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  • CLASSES

    GLP-1 Receptor Agonists

    BOXED WARNING

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

    Dulaglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). One case of MTC was reported in a patient treated with dulaglutide in the phase 3 clinical program. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial. In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. Other glucagon-like peptide (GLP-1) receptor agonists have also induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether dulaglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of this signal could not be determined from the clinical or nonclinical studies. The value of monitoring serum calcitonin or performing thyroid ultrasounds for early detection of thyroid C-cell tumors is uncertain; this may lead to a large number of unnecessary thyroid surgeries. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with dulaglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    DEA CLASS

    Rx

    DESCRIPTION

    Incretin mimetic (GLP-1 receptor agonist) administered as a once-weekly subcutaneous injection
    Used to improve glycemic control in patients 10 years and older with type 2 diabetes mellitus (T2DM) and for the reduction of cardiovascular (CV) mortality due to major cardiovascular events (MACE) in adult T2DM patients with established CV disease or multiple CV risk factors
    Not recommended as first-line therapy because of the boxed warning regarding rodent C-cell tumor findings and the uncertain relevance to humans

    COMMON BRAND NAMES

    Trulicity

    HOW SUPPLIED

    Dulaglutide/TRULICITY Subcutaneous Inj Sol: 0.5mL, 0.75mg, 1.5mg, 3mg, 4.5mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise.
    Subcutaneous dosage
    Adults

    0.75 mg subcutaneously once weekly, initially. Increase the dose to 1.5 mg subcutaneously once weekly for additional glycemic control; may increase the dose to 3 mg subcutaneously once weekly after at least 4 weeks on 1.5 mg/week and 4.5 mg subcutaneously once weekly after at least 4 weeks on 3 mg/week if additional glycemic control is needed. Max: 4.5 mg/week.

    Children and Adolescents 10 to 17 years

    0.75 mg subcutaneously once weekly, initially. After 4 weeks, may increase to 1.5 mg subcutaneously once weekly if additional glycemic control is needed. Treatment with dulaglutide at either dose was superior to placebo in improving glycemic control through 26 weeks in pediatric patients (10 to 17 years) who were being treated with or without metformin or basal insulin, without an effect on BMI.

    For the reduction of cardiovascular mortality due to major cardiovascular events (MACE) in T2DM patients with established cardiovascular disease or multiple CV risk factors.
    Subcutaneous dosage
    Adults

    0.75 mg subcutaneously once weekly (every 7 days), initially. Administer the dose at any time of day, with or without meals. May increase to 1.5 mg subcutaneously once weekly for additional glycemic control. If needed, may increase to 3 mg subcutaneously once weekly, after at least 4 weeks on the 1.5 mg/week dose, for further glycemic control. May further increase the dose to 4.5 mg subcutaneously once weekly after at least 4 weeks on the 3 mg/week dose, if needed for glycemic control. Max: 4.5 mg/week. MISSED DOSES: If a dose is missed, administer it as soon as noticed, as long as the next regularly scheduled dose is due at least 3 days later. After that, patients can resume their usual dosing schedule of once every 7 days (weekly). If it is more than 3 days after the missed dose, wait until the next regularly scheduled dose. The day of weekly administration can be changed if needed, as long as the last dose was administered at least 3 days before. LIMITATIONS OF USE: Dulaglutide is not a substitute for insulin. USE WITH OTHER ANTIDIABETIC AGENTS: May be used with basal insulin. When dulaglutide 1.5 mg was added onto insulin glargine therapy, significant A1C reduction was achieved compared to treatment with placebo plus insulin glargine. When initiating dulaglutide, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist.

    MAXIMUM DOSAGE

    Adults

    4.5 mg/week subcutaneously.

    Geriatric

    4.5 mg/week subcutaneously.

    Adolescents

    1.5 mg/week subcutaneously.

    Children

    10 to 12 years: 1.5 mg/week subcutaneously.
    1 to 9 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed; however, there is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Use with caution.

    Renal Impairment

    No dosage adjustment is needed in patients with renal impairment, including patients with end-stage renal disease (ESRD). Monitor renal function in patients with renal impairment who report severe adverse gastrointestinal reactions. There is limited clinical experience with dulaglutide in patients with severe renal impairment or ESRD.

    ADMINISTRATION

    Injectable Administration

    Administer by subcutaneous injection only. Do NOT administer by intravenous or intramuscular injection.
    Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit.
    When using dulaglutide concomitantly with insulin, administer as separate injections. Never mix them together. The two injections may be injected in the same body region, but the injections should not be adjacent to each other.

