Insulin Degludec And Liraglutide

Prescription

ชื่อทางการค้า: Xultophy 100/3.6

รูปแบบยา

Injection

เส้นทางการให้ยา

SUBCUTANEOUS

ผู้ผลิต

Novo Nordisk

About This Medication

11 DESCRIPTION Insulin degludec Insulin degludec is a long-acting basal human insulin analog. Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached (chemical name: LysB29(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin). Insulin degludec has a molecular formula of C 274 H 411 N 65 O 81 S 6 and a molecular weight of 6.104 kDa. It has the following structure: Figure 1. Structural Formula of Insulin degludec Liraglutide Liraglutide is an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae , has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C 172 H 265 N 43 O 51 and the molecular weight is 3.751 kDa. It has the following structure: Figure 2. Structural Formula of Liraglutide XULTOPHY 100/3.6 (insulin degludec and liraglutide) injection, for subcutaneous use, is a combination of a long-acting basal human insulin analog, insulin degludec, and a GLP-1 receptor agonist, liraglutide. XULTOPHY 100/3.6 is a sterile, aqueous, clear, and colorless solution. Each prefilled pen contains 3 mL equivalent to 300 units insulin degludec and 10.8 mg liraglutide. Each mL contains 100 units insulin degludec and 3.6 mg liraglutide. XULTOPHY 100/3.6 contains the following inactive ingredients per mL: glycerol (19.7 mg), phenol (5.7 mg), zinc (55 mcg), and Water for Injection, USP. XULTOPHY 100/3.6 has a pH of approximately 8.15. Hydrochloric acid or sodium hydroxide may be added to adjust pH. figure_1 figure_2

ส่วนประกอบออกฤทธิ์

ส่วนประกอบ	ความแรง
Insulin Degludec	-
Liraglutide	-

ข้อบ่งใช้และการใช้งาน

1 INDICATIONS AND USAGE XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: • XULTOPHY 100/3.6 contains liraglutide. Coadministration with any other product containing liraglutide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions ( 5.5 )]. • XULTOPHY 100/3.6 is not recommended for the treatment of diabetic ketoacidosis. • XULTOPHY 100/3.6 has not been studied in combination with prandial insulin. XULTOPHY 100/3.6 is a combination of insulin degludec, a long-acting human insulin analog, and liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use : ( 1 ) • Coadministration with any other product containing liraglutide or another GLP-1 receptor agonist is not recommended. • Not recommended for the treatment of diabetic ketoacidosis. • Has not been studied in combination with prandial insulin.

กลไกการทำงาน

12.1 Mechanism of Action XULTOPHY 100/3.6 XULTOPHY 100/3.6 is a combination product consisting of insulin degludec and liraglutide. Insulin degludec The primary activity of insulin degludec is the regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. Liraglutide Liraglutide is a GLP-1 receptor agonist that increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.

