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  • CLASSES

    Incretin mimetics Antidiabetics

    BOXED WARNING

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

    Extended-release exenatide suspension is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Extended-release exenatide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats. A statistically significant increase in malignant thyroid C-cell tumors was observed in female rats receiving extended-release exenatide at 25-times clinical exposure compared to controls. Higher incidences were noted in males above controls in all treated groups at >=2 times clinical exposure. The potential of extended-release exenatide to induce C-cell tumors in mice has not been evaluated. It is unknown whether extended-release exenatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. It is not known whether monitoring serum calcitonin or performing thyroid ultrasounds will diminish human risk of thyroid C-cell tumors. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with extended-release exenatide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    DEA CLASS

    Rx

    DESCRIPTION

    First of the antidiabetic agents called incretin mimetics.
    Used in patients with type 2 DM who have not achieved adequate glycemic control on metformin, a sulfonylurea, a thiazolidinedione, or a combination of either a sulfonylurea or a thiazolidinedione plus metformin.
    Available as injection solution formulation (given twice daily) and as an extended-release injection suspension; extended-release formulation is the first antidiabetic agent approved for once weekly administration.

    COMMON BRAND NAMES

    Bydureon, Byetta

    HOW SUPPLIED

    Bydureon Subcutaneous Inj Pwd F/Susp ER: 2mg
    Byetta Subcutaneous Inj Sol: 1mL, 250mcg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus in combination with diet and exercise.
    Subcutaneous dosage (regular-release injection solution, Byetta)
    Adults

    Initially, 5 mcg subcutaneously twice daily given within the 60-minute period before the morning and evening meal. Alternatively, administer before the 2 main meals of the day, with the doses approximately 6 hours or more apart. Exenatide should not be administered after a meal. Based on glucose monitoring and clinical response, may increase after 1 month to exenatide 10 mcg subcutaneously twice daily. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. May be used as monotherapy or with other antidiabetic medications. Dose adjustment of metformin or a thiazolidinedione is not usually required when exenatide is added. A reduction in the dose of a sulfonylurea may be needed to reduce the risk of hypoglycemia. CO-USE with INSULIN: Combined use with prandial insulin has not been studied and cannot be recommended. Exenatide is approved for use with insulin glargine. In a clinical trial, the dose of insulin glargine was decreased by 20% in patients with an HbA1c 8% or less to minimize the risk of hypoglycemia. An insulin glargine dose titration algorithm is in the exenatide package insert. When added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce hypoglycemia; the insulin detemir package label recommends a dose of insulin detemir 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist.

    Subcutaneous dosage (extended-release once weekly injection suspension, Bydureon)
    Adults

    2 mg subcutaneously once every 7 days (once weekly). Administer at any time of day, with or without meals. MISSED DOSE: If a dose is missed, administer it as soon as noticed, as long as the next regularly scheduled dose is due at least 3 days later. After that, patients can resume their usual dosing schedule of once every 7 days (weekly). If a dose is missed and the next regularly scheduled dose is 1 or 2 days later, the patient should not administer the missed dose, instead they should wait until the next regularly scheduled dose. The day of weekly administration can be changed if needed, as long as the last dose was administered 3 or more days before. Extended-release exenatide is not a first-line therapy for patients inadequately controlled on diet and exercise. CO-USE of INSULIN: Extended-release exenatide has not been studied in combination with insulin; co-use is not recommended. PRIOR TREATMENT WITH BYETTA: Prior treatment with Byetta is not required when initiating Bydureon therapy. If a patient is already receiving Byetta and the decision is made to switch to Bydureon, then discontinue Byetta. Patients changing from Byetta to Bydureon may experience transient (approximately 2 weeks) elevations in blood glucose concentrations.

    MAXIMUM DOSAGE

    Adults

    2 mg/week subcutaneous for extended-release injection (e.g., Bydureon); 20 mcg/day subcutaneous for regular-release exenatide injection (e.g., Byetta).

    Geriatric

    2 mg/week subcutaneous for extended-release injection (e.g., Bydureon); 20 mcg/day subcutaneous for regular-release exenatide injection (e.g., Byetta).