    Subcutaneous Administration

    Prior to initiation, train patients and caregivers on proper injection technique.
    Administer at any time of day, with or without meals.
    Double-check dosage prior to administration. Available in a pre-filled single-dose pen containing either dulaglutide 0.75 mg/0.5 mL, dulaglutide 1.5 mg/0.5 mL, dulaglutide 3 mg/0.5 mL, or dulaglutide 4.5 mg/0.5 mL.
    Storage: The pen is for single-use only. Store unused, unopened pens in the refrigerator at 36 to 46 degrees F (2 to 8 degrees C). Do not freeze or use the pen if the product has been frozen. Protect from light; it is recommended that the pen be stored in the original carton. If needed, a single pen may be stored at room temperature not to exceed 86 degrees F (30 degrees C) for up to 14 days.[57946]
     
    Pre-filled Pen Administration (Trulicity Pen):
    Inspect the pen visually before use. The medicine should appear clear and colorless. Do not use if particulate matter or coloration is seen or if there is any damage to the pen.
    The pen has glass parts. Handle it carefully. If a pen is dropped on a hard surface, do not use it. Use a new pen for the injection.
    Uncap the pen by ensuring the pen is locked and pulling the base cap straight off. Throw the base cap in the trash; do not put it back on the pen since this could damage the needle. Do not touch the needle.
    Do NOT prime the pen.
    Inject subcutaneously into the thigh, abdomen, or upper arm.
    Place the clear base flat and firmly against the patient's skin at the injection site. Unlock by turning the lock ring.
    Press and hold the green injection button; you will hear a loud click. Continue holding the clear base firmly against the patient's skin until you hear a second click. This happens when the needle starts retracting in about 5 to 10 seconds. You will know the injection is complete when the gray plunger is visible.
    Remove the pen from the skin.
    After injection, properly dispose of the used pen.
    Rotate administration sites with each injection to prevent lipodystrophy.When using dulaglutide with insulin, administer as separate injections and never mix. It is acceptable to inject dulaglutide and insulin in the same body region, but the injections should not be adjacent to each other.
    See the manufacturer's instructions for use for complete administration directions and illustrations for use. These are available at www.trulicity.com.
    Missed dose: If a dose is missed, administer it as soon as noticed, as long as the next regularly scheduled dose is due at least 3 days later. After that, patients can resume their usual dosing schedule of once every 7 days (weekly). If it is more than 3 days after the missed dose, wait until the next regularly scheduled dose. The day of weekly administration can be changed if needed, as long as the last dose was administered at least 3 days before.

    STORAGE

    Trulicity:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Do not use if product has been frozen
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store at or below 86 degrees F, away from heat sources, for up to 14 days if refrigeration is not available
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema

    Dulaglutide is contraindicated in any patient who has exhibited dulaglutide hypersensitivity, history of angioedema or anaphylaxis to dulaglutide, or hypersensitivity to any of its inactive ingredients. There is a risk of serious hypersensitivity reactions with dulaglutide use. Angioedema and anaphylaxis have been reported in patients treated with dulaglutide. Use caution in patients with a history of angioedema or anaphylaxis to other GLP-1 receptor agonists because it is unknown whether such patients will be predisposed to serious reactions with dulaglutide. If a serious hypersensitivity reaction is suspected, discontinue dulaglutide; treat promptly per standard of care and monitor until signs and symptoms resolve.

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

    Dulaglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). One case of MTC was reported in a patient treated with dulaglutide in the phase 3 clinical program. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial. In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. Other glucagon-like peptide (GLP-1) receptor agonists have also induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether dulaglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of this signal could not be determined from the clinical or nonclinical studies. The value of monitoring serum calcitonin or performing thyroid ultrasounds for early detection of thyroid C-cell tumors is uncertain; this may lead to a large number of unnecessary thyroid surgeries. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with dulaglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

    Type 1 diabetes mellitus

    Dulaglutide should not be used for the treatment of type 1 diabetes mellitus.

    Hypoglycemia

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

    Pancreatitis

    Dulaglutide has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. There have been reports of pancreatitis in patients taking dulaglutide during pre-marketing trials and with the use of other GLP-1 receptor agonists. Other antidiabetic therapies should be considered in patients with a history of pancreatitis. After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted. In 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available.

    Renal failure, renal impairment

    Use caution when initiating or increasing doses of dulaglutide in patients with renal impairment or in patients reporting severe gastrointestinal adverse reactions; monitor renal function. There is limited information available on the use of dulaglutide in patients with severe renal impairment, renal failure, or end stage renal disease (ESRD). There have been postmarketing reports of acute kidney injury, renal failure, and worsening of chronic renal failure, which sometimes has required hemodialysis in patients treated with GLP-1 receptor agonists. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced gastrointestinal (GI) adverse reactions including nausea, vomiting, diarrhea, or dehydration. In many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents.

