PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Dipeptidyl Peptidase-4/DPP-4 Inhibitors and Biguanide Antidiabetic Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Combination agent; linagliptin is an oral dipeptidyl peptidase-4 (DPP-IV) inhibitor and metformin is an oral biguanide antidiabetic agent
    Used for type 2 diabetes mellitus in adults
    Boxed warning for lactic acidosis

    COMMON BRAND NAMES

    Jentadueto, Jentadueto XR

    HOW SUPPLIED

    Jentadueto Oral Tab: 2.5-1000mg, 2.5-500mg, 2.5-850mg
    Jentadueto XR Oral Tab ER: 2.5-1000mg, 5-1000mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus in combination with diet and exercise when treatment with both linagliptin and metformin is appropriate.
    Oral dosage (immediate-release tablets, Jentadueto)
    Adults

    Initiate treatment with linagliptin 2.5 mg; metformin 500 mg PO twice daily with meals; increase the dose gradually to reduce the GI side effects due to metformin. IF CURRENTLY TAKING METFORMIN: Initiate at a dose of metformin that the patient is taking at each of the 2 daily meals (e.g., patient taking metformin 1,000 mg twice daily would be started on linagliptin 2.5 mg; metformin 1,000 mg PO twice daily with meals). IF CURRENTLY RECEIVING BOTH DRUGS INDIVIDUALLY: May switch to combination product using the same doses of each component. IN ALL PATIENTS: Individualize the dose based on efficacy and tolerability. In older patients, the initial and maintenance dose of metformin should be conservative due to the potential for decreased renal function; adjust dose based on a careful assessment of renal function. Max: linagliptin 5 mg/day with metformin 2,000 mg/day PO.

    Oral dosage (extended-release tablets, Jentadueto XR)
    Adults not currently treated with metformin

    Initiate with linagliptin 5 mg; metformin 1,000 mg PO once daily with a meal. IF CURRENTLY TAKING METFORMIN: Initiate with linagliptin 5 mg and a similar total daily dose of metformin once daily with a meal (e.g., a patient on metformin 500 mg twice daily would be started on linagliptin 5 mg; metformin 1,000 mg PO once daily with a meal). IF CURRENTLY TAKING BOTH MEDICATIONS INDIVIDUALLY: May switch to combination product containing linagliptin 5 mg and a similar total daily dose of metformin once daily with a meal. IN ALL PATIENTS: Individualize the dose based on efficacy and tolerability. In older patients, dose conservatively due to the potential for decreased renal function; adjust dose based on a careful assessment of renal function. Max: linagliptin 5 mg/day and metformin 2,000 mg/day PO.

    MAXIMUM DOSAGE

    Adults

    2,000 mg/day PO metformin; 5 mg/day PO linagliptin.

    Geriatric

    2,000 mg/day PO metformin; 5 mg/day PO linagliptin.

    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

    Avoid use in patients with clinical or laboratory evidence of hepatic disease; increased risk of lactic acidosis secondary to metformin.

    Renal Impairment

    eGFR more than 45 mL/minute/1.73 m2: No dosage adjustment needed. Obtain an eGFR at least annually in all patients taking metformin.
    eGFR 30 to 45 mL/minute/1.73 m2: Initiation of linagliptin; metformin is not recommended. Obtain an eGFR at least annually in all patients taking linagliptin; metformin. In patients whose eGFR is initially greater than 45 mL/minute/1.73 m2, and then later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue linagliptin; metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. The ADA and others suggest it is reasonable to decrease the dose by 50% (or use one-half the maximum recommended dose) and monitor renal function every 3 months in those with an eGFR less than 45 mL/minute/1.73 m2. Do not initiate the drug in patients at this stage. Additional caution is required in patients with anticipated significant fluctuations in renal status or those at risk for abrupt deterioration in kidney function, based on previous history, other comorbidities, albuminuria, and medication regimen (e.g., potent diuretics or nephrotoxic agents).
    eGFR less than 30 mL/minute/1.73 m2: Use is contraindicated.
     
