HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING How SuppliedQTERN(R) (dapagliflozin and saxagliptin) tablets for oral use are available in packages as listed:Tablet StrengthFilm-Coated Tablet Color ShapeTablet MarkingsPack SizeNDC Code5 mg dapagliflozin /5 mg saxagliptinLight purple to reddish purple, biconvex, round1120 printed on both sides, in blue inkBottles of 30Bottles of 90Bottles of 5000310-6770-300310-6770-900310-6770-5010 mg dapagliflozin /5 mg saxagliptinLight brown to brown, biconvex, round1122 printed on both sides, in blue inkBottles of 30Bottles of 90Bottles of 5000310-6780-300310-6780-900310-6780-50Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE QTERN (dapagliflozin and saxagliptin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.Limitations of UseQTERN is not indicated for the treatment of type diabetes mellitus or diabetic ketoacidosis.. QTERN is sodium-glucose cotransporter (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1) Limitations of Use:QTERN is not indicated for the treatment of type diabetes mellitus or diabetic ketoacidosis. (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).PancreatitisoInform patients that acute pancreatitis has been reported during postmarketing use of saxagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.oInstruct patients to promptly discontinue QTERN and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS (5.1)].Heart FailureoInform patients of the signs and symptoms of heart failure. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see WARNINGS AND PRECAUTIONS (5.2)].HypotensionoInform patients that symptomatic hypotension may occur with QTERN and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake [see WARNINGS AND PRECAUTIONS (5.3)].KetoacidosisoInform patients that ketoacidosis is serious life-threatening condition and that cases of ketoacidosis have been reported during use of dapagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue QTERN and seek medical attention immediately [see WARNINGS AND PRECAUTIONS (5.4)].Acute Kidney InjuryoInform patients that acute kidney injury has been reported during use of dapagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue QTERN use in those settings [see WARNINGS AND PRECAUTIONS (5.5)]. Serious Urinary Tract Infections oInform patients of the potential for urinary tract infections, which may be serious. Inform them of the symptoms of urinary tract infections and advise them to seek medical advice if such symptoms occur [see WARNINGS AND PRECAUTIONS (5.6)].Necrotizing Fasciitis of the Perineum (Fourniers Gangrene)oInform patients that necrotizing infections of the perineum (Fourniers gangrene) have occurred with dapagliflozin, component of QTERN. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see WARNINGS AND PRECAUTIONS (5.8)].Hypersensitivity Reactions oInform patients that serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, and exfoliative skin conditions) have been reported with dapagliflozin and saxagliptin, components of QTERN. Symptoms of these allergic reactions include: rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.oAdvise patients to immediately report any signs or symptoms suggesting allergic reaction, angioedema or exfoliative skin conditions, and stop taking QTERN and seek medical advice promptly [see WARNINGS AND PRECAUTIONS (5.9)].Genital Mycotic Infections in Females (e.g., Vulvovaginitis) oInform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS (5.10)].Genital Mycotic Infections in Males (e.g., Balanitis) oInform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS (5.10)].Severe and Disabling ArthralgiaoInform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see WARNINGS AND PRECAUTIONS (5.11)].Bullous Pemphigoid oInform patients that bullous pemphigoid may occur with QTERN. Instruct patients to seek medical advice if blisters or erosions occur [see WARNINGS AND PRECAUTIONS (5.12)].PregnancyoAdvise pregnant patients of the potential risk to fetus with treatment with QTERN. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see USE IN SPECIFIC POPULATIONS (8.1)].Lactating MothersoAdvise patients that use of QTERN is not recommended while breastfeeding [see USE IN SPECIFIC POPULATIONS (8.2)].Laboratory TestsoInform patients that due to its mechanism of action, patients taking QTERN will test positive for glucose in their urine.Administration oInstruct patients that QTERN must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.Missing DoseoIf dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of QTERN at the same time.Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850QTERN is registered trademark of the AstraZeneca group of companies.. oInform patients that acute pancreatitis has been reported during postmarketing use of saxagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.. oInstruct patients to promptly discontinue QTERN and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS (5.1)].. oInform patients of the signs and symptoms of heart failure. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see WARNINGS AND PRECAUTIONS (5.2)].. oInform patients that symptomatic hypotension may occur with QTERN and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake [see WARNINGS AND PRECAUTIONS (5.3)].. oInform patients that ketoacidosis is serious life-threatening condition and that cases of ketoacidosis have been reported during use of dapagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue QTERN and seek medical attention immediately [see WARNINGS AND PRECAUTIONS (5.4)].. oInform patients that acute kidney injury has been reported during use of dapagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue QTERN use in those settings [see WARNINGS AND PRECAUTIONS (5.5)]. oInform patients of the potential for urinary tract infections, which may be serious. Inform them of the symptoms of urinary tract infections and advise them to seek medical advice if such symptoms occur [see WARNINGS AND PRECAUTIONS (5.6)].. oInform patients that necrotizing infections of the perineum (Fourniers gangrene) have occurred with dapagliflozin, component of QTERN. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see WARNINGS AND PRECAUTIONS (5.8)].. oInform patients that serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, and exfoliative skin conditions) have been reported with dapagliflozin and saxagliptin, components of QTERN. Symptoms of these allergic reactions include: rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.. oAdvise patients to immediately report any signs or symptoms suggesting allergic reaction, angioedema or exfoliative skin conditions, and stop taking QTERN and seek medical advice promptly [see WARNINGS AND PRECAUTIONS (5.9)].. oInform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS (5.10)].. oInform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS (5.10)].. oInform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see WARNINGS AND PRECAUTIONS (5.11)].. oInform patients that bullous pemphigoid may occur with QTERN. Instruct patients to seek medical advice if blisters or erosions occur [see WARNINGS AND PRECAUTIONS (5.12)].. oAdvise pregnant patients of the potential risk to fetus with treatment with QTERN. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see USE IN SPECIFIC POPULATIONS (8.1)].. oAdvise patients that use of QTERN is not recommended while breastfeeding [see USE IN SPECIFIC POPULATIONS (8.2)].. oInform patients that due to its mechanism of action, patients taking QTERN will test positive for glucose in their urine.. oInstruct patients that QTERN must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.. oIf dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of QTERN at the same time.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following important adverse reactions are described below or elsewhere in the labeling: oPancreatitis [see WARNINGS AND PRECAUTIONS (5.1)]oHeart Failure [see WARNINGS AND PRECAUTIONS (5.2)]oHypotension [see WARNINGS AND PRECAUTIONS (5.3)]oKetoacidosis [see WARNINGS AND PRECAUTIONS (5.4)]oAcute Kidney Injury [see WARNINGS AND PRECAUTIONS (5.5)]oUrosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS (5.6)]oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see WARNINGS AND PRECAUTIONS (5.7)]oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see WARNINGS AND PRECAUTIONS (5.8)] oHypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.9)]oGenital Mycotic Infections [see WARNINGS AND PRECAUTIONS (5.10)]oSevere and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.11)]oBullous Pemphigoid [see WARNINGS AND PRECAUTIONS (5.12)]. oPancreatitis [see WARNINGS AND PRECAUTIONS (5.1)]. oHeart Failure [see WARNINGS AND PRECAUTIONS (5.2)]. oHypotension [see WARNINGS AND PRECAUTIONS (5.3)]. oKetoacidosis [see WARNINGS AND PRECAUTIONS (5.4)]. oAcute Kidney Injury [see WARNINGS AND PRECAUTIONS (5.5)]. oUrosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS (5.6)]. oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see WARNINGS AND PRECAUTIONS (5.7)]. oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see WARNINGS AND PRECAUTIONS (5.8)] oHypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.9)]. oGenital Mycotic Infections [see WARNINGS AND PRECAUTIONS (5.10)]. oSevere and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.11)]. oBullous Pemphigoid [see WARNINGS AND PRECAUTIONS (5.12)]. Adverse reactions reported in >=5% of subjects treated with dapagliflozin and saxagliptin were: upper respiratory tract infection, urinary tract infection, and dyslipidemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 mg saxagliptin has been evaluated in adult subjects with type diabetes in pooled safety analysis of three phase active/placebo-controlled clinical trials with median exposure of 51 weeks. The pooled safety analysis included total of 1169 adults: 492 patients in the combination of saxagliptin and dapagliflozin plus metformin group, 341 patients in the dapagliflozin plus metformin group, 336 patients in the saxagliptin plus metformin group. 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 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% of Subjects Treated with 10 mg Dapagliflozin and mg Saxagliptin plus Metformin (>=1500 mg)Adverse ReactionPreferred TermAdverse reactions that are medically related were grouped to single preferred term.Frequency %Upper respiratory tract infection 13.6Urinary tract infection 5.7Dyslipidemia 5.1Headache4.3Diarrhea3.7Back pain3.3Genital infection 3.0Arthralgia2.4Additionally, 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.HypoglycemiaIn the pooled analysis, the incidences of hypoglycemia (defined as blood glucose <54 mg/dL regardless of the presence or absence of symptoms) and severe hypoglycemia (event requiring assistance due to neuroglycopenia, characterized by altered mental and/or physical status) was 1% and 0.2%, respectively.Genital Mycotic InfectionsGenital 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 InfectionsUrinary 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 DepletionDapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in subjects (0.4%) treated with QTERN plus metformin. Impairment of Renal FunctionAdverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with QTERN plus metformin. 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 were 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. KetoacidosisDapagliflozinIn the cardiovascular outcome study with dapagliflozin in patients with type diabetes mellitus, events of diabetic ketoacidosis were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.Laboratory FindingsIncreases in Serum Creatinine and Decreases in eGFRDapagliflozinInitiation of dapagliflozin causes an increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline 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) [see WARNINGS AND PRECAUTIONS (5.5) and MECHANISM OF ACTION (12.1) ].Decrease in Lymphocyte CountsSaxagliptinA dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin. In pool of placebo-controlled studies, mean decrease in absolute lymphocyte count of approximately 100 cells/microL relative to placebo was observed. The proportion of patients who were reported to have lymphocyte count <=750 cells/microL was 0.5%, 1.5%, and 0.4% in the 2.5 mg, mg saxagliptin and placebo groups, respectively.The clinical significance of this decrease in lymphocyte count relative to placebo is not known. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.Increase in HematocritDapagliflozinIn pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 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 10 mg dapagliflozin group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of 10 mg dapagliflozin-treated patients.Increase in Low-Density Lipoprotein CholesterolPatients treated with QTERN demonstrated mean percent increase from baseline LDL-cholesterol (ranging from 2.1 to 6.9%). Elevations in Creatine KinaseAn 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 subjects (1%) treated with QTERN. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which no obvious cause was identified.Decrease in Serum BicarbonateIn study of concomitant therapy of 10 mg dapagliflozin with exenatide extended-release (on background of metformin), four patients (1.7%) on concomitant therapy had serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups [see WARNINGS AND PRECAUTIONS (5.4) ].. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of dapagliflozin and saxagliptin. Because the following reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure. DapagliflozinoKetoacidosis oAcute Kidney InjuryoUrosepsis and pyelonephritis oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene)oRashSaxagliptin oHypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions oPancreatitisoSevere and disabling arthralgia oBullous pemphigoidoRhabdomyolysis. oKetoacidosis oAcute Kidney Injury. oUrosepsis and pyelonephritis oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene). oRash. oHypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions oPancreatitis. oSevere and disabling arthralgia oBullous pemphigoid. oRhabdomyolysis.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.


