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  • CLASSES

    Dipeptidyl Peptidase-4/DPP-4 Inhibitor Antidiabetics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral DPP-IV inhibitor that inhibits the breakdown of GLP-1; GLP-1 increases insulin secretion and decreases glucagon secretion in response to a meal
    For use in type 2 diabetes mellitus in adults
    Used as monotherapy or with other hypoglycemic agents, including insulin; mean HbA1c reduction 0.65—1%

    COMMON BRAND NAMES

    Januvia

    HOW SUPPLIED

    Januvia Oral Tab: 25mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus in combination with diet and exercise.
    NOTE: Sitagliptin is used as monotherapy or in combination with other drugs used to treat type 2 diabetes mellitus.
    Oral dosage
    Adults

    100 mg PO once daily. When used in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be necessary to minimize the risk of hypoglycemia.

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO.

    Geriatric

    100 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl >= 50 ml/min: No dosage adjustment needed.
    CrCl >= 30—50 ml/min: 50 mg PO once daily.
    CrCl < 30 ml/min: 25 mg PO once daily.
     
    Intermittent hemodialysis:
    The recommended dose is 25 mg PO once daily. The dose may be administered without regards to timing of hemodialysis.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    May be taken with or without food.

    STORAGE

    Januvia:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, risk of serious hypersensitivity reactions or anaphylaxis, serious rash

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

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Sitagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis (DKA). DKA should be treated with insulin.

    Burns, fever, infection, surgery, trauma

    Temporary use of insulin in place of oral antidiabetic agents such as sitagliptin may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever).

    Diarrhea, gastroparesis, GI obstruction, ileus, vomiting

    Changes in gastric emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully. Use sitagliptin with caution in these patients.

    Hypercortisolism, hyperglycemia, hyperthyroidism

    Conditions that predispose patients to developing hyperglycemia may alter sitagliptin efficacy. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions.

    Adrenal insufficiency, hypoglycemia, hypothyroidism, malnutrition, pituitary insufficiency

    Conditions that predispose patients to developing hypoglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Data regarding the use of sitagliptin in combination with drugs known to cause hypoglycemia (e.g., insulin, exenatide, nateglinide, repaglinide, sulfonylureas) are limited. During clinical trials, the incidence of hypoglycemia was higher in patients taking sitagliptin in combination with a sulfonylurea or insulin as compared to patients taking a sulfonylurea or insulin without sitagliptin.

    Renal failure, renal impairment

    A dosage adjustment is required in patients with moderate or severe renal impairment, including renal failure. There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin.

    Pancreatitis

    Use sitagliptin with caution in patients with a history of pancreatitis. During postmarketing surveillance between October 2006 and February 2009, acute pancreatitis was reported in 88 patients taking sitagliptin or metformin; sitagliptin. In 19 of the 88 reported cases (21%), pancreatitis occurred within 30 days of starting sitagliptin or metformin; sitagliptin. Upon discontinuation of sitagliptin, 47 of the 88 cases (53%) resolved. At least one other risk factor for developing pancreatitis was evident in 45 cases (51%). In March 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics, including the dipeptidyl peptidase 4 (DPP-4) inhibitors. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although the totality of the reviewed data provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available. Monitor patients carefully after initiation or dose increases; if pancreatitis is suspected, sitagliptin should be discontinued. Sitagliptin has not been studied in patients with a history of pancreatitis; therefore, it is not known whether these patients are at an increased risk for developing pancreatitis. Sitagliptin should be used with caution and with appropriate monitoring in these patients.

    Arthralgia

    Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking sitagliptin. Consider sitagliptin as a possible cause of joint pain and discontinue if appropriate. The FDA has identified 33 cases of severe arthralgia with the use of DPP-4 inhibitors, all of which resulted in substantial reduction of the patient’s prior level of activity and, in 10 cases, required hospitalization. In the reported cases, the onset of symptoms occurred from 1 day to several years after the start of therapy with a DPP-4 inhibitor. Symptoms resolved with discontinuation of therapy, usually in less than a month; however, some patients experienced a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor.