    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. Exenatide is cleared primarily by the kidney.

    Renal Impairment

    CrCl 30 mL/min or more: No dosage adjustment needed. Use with caution in patients with moderate renal impairment (CrCl 30 to 50 mL/min), especially when initiating treatment or increasing doses.
    CrCl less than 30 mL/min: Use is not recommended.
     
    Hemodialysis
    Exenatide is not recommended for use in patients with end-stage renal disease (ESRD) on continuous or intermittent hemodialysis or severe renal impairment (CrCl less than 30 mL/min).

    ADMINISTRATION

    Injectable Administration

    Administer by subcutaneous injection only. Do not administer by intravenous or intramuscular injection as no data is available on the safety or efficacy via these routes.
    Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit.
    Do NOT mix exenatide with insulin. When using exenatide with insulin detemir, administer as separate injections. It is acceptable to inject exenatide and insulin detemir in the same body region but the injections should not be adjacent to each other.
    Diabetes medication pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials instead if available, or, reserve use of any pen to 1 patient only.

    Subcutaneous Administration

    Regular-release injection solution (Byetta):
    Administer within the 60-minute time period prior to the morning and evening meals. Alternatively, administer before the two main meals of the day, approximately 6 hours or more apart. Do not administer after meals.
    Regular-release exenatide is available as a pre-filled pen; do not transfer exenatide from the pen to a syringe or a vial.
    Pen needles are not included and must be purchased separately.
    The following pen needles have been tested and are considered to be compatible with the Byetta pre-filled pen: BD 29G X 1/2' (12 or 12.7 mm), BD 29G X 5/16' (8 mm), BD 30G X 5/16' (8 mm), BD 31G X 5/16' (8 mm), Ypsomed Relion (Walmart) 29G X 1/2' (12 or 12.7 mm), Ypsomed Relion (Walmart) 31G X 5/16' (8 mm), and all Novo Nordisk pen needles. The pen needle that is recommended for most patients is the 31G X 5/16' (8 mm) size needle. For more information, contact the Amylin Lilly Customer Support Center toll-free at 1—800—868—1190.
    The following pen needles have been tested and have been determined to be INCOMPATIBLE with the Byetta pre-filled pen: Artsana InsuPen 29G and 31G pen needles. For more information, contact the Amylin Lilly Customer Support Center toll-free at 1—800—868—1190.
    The exenatide pen must be primed prior to the first use. See the pen user manual for directions.
    Inject subcutaneously into the thigh, abdomen, or upper arm.
    Double-check dosage prior to administration.
    Lightly pinch a fold of skin; insert the needle; release the skin; inject at a 90 degree angle. Children or thin individuals can use a 45 degree angle to avoid intramuscular injection. Aspiration is not necessary. Inject over 2—4 seconds.
    Rotate administration sites with each injection to prevent lipodystrophy.
    For patients who are to self-administering exenatide, adequate oral as well as written instructions on the use of the injector pen should be supplied before they self-administer a dose.
    Do not store the pen with the needle on, as the medication may leak out or air bubbles may form in the cartridge.
     
    Extended-release injection suspension (Bydureon):
    Administer once every seven days (weekly); the dose can be administered at any time of day, with or without meals. For missed dose information, see the Indications/Dosage section.
    Extended-release exenatide is available as a pre-filled single-dose pen containing exenatide 2 mg and a single dose tray containing a vial of exenatide 2 mg, a pre-filled syringe delivering 0.65 ml diluent, a vial connector, and two custom needles (23GX 5/16') specific to this delivery system (one is a spare needle).
    Do not substitute needles or any other components in the tray.
    Extended-release exenatide must be injected immediately after the white to off-white powder is suspended in the diluent, whether within the Pen device or if in the kit vial, which is then transferred to the syringe.
    Inject subcutaneously into the thigh, abdomen, or upper arm. See the manufacturers instructions for use for complete administration directions and illustrations. These are available at www.bydureon.com.
    Rotate administration sites with each injection to prevent lipodystrophy.