    Intermittent hemodialysis
    Linagliptin; metformin use is contraindicated. Metformin is dialyzable; hemodialysis will efficiently remove accumulated metformin in the case of drug-induced lactic acidosis, provided metformin use is halted.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Immediate-release tablets: Administer twice daily with meals.
    Extended-release tablets: Administer once daily with a meal. Swallow tablet whole; do not split, crush, dissolve, or chew. There have been reports of incompletely dissolved tablets being eliminated in the feces. If a patient reports seeing tablets in feces, assess the adequacy of glycemic control.

    STORAGE

    Jentadueto:
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Jentadueto XR :
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, exfoliative dermatitis, serious rash, urticaria

    Linagliptin; metformin is contraindicated in patients with a history of a serious hypersensitivity reaction to linagliptin or metformin, such as anaphylaxis, urticaria, angioedema, exfoliative dermatitis or other severe allergic skin conditions, or bronchial hypersensitivity. Use caution in patients with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with linagliptin. A risk for serious hypersensitivity reactions or anaphylaxis, including angioedema and severe cutaneous reactions, has been reported with the post-marketing use of linagliptin; metformin. Serious hypersensitivity reactions have occurred within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose. Postmarketing cases of serious rash, specifically bullous pemphigoid, requiring hospitalization have been reported with DPP4 inhibitor use. Treatment with topical or systemic immunosuppressives and discontinuation of the DPP-4 inhibitor has typically resulted in resolution of the rash. Inform patients of the risk of serious rash and tell them to report development of blisters or erosions while receiving linagliptin; metformin. If a serious reaction is suspected, discontinue linagliptin; metformin and refer the patient to a dermatologist for diagnosis and appropriate treatment.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Linagliptin; metformin use is contraindicated in patients with diabetic ketoacidosis (DKA); DKA is treated with insulin. This combination is also not intended for the treatment of type 1 diabetes mellitus; both conditions require insulin receipt.

    Acidemia, hypoxemia, lactic acidosis, metabolic acidosis

    Linagliptin; metformin is contraindicated in patients with acute or chronic metabolic acidosis. Metformin increases the risk for lactic acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction. Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. Educate patients and their families about the symptoms of lactic acidosis and instruct them to seek immediate medical attention if such symptoms occur. If ketoacidosis or lactic acidosis is suspected, immediately discontinue linagliptin; metformin and initiate supportive measures in a hospital setting. In those with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin. Hemodialysis has often resulted in reversal of symptoms and recovery. Serum electrolytes, ketones, blood glucose, blood pH, and lactate, pyruvate, and/or metformin levels may be useful to rule out lactic acidosis.

    Acute heart failure, acute myocardial infarction, cardiac disease, cardiogenic shock, heart failure

    Use linagliptin; metformin with caution in patients who have a history of or who have increased risk factors for heart failure, including patients with existing cardiac disease or kidney disease. Observe patients receiving linagliptin; metformin for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug and monitoring for diabetic control. In patients receiving other DPP-4 inhibitors, including linagliptin and saxagliptin, an increased risk of hospitalization for heart failure has been reported. In the EXAMINE trial, 5,380 patients with type 2 diabetes and established cardiovascular disease who had a recent acute coronary syndrome event were randomized to receive either alogliptin therapy or placebo. More patients randomized to the alogliptin group (3.9%) experienced at least 1 hospitalization for heart failure compared to patients randomized to placebo (3.3%). In the SAVOR trial, 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or a risk for cardiovascular events were randomized to receive either saxagliptin therapy or placebo. Although the SAVOR trial was not specifically designed to assess heart failure risk, results showed that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group (HR 1.27, 95% CI 1.07 to 1.51; p = 0.007). Linagliptin; metformin should also be used with caution in patients with congestive heart failure, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute heart failure, are at increased risk of lactic acidosis from metformin therapy. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia. A systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin is not associated with any measurable harm in patients with heart failure; in this analysis, metformin was associated with reduced mortality.

