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  • CLASSES

    Incretin mimetics Antidiabetics
    Other Antiobesity Products

    DEA CLASS

    Rx

    DESCRIPTION

    Incretin mimetic (GLP-1 receptor agonist) given by subcutaneous injection once daily
    Victoza is used to improve glycemic control in adults with type 2 diabetes mellitus (DM) and to reduce the risk of non-fatal cardiovascular events (e.g., myocardial infarction or stroke), including reduction of cardiovascular mortality, if patients also have cardiovascular disease
    Separate product (Saxenda) used for reduction of obesity as an adjunct to diet and exercise in adults
    Liraglutide products are not recommended as a first-line therapy due to the boxed warning regarding rodent C-cell tumor findings and the uncertain relevance to humans

    COMMON BRAND NAMES

    Saxenda, Victoza

    HOW SUPPLIED

    Saxenda/Victoza Subcutaneous Inj Sol: 1mL, 6mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus and to reduce the risk of cardiovascular events (e.g., non-fatal myocardial infarction or non-fatal stroke), including reduction of cardiovascular mortality, in type 2 DM patients who also have established cardiovascular disease.
    Subcutaneous dosage (Victoza)
    Adults

    Initially, 0.6 mg subcutaneously once daily for 1 week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal (GI) symptoms during initial titration and is not effective for glycemic control. After 1 week, increase the dose to 1.2 mg subcutaneously once daily. If acceptable glycemic control not achieved, the dose can be increased to 1.8 mg subcutaneously once daily. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg in order to alleviate any GI symptoms associated with re-initiation of treatment. The dose should then be re-titrated appropriately. The concurrent use of liraglutide and prandial insulin has not been studied. When liraglutide is added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist. When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia. In addition to improving glycemic control, a long-term, multicenter, randomized, double-blind, placebo-controlled clinical trial (LEADER) of 9,340 patients with inadequately controlled type 2 DM and established, stable, atherosclerotic cardiovascular disease reported that the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced in the liraglutide group (13 %) compared to the placebo group (14.9%) (HR 0.87; 95% CI 0.78 to 0.97; p less than 0.001 for noninferiority; p = 0.01 for superiority).

    For the treatment of obesity as an adjunct to a reduced-calorie diet and increased physical activity.
    Subcutaneous dosage (Saxenda)
    Adults

    0.6 mg subcutaneously once daily for 1 week to reduce gastrointestinal (GI) symptoms associated with initial therapy. Increase the daily dose by 0.6 mg at weekly intervals until the target dose of 3 mg subcutaneously once daily is attained. If patients do not tolerate a dose increase, consider delaying dose escalation for 1 additional week. Discontinue liraglutide if patients cannot tolerate the 3 mg dose as efficacy has not been established at lower doses. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at the 0.6 mg dose and re-titrate appropriately. Liraglutide is indicated for patients with an initial body mass index (BMI) of 30 kg/m2 or more or in those with a BMI of 27 kg/m2 or more in the presence of at least 1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). The BMI calculation = weight in kilograms divided by height in meters squared.

    Children† and Adolescents† 12 to 17 years

    Further study is needed to establish safety and efficacy. Preliminary studies suggest that a dosing regimen similar to that for obese adults may be appropriate for adolescent obese patients. In a small trial, pediatric patients (n = 21, age 12 to 17 years) at Tanner stage 2 to 5, with obesity [as defined by a body mass index (BMI) corresponding to both a BMI 95th percentile or more for age and sex and to a BMI of 30 kg/m2 for adults; additionally, BMI was 45 kg/m2 or less] were randomized (2:1) to receive 5 weeks of treatment with liraglutide (n = 14) or placebo (n = 7). Liraglutide was initiated at 0.6 mg subcutaneously once daily for 1 week to reduce gastrointestinal (GI) symptoms associated with initial therapy. The daily dose was increased by 0.6 mg at weekly intervals until the target dose of 3 mg subcutaneously once daily was attained. This was an exploratory study; gastrointestinal adverse effects were reported, and some hypoglycemia. Favorable effects of liraglutide in exploratory pharmacodynamic endpoints such as BMI, body weight, fasting glucose, A1C, were observed; none was statistically significant, but this was reflective of the short duration of treatment and the small number of participants.

