration of 100 mcg (10 times the maximum recommended dose). An adult developed vomiting and weakness without hypoglycemia after 90 mcg exenatide. The patient did have symptoms of nausea, vomiting, and weakness, but never developed low blood sugars. Healthy volunteers did not develop clinical hypoglycemia after a 10 microgram dose subcutaneously. LIRAGLUTIDE: During a clinical trial, an adult inadvertently received 17.4 mg subQ (10 times the recommended dose) of liraglutide and developed severe nausea and vomiting; hypoglycemia was not observed. Recovery was uneventful. Another adult intentionally injected 72 mg subcutaneously and developed severe nausea and vomiting, but did not develop hypoglycemia. LIXISENATIDE: An increased incidence of gastrointestinal effects were noted in type 2 diabetic patients who received doses up to 30 mcg twice daily (3 times the daily recommended dose) during a clinical trial.
    B) THERAPEUTIC DOSE: ALBIGLUTIDE: ADULT: 30 to 50 mg subQ once weekly. DULAGLUTIDE: ADULT: 0.75 to 1.5 mg subQ once weekly. EXENATIDE: ADULT: 5 to 10 mcg subQ twice daily. LIRAGLUTIDE: ADULT: Initial dose: 0.6 mg subQ daily for one week to minimize gastrointestinal symptoms and then increased to 1.2 mg (up to 1.8 mg daily) subQ daily for glycemic control. LIXISENATIDE: The recommended initial dose is 10 mcg subQ once daily for 14 days, increasing to a maintenance dose of 20 mcg subQ once daily starting on day 15.

