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Insulin Degludec And Liraglutide

FDA Drug Information • Also known as: Xultophy 100/3.6

Brand Names
Xultophy 100/3.6
Drug Class
Insulin Analog [EPC], GLP-1 Receptor Agonist [EPC]
Route
SUBCUTANEOUS
Dosage Form
INJECTION, SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: 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 at clinically relevant exposures in both genders of rats and mice. It is unknown whether XULTOPHY 100/3.6 causes 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 [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13 )] .
  • XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning.
  • Liraglutide, one of the components of XULTOPHY 100/3.6, causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether XULTOPHY 100/3.6 causes 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. ( 5.1 , 13.1 )
  • XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors. ( 4 , 5.1 )

    • Description

    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...

    What Is Insulin Degludec And Liraglutide Used For?

    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.

    • Dosage and Administration

    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...

    • Side Effects (Adverse Reactions)

    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...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Drugs that affect glucose metabolism : Adjustment of XULTOPHY 100/3.6 dosage may be needed; closely monitor blood glucose. ( 7.1 )
  • Anti-Adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced or absent. ( 7.1 )
  • Effects of delayed gastric emptying on oral medications : May impact absorption of concomitantly administered oral medications. ( 7.2 ) 7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of XULTOPHY 100/3.6 and particularly close monitoring [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 )]. Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. 7.2 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide-containing products, including XULTOPHY 100/3.6, cause a delay of gastric emptying, and thereby have the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide containing products.

    • Contraindications

    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 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide during pregnancy. XULTOPHY 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no available data with XULTOPHY 100/3.6, insulin degludec or liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). For insulin degludec, rats and rabbits were exposed in animal reproduction studies at 5 times (rat) and 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. No adverse outcomes were observed for pregnant animals and offspring (see Data) . For liraglutide, animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pregestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal...

    Overdosage

    10 OVERDOSAGE Hypoglycemia (from insulin and liraglutide) and gastrointestinal adverse reactions (from liraglutide) may develop if a patient is dosed with more XULTOPHY 100/3.6 than required. An excess of insulin-containing products like XULTOPHY 100/3.6 relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.6 , 5.10 )] . Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the drug dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately. Overdoses have been reported in clinical trials and postmarketing use of liraglutide, one of the components of XULTOPHY 100/3.6. Effects have included severe nausea and severe vomiting. In the event of overdosage, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied XULTOPHY 100/3.6 (insulin degludec and liraglutide) injection is an injection supplied as a clear, colorless solution in a 3 mL prefilled, disposable, single-patient-use pen injector. The XULTOPHY 100/3.6 pen dials in one-unit increments. Dosage Unit/Strength Package size NDC # 3 mL single-patient-use XULTOPHY 100/3.6 pen (100 units/mL insulin degludec and 3.6 mg/mL liraglutide) Package of 5 0169-2911-15 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Prior to first use, XULTOPHY 100/3.6 should be stored between 36°F to 46°F (2°C and 8°C) until the expiration date printed on the label. Store prefilled pens in the carton so they will stay clean and protected from light. Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use XULTOPHY 100/3.6 if it has been frozen. After first use, the XULTOPHY 100/3.6 pen can be stored for 21 days at controlled room temperature 59°F to 86°F (15°C to 30°C) or in a refrigerator 36°F to 46°F (2°C to 8°C). Keep all XULTOPHY 100/3.6 pens away from direct heat and light. Always remove the needle after each injection and store the XULTOPHY 100/3.6 pen without a needle attached. This prevents contamination and/or infection, or leakage of the XULTOPHY 100/3.6 pen, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination. The storage conditions are summarized in Table 11 : Table 11. Storage Conditions for XULTOPHY 100/3.6 Pen Prior to first use After first use Refrigerated 36°F to 46°F (2°C to 8°C) Room Temperature 59°F to 86°F (15°C to 30°C) Refrigerated 36°F to 46°F (2°C to 8°C) Until expiration date 21 Days

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.