Drug Safety-related Labeling Changes (SrLC)

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XULTOPHY 100/3.6 (BLA-208583)

(INSULIN DEGLUDEC; LIRAGLUTIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/14/2025 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

Additions and/or revisions underlined:

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.

5.8 Severe Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

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.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

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

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Acute Pancreatitis

Inform patients of the potential risk for pancreatitis acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by nausea or vomiting. Instruct patients to discontinue XULTOPHY 100/3.6 promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)].

. . .

05/28/2025 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

Subsection title revised

Additions and/or revisions underlined:

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 pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue XULTOPHY 100/3.6 and initiate appropriate management.

 

5.7 Acute Kidney Injury Due to Volume Depletion

Subsection title revised

Additions and/or revisions underlined

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

Newly added subsection

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)]. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis.

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

• Acute Pancreatitis [see Warnings and Precautions (5.2)]

. . .

• Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.7)]

• Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.8)]

. . .

 

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

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.

. . .

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 1000 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.

 

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

• Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, and nausea, vomiting and diarrhea leading to dehydration

. . .

• Hypersensitivity: Angioedema, anaphylactic reactions, rash, pruritus

• Neoplasms: Medullary thyroid carcinoma

• Neurologic: Dysgeusia, dysesthesia, dizziness

. . .

• Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine

• Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Acute Pancreatitis

Inform patients of the potential risk for pancreatitis acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue XULTOPHY 100/3.6 promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)].

. . .

Acute Kidney Injury Due to Volume Depletion

Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings

and Precautions (5.7)].

 

Severe Gastrointestinal Adverse Reactions

Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.8)].

. . .

Missed Dose

Inform patients not to take an extra dose of XULTOPHY 100/3.6 or increase the dose to make up for the missed dose. 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. 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 reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. XULTOPHY 100/3.6 should be titrated at the direction of a healthcare provider [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

 

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

• XULTOPHY 100/3.6 is an injectable prescription medicine that contains 2 diabetes medicines, insulin degludec,100 units/mL, and liraglutide, 3.6 mg/mL that is used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes mellitus.

• XULTOPHY 100/3.6 is not recommended as the first choice of medicine for treating diabetes.

• XULTOPHY 100/3.6 is not recommended for people who take liraglutide or other medicines called glucagon-like peptide-1 (GLP-1) receptor agonists.

• Do not use XULTOPHY 100/3.6 if:

. . .

Do not use XULTOPHY 100/3.6 if:

. . .

• you are allergic to insulin degludec, liraglutide or any of the ingredients in XULTOPHY 100/3.6. See the end of this Medication Guide for a complete list of ingredients in XULTOPHY 100/3.6. See “What are the possible side effects of XULTOPHY 100/3.6?” for symptoms of a serious allergic reaction.

. . .

• If you take too much XULTOPHY 100/3.6, call your healthcare provider or the Poison Help line at 1-800- 222-1222 or go to the nearest hospital emergency room right away

. . .

• dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Tell your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away.

• severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use XULTOPHY 100/3.6. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

. . .

11/01/2024 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Pulmonary Aspiration During General Anesthesia or Deep Sedation

Newly added information:

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.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.12)]

6.2 Postmarketing Experience

Newly added information:

…

• Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

…

Pulmonary Aspiration During General Anesthesia or Deep Sedation

Inform patients that XULTOPHY 100/3.6 may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking XULTOPHY 100/3.6 [see Warnings and Precautions (5.12)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

What should I tell my healthcare provider before using XULTOPHY 100/3.6?

Before using XULTOPHY 100/3.6, tell your healthcare provider about all your medical conditions, including if you:

…

• are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).

…

What are the possible side effects of XULTOPHY 100/3.6?

XULTOPHY 100/3.6 may cause serious side effects that can lead to death, including:

…

• food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). XULTOPHY 100/3.6 may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking XULTOPHY 100/3.6 before you are scheduled to have surgery or other procedures.

07/10/2023 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Liraglutide

• Gastrointestinal: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus


• General Disorders and Administration Site Conditions: Allergic reactions: rash and pruritus


• Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis


• Immune system: Angioedema and anaphylactic reactions


• Metabolism and nutrition: Dehydration resulting from nausea, vomiting and diarrhea


• Neoplasms: Medullary thyroid carcinoma


• Nervous system: Dysgeusia, dizziness


• Renal and urinary: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.