Clinical Effects

Summary Of Exposure

    A) USES: Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist and is used as adjunctive therapy to treat type 2 diabetes mellitus. Other GLP-1 receptor agonists include the following agents: albiglutide, dulaglutide, liraglutide, and lixisenatide.
    B) PHARMACOLOGY: GLP-1 receptor agonists activate the GLP-1 receptor, resulting in an increase in glucose-dependent insulin secretion by the beta-cells of the pancreas and a decrease in glucagon secretion. Gastric emptying is also delayed.
    C) EPIDEMIOLOGY: Overdose is rarely reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: Albiglutide (10% or greater incidence): nausea, diarrhea, injection site reaction, and upper respiratory tract infection. Dulaglutide (5% or greater incidence): nausea, vomiting, diarrhea, abdominal pain, and decreased appetite. Exenatide (5% or greater incidence): nausea, vomiting, diarrhea, constipation, feeling jittery, dizziness, headache, dyspepsia, and asthenia. Liraglutide (5% or greater incidence): nausea, diarrhea, and headache.
    2) LESS COMMON: Other adverse effects that may occur less frequently include hypersensitivity reactions (rash, pruritus, dyspnea) acute pancreatitis, and hypoglycemia. The risk of hypoglycemia may be increased with concomitant administration of a GLP-1 receptor agonist and insulin or an insulin secretagogue (eg sulfonylurea). Tachycardia and ECG abnormalities (increased PR intervals and first degree AV block) were infrequently reported with dulaglutide therapy.
    E) WITH POISONING/EXPOSURE
    1) Exposure information is limited for these agents. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. EXENATIDE: Three patients with type 2 diabetes experienced severe nausea, vomiting, and hypoglycemia following subcutaneous administration of 100 mcg exenatide (10 times the maximum recommended dose). Another patient developed vomiting, diarrhea, and weakness with normal blood glucose after 90 mcg exenatide. LIRAGLUTIDE: Two adults developed severe nausea and vomiting following liraglutide subcutaneous injections of 17.4 mg (10 times the maximum recommended dose) and 72 mg; hypoglycemia did not develop.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) DULAGLUTIDE
    1) Sinus tachycardia was reported in 2.8% and 5.6% of patients treated with dulaglutide 0.75 mg and 1.5 mg, respectively, compared to 3% of patients treated with placebo (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) An increase in heart rate from baseline to at least 15 bpm concomitantly associated with episodes of sinus tachycardia were reported in 1.3% and 2.2% of patients treated with dulaglutide 0.75 mg and 1.5 mg, respectively compared to 0.7% of patients treated with placebo (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) DULAGLUTIDE
    1) A PR interval increase to at least 220 ms, as noted on ECGs, was reported in 2.5% and 3.2% of patients treated with dulaglutide 0.75 mg and 1.5 mg, respectively, compared to 0.7% of patients treated with placebo (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) First degree AV block was reported in 1.7% and 2.3% of patients treated with dulaglutide 0.75 mg and 1.5 mg, respectively, compared to 0.9% of patients treated with placebo (Prod Info TRULICITY(TM) subcutaneous injection, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) ALBIGLUTIDE: Data from a pool of 4 placebo-controlled clinical studies reported the development of upper respiratory tract infections in 14.2% of patients receiving albiglutide (n=923) compared to 13% of patients receiving placebo (n=468) (Prod Info TANZEUM subcutaneous injection powder, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Headache has been commonly reported with the therapeutic use of these agents (Prod Info Victoza(R) subcutaneous injection solution, 2013; Prod Info BYETTA(R) subcutaneous injection, 2011).
    b) EXENATIDE
    1) Headaches may frequently occur with exenatide therapy, but appear to be transient and mild to moderate in intensity (Prod Info BYETTA(R) subcutaneous injection, 2011; Kendall et al, 2005; Fineman et al, 2004; Kolterman et al, 2003).
    2) INCIDENCE: Headaches were reported in 25% of patients (n=28) who received exenatide, 10 mcg subcutaneously daily, during a randomized open-label crossover study (Calara et al, 2005).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) EXENATIDE: Dizziness was frequently reported following therapeutic administration of exenatide (Prod Info BYETTA(R) subcutaneous injection, 2011; Calara et al, 2005; Fineman et al, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been relatively common and dose-limiting with non-titrated doses of exenatide (usually based on body weight) in phase II studies (Prod Info BYETTA(R) subcutaneous injection, 2011; Nielsen & Baron, 2003; Kolterman et al, 2003; Giannoukakis, 2003). Nausea appeared to occur early (within the first few weeks of therapy), generally subsiding as treatment continued (Kendall et al, 2005; DeFronzo et al, 2005; Nielsen & Baron, 2003; Fineman et al, 2003).
    b) Zinman et al (2007) compared exenatide with placebo in 233 adult, diabetic patients taking thiazolidinediones or metformin. Over the 16 week study period, nausea (40%) and vomiting (13%) were more common in the treatment group than placebo group (Zinman et al, 2007).
    c) The most common adverse events reported with therapeutic use of other GLP-1 receptor agonists include nausea and vomiting, which have been reported in greater than 5% of treated patients (Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info Victoza(R) subcutaneous injection solution, 2013).
    2) WITH POISONING/EXPOSURE
    a) EXENATIDE
    1) Severe nausea and vomiting were reported in three patients following subcutaneous administration of single 100 mcg dose of exenatide (10 times the maximum recommended dose) (Prod Info BYETTA(R) subcutaneous injection, 2011; Calara et al, 2005).
    2) CASE REPORT: A 40-year-old woman experienced symptoms of nausea and one bout of vomiting after an intentional overdose of 90 mcg exenatide (Cohen et al, 2008).
    b) LIRAGLUTIDE
    1) An adult inadvertently received 17.4 mg subQ of liraglutide (10 times the maximum recommended dose) and developed severe nausea and vomiting; hypoglycemia did not develop (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    2) CASE REPORT: A 33-year-old woman, with type 2 diabetes, intentionally injected 72 mg of liraglutide subcutaneously and subsequently developed severe nausea and vomiting. Hypoglycemia did not develop (Nakanishi et al, 2013).
    3) CASE REPORT: A 49-year-old woman, with type 2 diabetes mellitus, developed hypoglycemia and severe nausea and vomiting after injecting a 0.6 mg dose of liraglutide 30 times subcutaneously (total dose of 18 mg) instead of the prescribed 0.6 mg SubQ once daily. Her blood glucose concentration was 3.6 mmol/L approximately 1 hour after the overdose, and 2.5 hours post-overdose, the patient was admitted to the hospital where she was given supportive care. After vomiting a total of 19 times, her vomiting stopped approximately 13 hours post-overdose and her mean blood glucose concentration was 10.1 +/- 2.23 mmol/L (ranging from 4.49 to 12.93 mmol/L). She was discharged 24 hours post-admission (Elmehdawi & Elbarsha, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Mild-to-moderate diarrhea was reported in several patients following therapeutic administration of exenatide (Prod Info BYETTA(R) subcutaneous injection, 2011; Fineman et al, 2004). The incidence of diarrhea appeared to increase with increasing dose (Kendall et al, 2005). Diarrhea also occurred frequently following therapeutic administration of albiglutide (Prod Info TANZEUM subcutaneous injection powder, 2014) and dulaglutide (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    C) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) ALBIGLUTIDE