    Renal disease, renal failure, renal impairment

    Linagliptin; metformin is contraindicated for use in patients with renal failure or severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. Initiating linagliptin; metformin in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. Before initiation of treatment and at least annually thereafter, obtain an eGFR to assess renal function. In those patients at increased risk for the development of renal impairment, such as the elderly, renal function should be assessed more frequently. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. Certain medications that are eliminated via the kidney when used concomitantly with metformin may also increase the risk of lactic acidosis. In patients taking linagliptin; metformin whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue linagliptin; metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. If linagliptin; metformin is discontinued due to renal impairment, linagliptin may be continued as a single agent at the same total daily dose of 5 mg; renal dosage adjustment is not required for linagliptin. Based on the results of a comprehensive FDA safety review, the FDA concluded that metformin can be used safely in patients with mild renal impairment, and in some patients with moderate renal impairment. The measure of kidney function used to determine whether a patient can receive metformin has been changed from serum creatinine to the eGFR; this is because in addition to serum creatinine concentration, the eGFR takes into account additional parameters that are important, such as the patient’s age, gender, race and/or weight.

    Alcoholism, ethanol ingestion, ethanol intoxication, hepatic disease

    Use of linagliptin; metformin is not recommended in patients with hepatic disease. Metformin administration increases the risk for lactic acidosis. Since the liver is important for clearing accumulated lactic acid, patients with impairment are at increased risk for developing lactic acidosis. Hepatic disease also causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive ethanol ingestion (ethanol intoxication) while taking linagliptin; metformin due to the increased risk for lactic acidosis. Those with ethanol intoxication are also particularly susceptible to hypoglycemic effects of oral antidiabetic agents. Metformin use should be avoided by those patients with alcoholism. Fatty liver disease can occur in patients with type 2 diabetes which can result in abnormal liver function tests (LFTs). Prior to initiating therapy it is advisable to get baseline liver function tests (LFTs).

    Radiographic contrast administration

    Discontinue linagliptin; metformin at the time of or before radiographic contrast administration in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/minute/1.73 m2; in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate the eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable.

    Burns, dehydration, fever, infection, sepsis, surgery, trauma

    To reduce the risk of lactic acidosis, linaglitpin; metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Linagliptin; metformin should be temporarily suspended for surgery and other procedures, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any acute change in clinical status may also increase the risk of lactic acidosis and loss of diabetic control and may require laboratory evaluation in patients on linagliptin; metformin and may require the drug be withheld.

    Pernicious anemia

    Metformin may result in suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Measure hematologic parameters annually in patients receiving linagliptin; metformin; abnormalities should be investigated and managed appropriately. Certain individuals (those inadequate vitamin B12 or calcium intake or absorption) may be predisposed to this type of anemia; in these patients, serum vitamin B12 measurement at 2- to 3-year intervals may be useful. A nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15 to 3.87) as did taking metformin for 3 years or more (OR 2.39, 95% CI 1.46 to 3.91).

    Pancreatitis

    There have been postmarket reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin or other members of the dipeptidyl peptidase-4 (DPP4) inhibitors class. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin; metformin and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using linagliptin; metformin. In March 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics, including the dipeptidyl peptidase 4 (DPP-4) inhibitors. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although the totality of the reviewed data provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available.

    Adrenal insufficiency, diarrhea, gastroparesis, GI obstruction, hypercortisolism, hyperglycemia, hyperthyroidism, hypoglycemia, hypothyroidism, ileus, malnutrition, pituitary insufficiency, vomiting

    Gastrointestinal (GI) side effects, such as diarrhea, nausea, or vomiting, are common during metformin initiation. However, once a patient is stabilized on any dose of metformin, GI symptoms are unlikely to be drug related. Later occurrence of GI symptoms, such as nonspecific abdominal distress may be due to a change in clinical status and may increase the risk of lactic acidosis or other serious disease. Patients should be advised to contact their prescriber if an increase in GI symptoms occurs. Patients who complain of an increase in GI symptoms while stabilized on treatment should undergo laboratory investigation to determine the etiology of the symptoms. Withholding of linagliptin; metformin therapy until the cause is known may be necessary. Conditions such as diarrhea, gastroparesis, GI obstruction, ileus, and vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood sugar. Other conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. 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 while receiving linagliptin; metformin.

