Xultophy 100/3.6 (Page 5 of 12)

6.2 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 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 a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies (14.4)] , 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-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 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.

6.3 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.

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

7 DRUG INTERACTIONS

7.1 Medications that Can Affect Glucose Metabolism

A number of medications affect glucose metabolism and may require dose adjustment of XULTOPHY 100/3.6 and particularly close monitoring [see Dosage and Administration (2.2); Warnings and Precautions (5.6)].

Drugs That May Increase the Risk of Hypoglycemia

Drugs:

Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics

Intervention:

Dose reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.

Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6

Drugs:

Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.

Intervention:

Dose increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.

Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6

Drugs:

Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Intervention:

Dose adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.

Drugs That May Blunt Signs and Symptoms of Hypoglycemia

Drugs:

Beta-blockers, clonidine, guanethidine, and reserpine

Intervention:

Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.

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