ขนาดยาและวิธีการให้ยา

2 DOSAGE AND ADMINISTRATION • Administer once-daily at same time each day with or without food. ( 2.1 ) • XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection ( 2.1 , 2.2 ); each XULTOPHY 100/3.6 dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide. ( 2.1 ) • Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide). ( 2.1 ) • Recommended starting dosage in patients naïve to basal insulin or GLP-1 receptor agonist is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily. (2.2 ) • Discontinue therapy with liraglutide or basal insulin prior to initiation of XULTOPHY 100/3.6. ( 2.2 ) • Recommended starting dosage in patients currently on basal insulin or GLP-1 receptor agonist is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily. ( 2.2 ) • See Full Prescribing Information for titration recommendations. ( 2.3 ) • Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen. ( 2.5 ) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.5 ) • Do not administer intravenously or by an infusion pump. ( 2.5 ) • Do not dilute or mix with any other insulin products or solutions. ( 2.5 ) 2.1 Important Dosage Information • XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide. • Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food. • The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection. Table 1 presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6 [see Dosage and Administration ( 2.2 )]. • The maximum dosage of XULTOPHY 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide) [see Warnings and Precautions ( 5.5 )] . 2.2 Recommended Starting Dosage In patients naïve to basal insulin or a GLP-1 receptor agonist • The recommended starting dosage of XULTOPHY 100/3.6 is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). In patients currently on basal insulin or a GLP-1 receptor agonist • Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6. • The recommended starting dosage of XULTOPHY 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6 XULTOPHY 100/3.6 (dose counter display) * insulin degludec component dose liraglutide component dose Comment ▪▪ ─ --- --- Priming symbol 10 10 units 0.36 mg Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist 11 11 units 0.4 mg 12 12 units 0.43 mg 13 13 units 0.47 mg 14 14 units 0.5 mg 15 15 units 0.54 mg 16 16 units 0.58 mg Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist 17 17 units 0.61 mg 18 18 units 0.65 mg 19 19 units 0.68 mg 20 20 units 0.72 mg 21 21 units 0.76 mg 22 22 units 0.79 mg 23 23 units 0.83 mg 24 24 units 0.86 mg 25 25 units 0.9 mg 26 26 units 0.94 mg 27 27 units 0.97 mg 28 28 units 1.01 mg 29 29 units 1.04 mg 30 30 units 1.08 mg 31 31 units 1.12 mg 32 32 units 1.15 mg 33 33 units 1.19 mg 34 34 units 1.22 mg 35 35 units 1.26 mg 36 36 units 1.3 mg 37 37 units 1.33 mg 38 38 units 1.37 mg 39 39 units 1.4 mg 40 40 units 1.44 mg 41 41 units 1.48 mg 42 42 units 1.51 mg 43 43 units 1.55 mg 44 44 units 1.58 mg 45 45 units 1.62 mg 46 46 units 1.66 mg 47 47 units 1.69 mg 48 48 units 1.73 mg 49 49 units 1.76 mg 50 50 units 1.8 mg Maximum daily dosage [see Warnings and Precautions (5.5)] * The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units. 2.3 Titration of XULTOPHY 100/3.6 • After starting the recommended starting dosage of XULTOPHY 100/3.6 [see Dosage and Administration ( 2.2 )] , titrate the dosage upwards or downwards by two units (see Table 2 ) once weekly or twice weekly (every three to four days), based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal until the desired fasting plasma glucose is achieved. • To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or renal or hepatic function; during acute illness; or when used with other medications [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Table 2. Recommended Titration of XULTOPHY 100/3.6 (Once or Twice Weekly) Self-Monitored Fasting Plasma Glucose XULTOPHY 100/3.6 Dosage Adjustment Above target range + 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) Within target range 0 units Below target range - 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) 2.4 Recommendations Regarding Missed Doses • Instruct patients who miss a dose of XULTOPHY 100/3.6 to resume the once-daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than three days have elapsed since the last XULTOPHY 100/3.6 dose, reinitiate XULTOPHY 100/3.6 at the recommended starting dose to mitigate the risk of gastrointestinal adverse reactions associated with reinitiation of treatment [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . 2.5 Important Administration Instructions • The XULTOPHY 100/3.6 pen is for single-patient-use only [see Warnings and Precautions ( 5.3 )]. • Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6. • Always check the label on the XULTOPHY 100/3.6 pen before administration [see Warnings and Precautions ( 5.5 )]. • Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless. • Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen. • Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 , 6.3 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.4 )]. • Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • The XULTOPHY 100/3.6 pen dials in one-unit increments. • Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump. • Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions. • Do not split the dose of XULTOPHY 100/3.6.