    Cholelithiasis, gallbladder disease

    Use dulaglutide with caution in patients with a history of gallbladder disease. If cholelithiasis or cholecystitis are suspected in a patient taking dulaglutide, gallbladder studies are indicated. Acute gallbladder disease events have been reported in GLP-1 receptor agonist trials. In a cardiovascular outcomes trial (median follow up of 5.4 years), cholelithiasis occurred at a rate of 0.62/100 patient-years in dulaglutide-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on dulaglutide and placebo respectively.

    Gastroparesis, GI disease

    Dulaglutide has not been studied in patients with severe gastrointestinal (GI) disease, including severe gastroparesis. Dulaglutide may slow gastric emptying. Therefore, the use of dulaglutide is not recommended in patients with severe GI disease or severe gastroparesis.

    Diabetic retinopathy

    Monitor for visual changes in patients with a history of diabetic retinopathy. Inform patients to contact their prescriber if changes in vision are experienced during treatment. In a cardiovascular (CV) outcomes trial with a median follow up of 5.4 years involving patients with Type 2 diabetes and established CV disease or multiple CV risk factors, more events of diabetic retinopathy complications occurred in patients treated with dulaglutide (1.9%) compared to placebo (1.5%). There was an increased risk for diabetic retinopathy complications in patients with a history of diabetic retinopathy at baseline (8.5%) compared to patients without a known history of diabetic retinopathy (1%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.

    Geriatric

    Dulaglutide has been studied in adults 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric adults versus younger adults. In general, however, geriatric patients are especially at risk for hypoglycemic episodes. The specific reasons identified include intensive insulin therapy, decreased renal function, severe liver disease, alcohol ingestion, defective counter-regulatory hormone release, missing meals/fasting, and gastroparesis. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function.

    Pregnancy

    No adequate and well-controlled studies have been conducted with dulaglutide during pregnancy; use only if clearly needed and the benefit justifies the potential risk to the fetus. A drug-associated risk for major birth defects or miscarriage cannot be determined. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide. Increases in post-implantation loss also were observed in pregnant rats given dulaglutide. Female offspring of maternal rats who were given dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. The human relevance of these memory deficits in female rats is not known. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    Breast-feeding

    It is not known if dulaglutide is excreted into human milk. Decreased body weight in offspring was observed in rats treated with dulaglutide during gestation and lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure including the potential for tumorigenicity, and the risk of an untreated or inadequately treated condition. If dulaglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    ADVERSE REACTIONS

    Severe

    AV block / Early / 1.7-2.3
    cholecystitis / Delayed / 0.5-0.5
    pancreatitis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 1.6-6.0
    sinus tachycardia / Rapid / 2.8-5.6
    constipation / Delayed / 3.7-3.9
    PR prolongation / Rapid / 2.5-3.2
    cholelithiasis / Delayed / 0.6-0.6
    erythema / Early / 0.5-0.5
    edema / Delayed / 0.5-0.5
    hypoglycemia / Early / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    nausea / Early / 12.4-21.1
    vomiting / Early / 6.0-12.7
    diarrhea / Early / 8.9-12.6
    abdominal pain / Early / 6.5-9.4
    anorexia / Delayed / 4.9-8.6
    dyspepsia / Early / 4.1-5.8
    fatigue / Early / 4.2-5.6
    injection site reaction / Rapid / 0.5-3.9
    flatulence / Early / 1.4-3.4
    gastroesophageal reflux / Delayed / 1.7-2.0
    eructation / Early / 0.6-1.6
    rash / Early / 0.5-0.5
    urticaria / Rapid / 0.5-0.5

