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  • CLASSES

    Rapid-acting Human Insulins and Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Rapid-acting insulin analog
    Used in the treatment of type 1 and type 2 diabetes mellitus
    Quicker onset and shorter duration of action when compared to regular insulin

    COMMON BRAND NAMES

    Humalog, Humalog Junior KwikPen, Humalog KwikPen

    HOW SUPPLIED

    Humalog/Humalog KwikPen/Insulin Lispro Subcutaneous Inj Sol: 1mL, 100U, 200U

    DOSAGE & INDICATIONS

    For the treatment of type 1 diabetes mellitus.
    NOTE: When insulin lispro is administered as intermittent injections in patients with type 1 diabetes mellitus, a longer-acting insulin should be part of the therapeutic regimen to maintain adequate glucose control. An adjustment in the dosage regimen of the longer-acting insulin may be necessary to achieve optimal glycemic control when switching patients to rapid-acting insulin analogs. Regular self-monitoring of blood glucose is recommended.
    Intermittent subcutaneous dosage

    NOTE: Do not perform dose conversion when using either the Humalog 100 units/mL or 200 units/mL KwikPens; the dose window shows the number of insulin units to be delivered and no conversion is needed.

    Adults

    Insulin lispro is equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given via intermittent subcutaneous injection. Total daily insulin requirements vary between patients and depend on the patient's clinical condition and diet; however, a common dosage range is 0.5 to 1 unit/kg/day. When used for intermittent subcutaneous injection, the total daily dose is given as 2 to 4 subcutaneous injections, within 15 minutes before or immediately after a meal to avoid hypoglycemia. In general, 50 to 70% of total daily insulin requirements may be provided by insulin lispro; the remainder should be provided by an intermediate- or long-acting insulin. A common regimen is to administer insulin lispro just prior to the beginning of each meal with a dose of basal insulin (i.e., insulin glargine or insulin detemir) once daily. Insulin lispro can be given in combination with NPH or Lente insulin as 2 daily injections; about two-thirds of the daily insulin dose is given before breakfast and about one-third is given before the evening meal. An intermediate-to-insulin lispro ratio of 2:1 can be given within 5 to 10 minutes of breakfast and an intermediate-to-insulin lispro ratio of 1:1 can be given 5 to 10 minutes before dinner. Alternatively, the evening dose of intermediate insulin can be given at bedtime rather than at dinner.

    Children and Adolescents 3 years and older

    Insulin requirements are highly variable and must be individualized based on patient-specific factors and type of insulin regimen. During partial remission phase, total combined daily insulin requirement is often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirements are much greater, often between 1 to 2 units/kg/day. Administer pre-meal doses of insulin lispro immediately before a meal (i.e., meal starts within 15 minutes after injection). Alternatively, insulin lispro can be given immediately after eating. Use insulin lispro in combination with intermediate- or long-acting insulin as part of twice-daily regimens or basal-bolus regimens. Twice daily insulin regimens consist of 2 subcutaneous insulin injections given per day; approximately two-thirds of the total daily insulin dose is given in the morning and one-third in the evening. Initially, for each insulin dose, approximately one-third is given as a rapid-acting insulin and the other two-thirds is an intermediate-acting insulin. These ratios may change based on individual response. Basal-bolus regimens typically consist of 4 to 5 subcutaneous insulin injections given per day; 1 to 2 as an intermediate- or long-acting insulin plus 3 to 4 pre-meal rapid-acting insulin doses. Depending on the type of insulin used as the basal insulin, the proportion supplied as the rapid-acting insulin usually ranges from 40 to 60% of the total daily dose.

    Continuous subcutaneous infusion dosage (Humalog 100 units/mL only)
    Adults

    When insulin lispro 100 units/mL is used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), the total daily dose should be based on the insulin dose from the previous regimen. Initially, 50% of the total dose can be given as meal-related boluses and the remainder as a basal infusion; therapy is provided by a professional team trained in CSII therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week). Do NOT administer Humalog 200 units/mL using a continuous subcutaneous infusion pump.

    Children and Adolescents 3 years and older

    When used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), base the total daily subcutaneous dose on the insulin dose from the previous regimen. Initially, 50% of the total dose can be given as meal-related boluses and the remainder as a basal subcutaneous infusion. Infuse pre-meal boluses immediately before meals. Do NOT administer Humalog 200 units/mL using a continuous subcutaneous infusion pump.

    Intravenous dosage (infusions prepared with insulin lispro 100 units/mL only)

    NOTE: Use Humalog 100 units/mL only to prepare infusions. Do NOT administer Humalog 200 units/mL intravenously.

    Adults, Adolescents, and Children 3 years and older

    Insulin lispro 100 units/mL (Humalog 100 units/mL) can be administered intravenously under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia. Insulin lispro should be diluted and used intravenously at concentrations ranging from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% Sodium Chloride Injection. One study in 21 patients with type 1 diabetes (n = 21, starting blood glucose of 200 to 260 mg/dL) used an initial human lispro rate of 0.5 units/hour intravenously as a continuous infusion. The infusion rate was individualized and adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 and 160 mg/dL. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase.

    For the treatment of type 2 diabetes mellitus that is inadequately managed by diet, exercise, and oral hypoglycemics.
    NOTE: When insulin lispro is administered as intermittent injections in patients with type 1 diabetes mellitus or as monotherapy in patients with type 2 diabetes mellitus, a longer-acting insulin should be part of the therapeutic regimen to maintain adequate glucose control. An adjustment in the dosage regimen of the longer-acting insulin may be necessary to achieve optimal glycemic control when switching patients to rapid-acting insulin analogs. Regular self-monitoring of blood glucose is recommended.
    NOTE: A consensus algorithm issued by the ADA and the European Association for the Study of Diabetes lists basal or intermediate-acting insulin as a second line or third line agent in patients with type 2 diabetes not controlled on oral drugs; metformin is the initial recommended therapy in all type 2 diabetics without contraindications. Once insulin is added, therapy can be intensified (e.g., addition of prandial insulin) to achieve optimal glycemic control. In patients that are receiving a sulfonylurea, the sulfonylurea should be discontinued when insulin therapy is initiated.
    Intermittent subcutaneous dosage

    NOTE: Do NOT perform dose conversion when using either the Humalog 100 units/mL or 200 units/mL KwikPens; the dose window shows the number of insulin units to be delivered and no conversion is needed.

    Adults

    Insulin lispro is equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given via intermittent subcutaneous injection. Total daily insulin requirements vary between patients and depend on the patient's clinical condition and diet; however, a common dosage range is 0.5 to 1 unit/kg/day. When used for intermittent subcutaneous injection, the total daily dose is given as 2 to 4 subcutaneous injections, within 15 minutes before or immediately after a meal to avoid hypoglycemia. In general, 50 to 70% of total daily insulin requirements may be provided by insulin lispro; the remainder should be provided by an intermediate- or long-acting insulin. A common regimen is to administer insulin lispro just prior to the beginning of each meal with a dose of basal insulin (i.e., insulin glargine or insulin detemir) once daily. Insulin lispro can be given in combination with NPH or Lente insulin as 2 daily injections; about two-thirds of the daily insulin dose is given before breakfast and about one-third is given before the evening meal. An intermediate-to-insulin lispro ratio of 2:1 can be given within 5 to 10 minutes of breakfast and an intermediate-to-insulin lispro ratio of 1:1 can be given 5 to 10 minutes before dinner. Alternatively, the evening dose of intermediate insulin can be given at bedtime rather than at dinner.

    Children† and Adolescents†

    Dosage varies depending on previous regimen, concurrent medications, lifestyle, etc; initial total daily insulin doses have been reported to be in the range of 0.1 to 0.5 units/kg/day. Insulin lispro may be used in combination with oral agents (e.g., metformin), as part of multi-dose insulin regimens, in combination with a basal insulin in intensive insulin regimens, or as continuous subcutaneous insulin infusion (CSII). Specific dosage recommendations are not available; dosage should be individualized according to age, weight, activity level, and dietary habits. Titrate dosage according to blood glucose and A1C goals.

