Steglujan (ertugliflozin pidolate/sitagliptin phosphate)

Sitagliptin is commercially available as the phosphate or hydrochloride salt or free base; dosage is expressed in terms of sitagliptin.

Dosage of ertugliflozin L-pyroglutamic acid is expressed in terms of ertugliflozin.

Sitagliptin is commercially available as single-entity tablets (sitagliptin phosphate (Januvia(R)), sitagliptin (Zituvio(R) )) or oral solution (sitagliptin hydrochloride (Brynovin(R))); sitagliptin (as the phosphate salt or free base) is also available as fixed combination tablets with immediate- or extended-release metformin hydrochloride (Janumet(R), Zituvimet(R), Janumet(R) XR, Zituvimet(R) XR) or as fixed combination tablets with ertugliflozin (Steglujan(R)).

Ertugliflozin is administered orally once daily in the morning with or without food. The fixed combination of ertugliflozin and metformin hydrochloride is administered orally twice daily with meals to reduce the adverse GI effects of the metformin hydrochloride component. The fixed combination of ertugliflozin and sitagliptin is administered orally once daily in the morning with or without food. See the full prescribing information for additional administration instructions for the combination products.

If a dose of ertugliflozin 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 ertugliflozin tablets at 20-25degreesC; excursions are permitted between 15-30degreesC.

No dosing information is available for this tab.

The major metabolic pathway for ertugliflozin is glucuronidation; the drug is principally glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A9 and 2B7.

There are no contraindication interactions for this drug.

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 (e.g., anaphylaxis, angioedema) to sitagliptin or to any ingredient in the formulation.

*Hypersensitivity to ertugliflozin or any ingredient in the formulation.

• Acute pancreatitis
• 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

• 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
• Chronic pancreatitis
• Diabetic foot infection
• History of diabetes-related lower-extremity amputation
• Invasive surgical procedure
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Necrotizing fasciitis of perineum or genital area
• Peripheral vascular disease
• Pregnancy
• Type 1 diabetes mellitus

• Diabetic peripheral neuropathy
• Hypercholesterolemia
• Hypotension
• Kidney disease with likely reduction in glomerular filtration rate (GFr)

Adverse effects reported in at least 5% of patients receiving sitagliptin as monotherapy and more commonly than with placebo include upper respiratory tract infection, nasopharyngitis, and headache. In add-on trials with a sulfonylurea or insulin, hypoglycemia was more commonly reported in patients receiving sitagliptin than placebo.

Adverse effects reported in at least 5% of patients receiving sitagliptin concomitantly with metformin and more commonly than with placebo include diarrhea, upper respiratory tract infection, and headache.

Adverse effects reported in clinical trials of sitagliptin given concomitantly with ertugliflozin were similar in type and incidence to those reported with ertugliflozin and sitagliptin alone.

The most common adverse effects of ertugliflozin (>=5% of patients) reported in clinical trials were female genital mycotic infections.

The most common adverse effects of ertugliflozin in combination with metformin hydrochloride (>=5% of patients) reported in clinical trials were female genital mycotic infections, diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

The most common adverse effects of ertugliflozin in combination with sitagliptin (>=5% of patients) reported in clinical trials were female genital mycotic infections, upper respiratory tract infections, nasopharyngitis, and headache.

Less Frequent

• Dehydration
• Genitourinary tract infections
• Upper respiratory infection

Rare or Very Rare

• Acute kidney injury
• Acute pancreatitis
• Acute renal failure
• Anaphylaxis
• Angioedema
• Angioedema
• Bullous pemphigoid
• Cutaneous vasculitis
• Diabetic ketoacidosis
• Exfoliative dermatitis
• Heart failure
• Hypoglycemic disorder
• Hypovolemia
• Interstitial nephritis
• Ketoacidosis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Necrotizing fasciitis of perineum or genital area
• Necrotizing pancreatitis
• Pyelonephritis
• Rhabdomyolysis
• Skin rash
• Stevens-johnson syndrome
• Urosepsis
• Urticaria

More Frequent

• Vulvovaginal candidiasis

Less Frequent

• Back pain
• Candidal balanitis
• Genital organ pruritus
• Headache disorder
• Headache disorder
• Hypercholesterolemia
• Hyperphosphatemia
• Hypoglycemic disorder
• Increased hemoglobin
• Increased urinary frequency
• Pharyngitis
• Pharyngitis
• Polydipsia
• Polyuria
• Urinary tract infection
• Vaginitis
• Weight gain
• Weight loss
• Xerostomia

Rare or Very Rare

• Abnormal hepatic function tests
• Acute abdominal pain
• Arthralgia
• Back pain
• Constipation
• Diarrhea
• Hypotension
• Myalgia
• Nausea
• Pain in extremities
• Peripheral edema
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting

No enhanced messaging available.

Safety and efficacy of sitagliptin alone or in fixed combination with metformin or ertugliflozin have not been established in children younger than 18 years of age.

Three double-blind, placebo-controlled trials conducted in pediatric patients aged 10--17 years with inadequately controlled type 2 diabetes mellitus (with or without insulin therapy) failed to find a difference in efficacy between those that received sitagliptin versus placebo.

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

Data are lacking on the use of sitagliptin in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In embryofetal developmental studies, no adverse developmental effects were observed during organogenesis when sitagliptin was administered to pregnant rats and rabbits during organogenesis at doses of 250 and 125 mg/kg, respectively (up to 30 and 20 times, respectively, the 100-mg clinical dosage based on AUC).

There is insufficient evidence with ertugliflozin in pregnant women to evaluate a drug-associated risk of adverse developmental outcomes. Based on the results of reproductive and developmental toxicity studies in animals, ertugliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.

Poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus, including diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. Ertugliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

Sitagliptin is distributed into milk in rats; data are lacking regarding the presence of the drug in human milk, the effects on the breast-fed infant, or effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sitagliptin and any potential adverse effects on the breast-fed infant from sitagliptin or the underlying maternal condition.

There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Ertugliflozin 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. Because of the potential risk for serious adverse reactions in a breast-fed infant, ertugliflozin is not recommended for use while breastfeeding.

Dosage should be selected with caution because of age-related decreases in renal function. Dosage should be titrated carefully to the minimum dosage necessary for adequate glycemic control. The fixed combination of sitagliptin and ertugliflozin is expected to have diminished efficacy in geriatric patients with renal impairment.

Of the 3884 patients who received sitagliptin in clinical trials, 725 patients were >=65 years of age and 61 patients were >=75 years of age. No substantial differences in safety and efficacy of sitagliptin relative to younger adults, but increased sensitivity cannot be ruled out. Renal function should be assessed more frequently in geriatric patients.

In clinical trials in patients treated with ertugliflozin, 25.7% of patients were 65 years of age or older and 4.5% were 75 years of age or older. Patients 65 years of age and older who received ertugliflozin had a higher incidence of adverse reactions related to volume depletion compared with younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.

In the VERTIS CV trial, 50.5% of patients treated with ertugliflozin were 65 years of age and older, and 10.8% of patients were 75 years of age and older. Safety and efficacy were generally similar for patients aged 65 years and older compared to patients younger than 65 years.