13.2 Animal Toxicology and/or Pharmacology Saxagliptin Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility QTERNNo animal studies have been conducted with the combined products in QTERN to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and saxagliptin individually.Dapagliflozin CarcinogenesisCarcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Dapagliflozin did not increase the incidence of tumors in mice dosed orally at 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females (exposure less than or equal to 72-times (males) and 105-times (females) the 10 mg/day clinical dose, based on AUC). Dapagliflozin did not increase the incidence of tumors in rats (both males and females) dosed orally at 0.5, 2, and 10 mg/kg/day (exposure less than or equal to 131-times (males) and 186-times (females) the clinical dose of 10 mg/day, based on AUC).MutagenesisDapagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Dapagliflozin was mutagenic in series of in vitro clastogenicity assays at concentrations greater than or equal to 100 micrograms per mL, but not without metabolic activation. Dapagliflozin was not mutagenic or clastogenic in series of in vivo studies evaluating micronuclei or DNULL repair in rats at exposure multiples greater than 2100-times the clinical dose.Impairment of FertilityDapagliflozin had no effects on the ability of rats to mate and sire, maintain litter, or early embryonic development at exposure multiples less than or equal to 1708- and 998-times the maximum recommended human doses of 10 mg/day (based on AUC) in males and females, respectively.Saxagliptin CarcinogenesisCarcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1165-times (females) the mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females) the mg/day clinical dose, based on AUC.MutagenesisSaxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNULL repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.Impairment of FertilitySaxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action QTERN contains: dapagliflozin, sodium-glucose cotransporter (SGLT2) inhibitor, and saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor. Dapagliflozin Sodium-glucose cotransporter (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.Saxagliptin Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.. 12.2 Pharmacodynamics Dapagliflozin Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin. Dapagliflozin dose of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see ADVERSE REACTIONS (6.1) ]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about days from discontinuation for the 10 mg dose.Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type Diabetes Mellitus (T2DM) (Semi-Log Plot)Saxagliptin In patients with type diabetes mellitus, administration of saxagliptin inhibits DPP-4 enzyme activity for 24-hour period. After an oral glucose load or meal, this DPP-4 inhibition resulted in 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or meal.Cardiac ElectrophysiologyDapagliflozin Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum daily dose) of dapagliflozin in healthy subjects.Saxagliptin In randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the recommended maximum daily dose).. Figure 1. 12.3 Pharmacokinetics Overall, the pharmacokinetics of dapagliflozin and saxagliptin were not affected in clinically relevant manner when administered as QTERN. Saxagliptin The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.AbsorptionDapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately hour but does not alter AUC as compared with the fasted state. Saxagliptin The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions.DistributionDapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.Saxagliptin The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.MetabolismDapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.Saxagliptin The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see DRUG INTERACTIONS (7) ].EliminationDapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t1/2) for dapagliflozin is approximately 12.9 hours following single oral dose of dapagliflozin 10 mg.Saxagliptin Saxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of [14C]-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.Specific PopulationsEffects of Age, Gender, Race and Body Weight on PharmacokineticsBased on population pharmacokinetic analysis, age, gender, race, and body weight do not have clinically meaningful effect on the pharmacokinetics of saxagliptin and dapagliflozin.Renal ImpairmentDapagliflozinAt steady state (20 mg once daily dapagliflozin for days), patients with type diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see DOSAGE AND ADMINISTRATION (2.2) WARNINGS AND PRECAUTIONS (5.5) and USE IN SPECIFIC POPULATIONS (8.6) ].SaxagliptinA single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment (eGFR 30 to less than 45 mL/min/1.73 m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2.Hepatic ImpairmentDapagliflozinIn subjects with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see USE IN SPECIFIC POPULATIONS (8.7) ].SaxagliptinIn subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.PediatricPharmacokinetics of QTERN in the pediatric population has not been studied. Drug InteractionsSaxagliptin and DapagliflozinThe lack of pharmacokinetic interaction between dapagliflozin and saxagliptin was demonstrated in drug-drug interaction study between dapagliflozin and saxagliptin.DapagliflozinIn Vitro Assessment of Drug InteractionsThe metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.Effects of Other Drugs on DapagliflozinTable shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin.Table 3: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug (Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)DapagliflozinChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Oral Antidiabetic Agents Metformin (1000 mg)20 mg1%7% Pioglitazone (45 mg)50 mg0%9% Sitagliptin (100 mg)20 mg8%4% Glimepiride (4 mg)20 mg1%1% Voglibose (0.2 mg three times daily)10 mg1%4% Saxagliptin (5 mg single dose)10 mg (single dose)2%6%Other Medications Hydrochlorothiazide (25 mg)50 mg7%1% Bumetanide (1 mg)10 mg once daily for days5%8% Valsartan (320 mg)20 mg2%12% Simvastatin (40 mg)20 mg1%2%Anti-infective Agent Rifampin (600 mg once daily for days)10 mg22%7%Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg51%13%Effects of Dapagliflozin on Other DrugsTable shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 4: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug (Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Coadministered Drug ChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Oral Antidiabetic Agents Metformin (1000 mg)20 mg0%5% Pioglitazone (45 mg)50 mg0%7% Sitagliptin (100 mg)20 mg1%11% Glimepiride (4 mg)20 mg13%4%Other Medications Hydrochlorothiazide (25 mg)50 mg1%5% Bumetanide (1 mg)10 mg once daily for days13%13% Valsartan (320 mg)20 mg5%6% Simvastatin (40 mg)20 mg19%6% Digoxin (0.25 mg)20 mg loading dose then 10 mg once daily for days0%1% Warfarin (25 mg) S-warfarin R-warfarin20 mg loading dose then 10 mg once daily for days3%6%7%8%Saxagliptin In Vitro Assessment of Drug InteractionsThe metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substrate but is not significant inhibitor or inducer of P-gp. Effects of Other Drugs on Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinTable 5: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCoadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted.Dosage of SaxagliptinSaxagliptinChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Metformin1000 mg100 mgsaxagliptin5-hydroxy saxagliptin2%1%21%12%Glyburide5 mg10 mgsaxagliptin5-hydroxy saxagliptin2%ND8%NDPioglitazoneResults exclude one subject. 45 mg QD for 10 days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin11%ND11%NDDapagliflozin10 mg single dose5 mg single dosesaxagliptin5-hydroxy saxagliptin1%9%7%6%Digoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin5%6%1%2%Simvastatin40 mg QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin12%2%21%8%Diltiazem360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin109%34%63%43%RifampinThe plasma dipeptidyl peptidase-4 (DPP-4) activity inhibition over 24-hour dose interval was not affected by rifampin. 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin76%3%53%39%Omeprazole40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin13%ND2%NDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone:240 mg10 mgsaxagliptin5-hydroxy saxagliptin3%ND26%NDFamotidine40 mg10 mgsaxagliptin5-hydroxy saxagliptin3%ND14%NDSaxagliptin coadministered with strong CYP3A4/5 inhibitors [see DRUG INTERACTIONS (7) and DOSAGE AND ADMINISTRATION (2.3)]:Ketoconazole200 mg BID for days100 mgsaxagliptin5-hydroxy saxagliptin145%88%62%95%Ketoconazole200 mg BID for days20 mgsaxagliptin5-hydroxy saxagliptin267%ND144%NDND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.Effects of Saxagliptin on Other Drugs Table 6: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsCoadministered DrugDosage ofCoadministered DrugSingle dose unless otherwise noted.Dosage of SaxagliptinCoadministered DrugChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Changein CmaxMetformin1000 mg100 mgmetformin20%9%Glyburide5 mg10 mgglyburide6%16%PioglitazoneResults include all subjects. 45 mg QD for 10 days10 mg QDfor dayspioglitazonehydroxy-pioglitazone8%ND14%NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor daysdigoxin6%9%Simvastatin40 mg QD for days10 mg QDfor dayssimvastatinsimvastatin acid4%16%12%0%Diltiazem360 mg LA QD for days10 mgdiltiazem10%16%Ketoconazole200 mg BID for days100 mgketoconazole13%16%Ethinyl estradiol and Norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiol norelgestrominnorgestrel7%10%13%2%9%17% ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.. ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES The dapagliflozin and saxagliptin in combination with metformin has been studied in adult patients with type diabetes mellitus (T2DM) inadequately controlled on metformin in the following studies.Treatment with dapagliflozin and saxagliptin and metformin (combination or add-on therapy) at all doses produced statistically significant improvements in HbA1c compared to the active comparator or placebo study arms in combination with metformin.. 