    Continuous subcutaneous infusion dosage (Humalog 100 units/mL only)
    Adults

    When insulin lispro 100 units/mL is used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), the total daily dose should be based on the insulin dose from the previous regimen. Initially, 50% of the total dose can be given as meal-related boluses and the remainder as a basal infusion; therapy is provided by a professional team trained in CSII therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week). Do NOT administer Humalog 200 units/mL using a continuous subcutaneous infusion pump.

    Children† and Adolescents†

    Dosage varies depending on previous regimen, concurrent medications, lifestyle, etc.; initial total daily insulin doses have been reported to be in the range of 0.1 to 0.5 units/kg/day. Insulin lispro may be used in combination with oral agents (e.g., metformin), as part of multi-dose insulin regimens, in combination with a basal insulin in intensive insulin regimens, or as continuous subcutaneous insulin infusion (CSII). Specific dosage recommendations are not available; dosage should be individualized according to age, weight, activity level, and dietary habits. Titrate dosage according to blood glucose and A1C goals. Do NOT administer Humalog 200 units/mL using a continuous subcutaneous infusion pump.

    Intravenous dosage (infusions prepared with Insulin lispro 100 units/mL only)

    NOTE: Use Humalog 100 units/mL only to prepare infusions. Do NOT administer Humalog 200 units/mL intravenously.

    Adults

    Insulin lispro 100 unit/mL (Humalog 100 units/mL) can be administered intravenously under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia. Insulin lispro should be diluted and used intravenously at concentrations ranging from 0.1 unit/mL to 1 unit/mL in infusion systems containing 0.9% Sodium Chloride Injection. An initial starting dosage for patients with starting blood glucose of 200 to 260 mg/dL is 0.5 units/hour intravenously. Individualize dose and adjust at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.

    For the treatment of diabetic ketoacidosis†.
    For the treatment of uncomplicated diabetic ketoacidosis† (DKA) when continuous IV administration is not possible.
    Subcutaneous dosage
    Adults

    Initially, 0.3 units/kg subcutaneously followed by 0.1 unit/kg subcutaneously every 1 hour until blood glucose concentrations are 250 mg/dL or less; then, reduce insulin dosage to 0.05 units/kg subcutaneously every 1 or 2 hours. Blood glucose concentrations should be checked every hour. Blood glucose concentrations should fall at a rate of about 80 to 100 mg/dL/hour; faster lowering of blood glucose can result in adverse effects, like cerebral edema. In 40 patients with diabetic ketoacidosis, 20 patients each were randomized to either insulin lispro 0.3 units/kg subcutaneously followed by 0.1 units/kg subcutaneously every 1 hour or regular insulin 0.1 units/kg IV bolus followed by 0.1 units/kg/hour by continuous IV infusion. Treatment with subcutaneous insulin lispro has been shown to be an effective alternative to the use of intravenous regular insulin in the treatment of mild and moderate DKA. There were no differences between the 2 groups with respect to time to correction of hyperglycemia, resolution of ketoacidosis, total insulin dose administered, hospital length of stay, number of hypoglycemic events, or mortality. Patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU. In addition to insulin administration, adequate fluid therapy must be initiated (usually 0.45% or 0.9% NaCl infusion, fluid type and hourly requirements based on estimated patient need and serum osmolality). When the blood glucose is 250 mg/dL or less, fluid therapy is changed to a 5% dextrose-containing fluid infusion and adjusted to maintain a blood glucose roughly 200 to 250 mg/dL until the acidosis is corrected. Serum potassium concentrations should be monitored frequently and replaced as indicated.

    Children and Adolescents

    0.3 unit/kg subcutaneously, followed 1 hour later by 0.1 unit/kg/dose subcutaneously every 1 hour or 0.15 to 0.2 units/kg/dose subcutaneously every 2 hours. If blood glucose falls to less than 250 mg/dL before DKA resolves, reduce dosage to 0.05 unit/kg/dose every 1 hour to keep blood glucose approximately 200 mg/dL until resolution of DKA. Consider the addition of glucose to IV fluids if there is concern of hypoglycemia or a precipitous decline in blood glucose. Continue to monitor vital signs, fluid status, acid-base status, blood glucose, blood beta-hydroxybutyrate [if test is available], serum electrolytes, and neurological status until DKA is fully resolved. Treatment with subcutaneous insulin lispro has been shown to be an effective alternative to the use of intravenous regular insulin in the treatment of mild and moderate DKA; however, patients with severe DKA, hypotension, anasarca, or associated severe critical illness should be managed with intravenous regular insulin in the ICU.

    Intravenous dosage (continuous infusion)
    Adults

    Usual dosing of insulin IV for diabetic ketoacidosis: 0.1 to 0.15 units/kg IV bolus followed by 0.1 units/kg/hour via continuous IV infusion. Additionally, adequate fluid therapy must be initiated (usually 0.9% NaCl infusion for the first hour, then 0.45% NaCl if indicated); fluid type and hourly requirements based on estimated patient need and serum osmolality. Blood glucose levels are checked hourly and the insulin infusion rate is adjusted accordingly. The insulin infusion should cause blood glucose to fall at a rate of about 50 to 75 mg/dL/hour; faster lowering of blood glucose can result in adverse effects, like cerebral edema. When the blood glucose falls to 250 mg/dL or less, the insulin infusion rate is usually decreased to 0.05 to 0.1 unit/kg/hour IV and fluid therapy is changed to a 5% dextrose-containing fluid infusion; both are adjusted to maintain a blood glucose roughly 150 to 250 mg/dL until the acidosis is corrected. THERAPY GOALS: Correct dehydration, correct acidosis, reverse ketosis, slowly correct hyperosmolality, and restore blood glucose to near normal values. Monitor patient carefully and take precautions to avoid a precipitous fall in blood glucose concentrations.

    Children and Adolescents

    0.05 to 0.1 unit/kg/hour IV beginning 1 to 2 hours AFTER starting fluid replacement therapy. Do NOT administer an IV bolus at the start of therapy; a bolus is not necessary and may increase the risk of cerebral edema. Generally, the infusion rate should remain in the range of 0.05 to 0.1 unit/kg/hour until the resolution of DKA (pH more than 7.3, bicarbonate more than 15 mmol/L, blood beta-hydroxybutyrate less than 1 mmol/L, or closure of the anion gap). If the patient is particularly sensitive to insulin, the dosage may be reduced to prevent hypoglycemia if the metabolic acidosis continues to resolve. To prevent too rapid decrease in blood glucose and hypoglycemia, glucose should be added to the IV fluid when plasma glucose falls to approximately 250 to 300 mg/dL or sooner if the rate of glucose decline is precipitous. Continue to monitor vital signs, fluid status, acid-base status, blood glucose, blood beta-hydroxybutyrate [if test is available], serum electrolytes, and neurological status until DKA is fully resolved. Once ketoacidosis has resolved and the patient is tolerating oral intake, transition to subcutaneous insulin. Administer rapid-acting insulin 15 to 30 minutes or regular insulin 1 to 2 hours prior to stopping the insulin infusion and providing a meal; continue subcutaneous insulin at a dose individualized to the patient's response. THERAPY GOALS: Correct dehydration, correct acidosis, reverse ketosis, slowly correct hyperosmolality, and restore blood glucose to near normal values. Monitor patient carefully and take precautions to avoid a precipitous fall in blood glucose concentrations.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of blood glucose and other clinical parameters in all patient populations.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available. Some studies have noted increased circulating levels of insulin in patients with hepatic failure. Individualize dosage based on blood glucose and other clinical parameters.

    Renal Impairment

    The pharmacokinetics of insulin are generally unchanged with renal impairment, however, pharmacodynamic differences occur in insulin sensitivity as renal function declines, resulting in increased responses to a given dosage. Individualize dosage based on blood glucose and other clinical parameters.

    ADMINISTRATION

    Injectable Administration

    Administer Humalog U-100 insulin by subcutaneous injection or intravenous infusion only. Do not administer by intramuscular injection.
    Humalog U-200 insulin is for subcutaneous injection only; do NOT give Humalog U-200 insulin intravenously or by intramuscular injection.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually viscous, cloudy, or discolored.