    1) Across 8 phase 3 clinical trials, acute pancreatitis occurred in 0.3% of patients receiving albiglutide (n=2365) compared to 0% of patients receiving placebo (n=468) or 0.1% of patients receiving active comparators (n=2065) (Prod Info TANZEUM subcutaneous injection powder, 2014).
    b) DULAGLUTIDE
    1) During phase 2 and phase 3 clinical trials, confirmed pancreatitis was reported in 5 patients receiving dulaglutide (1.4 cases per 1000 patient years) compared to 1 patient receiving non-incretin comparators (0.88 cases per 1000 patient years) (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) Increases in lipase and /or pancreatic amylase of 14% to 20% from baseline were reported in patients treated with dulaglutide as compared to increases up to 3% in patients treated with placebo (Prod Info TRULICITY(TM) subcutaneous injection, 2014) .
    c) EXENATIDE
    1) CASE REPORT: A 69-year-old man developed epigastric pain within 24 hours of starting exenatide 5 mcg subcutaneous twice daily. He was hospitalized 5 days later with apparent acute pancreatitis. Peak serum lipase level was 346 Units/L. He recovered 3 days later with supportive care. The patient was also taking other medications including: metformin, pioglitazone, insulin, metoprolol, gabapentin, irbesartan, infliximab, ezetimibe, and esomeprazole. Metformin and pioglitazone were discontinued at the onset of symptoms. He had been taking the other medications chronically without adverse effects (Denker & Dimarco, 2006).
    d) LIRAGLUTIDE
    1) Pancreatitis was observed more frequently during clinical trials with liraglutide as compared to controls (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    D) ACUTE HEMORRHAGIC PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) EXENATIDE/CASE SERIES: Six cases of hemorrhagic or necrotizing pancreatitis in type 2 diabetic patients being treated with exenatide have been reported to the FDA between October 2007 and August 2008. Although exenatide was discontinued in all 6 patients, each patient required hospitalization, 2 died, and 4 were still recovering at the time of reporting (US Food and Drug Administration, 2008).
    E) ACUTE NECROTIZING PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) EXENATIDE/CASE SERIES: Six cases of hemorrhagic or necrotizing pancreatitis in type 2 diabetic patients being treated with exenatide have been reported to the FDA between October 2007 and August 2008. Although exenatide was discontinued in all 6 patients, each patient required hospitalization, 2 died, and 4 were still recovering at the time of reporting (US Food and Drug Administration, 2008).
    F) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) DULAGLUTIDE: Data from a pool of placebo-controlled clinical studies reported the occurrence of abdominal pain in 6.5% (n=836) and 9.4% (n=834) of patients receiving 0.75 mg and 1.5 mg dulaglutide, respectively, compared to 4.9% of patients receiving placebo (n=568) (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    G) DECREASE IN APPETITE
    1) WITH THERAPEUTIC USE
    a) DULAGLUTIDE: Data from a pool of placebo-controlled clinical studies reported a decreased appetite in 4.9% (n=836) and 8.6% (n=834) of patients receiving 0.75 mg and 1.5 mg of dulaglutide, respectively, compared to 1.6% of patients receiving placebo (n=568) (Prod Info TRULICITY(TM) subcutaneous injection, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Injection-site reactions (eg, injection-site rash, erythema) have occurred with these agents (Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info Victoza(R) subcutaneous injection solution, 2013; Prod Info BYETTA(R) subcutaneous injection, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Mild-to-moderate hypoglycemia has occurred with exenatide in some patients also receiving sulfonylureas (Buse et al, 2004; Fineman et al, 2003; Giannoukakis, 2003; Nielsen & Baron, 2003). Hypoglycemia can also develop with the concurrent use of other GLP-1 receptor agonists (albiglutide, dulaglutide, and liraglutide) and an insulin secretagogue (e.g., sulfonylurea) (Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    b) During a randomized, single-blind placebo-controlled trial, mild hypoglycemia was reported in one patient following administration of 0.1 mcg/kg/day exenatide as sole therapy (without concomitant sulfonylurea therapy) (Kolterman et al, 2005).
    c) INCIDENCE: The incidence of hypoglycemia in type 2 diabetic patients, during placebo-controlled trials involving concomitant administration of exenatide with a sulfonylurea, was 14.4% and 35.7% following exenatide doses of 5 mcg twice daily (n=125) and 10 mcg twice daily (n=129), respectively, as compared with 3.3% in the placebo-treated group (n=123). The incidence of hypoglycemia, in patients receiving combination therapy of exenatide with metformin and a sulfonylurea, was 19.2% and 27.8% following exenatide doses of 5 mcg twice daily (n=245) and 10 mcg twice daily (n=241), respectively, as compared with 12.6% in the placebo-treated group (n=247) (Prod Info BYETTA(R) subcutaneous injection, 2011).
    d) Severe hypoglycemia was not reported in patients receiving exenatide in combination with metformin (Yoo et al, 2006; Iltz et al, 2006). Incidence of mild hypoglycemia was similar to placebo (Iltz et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) EXENATIDE
    1) Severe hypoglycemia was reported in one patient following subcutaneous administration of a single 100 mcg dose of exenatide (10 times the maximum recommended dose). The patient recovered following parenteral glucose administration (Prod Info BYETTA(R) subcutaneous injection, 2011; Calara et al, 2005).
    2) LACK OF EFFECT: A 40-year-old woman injected 90 mcg of exenatide as a suicide attempt in addition to taking her routine morning diabetes medications, which included pioglitazone 25 mg, metformin 1000 mg, and glimepiride 4 mg. She developed nausea, vomiting, and weakness, but never became hypoglycemic (Cohen et al, 2008).
    b) LIRAGLUTIDE
    1) LACK OF EFFECT: Two adults developed severe nausea and vomiting following liraglutide subcutaneous injections of 17.4 mg (10 times the maximum recommended dose) and 72 mg; hypoglycemia did not develop (Nakanishi et al, 2013; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    2) CASE REPORT: A 49-year-old woman, with type 2 diabetes mellitus, developed hypoglycemia and severe nausea and vomiting after injecting a 0.6 mg dose of liraglutide 30 times subcutaneously (total dose of 18 mg) instead of the prescribed 0.6 mg SubQ once daily. Her blood glucose concentration was 3.6 mmol/L approximately 1 hour after the overdose, and 2.5 hours post-overdose, the patient was admitted to the hospital where she was given supportive care. After vomiting a total of 19 times, her vomiting stopped approximately 13 hours post-overdose and her mean blood glucose concentration was 10.1 +/- 2.23 mmol/L (ranging from 4.49 to 12.93 mmol/L). She was discharged 24 hours post-admission (Elmehdawi & Elbarsha, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANTIBODY
    1) WITH THERAPEUTIC USE
    a) The development of anti-exenatide antibodies has occurred in patients following exenatide therapy. The antibody titers seemed to diminish over time and the level of glycemic control (as measured by the HbA1c level) did not appear to be significantly affected by the presence of the antibodies (Prod Info BYETTA(TM) injection, 2005; Fineman et al, 2003).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Severe hypersensitivity reactions, (eg, anaphylaxis, severe urticaria, rash, facial edema, and lip swelling) have been reported in several patients following GLP-1 receptor agonist therapy (Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info Victoza(R) subcutaneous injection solution, 2013; Prod Info BYETTA(R) subcutaneous injection, 2011).