    STORAGE

    Bydureon:
    - Discard product if exposed to freezing
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Reconstituted product may be stored at room temperature (approximately 77 degrees F) for up to 4 weeks
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Byetta:
    - Discard 30 days after first use
    - Do not freeze
    - Do not use if product has been frozen
    - May be stored at a temperature not exceeding 77 degrees F after first use
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from light

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Exenatide is contraindicated in any patient who has exhibited exenatide hypersensitivity or hypersensitivity to any of its inactive ingredients. During post-marketing surveillance, allergic reactions such as generalized pruritus, urticaria, maculopapular rash, angioedema, and anaphylactoid reactions (< 1/10,000) have been reported.
     
    The effect of exenatide to slow gastric emptying may reduce the extent and rate of absorption of orally administered drugs. Exenatide should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption. Prolonged exposure to stomach acid may destroy the film coating on certain medications and may result in decreased efficacy. When possible it may be prudent to take any oral medication at least 1 hour prior to administration of injectable exenatide, although specific research addressing this issue is not available.
     
    Treatment with exenatide may result in a reduction in appetite, food intake, and/or body weight; there is no need to modify the dosing regimen due to such effects.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Exenatide is not a substitute for insulin in patients who require insulin. Exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Exenatide has not been evaluated in combination with insulin, D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors.

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

    Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can affect requirements of antidiabetic agents; dosage adjustments may be necessary. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring and their antidiabetic therapy, including exenatide, when acute illness is present. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever).

    Abdominal pain, colitis, Crohn's disease, gastroparesis, GI bleeding, GI disease, GI obstruction, GI perforation, ileus, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Exenatide may slow gastric emptying. Exenatide has not been studied in patients with severe gastrointestinal (GI) disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea. Therefore, the use of exenatide is not recommended in patients with severe GI disease (i.e., colitis, Crohn's disease, GI obstruction, GI perforation, gastroparesis, ileus, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis, undiagnosed GI bleeding). Patients who develop severe abdominal pain while on exenatide should be evaluated as this could be a warning sign for a serious condition.

    Geriatric, hypoglycemia

    Hypoglycemia should be monitored for by the patient and clinician when exenatide treatment is initiated and continued. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas, "glinides") or with insulin. Although specific dose recommendations are not available, the clinician should consider a dose reduction of the insulin secretagogue or insulin when used in combination with exenatide. Adequate blood glucose monitoring should be continued and followed. Hypoglycemia was not increased when regular-release exenatide injection solution was combined with metformin (without a sulfonylurea). When combined with a thiazolidinedione with or without metformin, the incidence of hypoglycemia was 11% in patients receiving regular-release exenatide injection solution vs. 7% in patients taking placebo. In five 24- to 30-week trials, no major hypoglycemia was reported for extended-release exenatide suspension or comparator-treated patients. Patient and family education regarding hypoglycemia management is crucial; the patient and patient's family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes (where deficiencies in the release or response to counter regulatory hormones exist), with autonomic neuropathy, intensified diabetes control, or taking beta-blockers, guanethidine, or reserpine. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Exenatide has been studied in patients 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric patients versus younger adult patients. In general, however, elderly patients are especially at risk for hypoglycemic episodes. The specific reasons identified include intensive insulin therapy, use of an excessive insulin dose, improper timing of insulin administration with regards to meals, injection of the wrong type of insulin, decreased renal function, severe liver disease, alcohol ingestion, defective counter regulatory hormone release, missing meals/fasting, and gastroparesis. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia in any patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.

    Dialysis, kidney transplant, renal disease, renal failure, renal impairment

    Severe renal impairment can alter exenatide pharmacokinetic parameters and lead to accumulation of the drug due to reduced clearance. Exenatide should not be used in patients with severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease (ESRD) or renal failure; it should be used with caution in patients with a kidney transplant and in patients with CrCl 30—50 mL/min. Among patients with end-stage renal disease receiving dialysis, the mean exenatide exposure increased by 3.37-fold as compared with values obtained from patients with normal renal function. In patients with ESRD receiving dialysis, single 5 mcg doses of exenatide were poorly tolerated due to gastrointestinal side effects (nausea, vomiting, diarrhea). Nausea and vomiting may cause transient hypovolemia, which may worsen renal function.