Side Effects Overview

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.6 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.7 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.8 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.10 )] • Hypokalemia [see Warnings and Precautions ( 5.11 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.13 )] • Most common adverse reactions (incidence ≥5%) in clinical trials are nasopharyngitis, headache, nausea, diarrhea, increased lipase and upper respiratory tract infection. ( 6 ) • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. XULTOPHY 100/3.6 The data in Table 3 reflect the exposure of 1881 patients to XULTOPHY 100/3.6 and a mean duration of exposure of 33 weeks in trials NCT01336023, NCT01618162, NCT02773368, NCT01676116, NCT01392573, NCT01952145 [see Clinical Studies ( 14.2 and 14.3 )] . The mean age was 57 years and 3% were older than 75 years; 53% were male, 75% were White, 6% were Black or African American and 16% were Hispanic or Latino. The mean body mass index (BMI) was 31.8 kg/m 2 . The mean duration of diabetes was 9 years and the mean HbA 1c at baseline was 8.2%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 25%, 12%, 7% and 6% respectively. The mean estimated glomerular filtration rate (eGFR) at baseline was 88.3 mL/min/1.73 m 2 and 6% of the patients had an eGFR less than 60 mL/min/1.73 m 2 . Table 3: Adverse Reactions Occurring in ≥5% of XULTOPHY 100/3.6-Treated Patients with Type 2 Diabetes Mellitus XULTOPHY 100/3.6 N = 1881 % Nasopharyngitis 10 Headache 9 Nausea 8 Diarrhea 8 Increased Lipase 7 Upper respiratory tract infection 6 Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin and insulin containing products, including XULTOPHY 100/3.6 [see Warnings and Precautions ( 5.6 )]. The number of reported hypoglycemia episodes depended on the definition of hypoglycemia used, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for XULTOPHY 100/3.6 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. In the phase 3 clinical program [see Clinical Studies ( 14 )] , events of severe hypoglycemia were defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions ( Table 4 ). Hypoglycemia episodes with a glucose level below 54 mg/dL associated with or without symptoms is shown in Table 4 . No clinically important differences in risk of severe hypoglycemia between XULTOPHY 100/3.6 and comparators were observed in clinical trials. Table 4. Hypoglycemia Episodes Reported in XULTOPHY 100/3.6-Treated Patients with T2DM † Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Patients naïve to basal insulin or GLP-1 receptor agonist Patients currently on GLP-1 receptor agonist Patients currently on basal insulin XULTOPHY 100/3.6 NCT01336023 XULTOPHY 100/3.6 NCT01618162 XULTOPHY 100/3.6 NCT02773368 XULTOPHY 100/3.6 NCT01676116 XULTOPHY 100/3.6 NCT01392573 XULTOPHY 100/3.6 NCT01952145 Total Subjects (N) 825 288 209 291 199 278 Severe Hypoglycemia (%)† 0.2 0.7 0.5 0.3 0.5 0 Hypoglycemia with a glucose level <54 mg/dL (%)* 27.6 37.2 14.4 27.1 22.1 24.8 * Episodes of hypoglycemia with a glucose level below 54 mg/dL that are associated with or without symptoms of hypoglycemia. Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, eructation, gastroesophageal reflux disease, abdominal distension and decreased appetite have been reported in patients treated with XULTOPHY 100/3.6. In a XULTOPHY 100/3.6 clinical trial severe gastrointestinal adverse reactions were reported among patients receiving XULTOPHY 100/3.6 (0.8%) and patients receiving the active comparators liraglutide (2.9%) and insulin degludec (0.2%) [see Clinical Studies ( 14.2 )] . Gastrointestinal adverse reactions may occur more frequently at the beginning of XULTOPHY 100/3.6 therapy and diminish within a few days or weeks on continued treatment. Papillary thyroid carcinoma Liraglutide In glycemic control trials of liraglutide, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis Liraglutide In glycemic control trials of liraglutide, there have been 13 cases of pancreatitis among liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis Liraglutide In glycemic control trials of liraglutide, the incidence of cholelithiasis was 0.3% in both liraglutide-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide treated and placebo-treated patients. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , the incidence of cholelithiasis was 1.5% (3.9 cases per 1,000 patient years of observation) in liraglutide-treated and 1.1% (2.8 cases per 1,000 patient years of observation) in placebo-treated patients, both on a background of standard of care. The incidence of acute cholecystitis was 1.1% (2.9 cases per 1,000 patient years of observation) in liraglutide-treated and 0.7% (1.9 cases per 1,000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Initiation of insulin containing products and intensification of glucose control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-term use of insulin containing products, including XULTOPHY 100/3.6, can cause lipodystrophy at the site of repeated injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect absorption [see Dosage and Administration ( 2.5 )] . Peripheral Edema XULTOPHY 100/3.6 may cause sodium retention and edema, particularly if previously poor metabolic control is improved rapidly by intensified therapy. Weight Gain Weight gain can occur with insulin containing products, including XULTOPHY 100/3.6, and has been attributed to the anabolic effects of insulin. In study A, after 26 weeks of treatment, patients converting to XULTOPHY 100/3.6 from liraglutide had a mean increase in body weight of 2 kg. Injection Site reactions As with any insulin and GLP-1 receptor agonist-containing products, patients taking XULTOPHY 100/3.6 may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, the proportion of injection site reactions occurring in patients treated with XULTOPHY 100/3.6 was 2.6%. These reactions were usually mild and transitory and they normally disappear during continued treatment. Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including XULTOPHY 100/3.6 and may be life threatening [see Warnings and Precautions ( 5.8 )] . Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported. Laboratory tests Bilirubin Liraglutide In the five glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin XULTOPHY 100/3.6 Calcitonin, a biological marker of MTC, was measured throughout the XULTOPHY 100/3.6 clinical development program. Among patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of XULTOPHY 100/3.6-treated patients, 0.7% of placebo-treated patients, and 1.1% and 0.7% of active-comparator-treated patients (basal insulins and GLP-1s respectively). The clinical significance of these findings is unknown. Liraglutide Calcitonin, a biological marker of MTC, was measured throughout the liraglutide clinical development program. At the end of the glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase Liraglutide In one glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , serum lipase and amylase were routinely measured. Among liraglutide-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of liraglutide-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )] . Vital signs Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed with XULTOPHY 100/3.6 which is attributable to the liraglutide component. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use. Because these events 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. Insulin degludec Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Liraglutide • Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, and nausea, vomiting and diarrhea leading to dehydration, intestinal obstruction, severe constipation including fecal impaction • Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Hypersensitivity: Angioedema, anaphylactic reactions, rash, pruritus • Neoplasms: Medullary thyroid carcinoma • Neurologic: Dysgeusia, dysesthesia, dizziness • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. • Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine • Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