14.1 Add-on Therapy with Dapagliflozin plus Saxagliptin in Patients on Metformin Adult patients with inadequately controlled type diabetes participated in active-controlled studies of 24-week duration to evaluate therapy with mg dapagliflozin/5 mg saxagliptin or 10 mg dapagliflozin/5 mg saxagliptin combinations on background of metformin.One study was 24-week randomized, double-blind, active-controlled, parallel-group study (NCT02681094) in T2DM patients with an HbA1c >=7.5% and <=10.0%. Patients were on stable dose of metformin HCl (>=1500 mg per day) for at least weeks prior to being randomized to one of three double-blind treatment groups to receive mg dapagliflozin and mg saxagliptin added to metformin, mg saxagliptin and placebo added to metformin, or mg dapagliflozin and placebo added to metformin.At Week 24, concomitant addition of mg dapagliflozin and mg saxagliptin plus metformin resulted in statistically significant decreases in HbA1c, and larger proportion of patients achieving the therapeutic glycemic goal of HbA1c <7%, compared to dapagliflozin plus metformin or saxagliptin plus metformin (see Table 7).Table 7: HbA1c Results at Week 24 with the Combination of mg Dapagliflozin and mg Saxagliptin plus MetforminAnalysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using control arm data for all subjects having missing Week 24 data. Efficacy Parameter5 mg Dapagliflozin and mg Saxagliptin Metformin5 mg Dapagliflozin and mg Saxagliptin +Metformin5 mg Dapagliflozin +Metformin5 mg Saxagliptin +MetforminNThe number of randomized subjects who took at least one dose of double-blind study medication and had baseline value for HbA1c.290289291Baseline (mean)8.18.28.3Change from baseline (adjusted mean)(95% CI)-1.02(-1.13, -0.90)-0.62(-0.73, -0.51)-0.69(-0.80, -0.59)Difference from dapagliflozin metformin(adjusted mean)(95% CI)-0.40p-value <0.0001. (-0.55, -0.24)Difference from saxagliptin metformin (adjusted mean)(95% CI)-0.32 (-0.48, -0.17)Percent of patients achieving HbA1c <7%42.821.8p-value <0.0001 vs. dapagliflozin and saxagliptin plus metformin. 28.5p-value 0.0018 vs. dapagliflozin and saxagliptin plus metformin. The adjusted mean change from baseline for body weight at Week 24, using values regardless of rescue or treatment discontinuation, was -2.0 kg for the mg dapagliflozin and mg saxagliptin plus metformin group, -2.1 kg for the mg dapagliflozin plus metformin group, and -0.4 kg for the mg saxagliptin plus metformin group. The difference in mean body weight between the mg dapagliflozin and mg saxagliptin plus metformin group and the mg dapagliflozin plus metformin group was -1.6 kg (95% CI [-2.1, -1.0]). The second study was 24-week randomized, double-blind, active comparator-controlled superiority study (NCT016060007) that compared once daily 10 mg dapagliflozin and mg saxagliptin coadministered in combination with metformin XR with either 10 mg dapagliflozin and placebo added to metformin or mg saxagliptin and placebo added to metformin in T2DM adult patients with inadequate glycemic control on metformin alone (HbA1c >=8% and <=12%). At Week 24, concomitant addition of 10 mg dapagliflozin and mg saxagliptin plus metformin resulted in statistically significant decreases in HbA1c, and larger proportion of patients achieving an HbA1c <7%, compared to dapagliflozin plus metformin or saxagliptin plus metformin (see Table 8).Table 8: HbA1c Results at Week 24 with the Combination of 10 mg Dapagliflozin and mg Saxagliptin plus MetforminAnalysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using control arm data for all subjects having missing Week 24 data. Efficacy Parameter10 mg Dapagliflozin and mg Saxagliptin Metformin10 mg Dapagliflozin and mg Saxagliptin +Metformin10 mg Dapagliflozin +Metformin5 mg Saxagliptin+MetforminNThe number of randomized subjects who took at least one dose of double-blind study medication and had baseline value for HbA1c.179179176Baseline (mean)8.98.99.0Change from baseline (adjusted mean)(95% CI)-1.49(-1.64, -1.34)-1.23(-1.38, -1.08)-1.00(-1.15, -0.85)Difference from dapagliflozin metformin(adjusted mean)(95% CI)-0.26p-value=0.0148. (-0.47, -0.05)Difference from saxagliptin metformin (adjusted mean)(95% CI)-0.49p-value <0.0001. (-0.70, -0.27)Percent of patients achieving HbA1c <7% 40.2Not statistically significant based on the prespecified method for controlling type error. 21.2 16.5 The adjusted mean change from baseline for body weight at Week 24, using values regardless of rescue or treatment discontinuation, was -2.0 kg for the 10 mg dapagliflozin and mg saxagliptin plus metformin group, -2.3 kg for the 10 mg dapagliflozin plus metformin group, and kg for the mg saxagliptin plus metformin group.. 14.2 Add-on Therapy with Saxagliptin in Patients on Dapagliflozin plus Metformin A total of 315 patients with type diabetes participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin added to dapagliflozin and metformin in patients with baseline of HbA1c >=7% to <=10.5% (NCT01619059). The mean age of these subjects was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% Other race. At baseline the population had diabetes for an average of 7.7 years and mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on stable dose of metformin (>=1500 mg per day) for at least weeks prior to enrollment. Eligible subjects who completed the screening period entered the lead-in treatment period, which included 16 weeks of open-label metformin and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to mg saxagliptin (N=153) or placebo (N=162).The group treated with add-on saxagliptin had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 9).Table 9: HbA1c Change from Baseline at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-on to Dapagliflozin and MetforminThere were 6.5% (n=10) of randomized subjects in the saxagliptin arm and 3.1% (n=5) in the placebo arm for whom change from baseline HbA1c data was missing at Week 24. Of the subjects who discontinued study medication early, 9.1% (1 of 11) in the saxagliptin arm and 16.7% (1 of 6) in the placebo arm had HbA1c measured at Week 24. Efficacy parameter5 mg Saxagliptin(N=153)N is the number of randomized and treated patients.Placebo(N=162)In combination with Dapagliflozin and MetforminHbA1c (%) at week 24Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing Week 24 data.Baseline (mean)8.07.9Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) 95% Confidence Interval-0.5(-0.6, -0.4)-0.2(-0.3, -0.1)Difference from placebo (adjusted mean) 95% Confidence Interval-0.4p-value <0.0001. (-0.5, -0.2)Percent of patients achieving HbA1c <7%35.323.1. 14.3 Cardiovascular Safety Trial The cardiovascular risk of saxagliptin was evaluated in SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction), multicenter, multinational, randomized, double-blind trial comparing saxagliptin (N=8280) to placebo (N=8212), in adult patients with type diabetes at high risk for atherosclerotic cardiovascular disease. Of the randomized study subjects, 97.5% completed the trial, and the median duration of follow-up was approximately years (NCT01107886).Subjects were at least 40 years of age, had HbA1c >=6.5%, and multiple risk factors (21% of randomized subjects) for cardiovascular disease (age >=55 years for men and >=60 years for women plus at least one additional risk factor of dyslipidemia, hypertension, or current cigarette smoking) or established (79% of the randomized subjects) cardiovascular disease defined as history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. Overall, the use of diabetes medications was balanced across treatment groups (metformin 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%).The majority of subjects were male (67%) and Caucasian (75%) with mean age of 65 years. Approximately 16% of the population had moderate (eGFR >=30 to <=50 mL/min/1.73 m2) to severe (eGFR <30 mL/min/1.73 m2) renal impairment, and 13% had prior history of heart failure. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2. Subjects had median duration of type diabetes mellitus of approximately 10 years and mean baseline HbA1c level of 8.0%.The primary analysis in SAVOR was time to first occurrence of Major Adverse Cardiac Event (MACE). major adverse cardiac event in SAVOR was defined as cardiovascular death or nonfatal myocardial infarction (MI) or nonfatal ischemic stroke. The incidence rate of MACE was similar in both treatment arms: 3.8 MACE per 100 patient-years on placebo vs. 3.8 MACE per 100 patient-years on saxagliptin with an estimated HR: 1.0; 95.1% CI: (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded risk margin larger than 1.3.Vital status was obtained for 99% of subjects in the trial. There were 798 deaths in the SAVOR trial. Numerically more patients (5.1%) died in the saxagliptin group than in the placebo group (4.6%). The risk of deaths from all-cause mortality was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters. (8.1) Lactation: QTERN is not recommended when breastfeeding. (8.2)Geriatrics: Higher incidence of adverse reactions related to volume depletion and reduced renal function. (5.3, 5.5, 8.5)Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (5.5, 8.6). 8.1 Pregnancy Risk SummaryBased 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 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 rats when dapagliflozin (a component of QTERN) was administered during period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data).No adverse developmental effects were observed when saxagliptin was administered to pregnant rats and rabbits (see Data). The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with an HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.DataAnimal DataDapagliflozinDapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation Day through lactation Day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21 day-old pup offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater than or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at mg/kg/day, (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).SaxagliptinIn embryofetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.In prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day through lactation day 21 at exposures up to 470-times the mg clinical dose, based on AUC.. 8.2 Lactation Risk SummaryThere is no information regarding the presence of QTERN or its components (dapagliflozin and saxagliptin) in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin and saxagliptin are present in the milk of lactating rats (see Data). However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in breastfed infant, advise women that use of QTERN is not recommended while breastfeeding.DataDapagliflozinDapagliflozin was present at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.SaxagliptinSaxagliptin is secreted in the milk of lactating rats at approximately 1:1 ratio with plasma drug concentrations.. 