Reproductive

    3.20.1) SUMMARY
    A) The brand name of liraglutide called Saxenda(R), which is indicated as an adjunct to diet and exercise for chronic weight management in overweight or obese patients, has a pregnancy category of X. Exenatide, albiglutide, dulaglutide, and another brand of liraglutide, Victoza(R), are classified as FDA pregnancy category C. There are no human data available on the effects of exenatide, albiglutide, or liraglutide during pregnancy, lactation, or fertility. Exenatide and liraglutide animal studies have demonstrated reduced fetal and neonatal growth, skeletal abnormalities, and an increased incidence of neonatal deaths. Reproductive toxicity was reported in mice administered albiglutide up to 39 times the maximum recommended human dose during nonclinical studies; however, there were no reports of teratogenicity. In lactating mice, a low concentration of exenatide was present in milk. In studies of lactating rats, liraglutide was excreted in the milk of lactating rats at concentrations approximately 50% of maternal plasma concentrations.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of dulaglutide, exenatide, liraglutide, or lixisenatide use in pregnant women (Prod Info ADLYXIN(TM) subcutaneous injection, 2016; Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010; Prod Info BYETTA(R) subcutaneous injection, 2009).
    B) ANIMAL STUDIES
    1) DULAGLUTIDE
    a) RATS, RABBITS: During animal studies, administration of subQ dulaglutide 0.49, 1.63, or 4.89 mg/kg on gestation days 6, 9, 12, and 15 in pregnant rats resulted in decreased maternal food intake and decreased weight gain resulting in reduced fetal weight. Irregular skeletal ossifications and increased post-implantation loss were also reported at dulaglutide doses of 4.89 mg/kg (44-fold the maximum recommended human dose). In pregnant rabbits, subQ administration of dulaglutide 0.04, 0.12, or 0.41 mg/kg on gestation days 7, 10, 13, 16, and 19 resulted in fetal skeletal malformations of the vertebrae and/or ribs as well as decreased maternal food intake and decreased maternal weight gain. During a prenatal/postnatal study in maternal rats, subQ administration of dulaglutide 0.2, 0.49, or 1.63 mg/kg every 3 days from implantation through lactation resulted in lower mean body weight. Decreased forelimb and hindlimb grip strength was reported with the 1.63 mg/kg dose as well as delayed balano-preputial separation in male offspring and a decreased startle response in female offspring (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) EXENATIDE
    a) MICE - Cleft palate (some with holes) and irregular skeletal ossification of rib and skull bones occurred following administration of subcutaneous exenatide, 6 mcg/kg/day, to pregnant mice during organogenesis (gestation day 6 through 15). The 6 mcg/kg/day dose resulted in systemic exposure that was 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC (Prod Info BYETTA(R) subcutaneous injection, 2009).
    b) RABBITS - Irregular skeletal ossifications were reported following subcutaneous administration of exenatide, 2 mcg/kg/day, to pregnant rabbits during organogenesis (gestation day 6 through 18). The 2 mcg/kg/day dose resulted in systemic exposure that was 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC (Prod Info BYETTA(R) subcutaneous injection, 2009).
    3) LIRAGLUTIDE
    a) RATS: There was evidence of teratogenicity when female rats were given subQ liraglutide doses of 0.1, 0.25 and 1 mg/kg/day (0.8-, 3-, and 11-times the human exposure at the maximum recommended human dose based on plasma AUC comparison) beginning 2 weeks before mating through gestation day 17. Fetal abnormalities, kidney and blood vessel variations, irregular skull ossification, and ossification were observed at all doses (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    b) RABBITS: Teratogenicity was observed following subQ doses of 0.01, 0.025 and 0.05 mg/kg/day (less than the human exposure at the maximum recommended human dose at all doses) from gestation day 6 through day 18. Dose-dependent major fetal abnormalities were reported at all doses. Malformations at the various doses included kidney and scapula (0.01 mg/kg), the eyes and forelimbs (0.01 mg/kg or greater), the brain, tail and sacral vertebrae, major blood vessels and heart, and umbilicus (0.025 mg/kg), the sternum (0.025 mg/kg and greater), and parietal bones and major blood vessels (0.05 mg/kg). Ossification and/or skeletal abnormalities and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in major organs and bilobed or bifurcated gallbladder were observed in all treatment groups (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    4) LIXISENATIDE
    a) Visceral closure defects (eg, microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and reduced neonatal growth were seen in rats exposed to lixisenatide doses approximately equal to human clinical doses during organogenesis. Rat and rabbit embryofetal toxicities included malformations, skeletal effects, and retarded growth and ossification with 1-fold and 6-fold higher exposures to lixisenatide in utero, respectively, than with human exposure (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) DULAGLUTIDE
    1) There are no adequate or well controlled studies of dulaglutide use during human pregnancy. During animal studies, administration of dulaglutide during organogenesis in pregnant rats and rabbits resulted in decreased fetal growth, skeletal abnormalities, and ossification deficits. In pregnancies complicated by hyperglycemia, good metabolic control is essential prior to conception and throughout the pregnancy, as good metabolic control may decrease the risk of birth defects, pregnancy loss, and other adverse outcomes. Due to the lack of human data and the potential for adverse effects, the manufacturer recommend the use of dulaglutide during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    B) LIXISENATIDE
    1) Administer lixisenatide during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).
    C) PREGNANCY CATEGORY
    1) The brand name of liraglutide called Saxenda(R), which is indicated as an adjunct to diet and exercise for chronic weight management in overweight or obese patients, has a pregnancy category of X. Saxenda(R) is contraindicated in all pregnant women, including those who are already overweight or obese, because weight loss may result in fetal harm. If a woman becomes or wishes to become pregnant while on Saxenda, discontinue treatment (Prod Info SAXENDA(R) subcutaneous injection solution, 2014).
    2) The manufacturer has classified the following as FDA pregnancy category C.
    1) ALBIGLUTIDE (Prod Info TANZEUM subcutaneous injection powder, 2014)
    2) DULAGLUTIDE (Prod Info TRULICITY(TM) subcutaneous injection, 2014)
    3) EXENATIDE (Prod Info BYETTA(R) subcutaneous injection, 2009)
    4) LIRAGLUTIDE brand, Victoza(R) (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010)
    D) ANIMAL STUDIES
    1) ALBIGLUTIDE
    a) Reproductive toxicity was reported in mice administered albiglutide up to 39 times the maximum recommended human dose during nonclinical studies; however, there were no reports of teratogenicity. No effects on fertility were noted (Prod Info TANZEUM subcutaneous injection powder, 2014).
    2) EXENATIDE
    a) MICE - An increased number of neonatal deaths occurred on postpartum days 2 through 4 following subcutaneous administration of exenatide, 6 mcg/kg/day, to pregnant mice from gestation day 6 through lactation day 20. The 6 mcg/kg/day dose resulted in systemic exposure that was 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC (Prod Info BYETTA(R) subcutaneous injection, 2009).
    3) LIRAGLUTIDE
    a) RATS - Pregnant rats given subQ liraglutide doses of 0.1, 0.25 and 1 mg/kg/day (0.8, 3, and 11 times the human exposure at the maximum recommended human dose (MRHD) based on plasma AUC comparison) beginning 2 weeks before mating through gestation day 17 had slightly increased in the number of early embryonic deaths at the 1 mg/kg/day group (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    4) LIXISENATIDE
    a) Increased pup mortality was seen in rats given doses approximately 200 times the exposure from the clinical human dose (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether albiglutide, dulagutide, exenatide, liraglutide, or lixisenatide is excreted in human breast milk (Prod Info ADLYXIN(TM) subcutaneous injection, 2016; Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010; Prod Info BYETTA(R) subcutaneous injection, 2009).
    B) ALBIGLUTIDE
    1) Lactation studies with albiglutide have not been conducted. It is not known whether albiglutide is present in human milk. Albiglutide is an albumin-based protein therapeutic and is likely to be present in human milk. In animal studies, decreased body weight was reported in the offspring of mice administered albiglutide during gestation and lactation. Because many drugs are known to be present in human milk and due to the potential for adverse effects in a nursing infant, the manufacturer recommends discontinuing drug or discontinuing nursing, taking into account the importance of the drug to the mother (Prod Info TANZEUM subcutaneous injection powder, 2014).
    C) DULAGLUTIDE
    1) Lactation studies with dulaglutide have not been conducted. It is not known whether dulaglutide is excreted into human breast milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended to either discontinue nursing or discontinue dulaglutide, taking into account the importance of the drug to the mother (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    D) LIXISENATIDE
