Xultophy Injection

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.

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 C274H411N65O81S6 and a molecular weight of 6103.97. 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 C172H265N43O51 and the molecular weight is 3751.2 Daltons. The structural formula (Figure 2) is:

Figure 2: Structural Formula of Liraglutide

XULTOPHY 100/3.6 is a sterile, aqueous, clear, and colorless solution. Each pre-filled 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 5.70 mg, zinc 55 mcg, and water for injection. XULTOPHY 100/3.6 has a pH of approximately 8.15. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

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 inadequately controlled on basal insulin (less than 50 units daily) or liraglutide (less than or equal to 1.8 mg daily).

Limitations Of Use

• XULTOPHY 100/3.6 is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans [see WARNINGS AND PRECAUTIONS].
• XULTOPHY 100/3.6 has not been studied in patients with a history of pancreatitis [see WARNINGS AND PRECAUTIONS]. Consider other antidiabetic therapies in patients with a history of pancreatitis.
• XULTOPHY 100/3.6 is not recommended for use in combination with any other product containing liraglutide or another GLP-1 receptor agonist [see WARNINGS AND PRECAUTIONS].
• XULTOPHY 100/3.6 is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
• XULTOPHY 100/3.6 has not been studied in combination with prandial insulin.

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]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, 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 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 post-marketing 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, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

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

• Risk of Thyroid C-cell Tumors [see WARNINGS AND PRECAUTIONS]
• Pancreatitis [see WARNINGS AND PRECAUTIONS]
• Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Acute Kidney Injury [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity and Allergic Reactions [see WARNINGS AND PRECAUTIONS]
• Hypokalemia [see WARNINGS AND PRECAUTIONS]

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.

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 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 [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). No clinically important differences in risk of severe hypoglycemia between XULTOPHY 100/3.6 and comparators were observed in clinical trials.

Table 4: Severe 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.

Malignancy

In a pooled analysis of liraglutide clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for liraglutide, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events, no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among liraglutide-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established.

Papillary Thyroid Carcinoma

In clinical 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

In clinical 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 clinical trials of liraglutide at doses up to 3 mg, 1.5% and 0.6% of liraglutide-treated patients reported adverse reactions of cholelithiasis and cholecystitis versus 0.5% and 0.2% of placebo-treated patients. The majority of liraglutide-treated patients with adverse reactions of cholelithiasis and cholecystitis required cholecystectomy.

Initiation Of Insulin Containing Products And Intensification Of Glucose Control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long-term use of insulin containing products, including XULTOPHY 100/3.6, can cause lipodystrophy at the site of repeated injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect absorption [see DOSAGE AND ADMINISTRATION].

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

VICTOZA (liraglutide)

In the five clinical 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 liraglutidetreated 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.

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 clinical 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.

VICTOZA (liraglutide)

In one placebo-controlled 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%.The clinical significance of these changes is unknown.

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. The long-term clinical effects of the increase in pulse rate have not been established [see WARNINGS AND PRECAUTIONS].

Immunogenicity

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.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with liraglutide may develop anti-liraglutide antibodies. 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. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Crossreacting 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 liraglutidetreated patients in the double-blind 26-week add-on combination therapy trials.

Among liraglutide-treated patients who developed anti-liraglutide antibodies, the most common category of adverse reactions was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative liraglutide-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among liraglutide-treated antibody-positive patients were primarily non-serious upper respiratory tract infections, which occurred among 11% of liraglutide-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative liraglutide-treated, placebo-treated and active-control-treated patients, respectively. Among liraglutide-treated antibody-negative patients, the most common category of adverse reactions was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative liraglutide-treated, placebo-treated and active-control-treated patients, respectively. 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 clinical 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 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 studies of type 2 diabetes patients, 31.5% of patients who received insulin degludec once daily were positive for anti-insulin antibodies (AIA) at least once during the studies, including 14.5% that were positive at baseline. The antibody incidence rates for type 2 diabetes may be underreported due to potential assay interference by endogenous insulin in samples in these patients. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper or hypoglycemia. The incidence of anti-insulin degludec antibodies has not been established.

Post-Marketing 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.

• 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)