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    Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral sodium-glucose co-transporter 2 (SGLT2) inhibitor
    Used to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death if these patients also have cardiovascular disease
    Blocks reabsorption of glucose by kidneys, increasing glucose excretion; not effective in patients with severe renal impairment

    COMMON BRAND NAMES

    JARDIANCE

    HOW SUPPLIED

    JARDIANCE Oral Tab: 10mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment type 2 diabetes mellitus in combination with diet and exercise, and for the reduction of cardiovascular mortality in these patients who also have established cardiovascular disease.
    Oral dosage
    Adults

    10 mg PO once daily, taken in the morning, with or without food. The dose can be increased to 25 mg PO once daily in those who require additional glycemic control. In addition to improving glycemic control, a multicenter, multi-national, randomized, double-blind parallel group trial (EMPA-REG OUTCOME study) of 7,020 patients with inadequately controlled type 2 DM and established, stable, atherosclerotic cardiovascular disease reported that empagliflozin treatment reduced the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) by 14% relative to placebo (HR 0.86, 95% CI 0.74 to 0.99).

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO.

    Geriatric

    25 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    eGFR >= 45 mL/min/1.73 m2: No dosage adjustment needed.
    eGFR < 45 mL/min/1.73 m2: Do not initiate empagliflozin in these patients. In patients currently taking the drug, empagliflozin should be discontinued when eGFR is persistently < 45 mL/min/1.73 m2.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer tablets once daily in the morning, with or without food.

    STORAGE

    JARDIANCE:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Do not use empagliflozin in patients with a known history of a serious empagliflozin hypersensitivity reaction.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Empagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis (DKA). Fatal cases of ketoacidosis have been reported in patients receiving empagliflozin. In addition, the FDA has identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis. Signs and symptoms at presentation were consistent with severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. However, the presence of ketoacidosis was not immediately recognized, and treatment was delayed because the presenting blood glucose levels were below those typically expected for DKA (often less than 250 mg/dL). Factors identified in some reports as having potentially triggered the ketoacidosis included infection, low carbohydrate diet or an overall reduction of caloric intake, reduction in dose of exogenous insulin or discontinuation of exogenous insulin, discontinuation of an oral insulin secretagogue, and alcohol use. The FDA is continuing to investigate this issue and is requiring manufacturers of SGLT2 inhibitors to conduct a required postmarketing study, including specialized follow-up to collect additional information for a period of 5 years. Before initiating an SGLT2 inhibitor, consider factors in the patients’ histories that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with an SGLT2 inhibitor, consider monitoring for ketoacidosis and temporarily discontinuing the drug in clinical situations known to predispose to ketoacidosis, such as prolonged fasting due to acute illness or surgery. Patients should report any signs of ketoacidosis and immediately seek medical attention if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms. If ketoacidosis is suspected, discontinue empagliflozin and institute treatment, which may include insulin, fluids, and carbohydrate replacement.