8.4 Pediatric Use Safety and effectiveness of QTERN in patients under 18 years of age have not been established.. 8.5 Geriatric Use Because elderly patients are more likely to have decreased renal function, care should be taken when using QTERN in the elderly based on renal function [see DOSAGE AND ADMINISTRATION (2.2) ].DapagliflozinA total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), in clinical studies with dapagliflozin, efficacy was similar for patients under age 65 years and those 65 years and older. In patients 65 years and older, higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see WARNINGS AND PRECAUTIONS (5.3) ].SaxagliptinIn the seven double-blind, controlled clinical safety and efficacy trials of saxagliptin, total of 4751 (42.0%) of the 11,301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects >=65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal Impairment QTERN is contraindicated in patients with moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), ESRD, or on dialysis [see DOSAGE AND ADMINISTRATION (2.3) CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.5) ]. DapagliflozinDapagliflozin was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2, and an eGFR of 30 to less than 60 mL/min/1.73 m2). The safety profile of dapagliflozin in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type diabetes. Although patients in the dapagliflozin arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation. Patients with renal impairment using dapagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo. 8.7 Hepatic Impairment QTERN may be used in patients with hepatic impairment. However, the benefit-risk for the use of QTERN in patients with severe hepatic impairment should be individually assessed since safety and efficacy have not been studied in this population [see CLINICAL PHARMACOLOGY (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Pancreatitis: If pancreatitis is suspected, promptly discontinue QTERN. (5.1, 6.2) Heart Failure: Consider the risks and benefits of QTERN in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2) Hypotension: Before initiating QTERN, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.3, 6.1) Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue QTERN, evaluate and treat promptly. Before initiating QTERN, consider risk factors for ketoacidosis. Patients on QTERN may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.4, 6.2) Acute Kidney Injury: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy. (5.5, 6.2) Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.6, 6.2) Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating QTERN. (5.7, 6.1)Necrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.8) Hypersensitivity Reactions (e.g., urticaria, facial edema): There have been postmarketing reports of serious hypersensitivity reactions treated with saxagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue QTERN, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.9, 6.2) Genital Mycotic Infections: Monitor and treat if indicated. (5.10, 6.1) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.11, 6.1, 6.2) Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue QTERN. (5.12) Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with QTERN. (5.13) 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. In cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo.After initiation of QTERN, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue QTERN and initiate appropriate management. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using QTERN.. 5.2 Heart Failure In cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with prior history of heart failure and subjects with renal impairment had higher risk for hospitalization for heart failure, irrespective of treatment assignment.Consider the risks and benefits of QTERN prior to initiating treatment in patients at higher risk of heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of QTERN.. 5.3 Hypotension Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating QTERN [see ADVERSE REACTIONS (6.1) particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Before initiating QTERN volume status should be assessed and corrected. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2. Monitor for signs and symptoms of hypotension after initiating therapy.. 5.4 Ketoacidosis Reports of ketoacidosis, serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type and type diabetes mellitus receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERN is not indicated for the treatment of patients with type diabetes mellitus [see INDICATIONS AND USAGE (1)].Patients treated with QTERN who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with QTERN may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, QTERN should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement.In many of the postmarketing reports for dapagliflozin, and particularly in patients with type diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.Before initiating QTERN, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo elective surgery, consider temporarily discontinuing QTERN for at least days prior to surgery [see Clinical Pharmacology (12.2, 12.3)]. Consider monitoring for ketoacidosis and temporarily discontinuing QTERN in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post surgery) [see ADVERSE REACTIONS (6.2)]. Ensure risk factors for ketoacidosis are resolved prior to restarting QTERN.Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue QTERN and seek medical attention immediately if signs and symptoms occur.. 5.5 Acute Kidney Injury. Dapagliflozin causes intravascular volume contraction [see WARNINGS AND PRECAUTIONS (5.3)], and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving dapagliflozin. Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of QTERN. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating QTERN, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, and NSAIDs). Consider temporarily discontinuing QTERN in the setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue QTERN promptly and institute treatment.Renal function should be evaluated prior to initiation of QTERN and monitored periodically thereafter. QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see DOSAGE AND ADMINISTRATION (2.3), CONTRAINDICATIONS (4) and USE IN SPECIFIC POPULATIONS (8.6)].. 5.6 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see ADVERSE REACTIONS (6.2) ].. 5.7 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Both dapagliflozin and saxagliptin can individually increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia when these agents are used in combination with QTERN [see ADVERSE REACTIONS (6.1) ].. 5.8 Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) Reports of necrotizing fasciitis of the perineum (Fourniers Gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with QTERN presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue QTERN, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.9 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylactic reactions, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue QTERN, treat per standard of care, and monitor until signs and symptoms are resolved. Assess for other potential causes for the event. Institute alternative treatment for diabetes.Use caution in patient with history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin.. 5.10 Genital Mycotic Infections Dapagliflozin increases the risks of genital mycotic infections. Patients with history of genital mycotic infections were more likely to develop genital mycotic infections [see ADVERSE REACTIONS (6.1) ]. Monitor and treat appropriately.. 5.11 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. subset of patients experienced recurrence of symptoms restarting the same drug or different DPP-4 inhibitor. Consider DPP-4 inhibitors as possible cause for severe joint pain and discontinue drug if appropriate [see ADVERSE REACTIONS (6) ]. 5.12 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving QTERN. If bullous pemphigoid is suspected, QTERN should be discontinued and referral to dermatologist should be considered for diagnosis and appropriate treatment.. 5.13 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with QTERN.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS QTERN is contraindicated in patients with:oHistory of serious hypersensitivity reaction to dapagliflozin or to saxagliptin, including anaphylactic reactions, angioedema or exfoliative skin conditions [see WARNINGS AND PRECAUTIONS (5.9) and ADVERSE REACTIONS (6.1)].oModerate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis [see USE IN SPECIFIC POPULATIONS (8.6)].. oHistory of serious hypersensitivity reaction to dapagliflozin or to saxagliptin, including anaphylactic reactions, angioedema or exfoliative skin conditions [see WARNINGS AND PRECAUTIONS (5.9) and ADVERSE REACTIONS (6.1)].. oModerate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis [see USE IN SPECIFIC POPULATIONS (8.6)].. QTERN is contraindicated in patients with:oHistory of serious hypersensitivity reaction to dapagliflozin or to saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions. (4, 5.8, 6.2)oModerate to severe renal impairment (eGFR <45 mL/min/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis. (4). oHistory of serious hypersensitivity reaction to dapagliflozin or to saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions. (4, 5.8, 6.2). oModerate to severe renal impairment (eGFR <45 mL/min/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis. (4).

