Dapagliflozin-Saxagliptin (dapagliflozin/saxagliptin HCl)

Dosage of saxagliptin hydrochloride (anhydrous) is expressed in terms of saxagliptin.

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.

When saxagliptin is administered as monotherapy, the drug should be administered orally once daily without regard to meals. Saxagliptin tablets should be swallowed whole; they should not be cut, chewed, or crushed. If a dose of saxagliptin is missed, resume treatment with the next dose and do not take an extra dose.

When saxagliptin is administered in fixed combination with extended-release metformin, the combination should be administered orally once daily with the evening meal; dosage should be titrated gradually to minimize adverse GI effects of the metformin component. The fixed-combination tablets should be swallowed whole, and not cut, chewed, or crushed. If a dose is missed, resume treatment with the next dose and do not take an extra dose. Patients receiving saxagliptin in fixed combination with extended-release metformin hydrochloride should be advised that occasionally, the inactive ingredients of the fixed-combination tablet will be eliminated in the feces as a soft mass that may resemble the original tablet.

Store saxagliptin tablets alone or in fixed combination with extended-release metformin hydrochloride at 20--25degreesC; excursions permitted to 15--30degreesC.

Dapagliflozin is administered orally once daily. Dapagliflozin is commercially available as single-entity tablets that may be administered with or without food. Dapagliflozin is also available in fixed combination with saxagliptin (Qtern(R)) or extended-release metformin hydrochloride (Xigduo(R) XR); the fixed-combination dapagliflozin/saxagliptin tablets should be administered orally once daily in the morning, with or without food, and the fixed combination dapagliflozin/metformin tablets should be administered once daily in the morning with food to reduce the adverse GI effects of the metformin component. See the full prescribing information for additional administration instructions for the combination products.

If a dose of dapagliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

Store dapagliflozin tablets at 20 to 25oC (excursions permitted between 15 and 30oC).

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9; cytochrome P450 (CYP)-mediated metabolism is a minor clearance pathway.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Saxagliptin (>2.5 MG)/Strong Cyp3a4 Inhib;Atazanav;Darunavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Dipeptidyl Peptidase-Iv Inhibitors/Ace Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2)

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3)

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7)

Sglt2 Inhibitors/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

*History of serious hypersensitivity to saxagliptin or any ingredient in the formulation.

*History of serious hypersensitivity reaction to dapagliflozin or any ingredient in the formulation. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients receiving the drug.

• Acute pancreatitis

• Chronic heart failure
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Hypoglycemic disorder
• Hypovolemia
• Invasive surgical procedure
• Necrotizing fasciitis of perineum or genital area
• Pregnancy
• Type 1 diabetes mellitus

• Hypoglycemic disorder
• Lymphopenia

Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin and more frequently than with placebo include upper respiratory tract infection, urinary tract infection, and headache.

Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin in fixed combination with extended-release metformin and more frequently than placebo include headache and nasopharyngitis.

The most common adverse effects of dapagliflozin monotherapy (>=5% of patients) reported in clinical studies include female genital mycotic infections, nasopharyngitis, and urinary tract infections.

The most common adverse effects of dapagliflozin in combination with extended-release metformin hydrochloride (>5% of patients) reported in clinical trials include female genital mycotic infections, nasopharyngitis, urinary tract infection, diarrhea, and headache.

The most common adverse effects of dapagliflozin in combination with saxagliptin (>=5% of patients) reported in clinical trials include upper respiratory tract infection, urinary tract infection, and dyslipidemia.