    Arthralgia

    Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including linagliptin. The time to onset of symptoms following initiation of drug varied from 1 day to several years. Patients experienced relief of symptoms upon discontinuation of the medication, usually in less than a month. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking linagliptin; metformin. Consider linagliptin; metformin as a possible cause of joint pain and discontinue if appropriate. The FDA has identified 33 cases of severe arthralgia with the use of DPP-4 inhibitors, all of which resulted in substantial reduction of the patient’s prior level of activity and, in 10 cases, required hospitalization.

    Geriatric

    Geriatric patients have a greater likelihood of having hepatic, renal, or cardiac impairment, increasing the risk of metformin-associated lactic acidosis; use linagliptin; metformin with caution. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Do not initiate linagliptin; metformin treatment in patients 80 years of age and older unless measurement of creatinine clearance (CrCl) and calculation of the estimated glomerular filtration rate (eGFR) demonstrates that renal function is not reduced. Obtain an estimated glomerular filtration rate (eGFR) at least annually in all patients taking linagliptin; metformin. In patients at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently. Generally, geriatric or debilitated patients should not be titrated up to maximum metformin dosages. Geriatric, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently. 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. Metformin has been associated with lactic acidosis, which is more likely to occur under the following conditions: serum creatinine of 1.5 mg/dL or higher in males or 1.4 mg/dL or higher in females, abnormal creatinine clearance from any cause, age of 80 years or older unless measurement of creatinine clearance verifies normal renal function, radiologic studies in which intravascular iodinated contrast materials are given, congestive heart failure requiring pharmacologic management, or acute/chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).

    Polycystic ovary syndrome, pregnancy

    Premenopausal anovulatory females with insulin resistance, such as those with polycystic ovary syndrome (PCOS), may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used in those not desiring to become pregnant. The limited data with linagliptin; metformin use in pregnant women are not sufficient to inform a linagliptin; metformin-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed when the combination of linagliptin and metformin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure. Published data has not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. There are risks to the mother and fetus associated with poorly controlled diabetes during pregnancy. 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

    There is no information regarding the presence of linagliptin; metformin or linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited studies report metformin is present in human milk; however, there is insufficient information to determine the effects of metformin on the breastfed infant and no information on its effects on milk production. The benefits of breast-feeding should be considered along with the mother's clinical need for linagliptin; metformin and any potential adverse effects on the breastfed infant from the underlying maternal condition. In animal studies, linagliptin is excreted in milk at a milk-to-plasma ratio of 4:1, but no human data are available. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma, and small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Furthermore, the use of metformin 2,550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin monotherapy while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected ; therefore, this agent may represent a reasonable alternative for some patients. 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.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 0-1.0
    megaloblastic anemia / Delayed / 0-1.0
    lactic acidosis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pemphigus / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known

    Moderate

    vitamin B12 deficiency / Delayed / 7.0-7.0
    hypoglycemia / Early / 1.4-2.1
    metabolic acidosis / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    stomatitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 1.0-6.4
    pharyngitis / Delayed / 6.3-6.3
    diarrhea / Early / 6.3-6.3
    malaise / Early / 1.0-5.0
    myalgia / Early / 1.0-5.0
    dysgeusia / Early / 1.0-5.0
    anorexia / Delayed / 1.0-5.0
    vomiting / Early / 1.0-5.0
    metallic taste / Early / 1.0-5.0
    cough / Delayed / 2.0
    nausea / Early / 5.0
    dyspepsia / Early / 5.0
    flatulence / Early / 5.0
    asthenia / Delayed / 5.0
    headache / Early / 5.0
    urticaria / Rapid / Incidence not known
    rash (unspecified) / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    weight loss / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Caution is advised when administering dolutegravir with metformin, as coadministration may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. If these drugs are used in combination, the total daily dose of metformin must not exceed 1000 mg/day. Close monitoring of blood glucose and patient clinical status is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin was administered at a dose of 500 mg PO twice daily. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Abacavir; Lamivudine, 3TC: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
    Acebutolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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; Aspirin, ASA; Caffeine: (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, such as linagliptin.
    Acetaminophen; Butalbital: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Acetaminophen; Butalbital; Caffeine: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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, such as linagliptin.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (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, such as linagliptin.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetazolamide: (Moderate) 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. Carbonic anhydrase inhibitors frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase. Monitor electrolytes and renal function. (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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Adefovir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., adefovir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Aliskiren; Amlodipine; 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Alogliptin; Pioglitazone: (Major) Inducers of CYP3A4 (e.g., pioglitazone) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Amiloride; 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Aminosalicylate sodium, Aminosalicylic acid: (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, such as linagliptin.
    Amlodipine; Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amobarbital: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that amphetamines can be used concurrently.
    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 linagliptin 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, such as linagliptin, 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. (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) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of linagliptin with aprepitant due to substantially increased exposure of aprepitant. If coadministration cannot be avoided, use caution and monitor for an increase in aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Linagliptin is a weak-to-moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur.
    Aripiprazole: (Moderate) Patients taking linagliptin 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, 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Asenapine: (Moderate) Patients taking linagliptin 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, 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.
    Aspirin, ASA: (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, such as linagliptin.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (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, such as linagliptin.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (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, such as linagliptin.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (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, such as linagliptin.
    Aspirin, ASA; Carisoprodol: (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, such as linagliptin.
    Aspirin, ASA; Carisoprodol; Codeine: (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, such as linagliptin.
    Aspirin, ASA; Dipyridamole: (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, such as linagliptin.
    Aspirin, ASA; Omeprazole: (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, such as linagliptin.
    Aspirin, ASA; Oxycodone: (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, such as linagliptin.
    Aspirin, ASA; Pravastatin: (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, such as linagliptin.
    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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (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, such as linagliptin.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    atypical antipsychotic: (Moderate) Patients taking linagliptin 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, 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. (Moderate) Patients taking metformin 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, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. 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. (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. (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750-2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on linagliptin for changes in blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Azelastine; Fluticasone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Azilsartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Baclofen: (Minor) Because baclofen can increase blood glucose, doses of antidiabetic agents, such as linagliptin, may need adjustment in patients receiving these drugs concomitantly. (Minor) Coadministration of metformin and baclofen may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Baclofen can increase blood glucose. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with baclofen is instituted. Doses of metformin may need adjustment in patients receiving these drugs concomitantly.
    Barbiturates: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Beclomethasone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Bendroflumethiazide; Nadolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (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, such as linagliptin.
    Benzphetamine: (Moderate) Benzphetamine may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that benzphetamine can be used concurrently. (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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Beta-adrenergic blockers: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Beta-blockers: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, 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) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Betaxolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Bexarotene: (Moderate) Concomitant use of linagliptin with bexarotene may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; bexarotene is a moderate inducer of CYP3A4. Bexarotene may also enhance the hypoglycemic action of linagliptin. Caution and close monitoring of blood sugars are advised if these drugs are used together.
    Bismuth Subsalicylate: (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, such as linagliptin.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (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, such as linagliptin.
    Bisoprolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Boceprevir: (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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Bortezomib: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents, such as linagliptin, receiving bortezomib treatment may require close monitoring of their blood glucose concentrations and dosage adjustment of their medications.