    Tobacco smoking

    Monitor blood glucose for needed dosage adjustments with exenatide in diabetic patients whenever a change in either nicotine intake or tobacco smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose or an increase in absorption of subcutaneous absorption of injections.

    Pregnancy

    Exenatide is classified in FDA pregnancy risk category C. In rats, exenatide extended-release administered during the major period of organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects such as reduced dietary intake and reduced weight gain; however, exenatide extended-release was not teratogenic. In animal developmental studies (rabbits, mice), exenatide caused cleft palate, irregular skeletal ossification, and an increased number of neonatal deaths.In these animal studies, exenatide was given in doses 3—12 times the human dose, based on the maximum recommended dose of 20 mcg/day (determined from AUC). Exenatide has a short plasma half-life and a high molecular weight. As determined from ex vivo study of healthy, term, human placentas, the passage of exenatide through the placenta appears minimal; the fetal:maternal ratio of exenatide is <= 0.017. No adequate or well-controlled studies have been done in pregnant women. Per the manufacturer, exenatide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy; health care providers are encouraged to register patients by calling 1-800-633-9081. When possible, it may be prudent to avoid exenatide until data in human pregnancy is available. The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    Breast-feeding

    It is not known if exenatide is excreted into human milk; exenatide has been found in low concentrations (<= 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating rats. Because exenatide has a short elimination half-life and a high molecular weight, if it is excreted in human milk, it will probably be in low concentrations. Furthermore, because exenatide is a peptide, it will most likely be digested in the stomach of a nursing infant. Regardless, because many drugs are excreted in human milk, and because of the potential for clinically significant adverse reactions in breast-fed infants, caution should be exercised, and a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. If exenatide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. The American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding. Although other sulfonylureas have not been evaluated by the AAP, glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and effectiveness of exenatide has not been established in children; there is no role of exenatide in the treatment of infants or neonates.

    Pancreatitis

    Post-marketing reports of acute pancreatitis in patients taking exenatide have been reported, including necrotizing or hemorrhagic pancreatitis. 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. 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. No studies have been performed in patients with a history of pancreatitis; it is not known if these patients are at an increased risk of pancreatitis while taking exenatide. Consideration should be given to alternative antidiabetic therapy in patients with a history of pancreatitis.

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

    Extended-release exenatide suspension is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Extended-release exenatide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats. A statistically significant increase in malignant thyroid C-cell tumors was observed in female rats receiving extended-release exenatide at 25-times clinical exposure compared to controls. Higher incidences were noted in males above controls in all treated groups at >=2 times clinical exposure. The potential of extended-release exenatide to induce C-cell tumors in mice has not been evaluated. It is unknown whether extended-release exenatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. It is not known whether monitoring serum calcitonin or performing thyroid ultrasounds will diminish human risk of thyroid C-cell tumors. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with extended-release exenatide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 6.0-45.0
    hypoglycemia / Early / 0-10.7
    constipation / Delayed / 6.3-10.1
    dehydration / Delayed / Incidence not known

