dapagliflozin/saxagliptin (Rx)

Brand and Other Names:Qtern
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

dapagliflozin/saxagliptin

tablet

  • 10mg/5mg

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) who have inadequate control with dapagliflozin or who are already treated with dapagliflozin and saxagliptin

1 tablet (ie, 10mg/5mg) PO qDay in AM with or without food

Dosage Modifications

Renal impairment

  • eGFR <60 mL/min/1.73 m²: Do not initiate
  • Discontinue if eGFR persistently falls to <60 mL/min/1.73 m²
  • eGFR <45 mL/min/1.73 m²: Contraindicated

Hepatic impairment

  • May be administered with hepatic impairment
  • Severe hepatic impairment: Individually assess benefit-risk

Coadministration with strong CYP3A4/5 inhibitors

  • Do not coadminister with strong CYP3A4/5 inhibitors
  • Examples include ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin

Dosing Considerations

In patients with volume depletion, correct this condition prior to initiating drug

Assess renal function before initiating and periodically thereafter

Limitations of use

  • Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis
  • Should only be used in patients who tolerate dapagliflozin 10 mg

Safety and efficacy not established

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Interactions

Interaction Checker

and dapagliflozin/saxagliptin

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    Contraindicated

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        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Upper respiratory tract infection (13.6%)

            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%)

            Renal impairment (2%)

            Increased serum inorganic phosphorus (1.7%)

            Hypoglycemia (1.6%)

            Increased hematocrit (1.3%)

            Elevated creatine kinase (1%)

            <1%

            Volume depletion (hypotension, dehydration, hypovolemia)

            Acute pancreatitis

            Decreased lymphocyte count

            Newly diagnosed bladder cancer

            Postmarketing Reports

            Saxagliptin

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

            Dapagliflozin

            • Ketoacidosis
            • Acute kidney injury and impaired renal function
            • Urosepsis and pyelonephritis
            • Rash
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            Warnings

            Contraindications

            History of hypersensitivity to dapagliflozin or saxagliptin, including anaphylaxis, angioedema, or exfoliative skin conditions

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

            Cautions

            Acute pancreatitis reported; after initiating drug, monitor for signs and symptoms of pancreatitis; if suspected, promptly discontinue dapagliflozin/saxagliptin and initiate appropriate management

            May increase risk for developing heart failure (HF) or exacerbation of existing HR; observe patients for signs and symptoms of HF

            Dapagliflozin causes intravascular volume contraction; symptomatic hypotension and acute kidney injury can occur, particularly with impaired renal function, elderly patients, chronic renal insufficiency, congestive HF, or coadministration of certain drugs (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); before initiating, volume status should be assessed and corrected; do not initiate if eGFR is <60 mL/min/1.73 m²

            Ketoacidosis has been associated with SGLT-2 inhibitors; before initiating, consider factors in the patient history that may predispose patient to ketoacidosis (eg, pancreatic insulin deficiency from any cause, caloric restriction, alcohol abuse)

            Hypoglycemia risk increased with insulin and insulin secretagogues; adjust dose

            Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

            Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate for signs and symptoms of UTIs and treat promptly, if indicated

            Dose-related increases in LDL-C reported with dapagliflozin

            Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10 (0.17%)/6045 patients treated with dapagliflozin and 1 (0.03%)/3512 patient treated with placebo/comparator; bladder cancer risk factors and hematuria (a potential indicator of preexisting tumors) were balanced between treatment arms at baseline and there were too few cases to determine whether the emergence of these events is related to dapagliflozin

            Therapy should not be administered to patients with active bladder cancer and should be administered with caution in patients with a prior history of bladder cancer

            No conclusive evidence of macrovascular risk reduction with dapagliflozin or any other antidiabetic agent

            GLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic control

            Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate

            Serious hypersensitivity reactions with saxagliptin reported (typically within the first 3 months of therapy)

            Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use; patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor

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            Pregnancy

            Pregnancy

            Not recommended during the second and third trimesters

            Adverse renal affects shown in animal studies

            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

            Lactation

            Unknown if distributed in human breast 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: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; 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; incretin hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner, but are inactivated by the DDP-4 enzyme within minutes

            Absorption

            Bioavailability

            • Dapagliflozin: 78%; high-fat meal decreases absolute bioavailability by 50%

            Peak plasma time

            • Dapagliflozin: 2 hr (fasting); 3 hr (high-fat meal)
            • Saxagliptin: 2 hr; 4 hr (active metabolite)

            Peak plasma concentration

            • Saxagliptin: 24 ng/mL
            • Saxagliptin active metabolite: 47 ng/mL

            AUC

            • Saxagliptin: 78 ng·h/mL
            • Saxagliptin active metabolite: 214 ng·h/mL

            Distribution

            Protein bound

            • Dapagliflozin: 91%
            • Saxagliptin and active metabolite: Negligible

            Metabolism

            Dapagliflozin

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

            Saxagliptin

            • 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

            Half-life

            • Dapagliflozin: 12.9 hr
            • Saxagliptin: 2.5 hr; 3.1 hr (active metabolite)

            Renal clearance

            • Saxagliptin: 230 mL/min

            Excretion

            • Dapagliflozin
              • Renal: 75% (<2% as parent drug)
              • Feces: 21% (15% as parent drug)
            • Saxagliptin
              • Renal: 24%; 36% (active metabolite); 75% (total radioactivity)
              • Feces: 22%
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            Administration

            Oral Administration

            Take once daily in the morning

            May take with or without food

            Do not split or cut tablets

            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.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            Code Definition
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