• Skin and subcutaneous tissue: Cutaneous amyloidosis

…

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of 1881 subjects in clinical studies of XULTOPHY 100/3.6, 375 (19.9%) were 65 years and over, while 52 (2.8%) were 75 years and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness of XULTOPHY 100/3.6 were observed between patients 65 years of age and older and younger patients.
Age had no clinically relevant effect on the pharmacokinetics of XULTOPHY 100/3.6 [see Clinical Pharmacology (12.3)].
In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be more difficult to recognize in geriatric patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:
…

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

Inform patients that hypoglycemia is the most common adverse reaction with insulin products. Inform patients of the symptoms of hypoglycemia (e.g. impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.

…

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of liraglutide, one of the components of XULTOPHY 100/3.6. Advise patients on the symptoms of hypersensitivity reactions and instruct them must stop taking XULTOPHY 100/3.6 and seek medical advice promptly [see Warnings and Precautions (5.8)].

…

Missed Dose

Inform patients not to take an extra dose of XULTOPHY 100/3.6 or increase the dose to make up for the missed dose. 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. 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 any gastrointestinal symptoms associated with reinitiation of treatment. XULTOPHY 100/3.6 should be titrated at the direction of a healthcare provider [see Dosage and Administration (2.1, 2.2, 2.3)].

…

06/10/2022 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hypoglycemia

Additions and/or revisions underlined:

…

The long-acting effect of insulin degludec may delay recovery from hypoglycemia compared to shorter acting insulins.

…

 

5.8 Hypersensitivity Reactions

Subsection title revised

Additions and/or revisions underlined:

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.

…

 

5.9 Acute Gallbladder Disease

Additions and/or revisions underlined:

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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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/m2. The mean duration of diabetes was 9 years and the mean HbA 1c at baseline was 8.2%. Ahistory 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 m2 and 6% of the patients had an eGFR less than 60 mL/min/1.73 m2.

…

Cholelithiasis and cholecystitis

…

The incidence of acute cholecystitis was 1.1% (2.9 cases per 1000 patient years of observation) in liraglutide-treated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy.

…

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.

…

6.3 Postmarketing Experience

Additions and/or revisions underlined:

…

Liraglutide

• Medullary thyroid carcinoma

• Dehydration resulting from nausea, vomiting and diarrhea.

• Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.

• Angioedema and anaphylactic reactions.

• Allergic reactions: rash and pruritus

• Skin and subcutaneous tissue disorder: cutaneous amyloidosis

• Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death

• Hepatobiliary disorders: elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

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 to10% in women with pre-gestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to25% 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 and/or Embryo/fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre- gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

• gallbladder problems. Gallbladder problems have happened in some people who take XULTOPHY 100/3.6. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include:

  • pain in your upper stomach (abdomen)        

  • yellowing of skin or eyes (jaundice)

  • fever                                                              

  • clay-colored stools

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Kidney Injury

Advise patients of the potential risk of dehydration and acute kidney injury due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis [see Warnings and Precautions (5.7)].

…

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin products. Inform patients of the symptoms of hypoglycemia (e.g. impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

…

Pregnancy

Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant.[see Use in Specific Populations (8.1)].

11/15/2019 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

(Subsection title revised; Additions and/or revisions are underlined)

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 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. 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.

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

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 (one of the components of XULTOPHY 100/3.6)

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

• Medullary thyroid carcinoma

• Dehydration resulting from nausea, vomiting and diarrhea.

• Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.

• Angioedema and anaphylactic reactions.

• Allergic reactions: rash and pruritus

• Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death

• Hepatobiliary disorders: elevations of liver enzymes, hyperbilirubinemia, cholestasis, hepatitis

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Newly added section; please refer to labeling)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)

Risk of Thyroid C-cell Tumors

Inform patients that liraglutide, one of the components of XULTOPHY 100/3.6, causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding is unknown. Patients should be counseled to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia or dyspnea) to their physician.

Dehydration and Renal Failure

Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis.

Pancreatitis

Inform patients of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue XULTOPHY 100/3.6 promptly and contact their physician if persistent severe abdominal pain occurs.

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up.

Overdose due to Medication Errors

Inform patients that XULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. 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.

Advise patients that the administration of more than 50 units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Instruct patients not to administer concurrently with other glucagon- like peptide-1 receptor agonists.

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin products. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision.

Never Share a XULTOPHY 100/3.6 Pen Between Patients

Advise patients that they must never share a XULTOPHY 100/3.6 pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of liraglutide, one of the components of XULTOPHY 100/3.6.

If symptoms of hypersensitivity reactions occur, patients must stop taking XULTOPHY 100/3.6 and seek medical advice promptly.

Hepatobiliary Disorders

Inform patients that hepatobiliary disorders including elevations of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis have been reported during postmarketing use of liraglutide. Instruct patients to contact their physician if they develop jaundice.