    MAXIMUM DOSAGE

    Adults

    1.8 mg/day SC for the treatment of type 2 diabetes mellitus; 3 mg/day SC for the treatment of obesity.

    Geriatric

    1.8 mg/day SC for the treatment of type 2 diabetes mellitus; 3 mg/day SC for the treatment of obesity.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is required.  

    Renal Impairment

    No dosage adjustment is required.

    ADMINISTRATION

    Injectable Administration

    Administer by subcutaneous injection only. Do not administer by intravenous or intramuscular injection.
    Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually viscous, cloudy, discolored, or if particles are present.
    Do NOT mix liraglutide with insulin. When using liraglutide (Victoza) concomitantly with insulin, administer as separate injections. The two injections may be injected in the same body region, but the injections should not be adjacent to each other.
    Liraglutide (Saxenda) for the treatment of obesity is not recommended in combination with insulin.
    Diabetic medication or other medication pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials, if available, or reserve the use of any pen to 1 patient only.

    Subcutaneous Administration

    Administer once daily at any time of day, independently of meals.
    Liraglutide is available as a pre-filled pen.
    Pen needles are not included and must be purchased separately.
    Liraglutide pen should be used with Novo Nordisk disposable needles.
    The liraglutide pen must be primed prior to the first use. See the pen user manual for directions.
    Inject subcutaneously into the thigh, abdomen, or upper arm.
    Double-check dosage prior to administration.
    Press down on the center of the dose button to inject until 0 mg lines up with the pointer. Inject over 6 seconds to ensure the full dose is injected. Keep thumb on the injection button until the needle is removed from the skin.
    Rotate administration sites with each injection to prevent lipodystrophy.
    For patients who are to self administering liraglutide, adequate oral as well as written instructions on the use of the injector pen should be supplied before they self-administer a dose.
    Do not store the pen with the needle on; this will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.

    STORAGE

    Saxenda:
    - After initial use, may be stored for 30 days at controlled room temperature (59 to 86 degrees F) or in refrigerator (36 to 46 degrees F)
    - Avoid direct heat and sunlight
    - Avoid excessive heat (above 104 degrees F)
    - Discard 30 days after first use
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not use if product has been frozen
    - Refrigerate (between 36 and 46 degrees F)
    Victoza:
    - After initial use, may be stored for 30 days at controlled room temperature (59 to 86 degrees F) or in refrigerator (36 to 46 degrees F)
    - Avoid direct heat and sunlight
    - Avoid excessive heat (above 104 degrees F)
    - Discard 30 days after first use
    - Discard if product has been frozen
    - Do not freeze
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with liraglutide or any other antidiabetic drug.

    History of angioedema, serious hypersensitivity reactions or anaphylaxis

    Liraglutide is contraindicated in patients with a history of a serious hypersensitivity reaction to liraglutide. There is a risk of serious hypersensitivity reactions or anaphylaxis with liraglutide use. Serious hypersensitivity reactions have been reported during postmarketing use with liraglutide, such as anaphylaxis or angioedema. Use caution in patients with a history of angioedema or anaphylaxis to other GLP-1 receptor agonists because it is unknown whether such patients will be predisposed to serious reactions with liraglutide. If a serious hypersensitivity reaction is suspected, discontinue liraglutide and consider other potential causes for the event, then initiate alternative therapy.

    Medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN 2), thyroid cancer, thyroid C-cell tumors

    Liraglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Liraglutide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Cases of MTC in patients treated with liraglutide for diabetes have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. In clinical trials, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and were diagnosed after thyroidectomy, which was prompted by finding on protocol-specified screening with serum calcitonin or thyroid ultrasound. Patients should be counseled on the potential risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with liraglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Liraglutide is not a substitute for insulin in patients who require insulin. Liraglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Liraglutide has not been evaluated for use in combination with prandial insulin.

    Burns, diarrhea, fever, infection, surgery, thyroid disease, trauma, vomiting

    Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can affect requirements of antidiabetic agents; dosage adjustments may be necessary. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring and their antidiabetic therapy, including liraglutide, when acute illness is present. 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).

