QTERN

QTERN tablets for oral use contain dapagliflozin and saxagliptin.

QTERN® is a prescription medication that combines two different drugs, dapagliflozin and saxagliptin, to treat type 2 diabetes. Dapagliflozin is a type of medication called a sodium-glucose co-transporter 2 (SGLT2) inhibitor, which works by helping the kidneys remove excess glucose from the body through urine. Saxagliptin is a type of medication called a dipeptidyl peptidase-4 (DPP-4) inhibitor, which works by increasing the levels of incretin hormones in the body that help to regulate blood sugar levels.

Dapagliflozin propanediol is an active inhibitor of sodium-glucose cotransporter 2 (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 C₂₁H₂₅ClO₆•C₃H₈O₂•H₂O and the molecular weight of 502.98.

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-3carbonitrile hydrate. The empirical formula is C₁₈H₂₅N₃O₂•H₂O and the molecular weight is 333.43.

QTERN® (dapagliflozin and saxagliptin) tablets

QTERN INDICATIONS AND USAGE

QTERN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

QTERN is not recommended for patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

QTERN Mechanism of Action

Dapagliflozin

Sodium-glucose cotransporter 2 (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 thereby promotes 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 a 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 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a 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 a glucose-dependent manner in patients with type 2 diabetes mellitus.

QTERN DOSAGE AND ADMINISTRATION

For patients not already taking dapagliflozin, the recommended starting dose of QTERN is a 5 mg dapagliflozin/5 mg saxagliptin tablet taken orally once daily in the morning with or without food.

In patients tolerating 5 mg dapagliflozin and 5 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.

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 m^2.

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).

QTERN CONTRAINDICATIONS

QTERN is contraindicated in patients with:

History of a serious hypersensitivity reaction to dapagliflozin or to saxagliptin, including anaphylactic reactions, angioedema or exfoliative skin conditions.
Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m²), end-stage renal disease (ESRD), or patients on dialysis.

QTERN WARNINGS AND PRECAUTIONS

Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. In a 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 9 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 a history of pancreatitis are at increased risk for the development of pancreatitis while using QTERN.

Heart Failure: In a 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%).

Consider the risks and benefits of QTERN prior to initiating treatment in patients at a 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.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERN is not indicated for the treatment of patients with type 1 diabetes mellitus.

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 3 days prior to surgery.

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). Ensure risk factors for ketoacidosis are resolved prior to restarting QTERN.

Volume Depletion: Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating QTERN in patients with one or more of these characteristics, assess volume status and renal function. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m². Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.

Urosepsis and Pyelonephritis: Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported 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.

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, a 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.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a 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.

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 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a 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 a patient with a 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.

Genital Mycotic Infections: Dapagliflozin increases the risks of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately.

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. A subset of patients experienced a recurrence of symptoms restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

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 a dermatologist should be considered for diagnosis and appropriate treatment.

QTERN DRUG INTERACTIONS

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Do not coadminister QTERN with strong cytochrome P450 3A4/5 inhibitors.

SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

QTERN USE IN SPECIFIC POPULATIONS

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

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

Poorly 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.

Lactation: There 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. 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 2 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 a breastfed infant, advise women that use of QTERN is not recommended while breastfeeding.

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

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.

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.

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.

QTERN OVERDOSAGE

In the event of an overdose, contact the Poison Control Center. Appropriate supportive treatment should be initiated as dictated by the patient’s 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 4 hours).

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QTERN® (dapagliflozin and saxagliptin) tablets

QTERN