Pregnancy

Instruct female patients of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

08/08/2019 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

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. The mean age was 57 years and 2.8% were older than 75 years; 52.6% were male, 75.0% were White, 6.2% were Black or African American and 15.9% were Hispanic or Latino. The mean body mass index (BMI) was 31.8 kg/m2. The mean duration of diabetes was 8.7 years and the mean HbA1c at baseline was 8.2%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 25.4%, 12.0%, 6.5% and 6.3% respectively. The mean estimated glomerular filtration rate (eGFR) at baseline was 88.3 mL/min/1.73 m2 and 6.24% of the patients had an eGFR less than 60 mL/min/1.73 m2.

02/27/2019 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hyperglycemia or Hypoglycemia with Changes in XULTROPHY 100/3.6 Regimen

When initiating XULTOPHY 100/3.6, follow dosing recommendations …

6 Adverse Reactions

Addition to the bulleted line listing:

• Acute Gallbladder Disease

02/27/2019 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hyperglycemia or Hypoglycemia with Changes in XULTROPHY 100/3.6 Regimen

Additions and/or revisions underlined:

When initiating XULTOPHY 100/3.6, follow dosing recommendations …

6 Adverse Reactions

Addition to the bulleted line listing:

• Acute Gallbladder Disease

02/01/2019 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

In patients with hypersensitivity to XULTOPHY 100/3.6, either insulin degludec or liraglutide, or any of its excipients. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide, one of the components of XULTOPHY 100/3.6.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Pancreatitis

… In glycemic control trials of liraglutide, there have been 13 cases of pancreatitis …

Liraglutide, one of the components of XULTOPHY 100/3.6, has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on liraglutide.

5.8 Hypersensitivity and Allergic Reactions

… 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.

Addition of the following subsection:

5.9 Acute Gallbladder Disease

In a cardiovascular outcomes trial (LEADER trial). 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. The majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 Adverse Reactions

Additions and/or revisions underlined:

6.1 Clinical Trial Experience

Xultophy 100/3.6

The data in Table 3 reflect the exposure …

… 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 …

Papillary thyroid carcinoma

VICTOZA (liraglutide)

In glycemic control trials of liraglutide …

Cholelithiasis and cholecystitis

VICTOZA (liraglutide)

In glycemic control trials of liraglutide …

In a cardiovascular outcomes trial (LEADER trial), the incidence of cholelithiasis was 1.5% (3.9 cases per 1000 patient years of observation) in liraglutide-treated and 1.1% (2.8 cases per 1000 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 1000 patient years of observation) in liraglutide- treated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients.

Laboratory tests

Bilirubin

VICTOZA (liraglutide)

In the five glycemic control trials …

VICTOZA (liraglutide)

… At the end of the glycemic control trials …

Lipase and Amylase VICTOZA (liraglutide)

In one glycemic control trial …

In a cardiovascular outcomes trial (LEADER trial), 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.

6.2 Immunogenicity

VICTOZA (liraglutide)

… The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to liraglutide cannot be directly compared with the incidence of antibodies of other products.

In five double-blind glycemic control trials of liraglutide …

… In a cardiovascular outcomes trial (LEADER trial), anti-liraglutide antibodies were detected in 11 out of the 1247 (0.9%) liraglutide-treated patients with antibody measurements.

Of the 11 liraglutide-treated patients who developed anti-liraglutide antibodies, none were observed to develop neutralizing antibodies to liraglutide, and 5 patients (0.4%) developed cross-reacting antibodies against native GLP-1.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

… Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities …

Clinical Considerations

… Poorly controlled diabetes mellitus increases the fetal risk …

… liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures …

8.6 Renal Impairment

Liraglutide

The safety and efficacy of liraglutide was evaluated in a 26-week clinical study that included patients with moderate renal impairment (eGFR 30 to 60 mL/min/1.73 m2). In the liraglutide treatment arm of a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies (14.2)], 1932 (41.4%) patients had mild renal impairment, 999 (21.4%) patients had moderate renal impairment and 117 (2.5%) patients had severe renal impairment at baseline. No overall differences in safety or efficacy were seen in these patients compared to patients with normal renal function.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up.

02/01/2019 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist

Additions and/or revisions underlined:

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor …

6 Adverse Reactions

6.2 Immunogenicity

Additions and/or revisions underlined:

TRESIBA (insulin degludec)

In a 52-week study of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received insulin degludec were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients anti-insulin degludec antibodies at least once during the study. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies.