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.

6.2 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 [see Contraindications (4)]

• Pancreatitis [see Indications and Usage (2)]

• Severe and disabling arthralgia

• Bullous pemphigoid

Dapagliflozin

• Ketoacidosis

• Acute Kidney Injury and Impairment in Renal Function

• Urosepsis and pyelonephritis

• Rash

7. DRUG INTERACTIONS 

7.1 Strong Inhibitors of CYP3A4/5 Enzymes

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). Do not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors [see Dosage and Administration (3.3) and Clinical Pharmacology].

7.2 Positive Urine Glucose Test

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT-2 inhibitors as SGLT-2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

7.3 Interference with 1,5-anhydroglucitol (1,5-AG) Assay

Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT-2 inhibitors. Use alternative methods to monitor glycemic control.

8. USE IN SPECIFIC POPULATIONS 

8.1 Pregnancy

Risk Summary

Based on animal data showing adverse renal effects, from dapagliflozin, QTERN is not recommended during the second and third trimesters of pregnancy.

The limited available data with QTERN or its components (dapagliflozin and saxagliptin) in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal studies, adverse renal pelvic and tubular dilatations, that were not fully reversible, were observed in juvenile rats when dapagliflozin (a component of QTERN) was administered at an exposure 15-times the exposure at the 10 mg clinical dose during a period of renal development corresponding to the late second and third trimesters of human pregnancy.

No adverse developmental effects were observed when saxagliptin was administered to pregnant rats and rabbits [see Data].

The estimated background risk o