DESCRIPTION SECTION.


11 DESCRIPTION QTERN tablets for oral use contain dapagliflozin and saxagliptin. Dapagliflozin propanediol is an active inhibitor of sodium-glucose cotransporter (SGLT2). It is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-. Dapagliflozin is compounded with (2S)-1,2-propanediol, hydrate (1:1:1) with an empirical formula as C21H25ClO6oC3H8O2oH2O and the molecular weight of 502.98. The structural formula is:Saxagliptin is an active inhibitor of the dipeptidyl-peptidase-4 (DPP-4) enzyme. It is isolated in the monohydrate form chemically known as (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo [3.3.1.1] dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C18H25N3O2oH2O and the molecular weight is 333.43. The structural formula is:QTERN is available as film-coated tablets of two strengths:o5 mg dapagliflozin/5 mg saxagliptin. Each tablet contains mg dapagliflozin (equivalent to 6.15 mg dapagliflozin propanediol) and mg saxagliptin (exists in the form of HCl salt). o10 mg dapagliflozin/5 mg saxagliptin. Each tablet contains 10 mg dapagliflozin (equivalent to 12.3 mg dapagliflozin propanediol) and mg saxagliptin (exists in the form of HCl salt).Each tablet also contains the following inactive ingredients: anhydrous lactose, croscarmellose sodium, iron oxides, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, silicon dioxide, talc, and titanium dioxide. Hydrochloric acid and sodium hydroxide (if needed) are added for pH adjustment.. o5 mg dapagliflozin/5 mg saxagliptin. Each tablet contains mg dapagliflozin (equivalent to 6.15 mg dapagliflozin propanediol) and mg saxagliptin (exists in the form of HCl salt). o10 mg dapagliflozin/5 mg saxagliptin. Each tablet contains 10 mg dapagliflozin (equivalent to 12.3 mg dapagliflozin propanediol) and mg saxagliptin (exists in the form of HCl salt).. dapagliflozin chemical structure. Saxagliptin checmical structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION oAssess renal function before initiation of therapy and periodically thereafter. (2.1)oTake QTERN orally, once daily in the morning with or without food. (2.2)oFor patients not already taking dapagliflozin, the recommended starting dose of QTERN is 5 mg dapagliflozin/5 mg saxagliptin tablet once daily. (2.2)oIn patients tolerating mg dapagliflozin and mg saxagliptin once daily who require additional glycemic control, the QTERN dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily. (2.2)oDo not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors. (2.4, 7)oSwallow tablet whole. Do not crush, cut or chew. (2.2). oAssess renal function before initiation of therapy and periodically thereafter. (2.1). oTake QTERN orally, once daily in the morning with or without food. (2.2). oFor patients not already taking dapagliflozin, the recommended starting dose of QTERN is 5 mg dapagliflozin/5 mg saxagliptin tablet once daily. (2.2). oIn patients tolerating mg dapagliflozin and mg saxagliptin once daily who require additional glycemic control, the QTERN dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily. (2.2). oDo not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors. (2.4, 7). oSwallow tablet whole. Do not crush, cut or chew. (2.2). 2.1 Prior to Initiation of QTERN. Assess renal function prior to initiation of QTERN therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS (5.5)].In patients with volume depletion, correct this condition prior to initiation of QTERN [see WARNINGS AND PRECAUTIONS (5.3) and USE IN SPECIFIC POPULATIONS (8.5, 8.6)]. 2.2 Dosage. For patients not already taking dapagliflozin, the recommended starting dose of QTERN is 5 mg dapagliflozin/5 mg saxagliptin tablet taken orally once daily in the morning with or without food.In patients tolerating mg dapagliflozin and mg saxagliptin once daily who require additional glycemic control, the QTERN dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily in the morning with or without food.Swallow whole. Do not crush, cut or chew QTERN tablets.. 2.3 Patients with Renal Impairment. No dose adjustment is needed in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m2.QTERN is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see CONTRAINDICATIONS (4) and USE IN SPECIFIC POPULATIONS (8.6)].. 2.4 Use with Strong CYP3A4/5 Inhibitors Do not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see DRUG INTERACTIONS (7) ].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Tablets:o5 mg dapagliflozin/5 mg saxagliptin as light purple to reddish purple, biconvex, round, film-coated tablet, with 1120 printed on both sides, in blue ink.o10 mg dapagliflozin/5 mg saxagliptin as light brown to brown, biconvex, round, film-coated tablet, with 1122 printed on both sides, in blue ink.. o5 mg dapagliflozin/5 mg saxagliptin as light purple to reddish purple, biconvex, round, film-coated tablet, with 1120 printed on both sides, in blue ink.. o10 mg dapagliflozin/5 mg saxagliptin as light brown to brown, biconvex, round, film-coated tablet, with 1122 printed on both sides, in blue ink.. oTablet: mg dapagliflozin/5 mg saxagliptin (3)oTablet: 10 mg dapagliflozin/5 mg saxagliptin (3). oTablet: mg dapagliflozin/5 mg saxagliptin (3). oTablet: 10 mg dapagliflozin/5 mg saxagliptin (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Table 2: Clinically Relevant Interactions Affecting Drugs Coadministered with QTERNStrong Inhibitors of CYP3A4/5 EnzymesClinical ImpactKetoconazole 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).InterventionDo not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3) ].Positive Urine Glucose TestClinical ImpactSGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.InterventionMonitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.Interference with 1,5-anhydroglucitol (1,5-AG) AssayClinical ImpactMeasurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.InterventionMonitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.. Strong CYP3A4/5 Inhibitors (e.g., Ketoconazole): Do not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors. (2.3, 7).