    Gastroparesis

    Liraglutide may slow gastric emptying. Liraglutide has not been studied in patients with gastroparesis, and should be used cautiously in this population. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea.

    Hypoglycemia

    Hypoglycemia should be monitored for by the patient and clinician when liraglutide treatment is initiated and continued. In clinical trials, hypoglycemia was increased when liraglutide was used in combination with a sulfonylurea. Although specific dose recommendations are not available, the clinician should consider a dose reduction of the sulfonylurea when used in combination with liraglutide. In addition, when liraglutide is used in combination with insulin detemir, the dose of insulin should be evaluated; in patients at increased risk of hypoglycemia consider reducing the dose of insulin at initiation of liraglutide, followed by careful titration. Adequate blood glucose monitoring should be continued and followed. Patient and family education regarding hypoglycemia management is crucial; the patient and patient's family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes (where deficiencies in the release or response to counter regulatory hormones exist), with autonomic neuropathy, intensified diabetes control, or taking beta-blockers, guanethidine, or reserpine. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia in a patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.

    Renal impairment

    Use caution when initiating or increasing doses of liraglutide in patients with renal impairment. There is limited information available on the use of liraglutide in patients with renal impairment. Although liraglutide has not been found to be directly nephrotoxic in animal studies or clinical trials, there have been post-marketing reports of acute renal failure and worsening of chronic renal failure, which sometimes has required hemodialysis in patients treated with liraglutide; in many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents, including liraglutide. In addition, the pharmacokinetics of a single dose of liraglutide were evaluated in patients with varying degrees of renal impairment. Compared to healthy subjects, the AUC in patients with varying degrees of renal impairment was lower.

    Alcoholism, cholelithiasis, gallbladder disease, pancreatitis

    Use liraglutide with caution in patients with risk factors for pancreatitis. Liraglutide has been studied in a limited number of patients with a history of pancreatitis; it is unknown if these patients are at increased risk for the development of pancreatitis while using liraglutide. There have been reports of acute and chronic pancreatitis in patients taking liraglutide during premarketing clinical trials. In some of these patients other risk factors for pancreatitis were present, such as gallstones (cholelithiasis) or alcoholism. Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has also been reported postmarketing in patients treated with liraglutide. Liraglutide has been studied in a limited number of patients with a history of pancreatitis; it is unknown if these patients are at increased risk for the development of pancreatitis while using liraglutide. The FDA and EMA have evaluated unpublished findings that suggested 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. The FDA and the EMA have stated that after review, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available. After initiation and dose increases, patients should be observed carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue liraglutide; if pancreatitis is confirmed do not resume liraglutide. Also use liraglutide with caution in patients with gallbladder disease. In the LEADER trial, 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute gallbladder disease events, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy. In patients for whom cholelithiasis is suspected, also consider evaluation for an acute gallbladder disease event and perform gallbladder studies and appropriate clinical follow-up.

    Hepatic disease

    There is limited information available on the use of liraglutide in patients with hepatic disease. The pharmacokinetics of a single dose of liraglutide were evaluated in patients with varying degrees of hepatic disease. Compared to healthy subjects, the AUC in patients with hepatic impairment was lower (see Pharmacokinetics). Liraglutide should be used with caution in patients with hepatic disease.

    Pregnancy

    Liraglutide (Saxenda) for the treatment of obesity is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus. There are no adequate data or clinical studies of liraglutide (Victoza) use for the treatment of type 2 diabetes mellitus in pregnant women; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the toxicities found in animal studies, it may be prudent to avoid liraglutide until data in human pregnancy are available. Rat studies have noted abnormalities and variations in the kidneys, and irregular skeletal ossification effects when liraglutide was given at or above 0.8 times the human systemic exposures, based on the maximum recommended human dose (MRHD) of 1.8 mg/day (determined from AUC). Reduced growth and increased total major abnormalities occurred in rabbits at systemic exposures below human exposure at the MRHD (determined from AUC). The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    Breast-feeding

    In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. Liraglutide excretion into human milk is unknown. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. If liraglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. The American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding. Although other sulfonylureas have not been evaluated by the AAP, 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.