    Intravenous Administration

    Insulin lispro can be administered intravenously under medical supervision; use Humalog U-100 insulin only to prepare intravenous infusions.
    Do NOT administer Humalog U-200 intravenously.
    Close monitoring of blood glucose and potassium levels are required to avoid hypoglycemia and hypokalemia.
    Infusion systems containing 0.9% NaCl injection should be used to prepare the infusion.
    Appropriate infusion concentrations range from 0.1 Unit/mL to 1 Unit/mL.
    Storage of infusion: Infusion bags prepared with insulin lispro U-100 are stable when stored in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F) for 48 hours and then may be used at room temperature for up to an additional 48 hours.

    Subcutaneous Administration

    For dosing using Humalog U-100, ONLY use insulin syringes marked in insulin units. There may be differences in the way units are indicated, depending on the size of the syringe and the manufacturer. Insulin syringes are manufactured with 0.25-mL, 0.3-mL, 0.5-mL, and 1-mL capacity. 
    Various lengths of needles are available: short (5, 6 mm) and long (8, 12.7 mm), studies have confirmed equal efficacy and safety/tolerability with short-length needles as compared to longer ones, even in obese patients.
    Do NOT use insulin syringes for Humalog U-200, as the markings on an insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia.
    Preferable administration for insulin lispro is within 15 minutes before or immediately after a meal.
    Subcutaneous injections are usually made into the anterior and lateral aspects of the thigh, the upper arms, the buttocks, or the abdomen.
    Double-check dosage in syringe or pen 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 short needle and a 45 degree angle to avoid intramuscular injection. Aspiration is not necessary. Inject over 2 to 4 seconds. The needle should be remain in the skin for 5 seconds after injection to ensure complete delivery of the dose.
    Rotate administration sites with each injection to prevent lipodystrophy. However, staying within the same area (e.g., abdomen) is generally recommended to decrease the variability in insulin absorption from dose to dose. This is especially important with insulin lispro as it is has a slightly shorter duration of action following abdominal injection when compared to other injection sites.
     
    Insulin Lispro KwikPens:
    Available for use in a prefilled pen (Humalog KwikPen). When using these pens, prime the pen after attaching a new needle and before each injection to assure an accurate dose is administered.
    Humalog U-100 and U-200 KwikPens are designed to dial doses in increments of 1 unit.
    Humalog Junior KwikPen is designed to dial doses in 0.5 unit increments.
    Do NOT transfer Humalog U-200 from the KwikPen to a syringe for administration. The markings on an insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia.
    Do NOT mix Humalog U-200 with any other insulins.
    Do NOT perform dose conversion when using either the Humalog U-100 or U-200 KwikPens; the dose window shows the number of insulin units to be delivered and no conversion is needed.
    The insulin 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 the use of any pen to 1 patient only.
     
    Insulin Lispro Cartridges:
    Do not mix any insulin with insulin lispro while contained within cartridges; insulin lispro in the cartridge should not be diluted. The cartridge should not be refilled with insulin of any type, including insulin lispro.
     
    Dilution and Mixing of insulin lispro for subcutaneous intermittent administration only:
    Humalog U-100 can be mixed with NPH human insulin; however, do NOT mix Humalog U-200 with any other insulins or with any diluents. The absorption rate or total bioavailability of insulin lispro is not changed when mixed with NPH human insulin. Administer immediately after mixing.
    Humalog U-100 may be diluted with sterile diluent for Humalog to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted insulin lispro may be used for 28 days when stored at 5 degrees C (41 degrees F) and for 14 days when stored at 30 degrees C (86 degrees F).
    When mixing Humalog U-100 with NPH insulin in a syringe, draw insulin lispro into the syringe first. This prevents contamination of the remaining insulin lispro in the vial by the longer-acting insulin.
    Per the manufacturer, insulin glargine should not be diluted or mixed with any other insulin or solution as the pharmacodynamic profile of insulin glargine and/or the other insulin may be altered in an unpredictable manner. However, 2 small studies have demonstrated that mixing insulin glargine with insulin lispro (Humalog U-100 only) does not affect glycemic control or rates of hypoglycemia in children with type 1 diabetes mellitus; one study was 10 days in duration and the other was 6 months in duration. The insulins were mixed immediately before injection, and, in one study, insulin lispro was drawn into the syringe first. Cloudiness upon mixing was noted in both studies, but neither pain upon injection nor clogging of the needle was reported.
    Data on mixing with any other insulins are not available.
     
    Continuous Subcutaneous Insulin Infusion (CSII) Administration
    Do not mix with other insulins or diluents when using in an external pump.
    Do NOT administer Humalog U-200 using a continuous subcutaneous infusion pump.
    Follow specific recommendations available from the manufacturer of insulin lispro and the pump only. However, for in-use time or frequency of changing infusion sets, follow information from the manufacturer of insulin lispro only.
    Insulin lispro U-100 in an external pump reservoir is recommended for use in the Disetronic H-TRONplus V100 insulin pump using the Disetronic Rapid infusion sets and with the MiniMed Models 506, 507, and 508 using the MiniMed Polyfin infusion sets. The insulin lispro in the external pump reservoir should be changed every 7 days and the infusion set and site of administration should be changed every 3 days.
    Insulin lispro U-100 3 mL cartridges are recommended for use in the Disetronic D-TRON or D-TRON plus pumps (with Humalog 3 mL cartridges) using Disetronic Rapid infusion sets. The site of administration, infusion set, and the D-TRON or D-TRON plus cartridge adapter should be changed every 3 days. The insulin lispro 3 mL cartridges should be replaced every 7 days, even if insulin remains in the cartridge.
    Change the injection site every 3 days. Medical personnel should be contacted and a new injection site should be selected if a current site becomes erythematous, pruritic, or thickened, as skin reactions or alterations in absorption can occur.
     
    Preparation and Administration Instructions for Patients:
    To prepare a dose from a vial:
    Clean the rubber stopper of the vial with an alcohol wipe. Pull back the plunger of a disposable syringe to fill the syringe with an amount of air equal to your dose of insulin (if your dose is 30 units, pull the plunger to the 30 unit mark). Insert the needle into the rubber stopper of the vial, and inject the air into the vial (this will make the insulin easier to remove). Turn the vial and syringe upside down. Making sure the tip of the needle is in the insulin, pull back on the plunger to fill the syringe with the prescribed number of units of insulin. Before removing the needle from the vial, check your syringe for air bubbles. If bubbles are present, hold the syringe straight up and flick the syringe firmly with your finger until the bubbles float to the top. Push them out with the plunger and withdraw the correct dose of insulin. Lift the vial off the syringe.
     
    Mixing of two types of insulin:
    Insulin lispro should be mixed with NPH insulin only on the advice of your prescriber. Insulin lispro and NPH should be mixed immediately before injection. Clean the rubber stopper of both vials of insulin with an alcohol wipe. Roll the vial of the NPH gently between the palms of your hands to mix and warm the insulin. Be sure to mix the insulin well, but do not shake vigorously. Pull back the plunger of a disposable syringe to fill the syringe with an amount of air equal to your dose of NPH (if your dose is 30 units, pull the plunger to the 30 unit mark). Insert the needle into rubber stopper of the NPH vial and inject the air into the vial (this will make the insulin easier to remove). Make sure that the tip of the needle does not touch the NPH insulin. Do not withdraw any NPH insulin into the syringe. Withdraw the needle. Follow the same steps for your insulin lispro dose, but do not withdraw the needle. Turn the vial of insulin lispro and syringe upside down. Making sure the tip of the needle is in the insulin, withdraw the prescribed number of units of insulin lispro into the syringe. Before removing the needle from the vial, check your syringe for air bubbles. If bubbles are present, hold the syringe straight up and flick the syringe firmly with your finger until the bubbles float to the top. Push them out with the plunger and withdraw the correct dose. Lift the vial of insulin lispro off the syringe and insert the syringe into the vial of NPH. Turn the vial and syringe upside down. Making sure the tip of the needle is in the insulin, withdraw the prescribed units of NPH. Lift the vial off the syringe.
     
