Xultophy

Last updated on RxList: 2/10/2021
Xultophy Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Xultophy?

Xultophy 100/3.6 (insulin degludec and liraglutide injection) is a combination of a long-acting human insulin analog and 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 inadequately controlled on basal insulin (less than 50 units daily) or liraglutide (less than or equal to 1.8 mg daily).

What Are Side Effects of Xultophy?

Common side effects of Xultophy 100/3.6 include:

Dosage for Xultophy

The recommended starting dosage of Xultophy 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) given subcutaneously once daily.

What Drugs, Substances, or Supplements Interact with Xultophy?

Xultophy 100/3.6 may interact with other antidiabetics, ACE inhibitors, angiotensin II receptor blockers, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs, sulfonamide antibiotics, atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens, protease inhibitors, somatropin, sympathomimetic agents, thyroid hormones, alcohol, beta-blockers, clonidine, lithium salts, pentamidine, clonidine, guanethidine, and reserpine. Tell your doctor all medications and supplements you use.

Xultophy During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Xultophy 100/3.6; it may harm a fetus. It is unknown if Xultophy 100/3.6 passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Xultophy 100/3.6 (insulin degludec and liraglutide injection) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

______________ is another term for type 2 diabetes. See Answer
Xultophy Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • severe nausea and vomiting;
  • shortness of breath (even with mild exertion);
  • swelling in your feet or ankles, rapid weight gain;
  • signs of pancreatitis--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
  • kidney problems--little or no urination, painful or difficult urination; or
  • low potassium level--leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling.

Common side effects may include:

  • nausea, diarrhea;
  • headache; or
  • cold symptoms such as stuffy or runny nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Xultophy (Insulin Degludec and Liraglutide)

SLIDESHOW

Type 2 Diabetes: Signs, Symptoms, Treatments See Slideshow
Xultophy Professional Information

SIDE EFFECTS

The following serious adverse reactions are described below or elsewhere in the prescribing information:

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. 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.

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 9.6
Headache 9.1
Nausea 7.8
Diarrhea 7.5
Increased Lipase 6.7
Upper respiratory tract infection 5.7

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin and insulin containing products, including XULTOPHY 100/3.6 [see WARNINGS AND PRECAUTIONS]. The number of reported hypoglycemia episodes depends 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], 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

  Patients naive 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 0.0
Hypoglycemia with a glucose level <54 mg/dL (%)* 27.6 37.2 14.4 27.1 22.1 24.8
† episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
*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. 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

VICTOZA (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 1000 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.

Cholelithiasis And Cholecystitis

VICTOZA (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], 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 liraglutidetreated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients.

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].

Peripheral Edema

Insulin containing products, including 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, pruritis, 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.

Systemic Allergy

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin-containing products including XULTOPHY 100/3.6 and may be life threatening [see WARNINGS AND PRECAUTIONS]. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported.

Laboratory Tests

Bilirubin

VICTOZA (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.

VICTOZA (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

VICTOZA (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], 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].

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.

Immunogenicity

XULTOPHY 100/3.6

As with all therapeutic proteins, there is potential for immunogenicity. 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, comparison of the incidence of antibodies to XULTOPHY 100/3.6 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Administration of XULTOPHY 100/3.6 may cause formation of antibodies against insulin degludec and/or liraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the XULTOPHY 100/3.6 dose in order to correct a tendency to hyper-or hypoglycemia. In the clinical trials where antibodies were measured in patients receiving XULTOPHY 100/3.6, 11.1% of patients were positive for insulin degludec specific antibodies at end of treatment vs. 2.4% at baseline, 30.8% of patients were positive for antibodies cross-reacting with human insulin at end of treatment vs. 14.6% at baseline. 2.1% of patients were positive for anti-liraglutide antibodies at end of treatment (no patients were positive at baseline). Antibody formation has not been associated with reduced efficacy of XULTOPHY 100/3.6.

VICTOZA (liraglutide)

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with liraglutide may develop anti-liraglutide antibodies. 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.

Approximately 50-70% of liraglutide-treated patients in five double-blind clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these liraglutide-treated patients. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the liraglutide-treated patients in the double-blind 52-week monotherapy trial and in 4.8% of the liraglutide-treated patients in the double-blind 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the liraglutide-treated patients in the double-blind 52-week monotherapy trial and in 1.0% of the liraglutide-treated patients in the double-blind 26-week add-on combination therapy trials.

Antibody formation was not associated with reduced efficacy of liraglutide when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with liraglutide treatment.

In five double-blind glycemic control trials of liraglutide, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of liraglutidetreated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for liraglutide-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies.

In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies], 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.

TRESIBA (insulin degludec)

In a 52-week study of adult insulin-naive 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 developed 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.

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.

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

Read the entire FDA prescribing information for Xultophy (Insulin Degludec and Liraglutide)

© Xultophy Patient Information is supplied by Cerner Multum, Inc. and Xultophy Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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