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Acetaminophen; Aspirin: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Acetohexamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aliskiren; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Benazepril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Olmesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Androgens: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Angiotensin II receptor antagonists: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Angiotensin-converting enzyme inhibitors: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Carisoprodol: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Dipyridamole: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aspirin, ASA; Pravastatin: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Atazanavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    atypical antipsychotic: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. 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.
    Azilsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Azilsartan; Chlorthalidone: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benazepril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Beta-blockers: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
    Bismuth Subsalicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Bortezomib: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
    Candesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Captopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Carbonic anhydrase inhibitors: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the incretin mimetics, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
    Chlorpromazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Chlorpropamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Chlorthalidone; Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    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.
    Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
    Codeine; Phenylephrine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Codeine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Corticosteroids: (Moderate) Monitor blood glucose during concomitant corticosteroid and incretin mimetic use; an incretin mimetic dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
    Cyclosporine: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including dulaglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
    Daclatasvir: (Moderate) Closely monitor blood glucose levels if daclatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as daclatasvir.
    Danazol: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Darunavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir : (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Diazoxide: (Minor) Diazoxide, when administered intravenously or orally, produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect. The hyperglycemic effect begins within an hour and generally lasts no more than 8 hours in the presence of normal renal function. The hyperglycemic effect of diazoxide is expected to be antagonized by certain antidiabetic agents (e.g., insulin or a sulfonylurea). Blood glucose should be closely monitored.
    Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving this combination should be monitored for changes in glycemic control.
    Elbasvir; Grazoprevir: (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
    Enalapril, Enalaprilat: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Enalapril; Felodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Eprosartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Esterified Estrogens; Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Ethotoin: (Minor) Ethotoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Fibric acid derivatives: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fluoxetine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fluoxymesterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Fluphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Fosamprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Fosphenytoin: (Minor) Fosphenytoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Garlic, Allium sativum: (Moderate) Patients receiving antidiabetic agents should use dietary supplements of Garlic, Allium sativum with caution. Constituents in garlic might have some antidiabetic activity, and may increase serum insulin levels and increase glycogen storage in the liver. Monitor blood glucose and glycemic control. Patients with diabetes should inform their health care professionals of their intent to ingest garlic dietary supplements. Some patients may require adjustment to their hypoglycemic medications over time. One study stated that additional garlic supplementation (0.05 to 1.5 grams PO per day) contributed to improved blood glucose control in patients with type 2 diabetes mellitus within 1 to 2 weeks, and had positive effects on total cholesterol and high/low density lipoprotein regulation over time. It is unclear if hemoglobin A1C is improved or if improvements are sustained with continued treatment beyond 24 weeks. Other reviews suggest that garlic may provide modest improvements in blood lipids, but few studies demonstrate decreases in blood glucose in diabetic and non-diabetic patients. More controlled trials are needed to discern if garlic has an effect on blood glucose in patients with diabetes. When garlic is used in foods or as a seasoning, or at doses of 50 mg/day or less, it is unlikely that blood glucose levels are affected to any clinically significant degree.
    Glecaprevir; Pibrentasvir: (Moderate) Closely monitor blood glucose levels if glecaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as glecaprevir. (Moderate) Closely monitor blood glucose levels if pibrentasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as pibrentasvir.
    Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glimepiride; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glipizide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glyburide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking incretin mimetics should be monitored closely for hypoglycemia if consuming green tea.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Hydroxychloroquine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and hydroxychloroquine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Hydroxyprogesterone: (Minor) Progestins, like hydroxyprogesterone, can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like incretin mimetics. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Insulin Aspart: (Moderate) Monitor blood glucose during concomitant insulin aspart and dulaglutide use; consider decreasing the insulin aspart dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Aspart: (Moderate) Monitor blood glucose during concomitant insulin aspart and dulaglutide use; consider decreasing the insulin aspart dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Aspart; Insulin Aspart Protamine: (Moderate) Monitor blood glucose during concomitant insulin aspart and dulaglutide use; consider decreasing the insulin aspart dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Degludec: (Moderate) Monitor blood glucose during concomitant insulin degludec and dulaglutide use; consider decreasing the insulin degludec dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant insulin degludec and dulaglutide use; consider decreasing the insulin degludec dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Detemir: (Moderate) Monitor blood glucose during concomitant insulin detemir and dulaglutide use; consider decreasing the insulin detemir dose when starting dulaglutide. The recommended starting dose of insulin detemir is 10 units/day in persons with type 2 diabetes mellitus inadequately controlled with a glucagon-like peptide-1 (GLP-1) receptor agonist. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glargine: (Moderate) Monitor blood glucose during concomitant insulin glargine and dulaglutide use; consider decreasing the insulin glargine dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant insulin glargine and dulaglutide use; consider decreasing the insulin glargine dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glulisine: (Moderate) Monitor blood glucose during concomitant insulin glulisine and dulaglutide use; consider decreasing the insulin glulisine dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro: (Moderate) Monitor blood glucose during concomitant insulin lispro and dulaglutide use; consider decreasing the insulin lispro dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro: (Moderate) Monitor blood glucose during concomitant insulin lispro and dulaglutide use; consider decreasing the insulin lispro dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor blood glucose during concomitant insulin lispro and dulaglutide use; consider decreasing the insulin lispro dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Regular: (Moderate) Monitor blood glucose during concomitant regular insulin and dulaglutide use; consider decreasing the regular insulin dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin, Inhaled: (Moderate) Monitor blood glucose during concomitant insulin and dulaglutide use; consider decreasing the insulin dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Irbesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Isocarboxazid: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lanreotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when lanreotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Lanreotide inhibits the secretion of insulin and glucagon. Patients treated with lanreotide may experience either hypoglycemia or hyperglycemia.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Ledipasvir; