Xultophy 100/3.6 (Page 4 of 12)

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

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, particularly when used in combination with insulin containing products, including XULTOPHY 100/3.6. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin containing products, including XULTOPHY 100/3.6 and a PPAR-gamma agonist should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

6 ADVERSE REACTIONS

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

Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1)]
Pancreatitis [see Warnings and Precautions ( 5.2)]
Hypoglycemia [see Warnings and Precautions (5.6)]
Acute Kidney Injury [see Warnings and Precautions (5.7)]
Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.8)]
Acute Gallbladder Disease [see Warnings and Precautions (5.9)]
Hypokalemia [see Warnings and Precautions ( 5.10)]

6.1 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 (5.6)]. 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 [see Clinical Studies (14)] , 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

† episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Patients naïve 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

*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 (14.4)] , 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 [see Dosage and Administration ( 2.5)].

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 (5.8)]. 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 (14.4)] , 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 (5.2)].

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.

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