คำเตือนและข้อควรระวัง

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never share a XULTOPHY 100/3.6 pen between patients, even if the needle is changed. ( 5.3 ) • Hyperglycemia or hypoglycemia with changes in insulin regimen : Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.4 ) • Overdose due to medication errors : XULTOPHY 100/3.6 contains two drugs. Instruct patients to check label before injection since accidental mix-ups with insulin containing products can occur. Do not exceed the maximum dose or administer with other GLP-1 receptor agonists. ( 5.5 ) • Hypoglycemia: May be life-threatening. Increase monitoring with changes to : dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.6 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.7 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. ( 5.8 ) • Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur. If a hypersensitivity reaction occurs, discontinue and treat per standard of care. ( 5.9 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.10 ) • Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.11 ) • Fluid retention and congestive heart failure with use of thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.12 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.13 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6 )]. After initiation of XULTOPHY 100/3.6, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue XULTOPHY 100/3.6 and initiate appropriate management. 5.3 Never Share a XULTOPHY 100/3.6 Pen Between Patients XULTOPHY 100/3.6 pen must never be shared between patients, even if the needle is changed. Sharing of the pen poses a risk for transmission of blood-borne pathogens. 5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.6 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6.1 , 6.3 )]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. Adjustments in concomitant oral anti-diabetic treatment may be needed. When initiating XULTOPHY 100/3.6, follow dosing recommendations [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . 5.5 Overdose due to Medication Errors XULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. Administration of more than 50 units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Do not exceed the 1.8 mg maximum recommended dose of liraglutide or use with other GLP-1 receptor agonists. Accidental mix-ups between insulin products have been reported. To avoid medication errors between XULTOPHY 100/3.6 (an insulin containing product) and other insulin products, instruct patients to always check the label before each injection. 5.6 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin containing products, including XULTOPHY 100/3.6 [see Adverse Reactions ( 6.1 )] . Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). XULTOPHY 100/3.6 (an insulin-containing product) or any insulin, should not be used during episodes of hypoglycemia [see C ontraindications ( 4 ) ] . Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7.1 ) ] , or who experience recurrent hypoglycemia. The long-acting effect of insulin degludec may delay recovery from hypoglycemia compared to shorter acting insulins. Risk Factors for Hypoglycemia The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology ( 12.2 )] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin containing products, the glucose lowering effect time course of XULTOPHY 100/3.6 may vary among different patients or at different times in the same patients and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions ( 7.1 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.7 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )]. Monitor renal function in patients reporting adverse reactions to XULTOPHY 100/3.6 that could lead to volume depletion, especially during dosage initiation and escalation of XULTOPHY 100/3.6. 5.8 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, one of the components of XULTOPHY 100/3.6, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )]. In a XULTOPHY 100/3.6 clinical trial severe gastrointestinal adverse reactions were reported among patients receiving XULTOPHY 100/3.6 (0.8 %) and patients receiving the active comparators liraglutide (2.9%) and insulin degludec (0.2%) [see Clinical Studies ( 14.2 )] . Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. 5.9 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including XULTOPHY 100/3.6. Allergic reactions (manifested with signs and symptoms such as urticaria, rash, pruritus) have been reported with XULTOPHY 100/3.6. There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue XULTOPHY 100/3.6; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with XULTOPHY 100/3.6. XULTOPHY 100/3.6 is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, liraglutide or one of the excipients of these products [see Contraindications (4) ]. 5.10 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , 3.1% of patients treated with liraglutide, one of the components of XULTOPHY 100/3.6, versus 1.9% of placebo treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis [see Adverse Reactions ( 6.1 )] . If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.11 Hypokalemia All insulin-containing products, including XULTOPHY 100/3.6, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.12 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, when used in combination with insulin containing products, including XULTOPHY 100/3.6. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin containing products, including XULTOPHY 100/3.6 and a PPAR-gamma agonist should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 5.13 Pulmonary Aspiration During General Anesthesia or Deep Sedation XULTOPHY 100/3.6 delays gastric emptying [see Clinical Pharmacology ( 12.1 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking XULTOPHY 100/3.6, including whether modifying preoperative fasting recommendations or temporarily discontinuing XULTOPHY 100/3.6 could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking XULTOPHY 100/3.6.