    Mild

    nausea / Early / 9.3-44.0
    diarrhea / Early / 6.1-20.0
    vomiting / Early / 4.0-18.0
    injection site reaction / Rapid / 1.6-17.1
    headache / Early / 6.1-14.0
    dizziness / Early / 9.0-9.0
    restlessness / Early / 9.0-9.0
    dyspepsia / Early / 5.0-7.4
    gastroesophageal reflux / Delayed / 2.0-7.4
    fatigue / Early / 5.6-6.1
    anorexia / Delayed / 1.0-5.0
    asthenia / Delayed / 4.0-5.0
    hyperhidrosis / Delayed / 3.0-3.0
    flatulence / Early / 2.0-2.0
    dysgeusia / Early / Incidence not known
    eructation / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    drowsiness / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Aspirin, ASA; Caffeine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Butalbital: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Butalbital; Caffeine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Butalbital; Caffeine; Codeine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Caffeine; Dihydrocodeine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Codeine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dextromethorphan: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dextromethorphan; Doxylamine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dextromethorphan; Phenylephrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Dichloralphenazone; Isometheptene: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Diphenhydramine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Guaifenesin; Phenylephrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Hydrocodone: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Oxycodone: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Pentazocine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Propoxyphene: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Pseudoephedrine: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetaminophen; Tramadol: Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Acetazolamide: 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.
    Acetohexamide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Aliskiren; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Aminosalicylate sodium, Aminosalicylic acid: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Amlodipine; Benazepril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Olmesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Telmisartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amlodipine; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Amprenavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: 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: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Angiotensin-converting enzyme inhibitors: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Aspirin, ASA: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Butalbital; Caffeine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Caffeine; Dihydrocodeine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Carisoprodol: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Carisoprodol; Codeine: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Dipyridamole: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Omeprazole: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Oxycodone: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Aspirin, ASA; Pravastatin: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Atazanavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    atypical antipsychotic: Patients taking incretin mimetics 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. Changes in lipid profiles and weight may also aggravate diabetes or associated conditions or complications. Temproal associations of atypical antipsychotic therapy with the aggravation or new onest of diabetes mellitus have been reported.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
    Azilsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Azilsartan; Chlorthalidone: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Benazepril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Beta-blockers: Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. Other manifestations such as dizziness and sweating may not be significantly affected. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been associated with potentiation of insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Selective beta-blockers, such as atenolol or metoprololl, do not appear to potentiate insulin-induced hypoglycemia. Hypoglycemia has been reported in patients taking non-selective beta-blockers during fasting for preparation for surgery, after prolonged physical exertion and in patients with renal insufficiency. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Bexarotene: Bexarotene may enhance the hypoglycemic action of exenatide. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving bexarotene in combination with exenatide.
    Bismuth Subsalicylate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Bortezomib: 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.
    Candesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Captopril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Carbonic anhydrase inhibitors: 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.
    Chlorpromazine: 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.
    Chlorpropamide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Chlorthalidone; Clonidine: Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Choline Salicylate; Magnesium Salicylate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Chromium: 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 aide 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: Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including the incretin mimetics, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Clonidine: Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Codeine; Phenylephrine; Promethazine: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Codeine; Promethazine: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Conjugated Estrogens; Medroxyprogesterone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Corticosteroids: When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia and cause blood glucose concentrations to rise. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted.
    Cyclosporine: Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Danazol: 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: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Desiccated Thyroid: Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Dextromethorphan; Promethazine: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Diazoxide: 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 the incretin mimetic may need to be adjusted when diazoxide is added to the regimen. Carefully monitor blood glucose concentrations when diazoxide is combined with an incretin mimetic.
    Dienogest; Estradiol valerate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Digoxin: Repeat doses of exenatide (10 mcg SQ twice daily) decreased the Cmax of digoxin (0.25 mg PO daily) by 17% and delayed Tmax by roughly 2.5 hours. Overall steady state AUC of digoxin was not altered. The mechanism of the interaction is not known (although it may be due to delayed gastric emptying), nor is the clinical significance of this potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of exenatide. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Disopyramide: Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving this combination should be monitored for changes in glycemic control.
    Drospirenone; Estradiol: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Drospirenone; Ethinyl Estradiol: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Drospirenone; Ethinyl Estradiol; Levomefolate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Enalapril, Enalaprilat: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Felodipine: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Eprosartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Esterified Estrogens; Methyltestosterone: 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.
    Estradiol Cypionate; Medroxyprogesterone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Levonorgestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Norethindrone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estradiol; Norgestimate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Estrogens: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, estrogens can impair glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving greater than 50 mcg of ethinyl estradiol or equivalent estrogen per day. However, any patient with diabetes may need to monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethanol: Alcohol 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.