    Children, infants

    The safety and efficacy of liraglutide have not been established in adolescents, children, or infants.

    Depression, suicidal ideation

    When liraglutide is used for weight management, administer with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation. Monitor patients receiving liraglutide for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue liraglutide in patients who develop suicidal thoughts or behaviors. In clinical trials of liraglutide (Saxenda) for the treatment of obesity, 0.3% of patients receiving liraglutide reported suicidal ideation compared to 0.1% of the patients receiving placebo; one of these liraglutide-treated patients attempted suicide.

    Geriatric

    Liraglutide has been studied in patients 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric patients versus younger adult patients. In general, however, elderly patients are especially at risk for hypoglycemic episodes. The specific reasons identified include intensive insulin therapy, decreased renal function, severe liver disease, alcohol ingestion, defective counter regulatory hormone release, missing meals/fasting, and gastroparesis. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals. 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.

    ADVERSE REACTIONS

    Severe

    cholecystitis / Delayed / 0.2-3.1
    pancreatitis / Delayed / 0-0.3
    AV block / Early / 0.3-0.3
    suicidal ideation / Delayed / 0.3-0.3
    new primary malignancy / Delayed / 0.2-0.2
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    palpitations / Early / 0-34.0
    hypoglycemia / Early / 1.6-23.0
    constipation / Delayed / 9.9-19.4
    antibody formation / Delayed / 8.6-8.6
    cholelithiasis / Delayed / 0.3-3.1
    hypertension / Early / 3.0-3.0
    erythema / Early / 0-2.0
    hypotension / Rapid / 1.1-1.1
    orthostatic hypotension / Delayed / 1.1-1.1
    sinus tachycardia / Rapid / 0.6-0.6
    bundle-branch block / Early / 0.3-0.3
    elevated hepatic enzymes / Delayed / 0.2-0.2
    hyperamylasemia / Delayed / 0.1-0.1
    gastritis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    nausea / Early / 23.9-39.0
    diarrhea / Early / 9.3-17.1
    vomiting / Early / 8.7-15.7
    injection site reaction / Rapid / 2.0-13.9
    anorexia / Delayed / 10.0-10.0
    dyspepsia / Early / 9.6-9.6
    headache / Early / 9.1-9.1
    fatigue / Early / 7.5-7.5
    influenza / Delayed / 7.4-7.4
    infection / Delayed / 4.3-6.0
    dizziness / Early / 5.8-5.8
    sinusitis / Delayed / 5.6-5.6
    abdominal pain / Early / 5.4-5.4
    back pain / Delayed / 5.0-5.0
    gastroesophageal reflux / Delayed / 4.7-4.7
    eructation / Early / 4.5-4.5
    flatulence / Early / 4.0-4.0
    insomnia / Early / 2.4-2.4
    xerostomia / Early / 2.3-2.3
    asthenia / Delayed / 2.1-2.1
    anxiety / Delayed / 2.0-2.0
    dysgeusia / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    Acetazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    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. Monitor blood glucose closely during coadministration.
    Amlodipine; Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Angiotensin II receptor antagonists: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    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. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Butalbital; 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. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Butalbital; Caffeine; 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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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. Monitor blood glucose closely during coadministration.
    atypical antipsychotic: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 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 and adjust dosages as clinically warranted
    Azilsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    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. Monitor blood glucose closely during coadministration.
    Beta-blockers: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    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. Monitor blood glucose closely during coadministration.
    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. Monitor blood glucose closely during coadministration.
    Bortezomib: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Candesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Captopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    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.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the incretin mimetics, 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.
    Chlorpromazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Chlorthalidone; Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    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. Monitor blood glucose closely during coadministration.
    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.
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including the incretin mimetics, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    Codeine; Phenylephrine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Codeine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Corticosteroids: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
    Cyclosporine: (Moderate) Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Danazol: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dextromethorphan; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Diazoxide: (Minor) Diazoxide, when administered intravenously or orally, produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect. The hyperglycemic effect begins within an hour and generally lasts no more than 8 hours in the presence of normal renal function. The hyperglycemic effect of diazoxide is expected to be antagonized by certain antidiabetic agents (e.g., insulin or a sulfonylurea). Blood glucose should be closely monitored.
    Dienogest; Estradiol valerate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving this combination should be monitored for changes in glycemic control.
    Drospirenone; Estradiol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Drospirenone; Ethinyl Estradiol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Enalapril, Enalaprilat: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Felodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Eprosartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Esterified Estrogens; Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Norgestimate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estrogens: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