    Heart failure

    Use sitagliptin with caution in patients who have a history of or who have increased risk factors for heart failure, including patients with existing cardiac disease or kidney disease. Observe patients receiving sitagliptin for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug and monitoring for diabetic control. An increased risk of hospitalization for heart failure has been reported with other DPP-4 inhibitors, including alogliptin and saxagliptin. In the EXAMINE trial, 5,380 patients with type 2 diabetes and established cardiovascular disease who had a recent acute coronary syndrome event were randomized to receive either alogliptin therapy or placebo. More patients randomized to the alogliptin group (3.9%) experienced at least 1 hospitalization for heart failure compared to patients randomized to placebo (3.3%). In the SAVOR trial, 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or a risk for cardiovascular events were randomized to receive either saxagliptin therapy or placebo. Although the SAVOR trial was not specifically designed to assess heart failure risk, results showed that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group (HR 1.27, 95% CI 1.07 to 1.51; p = 0.007).

    Pregnancy

    There are no adequate and well-controlled studies of sitagliptin use during human pregnancy; because animal reproductive studies are not always predictive of human response, this drug should only be used in pregnancy if clearly needed. In studies of rats and rabbits, doses of sitagliptin up to 125 mg/kg, or approximately 12 times the human exposure at the maximum recommended human dose (MRHD), did not impair fertility or harm the fetus. Doses of up to 30 times the human exposure at the MRHD were not teratogenic when administered during the time of organogenesis. A dose of 1,000 mg/kg (100 times the human exposure at the MRHD) caused rib malformations in offspring. Sitagliptin administered to pregnant rats on gestation days 6 through lactation day 21 at a dose of 1,000 mg/kg decreased male and female offspring weight; neither functional nor behavioral toxicity was observed in the offspring. The placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours post dose; in pregnant rabbits, placental transfer was 66% and 30% at 2 hours and 24 hours, respectively. Merck maintains a registry to monitor the pregnancy outcomes of women exposed to sitagliptin during pregnancy. Health care providers are encouraged to report any prenatal exposure to sitagliptin by calling the pregnancy registry at 1-800-986-8999.

    Breast-feeding

    According to the manufacturer, sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a woman who is breast-feeding her infant. If the drug 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. Metformin monotherapy may also be a consideration; data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Of the total number of subjects (n = 3,884) in clinical safety and efficacy studies of sitagliptin, 725 patients were 65 years and older, and 61 patients were 75 years and older. No overall differences in safety or effectiveness were observed between geriatric and younger adult subjects. Other reported clinical experience have not identified differences in responses, however, greater sensitivity of some older individuals cannot be ruled out. Furthermore, this drug is known to be substantially excreted by the kidney. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to assess renal function in these patients prior to initiating sitagliptin and periodically thereafter. 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.