    Ethinyl Estradiol; Desogestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Ethynodiol Diacetate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Etonogestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Levonorgestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norelgestromin: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone Acetate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norgestimate: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethinyl Estradiol; Norgestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Ethotoin: The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Etonogestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Fibric acid derivatives: Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Fluoxetine: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxetine; Olanzapine: Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxymesterone: 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: 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: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fosphenytoin: The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Garlic, Allium sativum: Limited animal data suggest that selected constituents in Garlic might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Patients with diabetes frequently purchase alternative remedies that have been purported to improve glycemic control, but there is no scientific or controlled evidence in humans of this action. Limited clinical evidence suggests that garlic does not affect blood glucose in those without diabetes. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gemifloxacin: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as gemifloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Glimepiride: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glimepiride; Pioglitazone: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glimepiride; Rosiglitazone: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glipizide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glipizide; Metformin: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glucagon: Endogenous counter-regulatory hormones such as glucagon are released in response to hypoglycemia. When released, blood glucose concentrations rise. When glucagon is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of incretin mimetics. Clinically, glucagon is often used to increase blood glucose concentrations in patients with severe hypoglycemia.
    Glyburide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Glyburide; Metformin: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Green Tea: Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking incretin mimetics should be monitored closely for hypoglycemia if consuming green tea.
    Hydantoins: The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Hydrochlorothiazide, HCTZ; Irbesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Lisinopril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Losartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Moexipril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Olmesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Quinapril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Telmisartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydrochlorothiazide, HCTZ; Triamterene: Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Hydroxyprogesterone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Indapamide: A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like incretin mimetics. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Insulin Aspart: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin Degludec: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin Degludec; Liraglutide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin Detemir: The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units SQ once daily when combining with a GLP-1 receptor agonist such as exenatide. Patients should also self-monitor blood glucose levels. It should be noted that extended-release exenatide has not been studied with insulin and concomitant administration cannot be recommended.
    Insulin Glargine: In a 30-week safety and efficacy trial, when exenatide was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA1c <= 8% to minimize the risk of hypoglycemia. The manufacturer of exenatide provides an insulin glargine dose titration algorithm to aide clinicians when using exenatide with insulin glargine. Patients should also self-monitor blood glucose levels. It should be noted that extended-release exenatide has not been studied with insulin and concomitant administration cannot be recommended.
    Insulin Glulisine: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin Lispro: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin Regular: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Insulin, Inhaled: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Irbesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Isocarboxazid: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Isoniazid, INH: Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Isoniazid, INH; Rifampin: Although rare, isoniazid, INH may increase blood sugar. Antidiabetic agent requirements may be increased when patients are administered isoniazid, INH concomitantly. Patients should be closely monitored for changes in glycemic control if isoniazid therapy is initiated or discontinued.
    Lanreotide: Lanreotide may cause increases or decreases in glucose concentrations. Patients receiving antidiabetic therapy should be closely monitored for changes in glycemic control; adjustments in the dosage of antidiabetic agents may be necessary.
    Leuprolide; Norethindrone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Levocarnitine: 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 aide 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: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as levofloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Levonorgestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Levothyroxine: Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Linezolid: Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
    Liothyronine: Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Liotrix: Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Lisinopril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Lithium: Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy iincluding incretin mimetics. Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments of insulin may be necessary.
    Lomefloxacin: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are co-administered.
    Loop diuretics: Loop diuretics, such as bumetanide, furosemide, and torsemide, may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, including incretin mimetics. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Lopinavir; Ritonavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Lorcaserin: 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: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Lovastatin; Niacin: Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
    Magnesium Salicylate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Mecasermin rinfabate: Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, hypoglycemia is possible with either agent. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin (rh-IGF-1) has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Mecasermin, Recombinant, rh-IGF-1: Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, hypoglycemia is possible with either agent. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin (rh-IGF-1) has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms.
    Medroxyprogesterone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Megestrol: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Meperidine; Promethazine: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Mesoridazine: 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.
    Mestranol; Norethindrone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Metformin; Repaglinide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as repaglinide. Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Methazolamide: Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methyltestosterone: 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: Metoclopramide can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms is not known. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide. Blood glucose should be closely monitored and antidiabetic agents adjusted accordingly in this situation.
    Metyrapone: In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Moexipril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Monoamine oxidase inhibitors: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Moxifloxacin: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as moxifloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Nandrolone Decanoate: 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.
    Nateglinide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as nateglinide. Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Nebivolol; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Nelfinavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Niacin, Niacinamide: Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