    To inject a dose:
    Select an injection site on the stomach, arm, buttocks, or thigh, and clean with an alcohol wipe. Pinch the skin up with your fingers about three inches apart, and insert the needle at an angle of 45 to 90 degrees. Release the skin and press the plunger all the way down to deliver the insulin. Keep the needle in the skin for at least 2 to 4 seconds so that all of the insulin is injected. Remove the needle from the skin and press gently on the injection site for a moment (but do not rub or massage). Rotate your injection site such that each site is not used more than once every 1 to 2 months. Do not use injection sites that are thickened, red, or bumpy. Never inject insulin into a vein.
     
    Storage of opened products:
    Do not use insulin lispro if it has been frozen. Protect from direct heat and light.
    Diluted insulin lispro for subcutaneous use may be used for 28 days when stored at 5 degrees C (41 degrees F) and for 14 days when stored at 30 degrees C (86 degrees F).
    Storage of vials: Insulin lispro vials may be stored in the refrigerator or at room temperature once opened. Once opened, vials must be used within 28 days or be discarded, even if they still contain insulin. The U.S. Pharmacopeia Dispensing Information (USP DI) recommends that an opened insulin vial may be kept at room temperature for up to one month (usually defined as 28 to 30 days). Insulin that has been kept at room temperature for longer than one month should be thrown away. The American Diabetes Association (ADA) also states that an opened insulin vial can be kept at room temperature for approximately one month. Extremes of temperature should be avoided because these can lead to significant changes in insulin action. If human insulin vials are stored under refrigeration while in use and are used beyond 30 days, the stability of these vials may be affected by a number of factors; such factors include the number of injections per day, volume of insulin remaining in the vial, exposure to light, agitation, and technique used for dose preparation. The impact of such factors is difficult to measure, and the health care professional should advise patients on an individual basis concerning long-term storage of opened insulin vials when refrigerated. The length of time an insulin can be stored while unopened is based on the expiration date.
    Storage of Kwikpens and cartridges: Insulin lispro cartridges and pens should be stored at room temperature only once opened; do not refrigerate after opening. Once removed from refrigeration, cartridges and pens should be discarded within 28 days, even if they have not been opened and even if they still contain insulin.
    Storage of external pump reservoir: Insulin lispro in an external pump reservoir should be discarded every 7 days.
    Storage in continuous subcutaneous pumps: Insulin used in continuous subcutaneous pumps that is exposed to temperatures higher than 37 degrees C (98.6 degrees F) should be discarded. The temperature of the insulin may exceed ambient temperature when the pump housing, tubing, or case is exposed to sunlight or radiant heat.

    STORAGE

    Humalog:
    - Avoid exposure to heat
    - Avoid use of product if it has been frozen
    - Opened container can be stored for up to 28 days at temperatures below 86 degrees F
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    Humalog Junior KwikPen:
    - Do not freeze
    - Do not use if product has been frozen
    - Opened container can be stored for up to 28 days at temperatures below 86 degrees F
    - Protect from extreme heat
    - Protect from light
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    - Unrefrigerated product must be used within 28 days or be discarded
    Humalog KwikPen:
    - Do not freeze
    - Do not use if product has been frozen
    - Opened container can be stored for up to 28 days at temperatures below 86 degrees F
    - Protect from extreme heat
    - Protect from light
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    - Unrefrigerated product must be used within 28 days or be discarded

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Insulin lispro differs from regular insulin by a more rapid onset and a shorter duration of activity. When used as a meal-time insulin, insulin lispro should be injected within 15 minutes before a meal or immediately after a meal. When insulin lispro is administered as intermittent injections in patients with type 1 diabetes mellitus, a longer-acting insulin should be part of the therapeutic regimen to maintain adequate glucose control. In patients with type 2 diabetes mellitus, if insulin lispro is used without any other antidiabetic medications, a longer-acting insulin should be part of the therapeutic regimen. Regular self-monitoring of blood glucose is recommended in all patients with diabetes mellitus, especially those on insulin therapy.

    Diarrhea, fever, infection, surgery, thyroid disease, trauma, vomiting

    Changes in insulin products like insulin lispro should be made by experienced medical personnel. Changes in insulin species source (i.e., animal versus human, etc.), purity, or brand can necessitate dosage adjustments. The physiologic response resulting from the mixing together of different insulins for subcutaneous administration may differ from the response occurring when the insulins are administered separately. Treatment must be individualized. Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. The timing of meals and exercise with insulin doses is extremely important, and should remain consistent, unless prescribed otherwise. Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can also affect insulin requirements, requiring dosage adjustments. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present.

    Hepatic disease, renal failure, renal impairment

    Hepatic disease, renal impairment, or renal failure may affect dosage requirements of insulin like insulin lispro. Some pharmacokinetic studies have shown increased circulating levels of insulin in patients with hepatic or renal failure. Insulin dosage adjustments may be needed in some patients.

    Diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS)

    Intermittent, subcutaneous insulin lispro has been studied in patients with uncomplicated mild to moderate diabetic ketoacidosis (DKA) indicating similar efficacy to that of intravenous regular insulin infusion. However, the American Diabetes Association recommends that regular insulin by continuous intravenous infusion be used to treat hyperglycemic crisis including DKA and hyperosmolar hyperglycemic state (HHS) (and diabetic coma) unless it is considered mild. Regular insulin is also preferred for those patients with poor tissue perfusion, shock, or cardiovascular collapse, or in patients requiring insulin for the treatment of hyperkalemia.

    Continuous subcutaneous insulin infusion (CSII) administration

    Only regular insulin, insulin lispro, insulin, glulisine, and insulin aspart should be used for continuous subcutaneous insulin infusion (CSII) administration in external pumps. Patients should be advised that self-monitoring of blood glucose is especially important when using CSII. Insulin lispro should not be diluted or mixed with any other insulins when used in an external pump. Physicians and patients should carefully evaluate information on pump use in the insulin lispro (Humalog) physician package insert, the insulin lispro (Humalog) patient package insert, and in the pump manufacturer's manual. Specific information for insulin lispro should be followed for in-use time, frequency of changing infusion sets, or other details as the manufacturer of the pump's or other insulin products' information may differ. Pump or infusion set malfunction or insulin degradation can lead to hyperglycemia and DKA or HHS in a short time because of the small subcutaneous depot of insulin. This is especially important for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action (e.g., insulin aspart, insulin glulisine, and insulin lispro). These differences may be particularly relevant when patients are switched from multiple injection therapy or infusion with buffered regular insulin. If hyperglycemia during CSII occurs, prompt identification of the cause of hyperglycemia is necessary. Interim therapy with subcutaneous injections may be required.

    Hypoglycemia


    Hypoglycemia is the most common adverse effect of insulin therapy; hypoglycemia is the major barrier to achieving optimal glycemic control long term. Insulin is contraindicated in patients during episodes of hypoglycemia. Elderly patients are at risk for hypoglycemia as well as those who have brittle diabetes, have received an overdose of insulin, have a delayed or decreased food intake, or undergo an excessive amount of exercise relative to their usual insulin dose. Patients at risk for severe, iatrogenic hypoglycemia include those with insulin deficiency (i.e., type 1 diabetes mellitus and advanced type 2 diabetes mellitus), those with a history of severe hypoglycemia or hypoglycemia unawareness, and those undergoing intensive insulin therapy. 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, or taking beta-blockers. 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 patients who are currently taking an alpha-glucosidase inhibitor (i.e., acarbose or miglitol) along with their insulin, oral glucose (dextrose) should be used to treat hypoglycemia; sucrose (table sugar) is unsuitable. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Insulin injections should not be used by the family to treat those patients who are unconscious. Severe or frequent hypoglycemia in a patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.

    Hypokalemia

    In addition to hypoglycemia, hypokalemia may also occur as insulin like insulin lispro facilitates the intracellular uptake of potassium. Patients at risk for hypokalemia (e.g., patients who are using potassium-lowering drugs or taking potassium concentration sensitive drugs) should be monitored closely for these effects.

    Cresol hypersensitivity

    Insulin lispro is contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. Minor, local sensitivity characterized by redness, swelling, or itching at the site of injection does not usually contraindicate therapy. Insulin lispro contains m-cresol and should be avoided in patients with m-cresol hypersensitivity; localized reactions and general myalgias have been reported with the use of cresol as an injectable excipient. Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis. Severe cases, including anaphylactoid reactions, may be life threatening.

    Neonates, pregnancy

    Insulin lispro is classified as FDA pregnancy category B. There are no adequate, well-controlled clinical studies of the use of insulin lispro in pregnant women. Fetal abnormalities in animal studies of insulin lispro have not been reported when used at doses up to 4 and 0.3 times the average human dose based on body surface area; however, high doses of insulin inducing maternal hypoglycemia have been associated fetal toxicity such as pre- and post-implantation losses and visceral/skeletal abnormalities. In animal studies with insulin aspart and regular human insulin, doses approximately 32 times and 10 times the human subcutaneous dose of 1 unit/kg/day have resulted in such abnormalities. Most experts recommend human 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. In general, insulin requirements decline during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient on insulin is required throughout pregnancy. Optimizing glycemic control before conception and during pregnancy appears to improve fetal outcome; this should include the avoidance of episodes of hypoglycemia as the toxic effects of maternal hypoglycemia on the fetus have been well-documented. During the perinatal period, careful monitoring of neonates born to mothers with diabetes is recommended. Post-partum, maternal insulin requirements may need adjustment.

    Breast-feeding

    It is unknown whether insulin lispro is excreted in significant amounts in human milk; however, many drugs, including human insulin, are excreted in human milk. Insulin is degraded in the gastrointestinal tract; therefore, any insulin secreted into breast milk would not be absorbed by a breast-feeding infant. The American Diabetes Association encourages breast-feeding in women with pre-existing diabetes mellitus or gestational diabetes ; accordingly, women on insulin therapy should be encouraged to breast-feed if no contraindications exist. Breast-feeding may decrease insulin requirements, despite the need for increased caloric intake. Careful observation of increased maternal caloric needs and maternal blood glucose concentrations are needed.

    Tobacco smoking

    Monitor blood glucose for needed dosage adjustments of insulin like insulin lispro in insulin-dependent 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 the subcutaneous absorption of insulin, respectively.

    Geriatric

    In clinical trials of insulin lispro, 12% of patients were aged 65 years or older; the majority of these patients had type 2 diabetes mellitus. When compared to regular human insulin, the HbA1C (A1C) response to or incidence of hypoglycemia with insulin lispro did not differ by age. Geriatric patients are especially at risk for hypoglycemic episodes when using insulin. Risk factors for hypoglycemia 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, renal failure, 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, the initial dosing and dosing increments of any insulin product should be conservative. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function.