    Dialysis, hypovolemia, renal failure, renal impairment

    Empagliflozin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal failure or in patients on dialysis. Empagliflozin is not expected to be effective in these patients.  Empagliflozin should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2. Discontinue empagliflozin in patients developing an eGFR that is persistently less than 45 mL/min/1.73 m2 while on treatment. Empagliflozin causes intravascular volume contraction and can cause renal impairment. Empagliflozin increases serum creatinine and decreases eGFR; patients with hypovolemia or the elderly may be more susceptible to these changes. The glucose lowering benefit of empagliflozin decreases in patients with worsening renal function. The efficacy and safety of empagliflozin were evaluated in a study that included patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2) and moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2). The risks of renal impairment, volume depletion adverse reactions, and urinary tract infection-related adverse reactions increased with worsening renal function. Before initiation of treatment and at least annually thereafter, obtain an estimated glomerular filtration rate (eGFR) to assess renal function. More frequent monitoring is recommended in patients with moderate renal impairment (eGFR less than 59 mL/min/1.73 m2) and the elderly at treatment initiation. Renal impairment may occur as a result of certain medical conditions such as cardiovascular collapse, acute heart attack, and septicemia. Acute kidney injury, some requiring hospitalization and dialysis, has been reported during the postmarketing period with empagliflozin and other SGLT2 inhibitors; some reports involved patients younger than 65 years of age. The FDA identified 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin (73 patients) or dapagliflozin (28 patients) use during the time period from March 2013 to October 2015. There are likely additional cases. In approximately half of the cases, acute kidney injury occurred within 1 month of starting the drug, and most patients improved after discontinuation. Hospitalization for evaluation and management of acute kidney injury was necessary in 96 of the 101 cases, and 22 cases involved admission to an intensive care unit. Four deaths occurred during hospitalization, 2 of which were cardiac-related. Fifteen patients received dialysis. Of the 101 cases, 51 reported concomitant angiotensin converting enzyme (ACE) inhibitor use, 26 reported concomitant diuretic use, and 6 reported concomitant nonsteroidal anti-inflammatory drug (NSAID) use. A prior history of chronic renal disease was reported in 10 of the 101 cases. Forty-five of the 101 cases reported a change in serum creatinine or eGFR at the time of diagnosis. Eleven patients did not recover, which included the 4 deaths noted previously. Three patients recovered with sequelae upon discontinuation. If acute kidney injury occurs, promptly discontinue the drug and treat the renal impairment. Consider factors that may predispose patients to acute kidney injury prior to starting them on empagliflozin, including hypovolemia; chronic renal insufficiency; congestive heart failure; and concomitant medications such as diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and NSAIDs. Consider temporarily discontinuing empagliflozin in any setting of reduced oral intake such as acute illness or fasting, or with fluid losses such as gastrointestinal illness or excessive heat exposure.

    Dehydration, hypotension

    Empagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating empagliflozin. Patients at risk include those with dehydration or hypovolemia, particularly in patients with impaired renal function (i.e., eGFR < 60 ml/min/1.73 m2),the elderly, patients receiving diuretics, or patients with low systolic blood pressure. Volume status should be assessed and corrected before initiating empagliflozin in patients with one or more of these characteristics. Monitor for signs and symptoms after initiating therapy.

    Balanitis, pyelonephritis, vaginitis

    There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Patients should be told to report any signs of urinary tract infection and seek medical attention if they experience symptoms such as a feeling of burning when urinating or the need to urinate often or right away, pain in the lower part of the stomach area or pelvis, increased temperature, or blood in the urine. If urinary tract infection is suspected, evaluate and treat promptly if indicated. Use empagliflozin cautiously in patients with a history of genital fungal infection, including vaginitis or balanitis, and in uncircumcised males since these patients may be more likely to develop genital mycotic infections during treatment with empagliflozin. Monitor and treat appropriately.

    Adrenal insufficiency, hypoglycemia, hypothyroidism, malnutrition, pituitary insufficiency

    Conditions that predispose patients to developing hypoglycemia may alter antidiabetic agent needs, and may require close monitoring during the use of empagliflozin. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Insulin and insulin secretagogues are also known to cause hypoglycemia. Empagliflozin can 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 minimize the risk of hypoglycemia when used in combination with empagliflozin.

    Burns, fever, hypercortisolism, hyperglycemia, hyperthyroidism, infection, surgery, trauma

    Conditions that predispose patients to developing hyperglycemia may alter empagliflozin efficacy. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Temporary use of insulin in place of oral antidiabetic agents (such as empagliflozin) may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever).

    Hypercholesterolemia

    Dose-related increases in LDL-C occur with empagliflozin, and these changes may require treatment or adjustment of previous therapy in patients with pre-existing hypercholesterolemia. Monitor LDL-C and treat per standard of care after initiating empagliflozin therapy.

    Geriatric

    A total of 2,721 (32%) patients 65 years and older and 491 patients (6%) 75 years and older were exposed to empagliflozin. No dosage adjustment is recommended based on age alone. Geriatric patients who were 75 years and older receiving empagliflozin experienced a higher incidence of adverse reactions related to reduced intravascular volume and urinary tract infection compared to patients treated with placebo. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function.

    Pregnancy

    There are no adequate and well-controlled studies of empagliflozin in pregnant women, and use is not recommended during the second and third trimesters of human pregnancy. Based on results from animal studies, empagliflozin may affect renal development and maturation. Rat studies demonstrate that empagliflozin crosses the placenta and reaches fetal tissues. In rat and rabbit studies, empagliflozin was not teratogenic at 48-times and 128-times, respectively, the maximum clinical human dose of 25 mg. However, at higher doses (139 to 154 times the 25 mg maximum human clinical dose), maternal and fetal toxicity, including malformations of limb bones, were evident. Maternal toxicity did not occur in pre- and postnatal development studies, starting at gestation day 6 through to lactation day 20 (weaning) at approximately 16 times the 25 mg maximum clinical dose in pregnant rats; reduced body weight was observed in the offspring. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. The potential risks to human kidney development are of concern. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    Breast-feeding

    It is not known if empagliflozin is excreted in human milk; however, due to a potential for serious adverse reactions in the nursing infant, it is recommended to avoid breast-feeding during its use, or to discontinue the drug, taking into account the importance of the therapy to the mother. Empagliflozin is secreted in the milk of lactating rats reaching levels 5 times higher than that in maternal plasma. 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. If empagliflozin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of empagliflozin have not been established in children under the age of 18 years; there is no role of empagliflozin in the treatment of infants or neonates.

    ADVERSE REACTIONS

    Severe

    phimosis / Delayed / 0-1.0
    diabetic ketoacidosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    hypoglycemia / Early / 0.4-28.4
    cystitis / Delayed / 7.6-9.3
    hypercholesterolemia / Delayed / 4.6-6.5
    candidiasis / Delayed / 1.6-6.4
    vaginitis / Delayed / 5.4-6.4
    hyperlipidemia / Delayed / 2.9-3.9
    balanitis / Delayed / 1.6-3.1
    hypovolemia / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    dehydration / Delayed / 0-1.0

    Mild

    infection / Delayed / 0-4.0
    polyuria / Early / 3.2-3.4
    increased urinary frequency / Early / 3.2-3.4
    arthralgia / Delayed / 2.3-2.4
    nausea / Early / 1.1-2.3
    polydipsia / Early / 1.5-1.7
    diuresis / Early / 0-1.0
    syncope / Early / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    nocturia / Early / 0-1.0