    Niacin; Simvastatin: Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted
    Nicotine: Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Norethindrone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Norfloxacin: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Norgestrel: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Octreotide: Administration of octreotide to patients receiving oral antidiabetic agents can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.
    Ofloxacin: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones, such as ofloxacin, and an antidiabetic agent, including incretin mimetics. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, are coadministered.
    Olmesartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Ombitasvir; Paritaprevir; Ritonavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: 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, including exenatide.
    Oxandrolone: 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: 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: 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: Patients who have both acromegaly and diabetes mellitus and are being treated with oral antidiabetic agents may require dose reductions of these medications after the initiation of pegvisomant. Growth hormone decreases insulin sensitivity by opposing the effects of insulin on carbohydrate metabolism; therefore, pegvisomant, which antagonizes growth hormone, is expected to have the opposite effect. Although none of the acromegalic patients with diabetes mellitus who were treated with pegvisomant during the clinical studies developed clinically relevant hypoglycemia, such patients should monitor their blood glucose regularly, with doses of antidiabetic medications reduced as necessary.
    Pentamidine: 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: Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
    Perindopril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perindopril; Amlodipine: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Perphenazine: 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: 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.
    Phenelzine: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Phenothiazines: 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: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phenytoin: The hydantoin anticonvulsants ethotoin, fosphenytoin and phenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): 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: 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.
    Progesterone: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Progestins: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Promethazine: It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Since promethazine is a phenothiazine antihistamine, it should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Protease inhibitors: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Quinapril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Ramipril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Rasagiline: 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.
    Regular Insulin; Isophane Insulin (NPH): The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Repaglinide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as repaglinide. Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Reserpine: Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents, such as incretin mimetics, should be monitored for changes in glycemic control.
    Ritonavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Salicylates: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Salsalate: Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration.
    Saquinavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Selegiline, Transdermal: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Selegiline: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Somatropin, rh-GH: Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Sparfloxacin: 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: Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Sulfonylureas: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Sympathomimetics: 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: Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including incretin mimetics.
    Tegaserod: Tegaserod can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms is not known. The dosing of antidiabetic agents may require adjustment and blood glucose should be closely monitored when coadministered with tegaserod.
    Telmisartan: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Testolactone: 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: 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: 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: 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: 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: Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
    Tipranavir: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: 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 and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Tolazamide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Tolbutamide: The risk of hypoglycemia is increased when exenatide is used in combination with insulins or insulin secretagogues such as the sulfonylureas and glinides (e.g., nateglinide, repaglinide, or metformin; repaglinide). Although specific dose recommendations are not available, a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Trandolapril: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Trandolapril; Verapamil: ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Tranylcypromine: Animal data indicate that monoamine oxidase inhibitors (MAOIs) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents.
    Triamterene: Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Trifluoperazine: 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: Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Warfarin: Cases of an increased INR have been reported with the concomitant use of warfarin and exenatide, sometimes associated with bleeding. Monitor for changes in INR and bleeding when these drugs are coadministered. Dosage adjustments of warfarin may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Exenatide is classified in FDA pregnancy risk category C. In rats, exenatide extended-release administered during the major period of organogenesis reduced fetal growth and produced skeletal ossification deficits in association with maternal effects such as reduced dietary intake and reduced weight gain; however, exenatide extended-release was not teratogenic. In animal developmental studies (rabbits, mice), exenatide caused cleft palate, irregular skeletal ossification, and an increased number of neonatal deaths.In these animal studies, exenatide was given in doses 3—12 times the human dose, based on the maximum recommended dose of 20 mcg/day (determined from AUC). Exenatide has a short plasma half-life and a high molecular weight. As determined from ex vivo study of healthy, term, human placentas, the passage of exenatide through the placenta appears minimal; the fetal:maternal ratio of exenatide is <= 0.017. No adequate or well-controlled studies have been done in pregnant women. Per the manufacturer, exenatide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy; health care providers are encouraged to register patients by calling 1-800-633-9081. When possible, it may be prudent to avoid exenatide until data in human pregnancy is available. The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    It is not known if exenatide is excreted into human milk; exenatide has been found in low concentrations (<= 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating rats. Because exenatide has a short elimination half-life and a high molecular weight, if it is excreted in human milk, it will probably be in low concentrations. Furthermore, because exenatide is a peptide, it will most likely be digested in the stomach of a nursing infant. Regardless, because many drugs are excreted in human milk, and because of the potential for clinically significant adverse reactions in breast-fed infants, caution should be exercised, and a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. If exenatide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may also be considered as possible alternatives in some patients. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, metformin may be a possible alternative for some patients. Data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. The American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding. Although other sulfonylureas have not been evaluated by the AAP, glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence. 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