    Children

    The safety and effectiveness of sitagliptin in children and adolescents under 18 years of age have not been established.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 8.3-8.3
    hypoglycemia / Early / 0.6-1.6
    constipation / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    infection / Delayed / 4.5-15.5
    pharyngitis / Delayed / 5.2-11.0
    headache / Early / 1.1-5.9
    diarrhea / Early / 3.0-3.0
    abdominal pain / Early / 2.3-2.3
    nausea / Early / 1.4-1.4
    vomiting / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Angiotensin II receptor antagonists: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Atenolol; Chlorthalidone: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    atypical antipsychotic: (Moderate) Patients taking sitagliptin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacinamide interferes with glucose metabolism and can result in hyperglycemia. Monitor patients taking antidiabetic agents for changes in glycemic control if niacinamide is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Azilsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Baclofen: (Minor) Because baclofen can increase blood glucose, doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly.
    Bendroflumethiazide; Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Beta-blockers: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Betaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bexarotene: (Moderate) Patients receiving bexarotene with antidiabetic agents that enhance insulin secretion like sitagliptin or saxagliptin should be monitored for hypoglycemia.
    Bisoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bortezomib: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Brimonidine; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bumetanide: (Minor) Bumetanide has been associated with hyperglycemia, possibly due to potassium depletion, and, glycosuria has been reported. Because of this, a potential pharmacodynamic interaction exists between bumetanide and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Candesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination 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.
    Carteolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Carvedilol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the dipeptidyl peptidase-4 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorpromazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    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 sitagliptin, 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) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Codeine; Phenylephrine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Codeine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Corticosteroids: (Moderate) Systemic corticosteroids increase blood glucose levels. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Cyclosporine: (Moderate) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving sitagliptin.
    Danazol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dextromethorphan; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Diazoxide: (Minor) Diazoxide increases blood glucose by inhibiting insulin release from the pancreas and/or by stimulating the release of catecholamines, which in turn stimulate glycogenolysis. The dosage of antidiabetic agents may need to be adjusted when diazoxide is added to the regimen.
    Digoxin: (Moderate) There was an 11% increase in the AUC and an 18% increase in the plasma Cmax of digoxin when digoxin 0.25 mg/day PO is administered with sitagliptin 100 mg PO once daily for 10 days. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving disopyramide concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Dorzolamide; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Eprosartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Esmolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Esterified Estrogens; Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Estrogens: (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Ethanol: (Moderate) Alcohol (ethanol) may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy. Alcohol ingestion can decrease endogenous glucose production potentiating the risk of hypoglycemia. Alternatively, alcohol can worsen glycemic control as it provides a source of additional calories. Blood glucose concentrations should be closely monitored and dosage adjustments of antidiabetic agents may be necessary if alcohol is consumed. Patients should be encouraged to limit or moderate their intake of alcoholic beverages. Because of its effects on endogenous glucose production, patients should be encouraged to avoid alcohol ingestion during the fasting state. Many non-prescription drug products may be formulated with ethanol; have patients scrutinize product labels prior to consumption.
    Fibric acid derivatives: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fluoxetine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxymesterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Fluphenazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Furosemide: (Minor) Furosemide 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. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Garlic, Allium sativum: (Moderate) Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gemifloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered.
    Glucagon: (Minor) Exogenously administered glucagon increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
    Hydantoins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the dipeptidyl peptidase-4 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like sitagliptin. 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Isoniazid, INH: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered.
    Isoniazid, INH; Rifampin: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered.
    Labetalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Lanreotide: (Moderate) Monitor blood glucose levels if administration of lanreotide is necessary with antidiabetic agents; adjust the dosage of the antidiabetic agent as clinically appropriate. Lanreotide inhibits the secretion of insulin and glucagon.
    Levobetaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Levobunolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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 dipeptidyl peptidase-4 inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    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.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy. Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments 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.
    Lomitapide: (Moderate) Concomitant use of lomitapide and sitagliptin may result in increased serum concentrations of sitagliptin. According to the manufacturer of lomitapide, dose reduction of sitagliptin should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and sitagliptin is a P-gp substrate.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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 (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Mecasermin rinfabate: (Moderate) Use caution in coadministering mecasermin products with antidiabetic agents. A hypoglycemic effect may be exacerbated in some patients. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in coadministering mecasermin products with antidiabetic agents. A hypoglycemic effect may be exacerbated in some patients. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Meperidine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Mesoridazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including sitagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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.
    Monoamine oxidase inhibitors: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Moxifloxacin: (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.
    Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nandrolone Decanoate: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Nebivolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nebivolol; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    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. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    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.
    Octreotide: (Moderate) Administration of octreotide to patients receiving oral antidiabetic agents can produce hypoglycemia. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.
    Ofloxacin: (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.
    Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Minor) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. Lower blood glucose may necessitate a dosage reduction of antidiabetic agents.
    Oxandrolone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Oxymetholone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Pasireotide: (Major) Pasireotide may cause hyperglycemia. Closely monitor patients receiving antidiabetic therapy for changes in glycemic control; adjustments in the dosage of antidiabetic agents may be necessary during pasireotide receipt and after its discontinuation.
    Pegvisomant: (Moderate) Pegvisomant, which antagonizes growth hormone, is expected to increase insulin sensitivity. Monitor blood glucose regularly, and reduce doses of antidiabetic medications as necessary.
    Penbutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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.
    Perphenazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Perphenazine; Amitriptyline: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phenothiazines: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phenylephrine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Pindolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sitagliptin, a P-gp substrate, may increase the exposure of sitagliptin.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prochlorperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Progestins: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Rasagiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor rasagiline, are added to any regimen containing antidiabetic agents.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia because of their sympatholytic activity. Patients receiving reserpine concomitantly with antidiabetic agents 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 anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients 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 (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Salicylates: (Moderate) Salicylates can indirectly increase insulin secretion, decreasing blood glucose concentrations. In large doses, salicylates may cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Somatropin, rh-GH: (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Sotalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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 should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sympathomimetics: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive tegaserod concomitantly.
    Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.
    Testolactone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Testosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Thiethylperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Thioridazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Thyroid hormones: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
    Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Torsemide: (Minor) 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. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Triamterene: (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
    Trifluoperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) 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 an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of sitagliptin use during human pregnancy; because animal reproductive studies are not always predictive of human response, this drug should only be used in pregnancy if clearly needed. In studies of rats and rabbits, doses of sitagliptin up to 125 mg/kg, or approximately 12 times the human exposure at the maximum recommended human dose (MRHD), did not impair fertility or harm the fetus. Doses of up to 30 times the human exposure at the MRHD were not teratogenic when administered during the time of organogenesis. A dose of 1,000 mg/kg (100 times the human exposure at the MRHD) caused rib malformations in offspring. Sitagliptin administered to pregnant rats on gestation days 6 through lactation day 21 at a dose of 1,000 mg/kg decreased male and female offspring weight; neither functional nor behavioral toxicity was observed in the offspring. The placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours post dose; in pregnant rabbits, placental transfer was 66% and 30% at 2 hours and 24 hours, respectively. Merck maintains a registry to monitor the pregnancy outcomes of women exposed to sitagliptin during pregnancy. Health care providers are encouraged to report any prenatal exposure to sitagliptin by calling the pregnancy registry at 1-800-986-8999.