    Ethanol: (Moderate) Patients should be advised to limit alcohol (ethanol) ingestion when treated with an antidiabetic agent. Ethanol inhibits gluconeogenesis, which can contribute to or increase the risk for hypoglycemia. In some patients, hypoglycemia can be prolonged. If a patient with diabetes ingests alcohol, they should be counselled to to avoid ingestion of alcohol on an empty stomach, which increases risk for low blood sugar. Patients should also be aware of the carbohydrate intake provided by certain types of alcohol in the diet, which can contribute to poor glycemic control. If a patient chooses to ingest alcohol, they should monitor their blood glucose frequently. Many non-prescription drug products may be formulated with alcohol; instruct patients to scrutinize product labels prior to consumption.
    Ethinyl Estradiol; Desogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norgestimate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethotoin: (Minor) The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Etonogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Fibric acid derivatives: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fluoxetine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Fluoxetine; Olanzapine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Fluoxymesterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Fluphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosphenytoin: (Minor) The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Garlic, Allium sativum: (Moderate) Patients receiving antidiabetic agents should use dietary supplements of Garlic, Allium sativum with caution. Constituents in garlic might have some antidiabetic activity, and may increase serum insulin levels and increase glycogen storage in the liver. Monitor blood glucose and glycemic control. Patients with diabetes should inform their health care professionals of their intent to ingest garlic dietary supplements. Some patients may require adjustment to their hypoglycemic medications over time. One study stated that additional garlic supplementation (0.05 to 1.5 grams PO per day) contributed to improved blood glucose control in patients with type 2 diabetes mellitus within 1 to 2 weeks, and had positive effects on total cholesterol and high/low density lipoprotein regulation over time. It is unclear if hemoglobin A1C is improved or if improvements are sustained with continued treatment beyond 24 weeks. Other reviews suggest that garlic may provide modest improvements in blood lipids, but few studies demonstrate decreases in blood glucose in diabetic and non-diabetic patients. More controlled trials are needed to discern if garlic has an effect on blood glucose in patients with diabetes. When garlic is used in foods or as a seasoning, or at doses of 50 mg/day or less, it is unlikely that blood glucose levels are affected to any clinically significant degree.
    Gemifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as gemifloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking incretin mimetics should be monitored closely for hypoglycemia if consuming green tea.
    Hydantoins: (Minor) The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the incretin mimetics, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (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. Monitor blood glucose closely during coadministration.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like incretin mimetics. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Insulin Aspart: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin aspart because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Degludec: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin degludec because of the risk of hypoglycemia. When liraglutide is used with insulin for the treatment of diabetes, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Degludec; Liraglutide: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin degludec because of the risk of hypoglycemia. When liraglutide is used with insulin for the treatment of diabetes, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Detemir: (Major) Liraglutide used for weight loss should not be given concomitantly with insulin detemir because of the risk of hypoglycemia. When liraglutide is added to insulin detemir for the treatment of diabetes, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 Units subcutaneously once daily when combining with a GLP-1 receptor agonist, such as liraglutide. Blood glucose concentrations should be closely monitored.
    Insulin Glargine: (Moderate) Liraglutid used for weight loss should not be given concomitantly with insulin glargine because of the risk of hypoglycemia. When liraglutide is used with insulin glargine for the treatment of diabetes, consider lowering the dose of the insulin glargine to reduce the risk of hypoglycemia and increase the frequency of blood glucose monitoring.
    Insulin Glargine; Lixisenatide: (Moderate) Liraglutid used for weight loss should not be given concomitantly with insulin glargine because of the risk of hypoglycemia. When liraglutide is used with insulin glargine for the treatment of diabetes, consider lowering the dose of the insulin glargine to reduce the risk of hypoglycemia and increase the frequency of blood glucose monitoring.
    Insulin Glulisine: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin glulisine because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Lispro: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Lispro: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Lispro; Insulin Lispro Protamine: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Regular: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin, Inhaled: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Irbesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Isocarboxazid: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Isoniazid, INH: (Minor) Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Rifampin: (Minor) Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Lanreotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when lanreotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Lanreotide inhibits the secretion of insulin and glucagon. Patients treated with lanreotide may experience either hypoglycemia or hyperglycemia.
    Leuprolide; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Levocarnitine: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including the incretin mimetics, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Levothyroxine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Levothyroxine; Liothyronine (Porcine): (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 antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Levothyroxine; Liothyronine (Synthetic): (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 antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Linezolid: (Moderate) Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
    Liothyronine: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy iincluding incretin mimetics. Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments of insulin may be necessary.