    1) Consider the developmental and health benefits of breastfeeding, along with the mother's clinical need for lixisenatide and any potential adverse effects on the nursing infant from the drug or from the underlying maternal condition (Prod Info ADLYXIN(TM) subcutaneous injection, 2016)
    E) ANIMAL STUDIES
    1) EXENATIDE
    a) MICE - In studies of lactating mice, exenatide was present at low concentrations in milk (less than or equal to 2.5% of the concentration in maternal plasma) following subcutaneous administration of exenatide (Prod Info BYETTA(R) Pen subcutaneous injection, 2008).
    2) LIRAGLUTIDE
    a) RATS - In studies of lactating rats, liraglutide was excreted unchanged in the milk of lactating rats at concentrations approximately 50% of maternal plasma concentrations (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    3) LIXISENATIDE
    a) Lixisenatide and its metabolites are present in the milk of lactating rats at low levels (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) EXENATIDE
    a) There was no impairment of fertility in male or female mice following subcutaneous administration of exenatide (Prod Info BYETTA(R) subcutaneous injection, 2009).
    2) LIRAGLUTIDE
    a) There were no adverse effects on fertility in male rats following subQ administration of liraglutide at doses up to 1 mg/kg/day. In female rats, an increase in early embryonic deaths and reduced body weight gain and food consumption were observed following subQ administration of liraglutide 1 mg/kg/day dose (11 times the human exposure at the maximum recommended human dose, based on plasma AUC) given 2 weeks prior to mating until gestation day 17 (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    3) LIXISENATIDE
    a) No adverse effects on male or female fertility were seen in rats at doses up to 400 times the clinical dose based on exposure (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS141758-74-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS204656-20-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of exenatide in humans. Liraglutide and dulaglutide cause thyroid C-cell tumors in rodents, and the relevance of this to humans could not be determined. Therefore, both drugs are contraindicated when the patient has a personal or family history of medullary thyroid carcinoma or has multiple endocrine neoplasia syndrome type 2 (MEN 2).
    3.21.3) HUMAN STUDIES
    A) MEDULLARY THYROID CARCINOMA
    1) ALBIGLUTIDE
    a) Albiglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma or who have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) because albiglutide causes thyroid C-cell adenomas and carcinomas in mice and rodents at clinically relevant exposures (Prod Info TANZEUM subcutaneous injection powder, 2014).
    2) DULAGLUTIDE
    a) Dulaglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma (MTC) or who have MEN 2 because dulaglutide causes a dose-related and treatment-duration-dependent increase in thyroid C-cell adenomas and carcinomas in rats when exposed during their lifetimes. C-cell adenomas and carcinomas have also been reported in mice and rats at clinically relevant exposures with other glucagon-like peptide receptor agonists. Neither clinical nor nonclinical studies could rule out this relevance to humans. One case of MTC was reported in a patient receiving dulaglutide and who had elevated pretreatment calcitonin levels (approximately 8 times the ULN) (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    3) LIRAGLUTIDE
    a) Liraglutide is contraindicated in patients who have a personal or family history of medullary thyroid carcinoma or who have MEN 2 because liraglutide causes thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. Neither clinical nor nonclinical studies could rule out this relevance to humans (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010). In clinical trials, thyroid C-cell hyperplasia occurred in 4 patients who were using liraglutide and in 1 patient who was using the comparator (1.3 and 0.6 cases per 1000 patient-years, respectively). One additional case of thyroid C-cell hyperplasia in a patient using liraglutide and 1 case of medullary thyroid carcinoma in a patient using the comparator have been reported. The majority of these patients had elevated calcitonin concentrations at baseline (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010). Medulla thyroid carcinoma has also been reported during postmarketing surveillance; however, a causal relationship could not be determined (Prod Info SAXENDA(R) subcutaneous injection solution, 2014).
    3.21.4) ANIMAL STUDIES
    A) ADENOMAS
    1) DULAGLUTIDE
    a) Dose-related and treatment-duration-dependent increases in the incidence of thyroid C-cell adenomas were reported in rats administered subQ dulaglutide at doses equal to or greater than 0.5 mg/kg (7-fold the maximum recommended human dose of 1.5 mg once per week, based on AUC) twice weekly for 2 years (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) EXENATIDE
    a) RATS: During a 104-week carcinogenicity study in male and female rats, benign thyroid C-cell adenomas occurred in the female rats at all doses following administration of subcutaneous exenatide at doses of 18, 70, or 250 mcg/kg/day (up to 130 times the human exposure resulting from the maximum recommended dose of 20 mcg/day) (Prod Info BYETTA(R) subcutaneous injection, 2009).
    3) LIRAGLUTIDE
    a) MICE: During a 104-week carcinogenicity study in male and female CD-1 mice, the incidence of benign thyroid C-cell adenomas was 13% and 19% in males and 6% and 20% in females following liraglutide administration by bolus subcutaneous injection at doses of 1 and 3 mg/kg/day (10 and 45 times the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma AUC comparison). C-cell adenomas were not observed in the control group or in mice treated with liraglutide at doses of 0.03 and 0.2 mg/kg/day (0.2 and 2 times the MRHD based on plasma AUC) (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    b) RATS: During a 104-week carcinogenicity study in male and female Sprague Dawley rats, the incidences of benign thyroid C-cell adenomas were 12%, 16%, 42%, and 46% in males and 10%, 27%, 33%, and 56% in females following liraglutide administration by bolus subcutaneous injection at doses of 0 (control group), 0.075, 0.25, and 0.75 mg/kg/day (0, 0.5, 2, and 8 times the MRHD based on plasma AUC comparison) (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    B) THYROID CARCINOMA
    1) DULAGLUTIDE
    a) Dose-related and treatment-duration-dependent increases in the incidence of thyroid C-cell carcinomas were reported in rats administered subQ dulaglutide at a dose of 5 mg/kg (58-fold the maximum recommended human dose of 1.5 mg once per week, based on AUC) twice weekly for 2 years (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) LIRAGLUTIDE
    a) MICE: During a 104-week carcinogenicity study in male and female CD-1 mice, malignant C-cell carcinomas that were treatment related occurred in 3% of females following liraglutide administration by bolus subcutaneous injection at doses of 3 mg/kg/day (45 times the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma AUC comparison). C-cell tumors are rarely observed during carcinogenicity testing in mice. The liraglutide concentration in the clinical formulation is 10 times higher than the concentration in the formulation used to administer a dose of 3 mg/kg/day to mice in this study (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    b) RATS: During a 104-week carcinogenicity study in male and female Sprague Dawley rats, the incidences of malignant thyroid C-cell adenomas were 2%, 8%, 6%, and 14% of male rats and 0%, 0%, 4%, and 6% in female rats following liraglutide administration by bolus subcutaneous injection at doses of 0 (control group), 0.075, 0.25 and 0.75 mg/kg/day (0, 0.5, 2, and 8 times the MRHD based on plasma AUC comparison). C-cell tumors are rarely observed during carcinogenicity testing in mice (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    C) FIBROSARCOMAS
    1) LIRAGLUTIDE
    a) MICE: During a 104-week carcinogenicity study in male and female CD-1 mice, there was an increase in fibrosarcomas in male rats following liraglutide administration by bolus subcutaneous injection at doses of 3 mg/kg/day (45 times the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma AUC comparison). These fibrosarcomas were attributed to the high local concentration of liraglutide near the injection site. The liraglutide concentration in the clinical formulation is 10 times higher than the concentration in the formulation used to administer a dose of 3 mg/kg/day to mice in this study (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    D) LACK OF EFFECT
    1) DULAGLUTIDE
    a) There was no increased incidence of thyroid C-cell hyperplasia or neoplasia in mice administered subQ dulaglutide for 6 months at doses up to 3 mg/kg twice weekly (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    2) EXENATIDE
    a) MICE: During a 104-week carcinogenicity study in mice, there was no evidence of the occurrence of tumors following subcutaneous exenatide administration at doses up to 250 mcg/kg/day (systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day based on AUC) (Prod Info BYETTA(R) subcutaneous injection, 2009).

