QTERN SIDE EFFECTS

SIDE EFFECTS

The following important adverse reactions are described below or elsewhere in the labeling:

• Pancreatitis
• Heart Failure
• Hypotension
• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
• Hypersensitivity Reactions
• Genital Mycotic Infections
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
• Bladder Cancer
• Severe and Disabling Arthralgia
• Bullous Pemphigoid

Clinical Trials 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 safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in 492 adult subjects with type 2 diabetes in a pooled safety analysis of three phase 3 active/placebo-controlled clinical trials with a median exposure of 51 weeks. The mean age of these subjects was 54 years, 0.8% were 75 years or older and 53.7% were female. The population was 80.9% White, 8.3% Black or African American, 3.7% Asian, and 6.6% Other race. At baseline the population had diabetes for an average of 7.5 years and a mean HbA1c of 8.4%. The mean eGFR at baseline was 94.4 mL/min/1.73 m².

The common adverse reactions were based on the pooled analyses of these studies as shown in Table 1.

Table 1. Adverse Reactions Reported in ≥2% Subjects Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin

Additionally, adverse reactions reported in <5% and ≥2% from the dapagliflozin development program and ≥1% more frequently compared to placebo included increased urination, and discomfort with urination.

Hypoglycemia

Hypoglycemia was reported in 8 subjects (1.6%) treated with QTERN. No episodes of major hypoglycemia (defined as a symptomatic episode requiring external assistance) were reported.

Genital Mycotic Infections

Genital mycotic infections were reported in 15 subjects (3%) treated with QTERN. Reported adverse reactions by frequency included vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis. The majority of subjects (84.2%) who experienced genital infection adverse reactions were females.

Urinary Tract Infections

Urinary tract infections were reported in 28 subjects (5.7%) treated with QTERN. Reported adverse reactions by frequency included urinary tract infection, Escherichia urinary tract infection, prostatitis, and pyelonephritis. The majority of subjects (80.6%) who experienced urinary tract infection adverse reactions were females.

Volume Depletion

Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in 2 subjects (0.4%) treated with QTERN.

Renal Impairment

Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with QTERN. The reported adverse reactions included decreased glomerular filtration rate, renal impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of the adverse reactions was reported as serious and all but one were mild to moderate in intensity. Three subjects discontinued due to decreased eGFR. Subjects with AEs of renal impairment had lower mean eGFR values at baseline of 64.4 ml/min/1.73 m² compared to 94.4 ml/min/1.73 m² in overall population treated with QTERN.

Dapagliflozin

Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 2). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions.

Table 2. Changes in Serum Creatinine and eGFR Associated with Dapagliflozin

Laboratory Findings

Decrease in Lymphocyte Counts

Saxagliptin

A dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin. In a pool of 5 placebo-controlled studies, a mean decrease in absolute lymphocyte count of approximately 100 cells/microL relative to placebo. There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Increase in Hematocrit

Dapagliflozin

In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean hematocrit values were observed in dapagliflozin treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients.

Increase in Serum Inorganic Phosphorus

Dapagliflozin

In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin treated patients compared with placebo-treated patients (mean increase of 0.13 versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on dapagliflozin at Week 24 (0.9% versus 1.7% for placebo and dapagliflozin 10 mg, respectively).

Increase in Low-Density Lipoprotein Cholesterol

Patients treated with QTERN demonstrated a mean percent increase from baseline LDL-cholesterol (ranging from 2.1 to 6.9%).

Elevations in Creatine Kinase

In the pooled safety analysis, an imbalance in the number of subjects who experienced serum creatine kinase (CK) elevations >10x the upper limit of normal (a marker of muscle injury/necrosis) was observed in 5 subjects (1%) treated with QTERN. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which no obvious cause was identified.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of saxagliptin and dapagliflozin. Because the following reactions 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.

Saxagliptin

• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Pancreatitis
• Severe and disabling arthralgia
• Bullous pemphigoid

Dapagliflozin

• Ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function
• Urosepsis and pyelonephritis
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
• Rash

SRC: NLM .