    Lomefloxacin: (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 are co-administered.
    Loop diuretics: (Minor) Loop diuretics, such as bumetanide, furosemide, and torsemide, 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, including incretin mimetics. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
    Losartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 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 and adjust dosages as clinically warranted
    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. Monitor blood glucose closely during coadministration.
    Mecasermin rinfabate: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Megestrol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Meperidine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Mesoridazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Mestranol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Methazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metoclopramide: (Moderate) Metoclopramide can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms are not known. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide. Blood glucose should be closely monitored and antidiabetic agents adjusted accordingly in this situation.
    Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Monoamine oxidase inhibitors: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Moxifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as moxifloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Nandrolone Decanoate: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Nebivolol; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 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 and adjust dosages as clinically warranted
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 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 and adjust dosages as clinically warranted
    Nicotine: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Norfloxacin: (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 are coadministered.
    Norgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Octreotide: (Moderate) Monitor patients receiving octreotide concomitantly with insulin or other antidiabetic agents for changes in glycemic control and adjust doses of these medications accordingly. Octreotide alters the balance between the counter-regulatory hormones of insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. In patients with concomitant type1 diabetes mellitus, octreotide is likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in type 1 diabetic patients. In Type 2 diabetes patients with partially intact insulin reserves, octreotide administration may result in decreases in plasma insulin levels and hyperglycemia.
    Ofloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as ofloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Minor) Weight-loss may affect glycemic control in patients with diabetes mellitus. In many patients, glycemic control may improve. A reduction in dose of oral hypoglycemic medications may be required in some patients taking orlistat. Monitor blood glucose and glycemic control and adjust therapy as clinically indicated.
    Oxandrolone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Oxymetholone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Pasireotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pasireotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pasireotide inhibits the secretion of insulin and glucagon. Patients treated with pasireotide may experience either hypoglycemia or hyperglycemia.
    Pegvisomant: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pegvisomant treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pegvisomant increases sensitivity to insulin by lowering the activity of growth hormone, and in some patients glucose tolerance improves with treatment. Patients with diabetes treated with pegvisomant and antidiabetic agents may be more likely to experience hypoglycemia.
    Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
    Pentoxifylline: (Moderate) Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
    Perindopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perindopril; Amlodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Perphenazine; Amitriptyline: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenelzine: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Phenothiazines: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenylephrine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phenytoin: (Minor) The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Prochlorperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Progesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Progestins: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ramipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Regular Insulin: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Regular Insulin; Isophane Insulin (NPH): (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin isophane (NPH insulin) because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents, such as incretin mimetics, should be monitored for changes in glycemic control.
    Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Salicylates: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Salsalate: (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. Monitor blood glucose closely during coadministration.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Selegiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Somatropin, rh-GH: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
    Sparfloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Sulfonamides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. 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.
    Sympathomimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Tegaserod: (Moderate) Tegaserod can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms is not known. The dosing of antidiabetic agents may require adjustment and blood glucose should be closely monitored when coadministered with tegaserod.
    Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Testolactone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Testosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Thiethylperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thioridazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thyroid hormones: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: (Minor) Tobacco smoking is known to aggravate insulin resistance. The cessation of tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Trandolapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Trandolapril; Verapamil: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Tranylcypromine: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Trifluoperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents 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. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.