More Frequent

• Urinary tract infection

Less Frequent

• Dehydration
• Heart failure
• Hypotension

Rare or Very Rare

• Acquired phimosis
• Acute kidney injury
• Acute pancreatitis
• Anaphylaxis
• Angioedema
• Angioedema
• Arthralgia
• Bacterial sepsis
• Bullous pemphigoid
• Diabetic ketoacidosis
• Exfoliative dermatitis
• Fracture
• Fracture
• Hypersensitivity drug reaction
• Hypoglycemic disorder
• Infection
• Ketoacidosis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lymphopenia
• Malignant tumor of urinary bladder
• Metabolic acidosis
• Necrotizing fasciitis of perineum or genital area
• Pancreatitis
• Pyelonephritis
• Rhabdomyolysis
• Skin rash
• Urosepsis
• Urticaria

More Frequent

• Headache disorder
• Pharyngitis
• Upper respiratory infection
• Urinary tract infection
• Vulvovaginal candidiasis

Less Frequent

• Back pain
• Candidal balanitis
• Constipation
• Dysuria
• Gastroenteritis
• Genital organ pruritus
• Genitourinary tract infections
• Hypercholesterolemia
• Hyperphosphatemia
• Hypoglycemic disorder
• Hypovolemia
• Increased hemoglobin
• Increased urinary frequency
• Influenza
• Nausea
• Orthostatic hypotension
• Peripheral edema
• Pharyngitis
• Sinusitis
• Vomiting

Rare or Very Rare

• Facial edema
• Skin rash
• Urticaria

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Safety and efficacy of saxagliptin have not been established in patients younger than 18 years of age.

The safety and effectiveness of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of dapagliflozin for this indication is supported by a 26-week, placebo-controlled trial with a 26-week extension in 157 pediatric patients 10 to 17 years of age with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus. The safety profile observed in the placebo-controlled trial in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults. Safety and efficacy of dapagliflozin have not been established in pediatric patients younger than 10 years of age for glycemic control in type 2 diabetes mellitus.

Safety and efficacy of dapagliflozin have not been established in pediatric patients for other indications.

Data on the use of saxagliptin in pregnant women are insufficient to determine a drug-associated risk for major birth defects or miscarriage. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. In addition, poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the prenatal and postnatal period.

There is insufficient evidence with dapagliflozin in pregnant women to evaluate a drug-associated risk of major birth defects or miscarriage. Based on the results of reproductive and developmental toxicity studies in animals, dapagliflozin use during pregnancy may affect renal development and maturation. Adverse renal pelvic and tubule dilatations that were not fully reversible were observed in rats when dapagliflozin was administered during a 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 dosage.

Poorly controlled diabetes mellitus and untreated heart failure also are associated with risks to the mother and fetus, including DKA, preeclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. The manufacturer states that dapagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

Saxagliptin is distributed into milk in rats at a milk-to-plasma ratio of approximately 1:1. Data are lacking regarding the presence of saxagliptin in human milk and on the effects of the drug on the breast-fed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for saxagliptin and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.

There are no data on the presence of dapagliflozin in human milk, the effects on the breast-fed child, or the effects on milk production. Dapagliflozin is distributed into milk in 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. Use of dapagliflozin in women who are breast-feeding is not recommended.

The manufacturer states that no specific dosage adjustment of saxagliptin is necessary for age alone. Because geriatric patients are more likely to have decreased renal function, care should be taken in dosage selection based on renal function.

No adjustment of dapagliflozin dosage is necessary based solely on age.

Of the 11,301 patients enrolled in clinical trials with saxagliptin, 4751 (42%) were >=65 years of age and 1210 (10.7%) were >=75 years of age. No substantial differences in safety and efficacy in patients >=65 years of age relative to younger adults have been observed, but increased sensitivity cannot be ruled out.

Saxagliptin and its active metabolite are eliminated in part by the kidneys; renal function should be assessed periodically since geriatric patients are more likely to have decreased renal function.

Among patients with type 2 diabetes mellitus in 21 clinical trials, 1424 (24%) were 65 years of age or older and 207 (3.5%) were 75 years of age or older. Efficacy of dapagliflozin was similar for patients younger than 65 years of age and those 65 years of age or older after controlling for renal function (eGFR). Geriatric patients receiving dapagliflozin for glycemic control were more likely to experience hypotension compared with patients treated with placebo.

In the DAPA-CKD, DAPA-HF, and DELIVER trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65 years of age. In the DAPA-CKD study, 42% of patients were older than 65 years of age. In the DAPA-HF study, 57% of patients were older than 65 years. In the DELIVER study, 76% of patients were older than 65 years.