Genotoxicity

    A) ALBIGLUTIDE
    1) Genotoxicity studies have not been conducted (Prod Info TANZEUM subcutaneous injection powder, 2014).
    B) DULAGLUTIDE
    1) Genotoxicity studies have not been conducted with dulaglutide (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    C) EXENATIDE
    1) Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay, in the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse micronucleus assay (Prod Info BYETTA(R) subcutaneous injection, 2009).
    D) LIRAGLUTIDE
    1) Liraglutide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay, in a human peripheral blood lymphocyte chromosome aberration test, and in repeat-dose in vivo micronucleus tests in rats (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    E) LIXISENATIDE
    1) Lixisenatide was not mutagenic or clastogenic in the Ames bacterial mutagenicity assay, in a human lymphocyte chromosome aberration test, and a mouse bone marrow micronucleus assay (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor electrolytes and fluid status as indicated in patients with significant gastrointestinal symptoms following exposure.
    B) Monitor serum lipase in patients showing signs and symptoms consistent with pancreatitis.
    C) Hypoglycemic effects are enhanced in patients with concurrent administration of insulin or insulin secretagogues; obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    D) Monitor dermal injection sites for irritation or hypersensitivity reactions.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) All children with inadvertent injections should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent injection of an extra dose who are asymptomatic can be monitored at home. Asymptomatic nondiabetic adults with an inadvertent injection of an extra dose can be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) There is no information on the onset or duration of hypoglycemia after overdose of these patients; however, due to the prolonged half-lives of these agents, patients may need to be monitored for a minimum of 8 to 12 hours if they are also taking insulin or an insulin secretagogue.

Monitoring

    A) Monitor electrolytes and fluid status as indicated in patients with significant gastrointestinal symptoms following exposure.
    B) Monitor serum lipase in patients showing signs and symptoms consistent with pancreatitis.
    C) Hypoglycemic effects are enhanced in patients with concurrent administration of insulin or insulin secretagogues; obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    D) Monitor dermal injection sites for irritation or hypersensitivity reactions.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) These agents are administered subcutaneously. Please refer to the PARENTERAL exposure section for further treatment information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to high protein binding (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010) and large volumes of distribution (Prod Info TANZEUM subcutaneous injection powder, 2014; Prod Info TRULICITY(TM) subcutaneous injection, 2014; Prod Info BYETTA(R) subcutaneous injection, 2011; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010), hemodialysis is unlikely to be of value.

