dapagliflozin/saxagliptin/metformin (Rx)

Brand and Other Names:Qternmet XR
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

dapagliflozin/saxagliptin/metformin HCl extended-release

tablet

  • 2.5mg/2.5mg/1000mg
  • 5mg/2.5mg/1000mg
  • 5mg/5mg/1000mg
  • 10mg/5mg/1000mg

Type 2 Diabetes Mellitus

Sodium-glucose cotransporter 2 (SGLT2) inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and a biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (DM)

Individualize starting total daily dose based on the patient’s current regimen, effectiveness, and tolerability

For patients not currently taking dapagliflozin, recommended starting dose is dapagliflozin 5 mg/saxagliptin 5 mg/metformin HCl extended-release 1000 mg or 2000 mg PO qDay

Maximum recommended daily dose is dapagliflozin 10 mg/saxagliptin 5 mg/metformin HCl extended-release 2000 mg

Dosage Modifications

Renal impairment

  • Mild (eGFR ≥45 mL/min/1.73 m²): No dosage adjustment necessary
  • Moderate-to-severe (eGFR <45 mL/min/1.73 m²): Contraindicated
  • End-stage renal disease (ESRD) or patients on dialysis: Contraindicated

Hepatic impairment

  • Not recommended; use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis

Dosing Considerations

Discontinuation for iodinated contrast imaging procedures

  • Discontinue at time of, or prior to, an iodinated contrast imaging procedure in patients with a history of liver disease, alcoholism, or heart failure, or in patients who will be administered intra-arterial iodinated contrast
  • Reevaluate eGFR 48 hr after imaging procedure; restart Qternmet XR if renal function is stable

Limitations of use

  • Not indicated for treatment of type 1 diabetes mellitus or diabetic ketoacidosis
  • Therapy initiation is intended only for patients currently taking metformin
  • Vitamin B12: Monitor hematologic parameters on an annual basis is advised in patients receiving therapy and appropriately investigate and manage any apparent abnormalities

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and dapagliflozin/saxagliptin/metformin

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            Adverse Effects

            1-10%

            Urinary tract infection (5.7%)

            Dyslipidemia (5.1%)

            Headache (4.3%)

            Diarrhea (3.7%)

            Back pain (3.3%)

            Genital infection (3%)

            Arthralgia (2.4%)

            Postmarketing Reports

            Dapagliflozin

            • Ketoacidosis
            • Acute kidney injury
            • Renal impairment
            • Urosepsis
            • Pyelonephritis
            • Necrotizing fasciitis of the perineum (Fournier gangrene)
            • Rash

            Saxagliptin

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

            Metformin

            • Cholestatic, hepatocellular, and mixed hepatocellular liver injury
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            Warnings

            Black Box Warnings

            Lactic acidosis

            • Postmarketing cases of metformin-associated lactic acidosis resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
            • Onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain)
            • Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL
            • Risk factors for metformin-associated lactic acidosis may include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors), patient age ≥65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment
            • Steps to reduce the risk of and to manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information
            • If metformin-associated lactic acidosis is suspected, immediately discontinue treatment and institute general supportive measures in a hospital setting
            • Prompt hemodialysis is recommended

            Contraindications

            Hypersensitivity to dapagliflozin, saxagliptin, or metformin

            Moderate-to-severe renal impairment (eGFR <45 mL/min/1.73 m²), ESRD, or patients on dialysis

            Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

            Cautions

            Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported (see Black Box Warnings)

            Postmarketing cases of serious urinary tract infections including urosepsis were reported; evaluate for signs and symptoms and treat appropriately

            In cardiovascular outcomes trial, cases of definite acute pancreatitis were confirmed with patients treated with saxagliptin; if pancreatitis suspected, promptly discontinue treatment and initiate appropriate management; unknown if patients with history of pancreatitis are at increased risk for the development of pancreatitis while using Qternmet XR

            Increased risk of hospitalization for heart failure in patients treated with saxagliptin reported; those with previous history of heart failure or renally impaired were at high risk

            Dapagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after starting therapy; assess volume status and correct

            Necrotizing fasciitis of the perineum (Fournier gangrene) reported in postmarketing surveillance with SGLT2 inhibitors; it is a rare life-threatening necrotizing infection requiring urgent surgical intervention

            Hypersensitivity reactions reported with saxagliptin; onset of reactions occurred within the first 3 months after initiating saxagliptin; exercise caution with history of angioedema to another DPP-4 inhibitor

            In controlled clinical trials of metformin, a decrease to subnormal levels of serum vitamin B12 levels, without clinical manifestations, was observed

            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

            Increased LDL–C may occur with dapagliflozin; monitor LDL-C and treat per standard of care

