Side Effects of Xultophy (insulin degludec and liraglutide injection)

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 used 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).

Common side effects of Xultophy include:

• stuffy or runny nose,
• sore throat,
• headache,
• nausea,
• diarrhea,
• increased blood levels of lipase,
• upper respiratory tract infection, and
• low blood sugar (hypoglycemia - symptoms include dizziness or light-headedness, sweating, confusion, drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, mood changes, hunger, weakness, and feeling jittery).

Serious side effects of Xultophy include:

• severe pain in your stomach area that will not go away, with or without vomiting;
• worsening kidney failure or sudden kidney failure,
• serious allergic reactions,
• gallbladder problems,
• low blood potassium, and
• heart failure.

Drug interactions of Xultophy include drugs that affect glucose metabolism and anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine) which may cause a reduction in symptoms of hypoglycemia.

Xultophy concomitantly administered with oral medications may impact their absorption.

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. Xultophy 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no data on the presence of liraglutide or insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xultophy 100/3.6 and any potential adverse effects on the breastfed infant from Xultophy 100/3.6 or the underlying maternal condition.

WARNING

Possible thyroid tumors, including cancer

Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rats and mice, liraglutide, one of the components of Xultophy 100/3.6, and medicines that work like liraglutide caused thyroid tumors, including thyroid cancer.

It is not known if Xultophy 100/3.6 will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people. • Do not use Xultophy 100/3.6 if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Common Side Effects

The most common side effects of Xultophy 100/3.6 include stuffy or runny nose, sore throat, headache, nausea, diarrhea, increased blood levels of lipase, and upper respiratory tract infection. Talk to your healthcare provider about any side effect that bothers you or does not go away.

Stop using Xultophy 100/3.6 and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia)

Your risk for getting low blood sugar may be higher if you use Xultophy 100/3.6 with another medicine that can cause low blood sugar.

Signs and symptoms of low blood sugar may include:

• dizziness or light-headedness
• sweating
• confusion or drowsiness
• headache
• blurred vision
• slurred speech
• shakiness
• fast heartbeat
• anxiety, irritability, or mood changes
• hunger
• weakness
• feeling jittery

Kidney problems (kidney failure)

Worsening of kidney failure and sudden kidney failure have happened in people with kidney problems and people without kidney problems, who have taken liraglutide, one of the ingredients in Xultophy 100/3.6.

Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. Tell your healthcare provider if you have diarrhea, nausea, or vomiting. Drink plenty of fluids to help reduce your risk of dehydration during treatment with Xultophy 100/3.6.

Serious allergic reactions

Stop using Xultophy 100/3.6 and get medical help right away, if you have any symptoms of a serious allergic reaction including:
• hives
• rash
• itching
• fast heartbeat
• fainting or feeling dizzy
• swelling of your face, lips, tongue, or throat
• problems breathing or swallowing
• sudden coughing
• chest pain or tightness

Gallbladder problems

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

• pain in the right or middle upper stomach area
• fever
• nausea and vomiting
• your skin or the white part of your eyes turns yellow

Low potassium in your blood (hypokalemia)

Heart failure

Taking certain diabetes pills called thiazolidinediones or TZDs with Xultophy 100/3.6 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure, it may get worse while you take TZDs with Xultophy 100/3.6. Your healthcare provider should monitor you closely while you are taking TZDs with Xultophy 100/3.6.

Tell your healthcare provider if you have any new or worse symptoms of heart failure including shortness of breath, tiredness, swelling of your ankles or feet, and sudden weight gain. Treatment with TZDs and Xultophy 100/3.6 may need to be adjusted or stopped by your healthcare provider if you have new or worsening heart failure.

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

• Risk of Thyroid C-cell Tumors
• Pancreatitis
• Hypoglycemia
• Acute Kidney Injury
• Hypersensitivity and Allergic Reactions
• Acute Gallbladder Disease
• Hypokalemia

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

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin and insulin-containing products, including Xultophy 100/3.6. 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, events of severe hypoglycemia were defined as an episode requiring the assistance of another person to actively administer carbohydrates glucagon, or other resuscitative actions (Table 4). Hypoglycemia episodes with a glucose level below 54 mg/dL associated with or without symptoms are 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

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), 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.

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.

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. Hypersensitivity (manifested with swelling of the 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 an 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), serum lipase and amylase were routinely measured. Among liraglutide-treated patients, 7.9% had a lipase value at any time during treatment 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.

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, the timing of sample collection, concomitant medications, and underlying disease.

For these reasons, a 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 the 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 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, the 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 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 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 the 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 liraglutide-treated patients and 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), 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 results 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 result in death
• Hepatobiliary disorders: elevations of liver enzymes, hyperbilirubinemia, cholestasis, hepatitis

Medications That Can Affect Glucose Metabolism

Several medications affect glucose metabolism and may require dose adjustment of Xultophy 100/3.6 and particularly close monitoring.

Effects Of Delayed Gastric Emptying On Oral Medications

Liraglutide-containing products, including Xultophy 100/3.6, cause a delay in 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. Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide-containing products.