GERIATRIC USE SECTION.


8.5 Geriatric Use Because elderly patients are more likely to have decreased renal function, care should be taken when using QTERN in the elderly based on renal function [see DOSAGE AND ADMINISTRATION (2.2) ].DapagliflozinA total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), in clinical studies with dapagliflozin, efficacy was similar for patients under age 65 years and those 65 years and older. In patients 65 years and older, higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see WARNINGS AND PRECAUTIONS (5.3) ].SaxagliptinIn the seven double-blind, controlled clinical safety and efficacy trials of saxagliptin, total of 4751 (42.0%) of the 11,301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects >=65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

LACTATION SECTION.


8.2 Lactation Risk SummaryThere is no information regarding the presence of QTERN or its components (dapagliflozin and saxagliptin) in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin and saxagliptin are present in the milk of lactating rats (see Data). However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in breastfed infant, advise women that use of QTERN is not recommended while breastfeeding.DataDapagliflozinDapagliflozin was present at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.SaxagliptinSaxagliptin is secreted in the milk of lactating rats at approximately 1:1 ratio with plasma drug concentrations.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action QTERN contains: dapagliflozin, sodium-glucose cotransporter (SGLT2) inhibitor, and saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor. Dapagliflozin Sodium-glucose cotransporter (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.Saxagliptin Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility QTERNNo animal studies have been conducted with the combined products in QTERN to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and saxagliptin individually.Dapagliflozin CarcinogenesisCarcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Dapagliflozin did not increase the incidence of tumors in mice dosed orally at 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females (exposure less than or equal to 72-times (males) and 105-times (females) the 10 mg/day clinical dose, based on AUC). Dapagliflozin did not increase the incidence of tumors in rats (both males and females) dosed orally at 0.5, 2, and 10 mg/kg/day (exposure less than or equal to 131-times (males) and 186-times (females) the clinical dose of 10 mg/day, based on AUC).MutagenesisDapagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Dapagliflozin was mutagenic in series of in vitro clastogenicity assays at concentrations greater than or equal to 100 micrograms per mL, but not without metabolic activation. Dapagliflozin was not mutagenic or clastogenic in series of in vivo studies evaluating micronuclei or DNULL repair in rats at exposure multiples greater than 2100-times the clinical dose.Impairment of FertilityDapagliflozin had no effects on the ability of rats to mate and sire, maintain litter, or early embryonic development at exposure multiples less than or equal to 1708- and 998-times the maximum recommended human doses of 10 mg/day (based on AUC) in males and females, respectively.Saxagliptin CarcinogenesisCarcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1165-times (females) the mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females) the mg/day clinical dose, based on AUC.MutagenesisSaxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNULL repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.Impairment of FertilitySaxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC.. 13.2 Animal Toxicology and/or Pharmacology Saxagliptin Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

OVERDOSAGE SECTION.


10 OVERDOSAGE In the event of an overdose, contact the Poison Control Center. Appropriate supportive treatment should be initiated as dictated by the patients clinical status. The removal of dapagliflozin by hemodialysis has not been studied. Saxagliptin and its major metabolite can be removed by hemodialysis (23% of dose over hours).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 5 mg/5 mg 30 tablets NDC 0310-6770-30Qtern(R) (dapagliflozin and saxagliptin)tablets mg/5 mg Dispense with Enclosed Medication GuideRx onlyMfd. for: AstraZeneca Pharmaceuticals LPWilmington, DE 19850AstraZeneca. 5mg5mg.

PEDIATRIC USE SECTION.


8.4 Pediatric Use Safety and effectiveness of QTERN in patients under 18 years of age have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics Dapagliflozin Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin. Dapagliflozin dose of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see ADVERSE REACTIONS (6.1) ]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about days from discontinuation for the 10 mg dose.Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type Diabetes Mellitus (T2DM) (Semi-Log Plot)Saxagliptin In patients with type diabetes mellitus, administration of saxagliptin inhibits DPP-4 enzyme activity for 24-hour period. After an oral glucose load or meal, this DPP-4 inhibition resulted in 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or meal.Cardiac ElectrophysiologyDapagliflozin Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum daily dose) of dapagliflozin in healthy subjects.Saxagliptin In randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the recommended maximum daily dose).. Figure 1.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics Overall, the pharmacokinetics of dapagliflozin and saxagliptin were not affected in clinically relevant manner when administered as QTERN. Saxagliptin The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.AbsorptionDapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately hour but does not alter AUC as compared with the fasted state. Saxagliptin The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions.DistributionDapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.Saxagliptin The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.MetabolismDapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.Saxagliptin The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see DRUG INTERACTIONS (7) ].EliminationDapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t1/2) for dapagliflozin is approximately 12.9 hours following single oral dose of dapagliflozin 10 mg.Saxagliptin Saxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of [14C]-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.Specific PopulationsEffects of Age, Gender, Race and Body Weight on PharmacokineticsBased on population pharmacokinetic analysis, age, gender, race, and body weight do not have clinically meaningful effect on the pharmacokinetics of saxagliptin and dapagliflozin.Renal ImpairmentDapagliflozinAt steady state (20 mg once daily dapagliflozin for days), patients with type diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see DOSAGE AND ADMINISTRATION (2.2) WARNINGS AND PRECAUTIONS (5.5) and USE IN SPECIFIC POPULATIONS (8.6) ].SaxagliptinA single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment (eGFR 30 to less than 45 mL/min/1.73 m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m2.Hepatic ImpairmentDapagliflozinIn subjects with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see USE IN SPECIFIC POPULATIONS (8.7) ].SaxagliptinIn subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.PediatricPharmacokinetics of QTERN in the pediatric population has not been studied. Drug InteractionsSaxagliptin and DapagliflozinThe lack of pharmacokinetic interaction between dapagliflozin and saxagliptin was demonstrated in drug-drug interaction study between dapagliflozin and saxagliptin.DapagliflozinIn Vitro Assessment of Drug InteractionsThe metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.Effects of Other Drugs on DapagliflozinTable shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin.Table 3: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug (Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)DapagliflozinChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Oral Antidiabetic Agents Metformin (1000 mg)20 mg1%7% Pioglitazone (45 mg)50 mg0%9% Sitagliptin (100 mg)20 mg8%4% Glimepiride (4 mg)20 mg1%1% Voglibose (0.2 mg three times daily)10 mg1%4% Saxagliptin (5 mg single dose)10 mg (single dose)2%6%Other Medications Hydrochlorothiazide (25 mg)50 mg7%1% Bumetanide (1 mg)10 mg once daily for days5%8% Valsartan (320 mg)20 mg2%12% Simvastatin (40 mg)20 mg1%2%Anti-infective Agent Rifampin (600 mg once daily for days)10 mg22%7%Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg51%13%Effects of Dapagliflozin on Other DrugsTable shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 4: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug (Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Coadministered Drug ChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Oral Antidiabetic Agents Metformin (1000 mg)20 mg0%5% Pioglitazone (45 mg)50 mg0%7% Sitagliptin (100 mg)20 mg1%11% Glimepiride (4 mg)20 mg13%4%Other Medications Hydrochlorothiazide (25 mg)50 mg1%5% Bumetanide (1 mg)10 mg once daily for days13%13% Valsartan (320 mg)20 mg5%6% Simvastatin (40 mg)20 mg19%6% Digoxin (0.25 mg)20 mg loading dose then 10 mg once daily for days0%1% Warfarin (25 mg) S-warfarin R-warfarin20 mg loading dose then 10 mg once daily for days3%6%7%8%Saxagliptin In Vitro Assessment of Drug InteractionsThe metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substrate but is not significant inhibitor or inducer of P-gp. Effects of Other Drugs on Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinTable 5: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCoadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted.Dosage of SaxagliptinSaxagliptinChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Change in Cmax Metformin1000 mg100 mgsaxagliptin5-hydroxy saxagliptin2%1%21%12%Glyburide5 mg10 mgsaxagliptin5-hydroxy saxagliptin2%ND8%NDPioglitazoneResults exclude one subject. 45 mg QD for 10 days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin11%ND11%NDDapagliflozin10 mg single dose5 mg single dosesaxagliptin5-hydroxy saxagliptin1%9%7%6%Digoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin5%6%1%2%Simvastatin40 mg QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin12%2%21%8%Diltiazem360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin109%34%63%43%RifampinThe plasma dipeptidyl peptidase-4 (DPP-4) activity inhibition over 24-hour dose interval was not affected by rifampin. 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin76%3%53%39%Omeprazole40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin13%ND2%NDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone:240 mg10 mgsaxagliptin5-hydroxy saxagliptin3%ND26%NDFamotidine40 mg10 mgsaxagliptin5-hydroxy saxagliptin3%ND14%NDSaxagliptin coadministered with strong CYP3A4/5 inhibitors [see DRUG INTERACTIONS (7) and DOSAGE AND ADMINISTRATION (2.3)]:Ketoconazole200 mg BID for days100 mgsaxagliptin5-hydroxy saxagliptin145%88%62%95%Ketoconazole200 mg BID for days20 mgsaxagliptin5-hydroxy saxagliptin267%ND144%NDND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.Effects of Saxagliptin on Other Drugs Table 6: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsCoadministered DrugDosage ofCoadministered DrugSingle dose unless otherwise noted.Dosage of SaxagliptinCoadministered DrugChangePercent change (with/without coadministered drug and no change=0%); and indicate the exposure increase and decrease, respectively. in AUCAUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.Changein CmaxMetformin1000 mg100 mgmetformin20%9%Glyburide5 mg10 mgglyburide6%16%PioglitazoneResults include all subjects. 45 mg QD for 10 days10 mg QDfor dayspioglitazonehydroxy-pioglitazone8%ND14%NDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor daysdigoxin6%9%Simvastatin40 mg QD for days10 mg QDfor dayssimvastatinsimvastatin acid4%16%12%0%Diltiazem360 mg LA QD for days10 mgdiltiazem10%16%Ketoconazole200 mg BID for days100 mgketoconazole13%16%Ethinyl estradiol and Norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiol norelgestrominnorgestrel7%10%13%2%9%17% ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.. ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk SummaryBased 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 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 rats when dapagliflozin (a component of QTERN) was administered during period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data).No adverse developmental effects were observed when saxagliptin was administered to pregnant rats and rabbits (see Data). The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with an HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.DataAnimal DataDapagliflozinDapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation Day through lactation Day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21 day-old pup offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater than or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at mg/kg/day, (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).SaxagliptinIn embryofetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.In prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day through lactation day 21 at exposures up to 470-times the mg clinical dose, based on AUC.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1) 05/2019Dosage and Administration (2.1, 2.2, 2.3) 05/2019Warnings and Precautions (5.4, 5.5) 01/2020Warnings and Precautions (5.11, 5.12) Removed 01/2020.