    According to the manufacturer, sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a woman who is breast-feeding her infant. If the drug 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. Metformin monotherapy may also be a consideration; data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Sitagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active, intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-IV. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells leading to reduced hepatic glucose production, and GLP-1 slows gastric emptying time. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is < 90 mg/dl. The contributions of GIP, which increases insulin secretion and regulates fat metabolism, to the overall effects of sitagliptin are unclear at this time. Sitagliptin is of benefit in patients with type 2 diabetes mellitus as their GLP-1 concentrations are decreased in response to a meal. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses. The long-term safety of DPP-IV inhibitors are currently under investigation as DPP-IV is not an enzyme specific for the breakdown of incretin hormones. In fact, DPP-IV is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, and growth hormone-releasing hormone. DPP-IV is involved with T-cell activation and is expressed on lymphocytes as CD26. Whether there are long-term neurological or immunological consequences of inhibiting DPP-IV is unclear at this time.

    PHARMACOKINETICS

    Sitagliptin is administered orally. Pharmacokinetics of the drug were established with various PO and intravenous (IV) studies. The mean volume of distribution at steady state following a single 100 mg IV dose in healthy subjects is 198 L; sitagliptin is not highly bound to plasma proteins (38%).
     
    Metabolism is a minor pathway of elimination for sitagliptin with approximately 16% of a dose excreted as metabolites. Six metabolites have been detected at trace concentrations and are not expected to contribute significantly to sitagliptin activity. The primary enzymes responsible for metabolism are CYP3A4 and CYP2C8. Elimination occurs primarily via renal excretion and involves active tubular secretion; approximately 79% of a dose is excreted unchanged in the urine. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in it's renal elimination. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating renal elimination. The apparent terminal half-life of sitagliptin 100 mg is 12.4 hours with a renal clearance of approximately 350 ml/min. 100% of an administered dose is excreted in the urine (87%) or feces (13%) within 1 week of dosing.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP2C8, P-gp
    Sitagliptin is not an inhibitor of CYP isozymes 3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6, and is not an inducer of CYP 3A4. Sitagliptin is a p-glycoprotein (P-gp) substrate, but does not inhibit P-gp mediated transport. Based on these results, sitagliptin is considered unlikely to cause interactions with drugs that utilize these pathways.
     

    Oral Route

    After oral administration, it is rapidly absorbed with peak plasma concentrations occurring in 1—4 hours in healthy subjects; the absolute bioavailability of a 100 mg dose is 87%. The plasma AUC of sitagliptin increases in a dose-proportional manner; following a single 100 mg dose in healthy subjects, the mean plasma AUC is 8.52 mcM/hr and Cmax is 950 nM. At steady state, plasma AUC increases approximately 14%.