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4 CONTRAINDICATIONS XULTOPHY 100/3.6 is contraindicated: • In patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . • During episodes of hypoglycemia [see Warnings and Precautions ( 5.6 )] . • In patients with hypersensitivity to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide, one of the components of XULTOPHY 100/3.6 [see Warnings and Precautions ( 5.9 )]. • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 ) • During episodes of hypoglycemia ( 4 ) • Patients with a serious hypersensitivity reaction to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6 ( 4 )

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12.3 Pharmacokinetics Overall, the pharmacokinetics of insulin degludec and liraglutide were not affected in a clinically relevant manner when administered as XULTOPHY 100/3.6. Absorption In patients with type 2 diabetes mellitus (mean body weight 87.5 kg) reaching the maximum daily dose (50 units/1.8 mg) of XULTOPHY 100/3.6, the estimated mean steady-state exposure (AUC 0-24 h) of insulin degludec was 113 h*nmol/L and of liraglutide 1227 h*ng/mL based on population pharmacokinetic analysis. The corresponding maximum concentrations were 5196 pmol/L for insulin degludec and 55 ng/mL for liraglutide. Steady state concentrations of insulin degludec and liraglutide are reached after 2-3 days of daily administration. Distribution Insulin degludec and liraglutide are extensively bound to plasma proteins >99% and >98%, respectively. Elimination The half-life of insulin degludec is approximately 25 hours and the half-life of liraglutide is approximately 13 hours. Metabolism Insulin degludec Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive. Liraglutide During the initial 24 hours following administration of a single [ 3 H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination. Specific Populations Geriatric Patients Age had no clinically relevant effect on the pharmacokinetics of XULTOPHY 100/3.6 based on results from a population pharmacokinetic analysis including adult patients up to 83 years treated with XULTOPHY 100/3.6 [see Use in Specific Populations ( 8.5 )] . Male and Female Patients There were no clinically relevant differences in the pharmacokinetics of XULTOPHY 100/3.6 in male and female patients, based on results from a population pharmacokinetic analysis. Racial or Ethnic Groups There were no clinically relevant differences in the pharmacokinetics of XULTOPHY 100/3.6 between the racial and ethnic groups investigated, based on results from a population pharmacokinetic analysis. Body weight The effect of body weight on the exposure level of the components of XULTOPHY 100/3.6 was investigated in the population pharmacokinetic analysis. Exposure levels decreased with increase in baseline body weight for both insulin degludec and liraglutide. Patients with Renal Impairment XULTOPHY 100/3.6 There is limited experience with XULTOPHY 100/3.6 in patients with mild and moderate renal impairment. XULTOPHY 100/3.6 has not been studied in patients with severe renal impairment [see Warnings and Precautions ( 5.7 )]. Insulin degludec Insulin degludec has been studied in a pharmacokinetic study in 32 subjects (n=6/group) with normal or impaired renal function/end-stage renal disease following administration of a single dose (0.4 U/kg) of insulin degludec. Renal function was defined using creatinine clearance (Clcr) as follows: >80 mL/min (normal), 50-80 mL/min (mild), 30-50 mL/min (moderate) and <30 mL/min (severe). Subjects requiring dialysis were classified as having end-stage renal disease (ESRD). Total exposure (AUC IDeg,0-120h,SD ) of insulin degludec was similar in subjects with normal and impaired renal function. No clinically relevant difference in the pharmacokinetics of insulin degludec was identified between healthy subjects and subjects with renal impairment. Hemodialysis did not affect clearance of insulin degludec (CL/F IDeg,SD ) in subjects with ESRD [see Warnings and Precautions ( 5.7 )] . Liraglutide The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance <30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Warnings and Precautions ( 5.7 )] . Patients with Hepatic Impairment XULTOPHY 100/3.6 XULTOPHY 100/3.6 has not been studied in patients with hepatic impairment. Insulin degludec Insulin degludec has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with normal or impaired hepatic function (mild, moderate, and severe hepatic impairment) following administration of a single dose (0.4 U/kg) of