    Bosentan: (Moderate) Concomitant use of linagliptin with bosentan may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; bosentan is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Brexpiprazole: (Moderate) Patients taking linagliptin 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, 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) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Budesonide: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Budesonide; Formoterol: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Bumetanide: (Minor) Bumetanide has been associated with hyperglycemia, possibly due to potassium depletion, and, glycosuria has been reported. Because of this, a potential pharmacodynamic interaction exists between bumetanide and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely. (Minor) Loop diurectics may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, such as linagliptin. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Butabarbital: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Candesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Captopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Carbamazepine: (Major) Carbamazepine is an inducer of CYP3A4 and p-glycoprotein; oxcarbazepine is an inducer of CYP3A4. Inducers of CYP3A4 or p-glycoprotein can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin 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, 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) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Cephalexin: (Moderate) In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively; metformin renal clearance decreased by an average of 14%. No information is available about the interaction of cephalexin and metformin following multiple dose administration.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 metformin, 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. (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the dipeptidyl peptidase-4 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 taking antidiabetic medications, such as linagliptin, 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these 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. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents, such as linagliptin, 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Choline Salicylate; Magnesium Salicylate: (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, such as linagliptin.
    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.
    Cimetidine: (Moderate) Caution is advised when administering cimetidine with metformin. Cimetidine inhibits renal elimination of metformin. Increased metformin exposure may lead to hypoglycemia, gastrointestinal complaints, and an increased risk for lactic acidosis. Consider alternatives to cimetidine. If medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including linagliptin, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including metformin, 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.
    Clarithromycin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Clofarabine: (Moderate) Concomitant use of clofarabine and metformin may result in altered clofarabine levels because both agents are a substrate of OCT1. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 substrates.
    Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Clozapine: (Moderate) Patients taking linagliptin 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, 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.
    Cobicistat: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Codeine; Promethazine: (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Colesevelam: (Moderate) Colesevelam increases the Cmax and AUC of extended-release metformin (metformin ER) by approximately 8% and 44%, respectively. According to the manufacturer of colesevelam, the clinical response to metformin ER should be monitored in patients receiving concomitant therapy. Colesevelam has no significant effect on the bioavailability of immediate-release metformin.
    Conjugated Estrogens: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Corticosteroids: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. In addition, blood lactate concentrations and the lactate to pyruvate ratio increase when metformin is coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with increased morbidity rates. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Corticotropin, ACTH: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Cortisone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Crizotinib: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    Cyanocobalamin, Vitamin B12: (Minor) Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Cyclosporine: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving linagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    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. (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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) 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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of CYP3A4 (e.g., ritonavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Desiccated Thyroid: (Minor) Addition of thyroid hormones to metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed. (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, such as linagliptin, 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dexamethasone: (Major) Concomitant use of linagliptin with dexamethasone may result in decreased efficacy of linagliptin. When corticosteroids are administered exogenously, increases in blood glucose concentrations are expected, thereby decreasing the hypoglycemic effect of antidiabetic agents. In addition, linagliptin is a substrate of hepatic isoenzyme CYP3A4 and dexamethasone is a moderate inducer of CYP3A4. Coadministration may result in decreased concentrations of linagliptin and decreased efficacy. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when dexamethasone is coadministered.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with a sympathomimetic agent, such as dexmethylphenidate, 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 linagliptin 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dextromethorphan; Promethazine: (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Diazoxide: (Minor) Because diazoxide increases blood glucose, a pharmacodynamic interaction exists between this drug and all other antidiabetic agents, including metformin. (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, such as linagliptin, may need to be adjusted when diazoxide is added to the regimen.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and metformin together with caution. Lactic acidosis, a rare and serious form of metabolic acidosis, has been reported with the use of metformin, and metabolic acidosis has been reported with the use of dichlorphenamide. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Minor) Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Dienogest; Estradiol valerate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Diethylpropion: (Moderate) Diethylpropion exhibits intrinsic hypoglycemic activity and can lower postprandial blood glucose concentrations. Diethylpropion should be used cautiously in diabetic patients who are stabilized on antidiabetic agents. (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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diethylstilbestrol, DES: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving disopyramide concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving disopyramide concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dofetilide: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
    Dolutegravir: (Major) Caution is advised when administering dolutegravir with metformin, as coadministration may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. If these drugs are used in combination, the total daily dose of metformin must not exceed 1000 mg/day. Close monitoring of blood glucose and patient clinical status is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin was administered at a dose of 500 mg PO twice daily. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Dolutegravir; Rilpivirine: (Major) Caution is advised when administering dolutegravir with metformin, as coadministration may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. If these drugs are used in combination, the total daily dose of metformin must not exceed 1000 mg/day. Close monitoring of blood glucose and patient clinical status is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin was administered at a dose of 500 mg PO twice daily. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Donepezil; Memantine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dorzolamide; Timolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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 decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Efavirenz: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Emtricitabine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Enalapril, Enalaprilat: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Enalapril; Felodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Entecavir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Eprosartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Erythromycin; Sulfisoxazole: (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, such as linagliptin. (Moderate) 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.