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Acrivastine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Aliskiren; Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Aliskiren; Valsartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amiloride: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Amlodipine; Atorvastatin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Amlodipine; Benazepril: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Olmesartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Telmisartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Valsartan: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amphetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Amphetamine; Dextroamphetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Angiotensin II receptor antagonists: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Aripiprazole: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Articaine; Epinephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Asenapine: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Atenolol; Chlorthalidone: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    atypical antipsychotic: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Azelastine; Fluticasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Azilsartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Baclofen: (Minor) Because baclofen can increase blood glucose, doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly.
    Beclomethasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Benazepril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Bendroflumethiazide; Nadolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Benzphetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Beta-adrenergic blockers: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Betamethasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Betaxolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Bisoprolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Bortezomib: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Brexpiprazole: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Brimonidine; Timolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Brompheniramine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Budesonide: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Budesonide; Formoterol: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Bumetanide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Calcium-channel blockers: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Candesartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Captopril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbonic anhydrase inhibitors: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Cariprazine: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Carteolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Carvedilol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Cetirizine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the SGLT2 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorothiazide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpromazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Chlorthalidone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Ciclesonide: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Cisapride: (Moderate) Because cisapride can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive cisapride concomitantly.
    Clevidipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Clozapine: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Codeine; Phenylephrine; Promethazine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Conjugated Estrogens: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Corticosteroids: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Corticotropin, ACTH: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Cortisone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Cyclosporine: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving empagliflozin.
    Danazol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Deflazacort: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Desiccated Thyroid: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Desloratadine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dexamethasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dexmethylphenidate: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextroamphetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diazoxide: (Minor) Diazoxide increases blood glucose by inhibiting insulin release from the pancreas and/or by stimulating the release of catecholamines, which in turn stimulate glycogenolysis. The dosage of antidiabetic agents may need to be adjusted when diazoxide is added to the regimen.
    Dienogest; Estradiol valerate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Diethylpropion: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diethylstilbestrol, DES: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diltiazem: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diphenhydramine; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dobutamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dopamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dorzolamide; Timolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Drospirenone; Estradiol: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Enalapril, Enalaprilat: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Felodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Ephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Epinephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Eprosartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Esmolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Esterified Estrogens: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Esterified Estrogens; Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Estradiol; Levonorgestrel: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norethindrone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norgestimate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estrogens: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Estropipate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Ethacrynic Acid: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Ethanol: (Moderate) Alcohol (ethanol) may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy. Alcohol ingestion can decrease endogenous glucose production potentiating the risk of hypoglycemia. Alternatively, alcohol can worsen glycemic control as it provides a source of additional calories. Blood glucose concentrations should be closely monitored and dosage adjustments of antidiabetic agents may be necessary if alcohol is consumed. Patients should be encouraged to limit or moderate their intake of alcoholic beverages. Because of its effects on endogenous glucose production, patients should be encouraged to avoid alcohol ingestion during the fasting state. Many non-prescription drug products may be formulated with ethanol; have patients scrutinize product labels prior to consumption.
    Ethinyl Estradiol: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethotoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Etonogestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Felodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Fenofibrate: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fenofibric Acid: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fexofenadine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Fibric acid derivatives: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fludrocortisone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Flunisolide: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluoxetine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Fluoxymesterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Fluphenazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Fluticasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Salmeterol: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fluticasone; Vilanterol: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Formoterol; Mometasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Fosphenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Furosemide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Garlic, Allium sativum: (Moderate) Limited animal data suggest that selected constituents in Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Patients with diabetes frequently purchase alternative remedies that have been purported to improve glycemic control, but there is no scientific or controlled evidence in humans of this action. Limited clinical evidence suggests that garlic does not affect blood glucose in those without diabetes. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gemfibrozil: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Gemifloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Glucagon: (Minor) Endogenous counter-regulatory hormones such as glucagon are released in response to hypoglycemia. When released, blood glucose concentrations rise. When glucagon is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Clinically, glucagon is often used to increase blood glucose concentrations in patients with severe hypoglycemia.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Guaifenesin; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Guaifenesin; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydantoins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Hydrocodone; Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydrocodone; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydrocortisone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the SGLT2 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ibuprofen; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Iloperidone: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Indapamide: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Irbesartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Isocarboxazid: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Isoniazid, INH: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood glucose concentrations. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoproterenol: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Isradipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Labetalol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lanreotide: (Moderate) Monitor blood glucose levels if administration of lanreotide is necessary with antidiabetic agents; adjust the dosage of the antidiabetic agent as clinically appropriate. Lanreotide inhibits the secretion of insulin and glucagon.
    Leuprolide; Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levobetaxolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Levobunolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Levocarnitine: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Levonorgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levothyroxine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Liothyronine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Liotrix: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Lisdexamfetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Lisinopril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic agents. While early reports of hyperglycemia in patients treated with lithium have not been confirmed by more recent studies, it may be prudent to monitor blood glucose concentrations closely if lithium is coadministered with antidiabetic agents. Dosage adjustments of antidiabetic agents may be necessary.
    Lomefloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Loop diuretics: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Loratadine; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Losartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Lurasidone: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Mecasermin rinfabate: (Moderate) Use caution in coadministering mecasermin rinfabate with antidiabetic agents. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, a hypoglycemic effect may be exacerbated in some patients. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with the insulin receptor is possible. Treatment with unbound rh-IGF-1 has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus, when used alone or in conjunction with insulin. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in coadministering mecasermin rinfabate with antidiabetic agents. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, a hypoglycemic effect may be exacerbated in some patients. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with the insulin receptor is possible. Treatment with unbound rh-IGF-1 has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus, when used alone or in conjunction with insulin. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Medroxyprogesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Megestrol: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Mepivacaine; Levonordefrin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Mesoridazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Mestranol; Norethindrone: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. The presence or absence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Methamphetamine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methyclothiazide: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Methylphenidate: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methylprednisolone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including empagliflozin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metolazone: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Metoprolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Midodrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Moexipril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Mometasone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Monoamine oxidase inhibitors: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Moxifloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Nadolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Nandrolone Decanoate: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Naproxen; Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Nebivolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Nebivolol; Valsartan: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Nicardipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nicotine: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Nifedipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nimodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Nisoldipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Norepinephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Norethindrone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Norfloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Norgestrel: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Octreotide: (Moderate) Administration of octreotide to patients receiving oral antidiabetic agents can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.
    Ofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Olanzapine: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Olmesartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Minor) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. A statistically significant number of obese, type 2 diabetics stabilized on sulfonylureas who received orlistat during a one-year double-blind, placebo-controlled study required a reduction in dose or discontinuation of drug therapy compared to the placebo group. Lower blood glucose may necessitate a dosage reduction of antidiabetic agents.
    Oxandrolone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Oxymetholone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Paliperidone: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Pegvisomant: (Moderate) Patients who have both acromegaly and diabetes mellitus and are being treated with oral antidiabetic agents may require dose reductions of these medications after the initiation of pegvisomant. Growth hormone decreases insulin sensitivity by opposing the effects of insulin on carbohydrate metabolism; therefore, pegvisomant, which antagonizes growth hormone, is expected to have the opposite effect. Although none of the acromegalic patients with diabetes mellitus who were treated with pegvisomant during the clinical studies developed clinically relevant hypoglycemia, such patients should monitor their blood glucose regularly, with doses of antidiabetic medications reduced as necessary.
    Pemoline: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Penbutolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