    ADVERSE REACTIONS

    Severe

    insulin shock / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0

    Moderate

    infusion-related reactions / Rapid / 2.6-2.6
    hypoglycemia / Early / 10.0
    hyperinsulinemia / Early / Incidence not known
    Somogyi effect / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    antibody formation / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    pharyngitis / Delayed / 6.6-33.3
    headache / Early / 11.6-29.6
    rhinitis / Early / 8.1-24.7
    injection site reaction / Rapid / 1.0-21.0
    cough / Delayed / 17.3-17.3
    infection / Delayed / 10.1-13.6
    diarrhea / Early / 8.6-8.6
    asthenia / Delayed / 0-7.4
    abdominal pain / Early / 7.4-7.4
    nausea / Early / 0-6.2
    dysmenorrhea / Delayed / 6.2-6.2
    fever / Early / 6.2-6.2
    pruritus / Rapid / 1.0-1.0
    rash (unspecified) / Early / 0-1.0
    weight gain / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    insulin resistance / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Acetaminophen; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Acetazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Acrivastine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Aliskiren; Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Alogliptin; Pioglitazone: (Major) The risk of heart failure and/or edema is increased when thiazolidinediones (including pioglitazone) are combined with insulins; monitor combined therapy closely for signs or symptoms of congestive heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Amlodipine; Benazepril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Amlodipine; Olmesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Amlodipine; Telmisartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Amlodipine; Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amphetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Amphetamine; Dextroamphetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Amprenavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Androgens: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Angiotensin II receptor antagonists: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Angiotensin-converting enzyme inhibitors: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Aripiprazole: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Articaine; Epinephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Asenapine: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Aspirin, ASA: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Carisoprodol: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Dipyridamole: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Omeprazole: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Oxycodone: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Aspirin, ASA; Pravastatin: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Atazanavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Atazanavir; Cobicistat: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Atenolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Atenolol; Chlorthalidone: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    atypical antipsychotic: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when niacin, niacinamide is instituted or discontinued. Dosage adjustments may be necessary. Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. (Moderate) Niacin interferes with glucose metabolism and can result in hyperglycemia; monitor patients on antidiabetic agents for loss of blood glucose control if niacin therapy is added.
    Azelastine; Fluticasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Azilsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Azilsartan; Chlorthalidone: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Baclofen: (Moderate) Because baclofen can increase blood glucose, doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly.
    Beclomethasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Benazepril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Bendroflumethiazide; Nadolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Benzphetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Beta-blockers: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Betamethasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Betaxolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Bexarotene: (Moderate) Systemic bexarotene may enhance the action of insulins resulting in hypoglycemia. Patients should be closely monitored while receiving bexarotene capsules in combination with insulin; monitor for hypoglycemia and the need for diabetic therapy adjustments.
    Bismuth Subsalicylate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Bisoprolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Bortezomib: (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Brexpiprazole: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Brimonidine; Timolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Brompheniramine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Budesonide: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Budesonide; Formoterol: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Bumetanide: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when bumetanide, furosemide, and torsemide are instituted. 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.
    Candesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Captopril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbetapentane; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbetapentane; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbinoxamine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbinoxamine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Carbonic anhydrase inhibitors: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Cariprazine: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Carteolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Carvedilol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Cetirizine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including insulin, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorothiazide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Chlorpromazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Chlorthalidone: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Chlorthalidone; Clonidine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. (Moderate) Monitor patients receiving insulin closely for changes in glycemic control when clonidine is instituted. Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Ciclesonide: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including insulins, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Cisapride: (Moderate) Because cisapride can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive cisapride concomitantly.
    Clarithromycin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Clonidine: (Moderate) Monitor patients receiving insulin closely for changes in glycemic control when clonidine is instituted. Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia.
    Clozapine: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Codeine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Colesevelam: (Moderate) In patients with type 2 diabetes mellitus receiving insulins, colesevelam increased serum triglyceride concentrations by 22% compared to placebo. Monitor patients for increase in triglyceride concentrations. Discontinue colesevelam if triglyceride concentrations are > 500 mg/dl or if hypertriglyceridemia-induced pancreatitis occurs.
    Conjugated Estrogens: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Conjugated Estrogens; Bazedoxifene: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Corticosteroids: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Corticotropin, ACTH: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Cortisone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Cyclosporine: (Moderate) Cyclosporine may cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving insulin.
    Danazol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Darunavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Darunavir; Cobicistat: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Deflazacort: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Desiccated Thyroid: (Minor) Monitor patients receiving insulin closely for changes in diabetic control 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. 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.
    Desloratadine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dexamethasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dexmethylphenidate: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dextroamphetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dextromethorphan; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Diazoxide: (Minor) The hyperglycemic action of diazoxide can be diminished in patients receiving insulin, and, conversely, the dosage of insulin may need to be adjusted when diazoxide is added to the regimen.
    Dienogest; Estradiol valerate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Diethylpropion: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Diethylstilbestrol, DES: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Diphenhydramine; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Disopyramide: (Moderate) Monitor patients receiving disopyramide concomitantly with insulin for changes in glycemic control. Disopyramide may enhance the hypoglycemic effects of insulin.
    Dobutamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dopamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Dorzolamide; Timolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Drospirenone; Estradiol: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Edetate Calcium Disodium, Calcium EDTA: (Minor) Use caution in administration of calcium EDTA to patients with diabetes mellitus who are receiving insulin therapy. Calcium EDTA chelates the zinc in selected exogenous insulins, thereby increasing the amount of insulin available to the body and decreasing the duration of the insulin dose. Alterations in blood glucose control may result. Diabetic patients receiving calcium EDTA may require adjustments in their insulin dosage.
    Edetate Disodium, Disodium EDTA: (Minor) Use caution in administration of calcium EDTA to patients with diabetes mellitus who are receiving insulin therapy. Calcium EDTA chelates the zinc in selected exogenous insulins, thereby increasing the amount of insulin available to the body and decreasing the duration of the insulin dose. Alterations in blood glucose control may result. Diabetic patients receiving calcium EDTA may require adjustments in their insulin dosage.
    Enalapril, Enalaprilat: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Enalapril; Felodipine: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Ephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Epinephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Eprosartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Esmolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Esterified Estrogens: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Esterified Estrogens; Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Estradiol; Levonorgestrel: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norethindrone: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Norgestimate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estramustine: (Moderate) Estramustine may decrease glucose tolerance leading to hyperglycemia. Patients receiving antidiabetic agents should monitor their blood glucose levels frequently due to this potential pharmacodynamic interaction.
    Estrogens: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Estropipate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Ethanol: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control if alcohol (ethanol) is consumed; dosage adjustments of insulin may be necessary. Alcohol may cause variable effects on glycemic control when used in patients receiving insulin or other 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. Encourage patients to limit or moderate their intake of alcoholic beverages. Because of its effects on endogenous glucose production, patients should be encouraged to avoid alcohol ingestion during the fasting state. Many non-prescription drug products may be formulated with ethanol; have patients scrutinize product labels prior to consumption.
    Ethinyl Estradiol: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect.
    Ethinyl Estradiol; Desogestrel: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Etonogestrel: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norelgestromin: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestimate: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Norgestrel: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethotoin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Etonogestrel: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Exenatide: (Moderate) 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.
    Fenofibrate: (Moderate) Monitor patients receiving fibric acid derivatives concomitantly with insulin for changes in glycemic control. Fibric acid derivatives may enhance the hypoglycemic effects of insulin or other antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fenofibric Acid: (Moderate) Monitor patients receiving fibric acid derivatives concomitantly with insulin for changes in glycemic control. Fibric acid derivatives may enhance the hypoglycemic effects of insulin or other antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fexofenadine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Fibric acid derivatives: (Moderate) Monitor patients receiving fibric acid derivatives concomitantly with insulin for changes in glycemic control. Fibric acid derivatives may enhance the hypoglycemic effects of insulin or other antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fludrocortisone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Flunisolide: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Fluoxetine: (Moderate) Monitor patients receiving fluoxetine concomitantly with insulin for changes in glycemic control. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents.
    Fluoxetine; Olanzapine: (Moderate) Monitor patients receiving fluoxetine concomitantly with insulin for changes in glycemic control. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Fluoxymesterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Fluphenazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Fluticasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Fluticasone; Salmeterol: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Fluticasone; Vilanterol: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Formoterol; Mometasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Fosamprenavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Fosinopril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Fosphenytoin: (Minor) Fosphenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Furosemide: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when bumetanide, furosemide, and torsemide are instituted. 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.
    Garlic, Allium sativum: (Moderate) Selected constituents in Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gemfibrozil: (Moderate) Monitor patients receiving fibric acid derivatives concomitantly with insulin for changes in glycemic control. Fibric acid derivatives may enhance the hypoglycemic effects of insulin or other antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Gemifloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered.
    Glimepiride; Pioglitazone: (Major) The risk of heart failure and/or edema is increased when thiazolidinediones (including pioglitazone) are combined with insulins; monitor combined therapy closely for signs or symptoms of congestive heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently.
    Glimepiride; Rosiglitazone: (Major) Use of insulins with rosiglitazone is not recommended by the manufacturer due to a potential increased risk for edema or heart failure. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently. In five 26-week trials involving patients with type 2 diabetes, rosiglitazone added to insulin therapy (n=867) was compared with insulin therapy alone (n=663). These trials included patients with chronic diabetes and a high prevalence of coexisting medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. In these clinical studies, an increased incidence of heart failure and other cardiovascular adverse events was seen in patients receiving combination rosiglitazone and insulin therapy compared to insulin monotherapy; the incidence of new onset or exacerbated heart failure was 0.9% in patients treated with insulin alone vs. 2% in patients treated with insulin plus rosiglitazone. Some of the patients who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. Additionally, the results of a meta-analysis that included the same 5 randomized, controlled trials mentioned previously indicate that the rate of myocardial ischemia may be increased in patients taking rosiglitazone in combination with insulin; the incidence of myocardia ischemia was 1.4% in patients receiving insulin monotherapy vs. 2.8% in patients receiving rosiglitazone and insulin combination therapy (OR 2.1 95% CI 0.9-5.1). The cardiovascular events were noted at doses of both 4 mg/day and 8 mg/day of rosiglitazone. In a sixth 26-week study, patients with baseline congestive heart failure were excluded; in this study, compared to insulin monotherapy (n=158), the addition of rosiglitazone to insulin therapy (n=161) did not increase the risk of congestive heart failure. One each of myocardial ischemia and sudden death were reported in patients taking combination therapy compared to zero patients taking insulin monotherapy. When rosiglitazone was added to insulin therapy, the incidence of hypoglycemia was higher with 8 mg/day of rosiglitazone (67%) compared to 4 mg/day (53%).
    Glucagon: (Minor) Endogenous counter-regulatory hormones 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 insulin degludec. Glucagon is often used to treat hypoglycemia in patients with diabetes mellitus.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Guaifenesin; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Guaifenesin; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. (Minor) Triamterene can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. Patients receiving insulin should be closely monitored for signs indicating loss of diabetic control when therapy with triamterene is instituted. In addition, patients receiving insulin should be closely monitored for signs of hypoglycemia when therapy with any of these other agents is discontinued.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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. (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Hydrocodone; Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Hydrocortisone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including insulins, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Iloperidone: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like insulins. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Insulin Degludec; Liraglutide: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Insulin Glargine; Lixisenatide: (Moderate) The risk of hypoglycemia is increased when lixisenatide is used in combination with insulin lispro. Although specific dose recommendations are not available, a lower dose of the insulin lispro may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Irbesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Isocarboxazid: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Isoniazid, INH: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when isoniazid, INH is instituted or discontinued. Although rare, isoniazid, INH may increase blood sugar. Insulin requirements may be increased when patients are administered isoniazid, INH concomitantly.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when isoniazid, INH is instituted or discontinued. Although rare, isoniazid, INH may increase blood sugar. Insulin requirements may be increased when patients are administered isoniazid, INH concomitantly.
    Isoniazid, INH; Rifampin: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when isoniazid, INH is instituted or discontinued. Although rare, isoniazid, INH may increase blood sugar. Insulin requirements may be increased when patients are administered isoniazid, INH concomitantly.
    Isoproterenol: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Labetalol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Lanreotide: (Moderate) Monitor blood glucose levels if administration of lanreotide is necessary with antidiabetic agents; adjust the dosage of the antidiabetic agent as clinically appropriate. Lanreotide inhibits the secretion of insulin and glucagon.
    Leuprolide; Norethindrone: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levobetaxolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Levobunolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Levocarnitine: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including insulins, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Levonorgestrel: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Levothyroxine: (Minor) Monitor patients receiving insulin closely for changes in diabetic control 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. 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.
    Linezolid: (Moderate) Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