Range Of Toxicity

Summary

    A) TOXICITY: Specific toxic doses for these agents have not been established. EXENATIDE: Severe nausea, vomiting, and hypoglycemia occurred in three patients with type 2 diabetes following subcutaneous administration of 100 mcg (10 times the maximum recommended dose). An adult developed vomiting and weakness without hypoglycemia after 90 mcg exenatide. The patient did have symptoms of nausea, vomiting, and weakness, but never developed low blood sugars. Healthy volunteers did not develop clinical hypoglycemia after a 10 microgram dose subcutaneously. LIRAGLUTIDE: During a clinical trial, an adult inadvertently received 17.4 mg subQ (10 times the recommended dose) of liraglutide and developed severe nausea and vomiting; hypoglycemia was not observed. Recovery was uneventful. Another adult intentionally injected 72 mg subcutaneously and developed severe nausea and vomiting, but did not develop hypoglycemia. LIXISENATIDE: An increased incidence of gastrointestinal effects were noted in type 2 diabetic patients who received doses up to 30 mcg twice daily (3 times the daily recommended dose) during a clinical trial.
    B) THERAPEUTIC DOSE: ALBIGLUTIDE: ADULT: 30 to 50 mg subQ once weekly. DULAGLUTIDE: ADULT: 0.75 to 1.5 mg subQ once weekly. EXENATIDE: ADULT: 5 to 10 mcg subQ twice daily. LIRAGLUTIDE: ADULT: Initial dose: 0.6 mg subQ daily for one week to minimize gastrointestinal symptoms and then increased to 1.2 mg (up to 1.8 mg daily) subQ daily for glycemic control. LIXISENATIDE: The recommended initial dose is 10 mcg subQ once daily for 14 days, increasing to a maintenance dose of 20 mcg subQ once daily starting on day 15.

Therapeutic Dose

    7.2.1) ADULT
    A) ALBIGLUTIDE
    1) The recommended dose is 30 mg once weekly administered subQ. If glycemic response is inadequate, the dose may be increased to 50 mg once weekly (Prod Info TANZEUM subcutaneous injection powder, 2014).
    B) DULAGLUTIDE
    1) The recommended dose is 0.75 mg once weekly administered subQ. If additional glycemic control is necessary, increase the dose to 1.5 mg once weekly. MAX DOSE, 1.5 mg once weekly (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    C) EXENATIDE
    1) The recommended initial dose of exenatide for the treatment of type 2 diabetes is 5 micrograms (mcg) per dose administered subcutaneously twice daily within a 60-minute period before the morning and evening meals (or prior to the 2 main meals of the day, at least 6 hours apart). After 1 month of therapy, the dose may be increased to 10 mcg subcutaneously twice daily (Prod Info BYETTA(R) subcutaneous injection, 2009).
    D) LIRAGLUTIDE
    1) TYPE 2 DIABETES
    a) Initial, 0.6 mg subQ once daily; after 1 week, dose should be increased to 1.2 mg; if glycemic control is inadequate, dose may be increased to 1.8 mg (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    2) OBESITY
    a) Initial, 0.6 mg subQ once daily; increased weekly at 0.6 mg intervals up to 3 mg (Prod Info SAXENDA(R) subcutaneous injection solution, 2014)
    E) LIXISENATIDE
    1) Initial, 10 mcg subQ once daily for 14 days; on Day 15, increase to 20 mcg as the maintenance dose (Prod Info ADLYXIN(TM) subcutaneous injection, 2016)
    7.2.2) PEDIATRIC
    A) ALBIGLUTIDE
    1) Safety and efficacy of albiglutide have not been established in pediatric patients (Prod Info TANZEUM subcutaneous injection powder, 2014).
    B) DULAGLUTIDE
    1) Safety and efficacy of dulaglutide have not been established in pediatric patients (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    C) EXENATIDE
    1) Safety and efficacy of exenatide have not been established in the pediatric population (Prod Info BYETTA(R) subcutaneous injection, 2009).
    D) LIRAGLUTIDE
    1) Safety and efficacy of liraglutide have not been established in the pediatric population, and use in pediatric patients is not recommended (Prod Info SAXENDA(R) subcutaneous injection solution, 2014; Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    E) LIXISENATIDE
    1) Safety and efficacy of lixisenatide have not been established in pediatric patients (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Maximum Tolerated Exposure

    A) EXENATIDE
    1) Severe nausea, vomiting, and hypoglycemia were reported in three patients with type 2 diabetes following subcutaneous administration of single 100 mcg doses of exenatide (10 times the maximum recommended dose). All patients recovered with supportive care (Prod Info BYETTA(R) subcutaneous injection, 2011; Calara et al, 2005).
    2) CASE REPORT: A 40-year-old woman administered 90 mcg of exenatide along with her routine morning diabetes medications in a suicide attempt. She developed nausea, vomiting, and weakness, but never became hypoglycemic nor required supportive dextrose therapy (Cohen et al, 2008).
    3) Healthy volunteers tolerated a 10 mcg dose subQ without developing hypoglycemia (Blase et al, 2005). Infusion of 0.5 picomol/kg/minute caused lower fasting and postprandial glucose levels in volunteers, but did not cause hypoglycemia(Edwards et al, 2001).
    B) LIRAGLUTIDE
    1) During a clinical trial, an adult inadvertently received 17.4 mg subQ (10 time the recommended dose) of liraglutide and developed severe nausea and vomiting; hypoglycemia was not observed. Recovery was uneventful (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    2) CASE REPORT: A 33-year-old woman, with type 2 diabetes, intentionally injected 72 mg of liraglutide subcutaneously and subsequently developed severe nausea and vomiting. Hypoglycemia did not develop (Nakanishi et al, 2013).
    3) CASE REPORT: A 49-year-old woman, with type 2 diabetes mellitus, developed hypoglycemia and severe nausea and vomiting after injecting a 0.6 mg dose of liraglutide 30 times subcutaneously (total dose of 18 mg) instead of the prescribed 0.6 mg SubQ once daily. Her blood glucose concentration was 3.6 mmol/L approximately 1 hour after the overdose, and 2.5 hours post-overdose, the patient was admitted to the hospital where she was given supportive care. After vomiting a total of 19 times, her vomiting stopped approximately 13 hours post-overdose and her mean blood glucose concentration was 10.1 +/- 2.23 mmol/L (ranging from 4.49 to 12.93 mmol/L). She was discharged 24 hours post-admission (Elmehdawi & Elbarsha, 2014).
    C) LIXISENATIDE
    1) An increased incidence of gastrointestinal effects were noted in type 2 diabetic patients who received doses up to 30 mcg twice daily (3 times the daily recommended dose) during a clinical trial (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Workplace Standards