    Exenatide is the first in a new class of antihyperglycemic agents called incretin mimetics. Endogenous human incretins, such as glucagon-like peptide-1 (GLP-1) enhance insulin secretion after release from the gut into the systemic circulation. Exenatide is a 39-amino acid GLP-1 agonist isolated from the salivary gland venom of the lizard Heloderma suspectum (Gila monster). Exenatide mimics the enhancement of glucose-dependent insulin secretion and other antihyperglycemic actions of incretins. The exenatide peptide has 53% amino acid similarity to mammalian GLP-1 and has a 3000-fold greater potency for glucose lowering in vivo. Exenatide binds and activates the human GLP-1 receptor site in vitro. Occupation of the GLP-1 receptor site by exenatide results in an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. Increased synthesis and release of insulin occurs via mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
     
    Exenatide acts to improve glucose control via several mechanisms. Exenatide suppresses glucagon secretion, slows gastric emptying, reduces food intake and promotes ß-cell proliferation. Exenatide acutely improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes. Exenatide leads to a release of insulin only in the presence of elevated glucose concentrations. Insulin secretion subsides as euglycemia occurs. First-phase insulin response (release of insulin within 10 minutes following a glucose load) is lost in patients with type 2 diabetes. Loss of first-phase response is a beta cell defect. Exenatide restores first-phase insulin response to an IV bolus of glucose. Both first- and second-phase insulin secretion improved significantly over placebo in patients with type 2 diabetes. In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. Exenatide does not impair the normal glucagon response to hypoglycemia. Exenatide also slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation. Exenatide has also been shown to reduce food intake in both animals and humans, which may help to control weight. Exenatide does not increase insulin activity in nondiabetics.

    PHARMACOKINETICS

    Exenatide is given via subcutaneous (SC) administration. Exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and is independent of the dose. The mean terminal half-life of the injection solution (Byetta) is 2.4 hours. In most individuals, concentrations of the regular-release injection (Byetta) are measurable for approximately 10 hours post-dose. Approximately 10 weeks after discontinuation of exenatide extended-release injection (Bydureon), plasma concentrations generally fall below the minimal detectable concentration of 10 pg/ml.

    Subcutaneous Route

    Exenatide regular-release injection solution (Byetta): Following subcutaneous injection to patients with type 2 diabetes, exenatide reaches peak plasma concentrations in roughly 2 hours. Mean peak exenatide concentration was 211 pg/mL and overall mean area under the curve (AUC) was 1036 pg x hour/mL following subcutaneous administration of a 10 mcg dose. Exenatide AUC increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar absorption is achieved with SC administration of exenatide in the abdomen, thigh, or arm. The mean apparent volume of distribution of exenatide following SC administration of a single dose of exenatide is 28.3 liters.
    Exenatide extended-release injection suspension (Bydureon): Following a single subcutaneous injection, exenatide is released from the microspheres over approximately 10 weeks. Initially, surface-bound exenatide is released resulting in a peak around week 2. This is followed by a gradual release of exenatide from the microspheres and a second peak around week 6—7. The two peaks represent the hydration and erosion of the microspheres. Following initiation of once weekly exenatide, plasma exenatide concentrations gradually increase over 6—7 weeks; mean exenatide concentrations of approximately 300 pg/mL were then maintained over once weekly dosing intervals indicating that steady-state was achieved. The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28.3 liters.