    PREGNANCY AND LACTATION

    Pregnancy

    Liraglutide (Saxenda) for the treatment of obesity is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus. There are no adequate data or clinical studies of liraglutide (Victoza) use for the treatment of type 2 diabetes mellitus in pregnant women; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the toxicities found in animal studies, it may be prudent to avoid liraglutide until data in human pregnancy are available. Rat studies have noted abnormalities and variations in the kidneys, and irregular skeletal ossification effects when liraglutide was given at or above 0.8 times the human systemic exposures, based on the maximum recommended human dose (MRHD) of 1.8 mg/day (determined from AUC). Reduced growth and increased total major abnormalities occurred in rabbits at systemic exposures below human exposure at the MRHD (determined from AUC). The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. Liraglutide excretion into human milk is unknown. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. If liraglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. The American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding. Although other sulfonylureas have not been evaluated by the AAP, 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.

    MECHANISM OF ACTION

    Liraglutide is an incretin mimetic; specifically, liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous GLP-1 (7—37). GLP-1 (7—37) represents < 20% of total circulating endogenous GLP-1. Liraglutide binds and activates the GLP-1 receptor. GLP-1 is an important, gut-derived, glucose homeostasis regulator that is released after the oral ingestion of carbohydrates or fats. In patients with type 2 diabetes, GLP-1 concentrations are decreased in response to an oral glucose load. GLP-1 enhances insulin secretion; it increases glucose-dependent insulin synthesis and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. In addition to increases in insulin secretion and synthesis, GLP-1 suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta-cell proliferation. Liraglutide does not increase insulin secretion or suppress glucagon secretion at normal or low glucose concentrations.
     
    GLP-1 is also a physiological regulator of appetite and caloric intake and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Liraglutide acts to reduce body weight through decreased caloric intake; it does not increase 24-hour energy expenditure.

    PHARMACOKINETICS

    Liraglutide is given via subcutaneous administration. Liraglutide is more than 98% bound to plasma protein. After a single radioactive liraglutide dose was administered to healthy subjects, the major component in plasma was intact liraglutide for the initial 24 hours. The metabolism of liraglutide mirrors that of large proteins without a specific organ as a major route of elimination. Following a radioactive liraglutide dose, intact liraglutide was not detected in urine or feces; only a minor part of the administered dose was excreted as metabolites in the urine (6%) or feces (5%). The mean apparent clearance following subcutaneous injection of a single dose of liraglutide is approximately 0.9 to 1.4 L/hour. Liraglutide is resistant to dipeptidyl peptidase-IV (DDP-IV), the endogenous enzyme responsible for the degradation of GLP-1; this allows for a long half-life (13 hours) and once daily dosing.

    Intravenous Route

    The mean volume of distribution after IV administration is 0.07 L/kg.

    Subcutaneous Route

    Following subcutaneous injection, liraglutide binds to albumin at the injection site, and thereafter, is released slowly into circulation. Peak plasma concentrations are achieved in roughly 8 to 12 hours; after a 0.6 mg subcutaneous dose, mean peak concentration was 35 ng/mL and total area under the curve (AUC) was 960 ng x h/mL. Liraglutide Cmax and AUC increased proportionally over the therapeutic dose range of 0.6 to 1.8 mg. At a dose of 1.8 mg, the average steady state concentration over 24 hours was approximately 128 ng/mL. In obese patients (BMI 30 to 40 kg/m2), the average steady state concentration over 24 hours was approximately 116 ng/mL. Similar absorption is achieved with subcutaneous administration of liraglutide in the abdomen, thigh, or arm. The absolute bioavailability of liraglutide following subcutaneous injection is approximately 55%. The mean apparent volume of distribution following subcutaneous administration of 0.6 mg and 3 mg of liraglutide is approximately 13 liters and 20 to 25 liters, respectively. Liraglutide is resistant to dipeptidyl peptidase-IV (DDP-IV), the endogenous enzyme responsible for the degradation of GLP-1; this allows for a long half-life (12 to 13 hours) and once daily dosing.