    A) ACGIH TLV Values for CAS141758-74-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS204656-20-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS141758-74-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS204656-20-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS141758-74-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS204656-20-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS141758-74-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS204656-20-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DULAGLUTIDE
    1) Dulaglutide is a glucagon-like peptide (GLP-1) receptor agonist. Insulin release is stimulated in a glucose-dependent manner via activation of GLP-1 receptors on pancreatic beta cells. Dulaglutide is 90% homologous with endogenous human GLP-1. Glucagon secretion is also reduced and gastric emptying is delayed (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    B) EXENATIDE
    1) Exenatide (synthetic exendin-4) is a 39-amino acid peptide with antidiabetic activity. It is an agonist at the GLP-1 receptor (Giannoukakis, 2003; Nielsen & Baron, 2003; Doyle & Egan, 2001) and produces effects similar to GLP-1; many (or all) antidiabetic actions of exenatide appear related to binding to the GLP-1 receptor (Kolterman et al, 2003). However, all observed pharmacodynamic effects of exenatide have not been consistent with those of GLP-1, and some investigators suggest that exenatide may also produce some actions via a functionally different receptor (Dungan & Buse, 2005; Nielsen et al, 2004; Nielsen & Baron, 2003; Kolterman et al, 2003). There is some evidence of the efficacy of exenatide in systems lacking the GLP-1 receptor (Giannoukakis, 2003).
    2) Actions of exenatide have included enhancement of insulin secretion (glucose-dependent), glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, reduction of food intake, promotion of beta-cell proliferation and neogenesis, reduction of food intake, promotion of beta-cell proliferation and neogenesis, reduction in adiposity, and insulin-sensitizing effects (animal models) (Nielsen et al, 2004; Nielsen & Baron, 2003; Giannoukakis, 2003; Kolterman et al, 2003). Studies with GLP-1 have demonstrated triggering of hepatic vagal afferents (intraportal infusion) and suppression of gastric acid secretion, whereas neither of these effects were seen with exendin-4 (Kolterman et al, 2003; Nielsen & Baron, 2003). In contrast, differentiated 3T3-L1 adipocytes were sensitized to insulin-dependent glucose uptake by exendin-4 but not GLP-1 (Nielsen & Baron, 2003).
    3) Natural exendin-4 was first isolated from the saliva of Heloderma suspectum (Gila monster). It shares 53% amino acid-sequence overlap with mammalian GLP-1, but is not an analog of GLP-1 (e.g. exenatide is not a modified GLP-1) (Dungan & Buse, 2005; Nielsen et al, 2004; Nielsen & Baron, 2003); exendin-4 is a gene product distinct from that of GLP-1 (Drucker, 2001). Unlike GLP-1, exenatide is relatively resistant to degradation by dipeptidyl peptidase IV; it has a longer half-life, which confers substantially greater in vivo potency compared to GLP-1 (Kolterman et al, 2003; Drucker, 2001).
    4) In healthy subjects, an intravenous infusion of exenatide, 0.05 picomol/kilogram/minute, significantly decreased fasting plasma glucose levels and decreased the peak change of postprandial glucose relative to baseline values in a placebo-controlled study; a delay in gastric emptying and reduced caloric intake were seen with exenatide (Edwards et al, 2001). Exenatide has been demonstrated to be a potent insulinotropic agent in both non-diabetic patients and patients with type 2 diabetes (Egan et al, 2002).
    C) LIRAGLUTIDE
    1) Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist that is able to activate the GLP-1 receptor. It has the ability to increase intracellular cyclic AMP (cAMP) leading to an increase in insulin release in the presence of an elevated glucose concentration. Liraglutide also the ability to reduce glucagon secretion in a glucose-dependent manner, as well as delay gastric emptying (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).

Physicochemical

Physical Characteristics

    A) ALBIGLUTIDE lyophilized powder is white to yellow in color. The solvent is a clear, colorless solution. Reconstituted solutions are yellow in color (Prod Info TANZEUM subcutaneous injection powder, 2014).
    B) DULAGLUTIDE is a sterile, clear, colorless solution (Prod Info TRULICITY(TM) subcutaneous injection, 2014).
    C) EXENATIDE is a clear, colorless solution (Prod Info BYETTA(R) subcutaneous injection, 2009).
    D) LIRAGLUTIDE is a clear, colorless solution (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010).
    E) LIXISENATIDE is a clear, colorless solution (Prod Info ADLYXIN(TM) subcutaneous injection, 2016).

Ph

    A) EXENATIDE: 4.5 (Prod Info BYETTA(R) subcutaneous injection, 2009)

Molecular Weight

    A) ALBIGLUTIDE: 72,970 daltons (Prod Info TANZEUM subcutaneous injection powder, 2014)
    B) DULAGLUTIDE: 63 kilodaltons (Prod Info TRULICITY(TM) subcutaneous injection, 2014)
    C) EXENATIDE: 4186.6 daltons (Prod Info BYETTA(R) subcutaneous injection, 2009)
    D) LIRAGLUTIDE: 3751.2 daltons (Prod Info VICTOZA(R) solution for subcutaneous injection, 2010)
    E) LIXISENATIDE: 4858.5 (Prod Info ADLYXIN(TM) subcutaneous injection, 2016)

References

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