    Esmolol: (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents, such as linagliptin. 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. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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 decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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. (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 decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Levonorgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Estradiol; Norethindrone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Estradiol; Norgestimate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Estramustine: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
    Estrogens: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estropipate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethacrynic Acid: (Moderate) Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations.Patients receiving antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (Minor) Loop diurectics may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, such as linagliptin. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Ethanol: (Major) Alcohol (ethanol) may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy, such as linagliptin. 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. In addition, alcohol is a CYP 3A4 inducer which can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. 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. (Moderate) Patients should be advised to limit their use of ethanol during use of metformin. Blood lactate concentrations and the lactate to pyruvate ratio are increased during excessive (acute or chronic) intake of alcohol with metformin. Elevated lactic acid concentrations are associated with increased morbidity rates as the risk for lactic acidosis is increased. Many non-prescription drug products may be formulated with alcohol; have patients scrutinize product labels prior to consumption. In patients with diabetes, alcohol intake can also cause hypoglycemia or worsen glycemic control as it provides a source of additional calories.
    Ethinyl Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ethotoin: (Moderate) Phenytoin, fosphenytoin, or ethotoin can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. In addition, potent inducers of CYP3A4 (e.g.,phenytoin, fosphenytoin) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin or fosphenytoin, an alternative to linagliptin is strongly recommended. Patients receiving linagliptin should be closely monitored for signs indicating loss of diabetic control when co-use of any of these hydantoins is necessary. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy is discontinued. (Minor) Ethotoin 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, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Etravirine: (Moderate) Concomitant use of linagliptin with etravirine may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; etravirine is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Famotidine: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Famotidine; Ibuprofen: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Fenofibrate: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (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, such as linagliptin, should be monitored for changes in glycemic control.
    Fenofibric Acid: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (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, such as linagliptin, 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Fibric acid derivatives: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (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, such as linagliptin, should be monitored for changes in glycemic control.
    Fludrocortisone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Flunisolide: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluocinolone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluocinolone; Hydroquinone; Tretinoin: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluocinonide: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluoxetine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin. (Moderate) Patients taking linagliptin 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, 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. (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 taking antidiabetic medications, such as linagliptin, should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Fluticasone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluticasone; Salmeterol: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fluticasone; Vilanterol: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Folic Acid, Vitamin B9: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Formoterol; Mometasone: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Fosamprenavir: (Major) 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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of CYP3A4 (e.g., fosamprenavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Fosinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents, such as linagliptin, by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Fosphenytoin: (Major) Potent inducers of CYP3A4 (e.g. fosphenytoin) can decrease exposure to linagliptin and result in subtherapeutic and likely ineffective concentrations. For patients requiring use of fosphenytoin, an alternative to linagliptin is strongly recommended. If these drugs must be used together, blood glucose should be closely monitored for changes in glycemic control. Phenytoin and other hydantoins have additionally been reported to cause an increase in blood glucose and interfere with antidiabetic agents pharnacodynamically. (Minor) Fosphenytoin 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: (Minor) Furosemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. (Minor) Loop diurectics may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, such as linagliptin. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Gadoterate meglumine: (Severe) Metformin and combination products containing metformin should be temporarily discontinued prior to the administration of iodinated contrast media. Metformin should be held for at least 48 hours after contrast administration and not restarted until renal function returns to normal post-procedure. Lactic acidosis has been reported in patients taking metformin that experience nephrotoxicity after use of iodinated contrast media.
    Garlic, Allium sativum: (Moderate) Limited animal data suggest that selected constituents in Garlic 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, such as linagliptin, should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring. (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 antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (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, such as linagliptin, should be monitored for changes in glycemic control.
    Gemifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including linagliptin, are coadministered. (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered.
    Glimepiride; Pioglitazone: (Major) Inducers of CYP3A4 (e.g., pioglitazone) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    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, such as linagliptin. Clinically, glucagon is often used to increase blood glucose concentrations in patients with severe hypoglycemia (Minor) Glucagon administration results in increases in blood glucose concentrations thereby decreasing the hypoglycemic effect of metformin.
    Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
    Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
    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. (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents, such as linagliptin, 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents 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 linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these 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. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of linagliptin by improving insulin sensitivity. In addition, 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 ARBs concomitantly with linagliptin should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and gly