            In clinical studies for dapagliflozin, newly diagnosed cases of bladder cancer were reported; there were too few cases to determine whether the emergence of these events is related to dapagliflozin

            Severe and disabling arthralgia in patients taking DPP-4 inhibitors have been reported; consider discontinuing drug if DPP-4 inhibitor is a cause for severe joint pain

            Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use

            No clinical studies establishing conclusive evidence of macrovascular risk reduction with treatment SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests

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

            Ketoacidosis

            • Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, were identified in postmarketing surveillance in patients with type 1 and type 2 DM receiving SGLT2 inhibitors, including dapagliflozin; fatal cases of ketoacidosis have been reported in patients taking dapagliflozin
            • 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

            Renal impairment

            • Consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
            • Before initiating, obtain an estimated glomerular filtration rate (eGFR)
            • Obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for the development of renal impairment (eg, the elderly), renal function should be assessed more frequentl

            Drug interactions overview

            • Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia; may require a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when these agents are used in combination with Qternmet XR Ketoconazole, a strong CYP3A4/5 inhibitor, significantly increased saxagliptin exposure; avoid coadministration with strong CYP3A4/5 inhibitors
            • Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis
            • Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
            • Alcohol potentiates the effects of metformin on lactate metabolism
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            Pregnancy & Lactation

            Pregnancy

            Not recommended during the second and third trimesters

            Limited available data with dapagliflozin and saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage

            Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

            Adverse renal effects shown in animal studies Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women

            Animal studies

            • Adverse renal pelvic and tubular dilatations, that were not fully reversible, were observed in juvenile rats when dapagliflozin was administered at an exposure 15-times the exposure at the 10-mg clinical dose during a period of renal development corresponding to the late second and third trimesters of human pregnancy
            • Saxagliptin did not show adverse effects during organogenesis, corresponding to the first trimester of human pregnancy

            Clinical considerations

            • Disease-associated maternal and/or embryo-fetal risk
            • 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

            Published clinical lactation studies report that metformin is present in human milk

            Saxagliptin and dapagliflozin are present in the milk of lactating rats; 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 dapagliflozin/saxagliptin is not recommended while breastfeeding

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Dapagliflozin: SGLT-2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

            Saxagliptin: Dipeptidyl peptidase IV (DPP-4) inhibition that results in increased incretin hormones and enhanced glycemic control

            Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and use; improves glucose tolerance and lowers both basal and postprandial plasma glucose

            Absorption

            Saxagliptin

            • Peak plasma concentration: 24-47 ng/mL
            • Peak plasma time: 2 hr (saxagliptin); 1.5 hr (active metabolite)
            • AUC: 78-214 ng·hr/mL

            Metformin

            • Both high- and low-fat meals had the same effect on the pharmacokinetics of metformin extended-release

            Dapagliflozin

            • Oral bioavailability: 78%
            • Peak plasma time: 2 hr

            Distribution

            Saxagliptin

            • Changes in blood protein levels in various disease states (eg, renal or hepatic impairment) are not expected to alter the disposition of saxagliptin

            Metformin

            • Vd: 654 L

            Dapagliflozin

            • Protein bound: ~91%; not altered by hepatic impairment

            Metabolism

            Saxagliptin

            • Primarily mediated by UGT1A9
            • CYP-mediated metabolism is a minor clearance pathway in humans Extensively metabolized, primarily to dapagliflozin 3-O-glucuronide (inactive)

            Metformin

            • Excreted unchanged in the urine and does not undergo hepatic metabolism

            Dapagliflozin

            • Primarily mediated by CYP3A4/5
            • The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is 50% as potent as saxagliptin
            • Strong CYP3A4/5 inhibitors and inducers alter the pharmacokinetics of saxagliptin and its active metabolite

            Elimination

            Saxagliptin

            • Excretion: Urine (24% [36% active metabolite]; feces (22%)
            • Half-life: 2.5 hr

            Metformin

            • Half-Life: 4-9 hr
            • Dialyzable: Yes (hemodialysis)
            • Renal clearance: 450-540 mL/min (regular-release)
            • Excretion: Urine (90%, by tubular secretion)

            Dapagliflozin

            • Excretion: Urine (75% [<2% as parent drug]; feces (21% [15% as parent drug])
            • Half-life: 12.9 hr
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            Administration

            Oral Administration

            Swallow whole; do not crush, cut, or chew tablet

            Occasionally, inactive ingredients will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet

            Missed dose

            • If a dose is missed and ≥12 hr until the next dose, take the dose
            • If missed dose is less than 12 hr until the next dose, skip missed dose and take the next dose at the usual time

            Storage

            Store at controlled room temperature; 20-25°C (68-77°F); excursion permitted to 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.