SPL MEDGUIDE SECTION.


MEDICATION GUIDEQTERN(R) (CUE-turn)(dapagliflozin and saxagliptin)tablets, for oral useWhat is the most important information should know about QTERNSerious side effects can happen to people taking QTERN, including:oInflammation of the pancreas (pancreatitis). Saxagliptin, one of the medicines in QTERN, can cause inflammation of the pancreas, which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking QTERN, tell your healthcare provider if you have ever had:inflammation of your pancreas (pancreatitis)stones in your gallbladder (gallstones)a history of alcoholismhigh blood triglyceride levels It is not known if having these medical problems will make you more likely to get pancreatitis with QTERN.Stop taking QTERN and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.oHeart failure. Heart failure means your heart does not pump blood well enough. Before you start taking QTERN, tell your healthcare provider if you have ever had heart failure or have problems with your kidneys.Contact your healthcare provider right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles, or legsan unusually fast increase in weightunusual tiredness These may be symptoms of heart failure.oDehydration. QTERN can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you:have low blood pressuretake medicines to lower your blood pressure, including water pills (diuretics)are 65 years of age or olderare on low salt diethave kidney problems What is QTERNQTERN is prescription medicine that contains dapagliflozin and saxagliptin. QTERN is used along with diet and exercise to improve blood sugar (glucose) control in adults with type diabetes.oQTERN is not for people with type diabetes. oQTERN is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).oIt is not known if QTERN is safe and effective in children younger than 18 years of age.Who should not take QTERNDo not take QTERN if you:oare allergic to dapagliflozin, saxagliptin, or any of the ingredients in QTERN. See the end of this Medication Guide for list of ingredients in QTERN. Symptoms of serious allergic reaction to QTERN may include:swelling of the face, lips, throat and other areas of your skindifficulty with swallowing or breathingskin rash, itching, flaking, or peelingraised red areas on your skin (hives) If you have any of these symptoms, stop taking QTERN and contact your healthcare provider or go to the nearest hospital emergency room right away.ohave moderate to severe kidney problems or are on dialysis.Before taking QTERN, tell your healthcare provider about all of your medical conditions, including if you:ohave type diabetes or have had diabetic ketoacidosis (increased ketones in your blood or urine). oare going to have surgery. Your doctor may stop your QTERN before you have surgery. Talk to your doctor if you are having surgery about when to stop taking QTERN and when to start it again.oare eating less, or there is change in your diet.odrink alcohol very often or drink lot of alcohol in the short term (binge drinking).ohave kidney problems.ohave liver problems.ohave history of urinary tract infections or problems urinating.ohave heart problems, including heart failure.ohave had history of swelling of the face, lips, tongue and throat (angioedema) when you have taken dipeptidyl peptidase (DPP-4) inhibitor like saxagliptin one of the medicines in QTERN. If you are not sure if you have taken this medicine before, ask your healthcare provider.ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.oare pregnant or plan to become pregnant. QTERN may harm your unborn baby. If you are pregnant or plan to become pregnant, talk to your healthcare provider about the best way to control your blood sugar.oare breastfeeding or plan to breastfeed. It is not known if QTERN passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking QTERN. Breastfeeding is not recommended while taking QTERN.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.QTERN may affect the way other medicines work, and other medicines may affect how QTERN works. Contact your healthcare provider if you will be starting or stopping certain other types of medicines such as antibiotics or medicines that treat fungus or HIV/AIDS, because your dose of QTERN might need to be changed.How should take QTERNoTake QTERN exactly as your healthcare provider tells you to take it.oDo not change your dose of QTERN without talking to your healthcare provider.oTake QTERN by mouth time each day in the morning with or without food.oSwallow QTERN whole. Do not cut, crush or chew QTERN tablets.oDuring periods of stress on the body, such as fever, trauma, infection, or surgery, contact your healthcare provider right away as your medicine may need to be changed.oStay on your prescribed diet and exercise program while taking QTERN.oYour healthcare provider may do certain blood tests before you start QTERN and during your treatment.oYour healthcare provider should test your blood to measure how well your kidneys are working before and during your treatment with QTERN.oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your HbA1c.oQTERN will cause your urine to test positive for glucose.oFollow your healthcare providers instructions for treating low blood sugar (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you.oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take doses of QTERN at the same time unless your healthcare provider tells you to do so. Talk to your healthcare provider if you have questions about missed dose.oIf you take too much QTERN, call your healthcare provider, or go to the nearest hospital emergency room right away.What are the possible side effects of QTERNQTERN may cause serious side effects, including:oSee What is the most important information should know about QTERNoKetoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type or type diabetes, during treatment with dapagliflozin, one of the medicines in QTERN. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with dapagliflozin Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with dapagliflozin even if your blood sugar is less than 250 mg/dL. Stop taking QTERN and call your healthcare provider right away if you get any of the following symptoms: nauseatirednessvomitingtrouble breathingstomach area (abdominal) painIf you get any of these symptoms during treatment with QTERN, if possible check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.oKidney problems. Sudden kidney injury has happened to people taking dapagliflozin. Talk to your healthcare provider right away if you:reduce the amount of food or liquid you drink, for example if you are sick and cannot eat, oryou start to lose liquids from your body with vomiting, diarrhea or being in the sun too long. oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking dapagliflozin. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.oLow blood sugar (hypoglycemia). If you take QTERN with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, this can increase your risk of getting low blood sugar. Tell your healthcare provider if you take other diabetes medicines. Signs and symptoms of low blood sugar may include:shaking or feeling jitteryhungerchange in moodsweatingheadacheconfusionrapid heartbeatdrowsinessirritabilitychange in visionweaknessoA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take dapagliflozin, one of the medicines in QTERN. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: pain or tenderness swelling redness of skin (erythema)oSerious allergic reaction. QTERN may cause serious allergic reactions. Stop taking QTERN and get medical help right away if you develop any of the following symptoms of serious allergic reaction including:swelling of the face, lips, tongue, and throat and other areas of your skindifficulty with swallowing or breathingskin rash, itching, flaking, or peelingraised red patches on your skin (hives)oVaginal yeast infection. Women who take QTERN may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itchingoYeast infection of the penis (balanitis). Men who take QTERN may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medicine and your symptoms do not go away.oJoint pain. Some people who take DPP-4 inhibitors like saxagliptin, may develop joint pain that can be severe. Call your healthcare provider right away if you have severe joint pain.oSkin reaction. Some people who take DPP-4 inhibitors like saxagliptin, one of the medicines in QTERN, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking QTERN.The most common side effects of QTERN include:oupper respiratory tract infectionourinary tract infectionoabnormal amounts of fats in the blood (dyslipidemia)These are not all of the possible side effects of QTERN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store QTERNStore QTERN at room temperature between 68F to 77F (20C to 25C).Keep QTERN and all medicines out of the reach of children.General information about the safe and effective use of QTERN.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use QTERN for condition for which it was not prescribed. Do not give QTERN to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or healthcare provider for information about QTERN that is written for health professionals.What are the ingredients in QTERNULLctive ingredients: dapagliflozin and saxagliptinInactive ingredients: anhydrous lactose, croscarmellose sodium, iron oxides, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, silicon dioxide, talc, and titanium dioxide.QTERN is registered trademark of the AstraZeneca group of companies.Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850For more information about QTERN, go to www.QTERN.com or call 1-800-236-9933.This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 01/2020. oInflammation of the pancreas (pancreatitis). Saxagliptin, one of the medicines in QTERN, can cause inflammation of the pancreas, which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking QTERN, tell your healthcare provider if you have ever had:inflammation of your pancreas (pancreatitis)stones in your gallbladder (gallstones)a history of alcoholismhigh blood triglyceride levels inflammation of your pancreas (pancreatitis). stones in your gallbladder (gallstones). history of alcoholism. high blood triglyceride levels. It is not known if having these medical problems will make you more likely to get pancreatitis with QTERN.Stop taking QTERN and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.. oHeart failure. Heart failure means your heart does not pump blood well enough. Before you start taking QTERN, tell your healthcare provider if you have ever had heart failure or have problems with your kidneys.Contact your healthcare provider right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles, or legsan unusually fast increase in weightunusual tiredness increasing shortness of breath or trouble breathing, especially when you lie down. swelling or fluid retention, especially in the feet, ankles, or legs. an unusually fast increase in weight. unusual tiredness. These may be symptoms of heart failure.. oDehydration. QTERN can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you:have low blood pressuretake medicines to lower your blood pressure, including water pills (diuretics)are 65 years of age or olderare on low salt diethave kidney problems have low blood pressure. take medicines to lower your blood pressure, including water pills (diuretics). are 65 years of age or older. are on low salt diet. have kidney problems. oQTERN is not for people with type diabetes. oQTERN is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).. oIt is not known if QTERN is safe and effective in children younger than 18 years of age.. oare allergic to dapagliflozin, saxagliptin, or any of the ingredients in QTERN. See the end of this Medication Guide for list of ingredients in QTERN. Symptoms of serious allergic reaction to QTERN may include:swelling of the face, lips, throat and other areas of your skindifficulty with swallowing or breathingskin rash, itching, flaking, or peelingraised red areas on your skin (hives) swelling of the face, lips, throat and other areas of your skin. difficulty with swallowing or breathing. skin rash, itching, flaking, or peeling. raised red areas on your skin (hives). If you have any of these symptoms, stop taking QTERN and contact your healthcare provider or go to the nearest hospital emergency room right away.. ohave moderate to severe kidney problems or are on dialysis.. ohave type diabetes or have had diabetic ketoacidosis (increased ketones in your blood or urine). oare going to have surgery. Your doctor may stop your QTERN before you have surgery. Talk to your doctor if you are having surgery about when to stop taking QTERN and when to start it again.. oare eating less, or there is change in your diet.. odrink alcohol very often or drink lot of alcohol in the short term (binge drinking).. ohave kidney problems.. ohave liver problems.. ohave history of urinary tract infections or problems urinating.. ohave heart problems, including heart failure.. ohave had history of swelling of the face, lips, tongue and throat (angioedema) when you have taken dipeptidyl peptidase (DPP-4) inhibitor like saxagliptin one of the medicines in QTERN. If you are not sure if you have taken this medicine before, ask your healthcare provider.. ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. oare pregnant or plan to become pregnant. QTERN may harm your unborn baby. If you are pregnant or plan to become pregnant, talk to your healthcare provider about the best way to control your blood sugar.. oare breastfeeding or plan to breastfeed. It is not known if QTERN passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking QTERN. Breastfeeding is not recommended while taking QTERN.. oTake QTERN exactly as your healthcare provider tells you to take it.. oDo not change your dose of QTERN without talking to your healthcare provider.. oTake QTERN by mouth time each day in the morning with or without food.. oSwallow QTERN whole. Do not cut, crush or chew QTERN tablets.. oDuring periods of stress on the body, such as fever, trauma, infection, or surgery, contact your healthcare provider right away as your medicine may need to be changed.. oStay on your prescribed diet and exercise program while taking QTERN.. oYour healthcare provider may do certain blood tests before you start QTERN and during your treatment.. oYour healthcare provider should test your blood to measure how well your kidneys are working before and during your treatment with QTERN.. oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your HbA1c.. oQTERN will cause your urine to test positive for glucose.. oFollow your healthcare providers instructions for treating low blood sugar (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you.. oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take doses of QTERN at the same time unless your healthcare provider tells you to do so. Talk to your healthcare provider if you have questions about missed dose.. oIf you take too much QTERN, call your healthcare provider, or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about QTERN. oKetoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type or type diabetes, during treatment with dapagliflozin, one of the medicines in QTERN. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with dapagliflozin Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with dapagliflozin even if your blood sugar is less than 250 mg/dL. Stop taking QTERN and call your healthcare provider right away if you get any of the following symptoms: nausea. tiredness. vomiting. trouble breathing. stomach area (abdominal) pain. oKidney problems. Sudden kidney injury has happened to people taking dapagliflozin. Talk to your healthcare provider right away if you:reduce the amount of food or liquid you drink, for example if you are sick and cannot eat, oryou start to lose liquids from your body with vomiting, diarrhea or being in the sun too long. reduce the amount of food or liquid you drink, for example if you are sick and cannot eat, or. you start to lose liquids from your body with vomiting, diarrhea or being in the sun too long.. oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking dapagliflozin. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.. oLow blood sugar (hypoglycemia). If you take QTERN with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, this can increase your risk of getting low blood sugar. Tell your healthcare provider if you take other diabetes medicines. Signs and symptoms of low blood sugar may include:. shaking or feeling jittery. hunger. change in mood. sweating. headache. confusion. rapid heartbeat. drowsiness. irritability. change in vision. weakness. oA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take dapagliflozin, one of the medicines in QTERN. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: pain or tenderness. pain or tenderness. swelling. swelling. redness of skin (erythema). redness of skin (erythema). oSerious allergic reaction. QTERN may cause serious allergic reactions. Stop taking QTERN and get medical help right away if you develop any of the following symptoms of serious allergic reaction including:swelling of the face, lips, tongue, and throat and other areas of your skindifficulty with swallowing or breathingskin rash, itching, flaking, or peelingraised red patches on your skin (hives). swelling of the face, lips, tongue, and throat and other areas of your skin. difficulty with swallowing or breathing. skin rash, itching, flaking, or peeling. raised red patches on your skin (hives). oVaginal yeast infection. Women who take QTERN may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching. vaginal odor. white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). vaginal itching. oYeast infection of the penis (balanitis). Men who take QTERN may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around the penis redness, itching, or swelling of the penis. rash of the penis. foul smelling discharge from the penis. pain in the skin around the penis. oJoint pain. Some people who take DPP-4 inhibitors like saxagliptin, may develop joint pain that can be severe. Call your healthcare provider right away if you have severe joint pain.. oSkin reaction. Some people who take DPP-4 inhibitors like saxagliptin, one of the medicines in QTERN, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking QTERN.. oupper respiratory tract infection. ourinary tract infection. oabnormal amounts of fats in the blood (dyslipidemia).

SPL UNCLASSIFIED SECTION.


2.1 Prior to Initiation of QTERN. Assess renal function prior to initiation of QTERN therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS (5.5)].In patients with volume depletion, correct this condition prior to initiation of QTERN [see WARNINGS AND PRECAUTIONS (5.3) and USE IN SPECIFIC POPULATIONS (8.5, 8.6)].