    Liothyronine: (Minor) Monitor patients receiving insulin closely for changes in diabetic control 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. 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.
    Liotrix: (Minor) Monitor patients receiving insulin closely for changes in diabetic control 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. 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.
    Liraglutide: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently.
    Lisdexamfetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Lisinopril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Lithium: (Moderate) Monitor patients receiving insulin closely for changes in glycemic control when lithium is instituted; dosage adjustments of insulin may be necessary. Lithium may cause variable effects on glycemic control when used in patients receiving insulin or other antidiabetic therapy.
    Lixisenatide: (Moderate) The risk of hypoglycemia is increased when lixisenatide is used in combination with insulin lispro. Although specific dose recommendations are not available, a lower dose of the insulin lispro may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Lomefloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are co-administered.
    Lopinavir; Ritonavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Loratadine; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
    Losartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Lovastatin; Niacin: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when niacin, niacinamide is instituted or discontinued. Dosage adjustments may be necessary. Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy.
    Lurasidone: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Magnesium Salicylate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Mecasermin rinfabate: (Moderate) Use caution in combining mecasermin with antidiabetic agents. The hypoglycemic effect induced by mecasermin may be exacerbated.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin with antidiabetic agents. The hypoglycemic effect induced by mecasermin may be exacerbated.
    Medroxyprogesterone: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Megestrol: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Meperidine; Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Mepivacaine; Levonordefrin: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Mesoridazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Mestranol; Norethindrone: (Minor) Monitor patients receiving insulin closely for changes in diabetic control when estrogens, progestins, or oral contraceptives are instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Pioglitazone: (Major) The risk of heart failure and/or edema is increased when thiazolidinediones (including pioglitazone) are combined with insulins; monitor combined therapy closely for signs or symptoms of congestive heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently.
    Metformin; Rosiglitazone: (Major) Use of insulins with rosiglitazone is not recommended by the manufacturer due to a potential increased risk for edema or heart failure. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently. In five 26-week trials involving patients with type 2 diabetes, rosiglitazone added to insulin therapy (n=867) was compared with insulin therapy alone (n=663). These trials included patients with chronic diabetes and a high prevalence of coexisting medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. In these clinical studies, an increased incidence of heart failure and other cardiovascular adverse events was seen in patients receiving combination rosiglitazone and insulin therapy compared to insulin monotherapy; the incidence of new onset or exacerbated heart failure was 0.9% in patients treated with insulin alone vs. 2% in patients treated with insulin plus rosiglitazone. Some of the patients who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. Additionally, the results of a meta-analysis that included the same 5 randomized, controlled trials mentioned previously indicate that the rate of myocardial ischemia may be increased in patients taking rosiglitazone in combination with insulin; the incidence of myocardia ischemia was 1.4% in patients receiving insulin monotherapy vs. 2.8% in patients receiving rosiglitazone and insulin combination therapy (OR 2.1 95% CI 0.9-5.1). The cardiovascular events were noted at doses of both 4 mg/day and 8 mg/day of rosiglitazone. In a sixth 26-week study, patients with baseline congestive heart failure were excluded; in this study, compared to insulin monotherapy (n=158), the addition of rosiglitazone to insulin therapy (n=161) did not increase the risk of congestive heart failure. One each of myocardial ischemia and sudden death were reported in patients taking combination therapy compared to zero patients taking insulin monotherapy. When rosiglitazone was added to insulin therapy, the incidence of hypoglycemia was higher with 8 mg/day of rosiglitazone (67%) compared to 4 mg/day (53%).
    Methamphetamine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Methazolamide: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methohexital: (Minor) The risk of developing hypothermia is increased when methohexital is used with hypothermia-producing agents such as ethanol, insulins, phenothiazines, or other general anesthetics.
    Methyclothiazide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Methylphenidate: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Methylprednisolone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including insulin. The dosing of insulin may require adjustment in patients who receive metoclopramide concomitantly.
    Metolazone: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Metoprolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Metreleptin: (Moderate) Use caution when administering metreleptin to patients treated with concomitant insulins or insulin secretagogue therapy (i.e., sulfonylureas, nateglinide, repaglinide). In clinical evaluation of metreleptin, hypoglycemia occurred in 13% of patients with generalized lipodystrophy. Most reported cases occurred with concomitant insulin use, with or without oral antihyperglycemic agents. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. Dosage adjustments to their antihyperglycemic medications may be necessary.
    Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Midodrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Moexipril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Mometasone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Monoamine oxidase inhibitors: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Moxifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Monitor blood glucose when quinolones and antidiabetic agents are coadministered.
    Nadolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Nandrolone Decanoate: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Naproxen; Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Nebivolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Nebivolol; Valsartan: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus. (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Nelfinavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Niacin, Niacinamide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when niacin, niacinamide is instituted or discontinued. Dosage adjustments may be necessary. Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy.
    Niacin; Simvastatin: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when niacin, niacinamide is instituted or discontinued. Dosage adjustments may be necessary. Niacin interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy.
    Nicotine: (Minor) Nicotine may increase plasma glucose. Monitor blood sugar for needed insulin dosage adjustments in insulin-dependent diabetic patients whenever a change in either nicotine intake or smoking status occurs. In addition, the use of inhaled insulin is not recommended in patients who smoke. Smoking tobacco can alter the effect of inhaled insulin in several ways. First, nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Second, tobacco smoking is known to aggravate insulin resistance. Finally, compared with non-smokers, insulin exposure after inhalation may be greater in patients who smoke. If inhaled insulin is used in this population, patients should be instructed to monitor blood glucose concentrations closely. If a change in smoking status or nicotine intake occur, patients should continue to monitor their blood glucose concentrations closely and clinicians should adjust the dose of insulin when indicated.
    Norepinephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Norethindrone: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Norfloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Monitor blood glucose when quinolones and antidiabetic agents are coadministered.
    Norgestrel: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Octreotide: (Moderate) Monitor patients receiving octreotide concomitantly with insulin for changes in glycemic control and adjust doses of these medications accordingly. Administration of octreotide to patients receiving oral antidiabetic agents or insulin can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations.
    Ofloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Olanzapine: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Olmesartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Orlistat: (Minor) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. Lower blood glucose may necessitate a dosage reduction of antidiabetic agents.
    Oxandrolone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Oxymetholone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Paliperidone: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Pasireotide: (Major) Pasireotide may cause hyperglycemia. Closely monitor patients receiving antidiabetic therapy for changes in glycemic control; adjustments in the dosage of antidiabetic agents may be necessary during pasireotide receipt and after its discontinuation.
    Pegvisomant: (Moderate) 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. Diabetic patients should monitor their blood glucose regularly with doses of anti-diabetic medications reduced as necessary.
    Pemoline: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Penbutolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Pentamidine: (Moderate) Monitor patients receiving insulin closely for changes in glycemic control during the use of pentamidine; dosage adjustments of insulin may be necessary. Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed hyperglycemia with prolonged pentamidine therapy.
    Pentoxifylline: (Moderate) Monitor patients receiving pentoxifylline concomitantly with insulin for changes in glycemic control. Pentoxifylline may enhance the hypoglycemic action of insulin.
    Perindopril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Perindopril; Amlodipine: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Perphenazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Perphenazine; Amitriptyline: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Phendimetrazine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Phenelzine: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Phenothiazines: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Phentermine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Phentermine; Topiramate: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Phenylephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Phenylephrine; Promethazine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Pindolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Pioglitazone: (Major) The risk of heart failure and/or edema is increased when thiazolidinediones (including pioglitazone) are combined with insulins; monitor combined therapy closely for signs or symptoms of congestive heart failure. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently.
    Pramlintide: (Major) Pramlintide is indicated to be used in combination with insulins; however, pramlintide increases the risk of insulin-induced hypoglycemia. Because of this increased risk, a dose reduction in mealtime insulin is warranted during the titration period with pramlintide. Per the manufacturer, insulin and pramlintide should not be combined in the same syringe or administered in the same injection site as the pharmacokinetic parameters of pramlintide are altered by regular, isophane (NPH), and premixed 70/30 insulin formulations; however, in a randomized, open-label crossover study in type 1 diabetes patients, the pharmacokinetics, pharmacodynamics, and safety of 30 mcg of pramlintide were not changed significantly when mixed with various short-acting insulins, long-acting insulins, or both immediately before injection. Because not all insulin types, doses of insulin, and doses of pramlintide were studied, mixing pramlintide with insulin prior to injection should be avoided. Furthermore, most insulins are formulated at a pH of approximately 7 and are not compatible with pramlintide which is formulated at a pH of 4.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prednisolone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Prednisone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Prilocaine; Epinephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Prochlorperazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Progesterone: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Progestins: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Promethazine: (Minor) It is unclear if phenothiazines directly interact with antidiabetic agents, phenothiazines have been reported to increase blood glucose concentrations. Promethazine should be used cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Propranolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Protease inhibitors: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Pseudoephedrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Pyrimethamine; Sulfadoxine: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Quetiapine: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Quinapril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Racepinephrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Ramipril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Rasagiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor rasagiline, are added to any regimen containing antidiabetic agents.
    Reserpine: (Moderate) Monitor patients receiving insulin closely for changes in glycemic control during the use of reserpine. Reserpine may mask the signs and symptoms of hypoglycemia.
    Risperidone: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Ritodrine: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Ritonavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Rosiglitazone: (Major) Use of insulins with rosiglitazone is not recommended by the manufacturer due to a potential increased risk for edema or heart failure. If heart failure develops in a patient receiving insulin and a thiazoladinedione, manage the patient according to standards of care, and discontinue or consider reducing the dose of the thiazoladinedione. Since the incidence of hypoglycemia may also be higher with combined therapy, patients should also be instructed to monitor blood glucose concentrations more frequently. In five 26-week trials involving patients with type 2 diabetes, rosiglitazone added to insulin therapy (n=867) was compared with insulin therapy alone (n=663). These trials included patients with chronic diabetes and a high prevalence of coexisting medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. In these clinical studies, an increased incidence of heart failure and other cardiovascular adverse events was seen in patients receiving combination rosiglitazone and insulin therapy compared to insulin monotherapy; the incidence of new onset or exacerbated heart failure was 0.9% in patients treated with insulin alone vs. 2% in patients treated with insulin plus rosiglitazone. Some of the patients who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. Additionally, the results of a meta-analysis that included the same 5 randomized, controlled trials mentioned previously indicate that the rate of myocardial ischemia may be increased in patients taking rosiglitazone in combination with insulin; the incidence of myocardia ischemia was 1.4% in patients receiving insulin monotherapy vs. 2.8% in patients receiving rosiglitazone and insulin combination therapy (OR 2.1 95% CI 0.9-5.1). The cardiovascular events were noted at doses of both 4 mg/day and 8 mg/day of rosiglitazone. In a sixth 26-week study, patients with baseline congestive heart failure were excluded; in this study, compared to insulin monotherapy (n=158), the addition of rosiglitazone to insulin therapy (n=161) did not increase the risk of congestive heart failure. One each of myocardial ischemia and sudden death were reported in patients taking combination therapy compared to zero patients taking insulin monotherapy. When rosiglitazone was added to insulin therapy, the incidence of hypoglycemia was higher with 8 mg/day of rosiglitazone (67%) compared to 4 mg/day (53%).
    Sacubitril; Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Salicylates: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Salsalate: (Moderate) Use large doses of aspirin cautiously in patients receiving insulin. 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.
    Saquinavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Selegiline: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Sodium Polystyrene Sulfonate: (Moderate) Sodium polystyrene sulfonate should be used cautiously with other agents that can induce hypokalemia such as loop diuretics, insulins, or intravenous sodium bicarbonate. Because of differences in onset of action, sodium polystyrene sulfonate is often used with these agents. With appropriate monitoring, hypokalemia can be avoided.
    Somatropin, rh-GH: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when somatropin, rh-GH is instituted and for signs of hypoglycemia when somatropin, rh-GH is discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., somatropin, rh-GH) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Sotalol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Sparfloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Sulfadiazine: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Sulfasalazine: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Sulfinpyrazone: (Moderate) A case report describes an episode of brief hypoglycemia in a diabetic patient receiving both insulins and sulfinpyrazone. The patient responded spontaneously, and an association with sulfinpyrazone was not clearly established. In another report, no changes in insulin requirements were required when sulfinpyrazone therapy was added.
    Sulfisoxazole: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Sulfonamides: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Sympathomimetics: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
    Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents.
    Telmisartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Testolactone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Testosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thiazide diuretics: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control when thiazide diuretics are instituted or discontinued; dosage adjustments may be required. Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.
    Thiethylperazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Thioridazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Thyroid hormones: (Minor) Monitor patients receiving insulin closely for changes in diabetic control 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. 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.
    Timolol: (Moderate) Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and insulin concomitantly should be closely monitored for an inappropriate response. Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Tipranavir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Torsemide: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when bumetanide, furosemide, and torsemide are instituted. 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.
    Trandolapril: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Trandolapril; Verapamil: (Moderate) Monitor patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors) concomitantly with insulin for changes in glycemic control. ACE inhibitors may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.
    Tranylcypromine: (Moderate) Monitor patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly with insulin for changes in glycemic control. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.
    Triamcinolone: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., corticosteroids) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. Patients receiving insulin should be closely monitored for signs indicating loss of diabetic control when therapy with triamterene is instituted. In addition, patients receiving insulin should be closely monitored for signs of hypoglycemia when therapy with any of these other agents is discontinued.
    Trifluoperazine: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when phenothiazines are instituted. The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations.
    Valsartan: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin 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.
    Ziprasidone: (Moderate) Patients taking insulin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.