    Perindopril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perindopril; Amlodipine: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perphenazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Perphenazine; Amitriptyline: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Phendimetrazine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenelzine: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Phenothiazines: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Phentermine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phentermine; Topiramate: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenylephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenylephrine; Promethazine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Pindolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Potassium-sparing diuretics: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prednisolone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Prednisone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Prilocaine; Epinephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Prochlorperazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Progesterone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Progestins: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Propranolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Pseudoephedrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Quetiapine: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Quinapril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Racepinephrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Ramipril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Rasagiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor rasagiline, are added to any regimen containing antidiabetic agents.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Risperidone: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Ritodrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Salicylates: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Selegiline: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Somatropin, rh-GH: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Sparfloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Spironolactone: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Sulfonamides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sympathomimetics: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive tegaserod concomitantly.
    Telmisartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Testolactone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Testosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Thiethylperazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Thioridazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Thyroid hormones: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Timolol: (Moderate) Pharmacodynamic interactions are possible between beta-blockers and antidiabetic agents. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic response and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Torsemide: (Moderate) When empagliflozin is initiated in patients already receiving loop diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving empagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
    Trandolapril: (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Trandolapril; Verapamil: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Moderate) Angiotensin-converting enzyme inhibitors (ACE inhibitors) may enhance the hypoglycemic effects antidiabetic agents, such as empagliflozin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Tranylcypromine: (Moderate) Selected monoamine oxidase inhibitors (MAOIs) have potentiated hypoglycemia in animal models; there are conflicting data regarding hypoglycemic reactions in humans. These effects do not appear to be due to MAO activity, but rather, a change in gluconeogenesis or insulin sensitivity related to a hydrazine chemical structure. It is not clear if all MAOIs affect blood glucose control or potentiate antidiabetic medications. When initiating MAOIs in a patient receiving antidiabetic agents, the patient should monitor their blood glucose and report any changes in blood sugar control.
    Triamcinolone: (Moderate) Systemic corticosteroids increase blood glucose levels. Because of this action, a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Triamterene: (Moderate) Administer empagliflozin; metformin with caution in patients receiving diuretics. When empagliflozin is initiated in patients already receiving diuretics, volume depletion can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may also be at a greater risk for volume depletion and perhaps symptomatic hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and correct if necessary. Monitor for signs and symptoms after initiating therapy.
    Trifluoperazine: (Minor) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. In addition, the atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Trovafloxacin, Alatrofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when other quinolones andantidiabetic agents, including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Valsartan: (Moderate) When empagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating empagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, empagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of empagliflozin by improving insulin sensitivity. ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Verapamil: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Ziprasidone: (Moderate) Patients taking empagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of empagliflozin in pregnant women, and use is not recommended during the second and third trimesters of human pregnancy. Based on results from animal studies, empagliflozin may affect renal development and maturation. Rat studies demonstrate that empagliflozin crosses the placenta and reaches fetal tissues. In rat and rabbit studies, empagliflozin was not teratogenic at 48-times and 128-times, respectively, the maximum clinical human dose of 25 mg. However, at higher doses (139 to 154 times the 25 mg maximum human clinical dose), maternal and fetal toxicity, including malformations of limb bones, were evident. Maternal toxicity did not occur in pre- and postnatal development studies, starting at gestation day 6 through to lactation day 20 (weaning) at approximately 16 times the 25 mg maximum clinical dose in pregnant rats; reduced body weight was observed in the offspring. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. The potential risks to human kidney development are of concern. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    It is not known if empagliflozin is excreted in human milk; however, due to a potential for serious adverse reactions in the nursing infant, it is recommended to avoid breast-feeding during its use, or to discontinue the drug, taking into account the importance of the therapy to the mother. Empagliflozin is secreted in the milk of lactating rats reaching levels 5 times higher than that in maternal plasma. 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. If empagliflozin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Empagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the tubular lumen in the kidney. SGLT2 is expressed in the proximal renal tubules. By inhibiting SGLT2, empagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion, improving blood glucose control. This urinary glucose excretion with empagliflozin also results in increased urinary volume. Following the administration of empagliflozin 10 mg and 25 mg orally once daily, increases in the amount of glucose excreted in the urine were observed immediately in adult patients with type 2 diabetes mellitus and were maintained at the end of a 4-week treatment period averaging at approximately 64 grams/day and 78 grams/day, respectively.

    PHARMACOKINETICS

    Empagliflozin is administered orally. The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Empagliflozin is approximately 86.2% protein bound. No major metabolites of empagliflozin were detected in human plasma. In vitro studies suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. The apparent terminal elimination half-life was estimated to be 12.4 hours and apparent oral clearance was 10.6 L/hour based on population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Following a dose of empagliflozin, 54.4% and 41.2% total radioactivity is excreted in urine and feces, respectively. The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
     
    Affected Cytochrome P450 (CYP450) enzymes and drug transporters: None
    Based on in vitro data, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. No effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.

    Oral Route

    Following oral administration, peak plasma concentrations (Cmax) of empagliflozin occurred at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol/hour/L and 259 nmol/L, respectively, with empagliflozin 10 mg/day. The steady state mean plasma AUC and Cmax were 4740 nmol/hour/L and 687 nmol/L, respectively, with 25 mg/day empagliflozin. Systemic exposure of empagliflozin increased in a dose proportional manner within the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Administration of a high-fat and high-calorie meal prior to empagliflozin administration resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted conditions; however, the observed effect of food on empagliflozin was not considered clinically relevant. Empagliflozin may be administered with or without food.