insulin degludec. Hepatic function was defined using Child-Pugh Scores ranging from 5 (mild hepatic impairment) to 15 (severe hepatic impairment). No clinically relevant differences in the pharmacokinetics of insulin degludec were identified between healthy subjects and subjects with hepatic impairment [see Hepatic Impairment ( 8.7 )] . Liraglutide The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score >9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively. Drug Interaction Studies In vitro assessment of drug-drug interactions In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction and protein binding is low for both the liraglutide and insulin degludec components of XULTOPHY 100/3.6. The delay of gastric emptying with liraglutide one of the components of XULTOPHY 100/3.6 may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption. In vivo assessment of drug-drug interactions Liraglutide The drug-drug interaction studies were performed at steady state with liraglutide 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that C max of liraglutide (8-12 h) would coincide with the absorption peak of the coadministered drugs. Digoxin A single dose of digoxin 1 mg was administered 7 hours after the dose of liraglutide at steady state. The concomitant administration with liraglutide resulted in a reduction of digoxin AUC by 16%; C max decreased by 31%. Digoxin median time to maximal concentration (T max ) was delayed from 1 h to 1.5 h. Lisinopril A single dose of lisinopril 20 mg was administered 5 minutes after the dose of liraglutide at steady state. The co-administration with liraglutide resulted in a reduction of lisinopril AUC by 15%; C max decreased by 27%. Lisinopril median T max was delayed from 6 h to 8 h with liraglutide. Atorvastatin Liraglutide did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of liraglutide at steady state. Atorvastatin C max was decreased by 38% and median T max was delayed from 1 to 3 hours with liraglutide. Acetaminophen Liraglutide did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1,000 mg, administered 8 hours after the dose of liraglutide at steady state. Acetaminophen C max was decreased by 31% and median T max was delayed up to 15 minutes. Griseofulvin Liraglutide did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with liraglutide at steady state. Griseofulvin C max increased by 37% while median T max did not change. Oral Contraceptives A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of liraglutide at steady state. Liraglutide lowered ethinylestradiol and levonorgestrel C max by 12% and 13%, respectively. There was no effect of liraglutide on the overall exposure (AUC) of ethinylestradiol. Liraglutide increased the levonorgestrel AUC 0-∞ by 18%. Liraglutide delayed T max for both ethinylestradiol and levonorgestrel by 1.5 hours.

Frequently Asked Questions

1 INDICATIONS AND USAGE XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: • XULTOPHY 100/3.6 contains liraglutide. Coadministration with any other product containing liraglutide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions ( 5.5 )]. • XULTOPHY 100/3.6 is not recommended for the treatment of diabetic ketoacidosis. • …

2 DOSAGE AND ADMINISTRATION • Administer once-daily at same time each day with or without food. ( 2.1 ) • XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection ( 2.1 , 2.2 ); each XULTOPHY 100/3.6 dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide. ( 2.1 ) • Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide). ( 2.1 ) • Recommended starting …

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never share a XULTOPHY 100/3.6 pen between patients, even if the needle is changed. ( 5.3 ) • Hyperglycemia or hypoglycemia with changes in insulin regimen : Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased …

4 CONTRAINDICATIONS XULTOPHY 100/3.6 is contraindicated: • In patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . • During episodes of hypoglycemia [see Warnings and Precautions ( 5.6 )] . • In patients with hypersensitivity to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been …

Insulin Degludec And Liraglutide is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Insulin Degludec And Liraglutide drug label (National Library of Medicine)
• openFDA — Insulin Degludec And Liraglutide label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 1860167 (NLM Normalized Drug Names)
• NDC Directory — Insulin Degludec And Liraglutide (FDA National Drug Code)

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