    PREGNANCY AND LACTATION

    Pregnancy

    It is unknown whether insulin lispro is excreted in significant amounts in human milk; however, many drugs, including human insulin, are excreted in human milk. Insulin is degraded in the gastrointestinal tract; therefore, any insulin secreted into breast milk would not be absorbed by a breast-feeding infant. The American Diabetes Association encourages breast-feeding in women with pre-existing diabetes mellitus or gestational diabetes ; accordingly, women on insulin therapy should be encouraged to breast-feed if no contraindications exist. Breast-feeding may decrease insulin requirements, despite the need for increased caloric intake. Careful observation of increased maternal caloric needs and maternal blood glucose concentrations are needed.

    MECHANISM OF ACTION

    Endogenous insulin regulates carbohydrate, fat, and protein metabolism by several mechanisms; in general, insulin promotes the storage and inhibits the breakdown of glucose, fat, and amino acids. Insulin lowers glucose concentrations by facilitating the uptake of glucose in muscle and adipose tissue and by inhibiting hepatic glucose production (glycogenolysis and gluconeogenesis). Insulin also regulates fat metabolism by enhancing the storage of fat (lipogenesis) and inhibiting the mobilization of fat for energy in adipose tissues (lipolysis and free fatty acid oxidation). Finally, insulin is involved in the regulation of protein metabolism by increasing protein synthesis and inhibiting proteolysis in muscle tissue.
     
    Diabetes mellitus type 1 is caused by insulin deficiency while diabetes mellitus type 2 is caused by a combination of insulin deficiency and resistance. Biosynthetic insulin is used as replacement therapy in patients with diabetes mellitus to temporarily restore their ability to use fats, carbohydrates, and proteins, and to convert glycogen to fat. Insulin administration also enables these patients to replete their liver glycogen stores. Commercially available insulin is prepared using recombinant DNA technology (E. coli bacteria) or enzymatic modification of beef or pork insulin to create a product identical in structure and function to endogenous human insulin.

    PHARMACOKINETICS

    Insulin lispro is administered via intermittent subcutaneous injection and can be used for administration via external SC insulin infusion pumps. It may also be administered via intravenous infusion.
     
    Endogenous insulin distributes widely throughout the body. A small portion is inactivated by peripheral tissues, but the majority is metabolized by the liver and kidneys. Insulin is filtered and reabsorbed by the kidneys; the plasma half-life of human endogenous insulin is approximately 5—6 minutes.

    Intravenous Route

    Insulin lispro exhibits similar pharmacokinetics to IV regular insulin when administered by the IV route. When administered intravenously as bolus injections of 0.1 and 0.2 units/kg dose in two separate groups of healthy subjects, the mean volume of distribution of insulin lispro appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 units/kg dose, respectively). In addition, IV insulin lispro and IV regular human insulin demonstrated similar dose dependent clearance, with a mean clearance of 21 mL/minute/kg and 21.4 mL/minute/kg, respectively (0.1 unit/kg dose), and 9.6 mL/minute/kg and 9.4 mL/minute/kg, respectively (0.2 unit/kg dose). Accordingly, insulin lispro demonstrated a mean half-life of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean half-life was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.

    Subcutaneous Route

    Pharmacodynamically, insulin lispro has an onset of glucose-lowering activity that is 15—30 minutes, which is more rapid than regular insulin. Insulin lispro reaches mean peak plasma concentrations faster (30—90 minutes) than regular insulin (60—120 minutes) when given SC. Insulin lispro has a duration of action of roughly 3—5 hours, which is shorter than regular insulin. After subcutaneous administration, the apparent half-life of insulin lispro is 1 hour compared with 1.5 hours for regular insulin. After abdominal administration, insulin lispro concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of insulin lispro is slightly shorter following abdominal injection, compared with deltoid and femoral injections. Intermittent subcutaneous injections of insulin lispro should be given within 15 minutes prior to or immediately after a meal because of the fast onset compared to regular insulin.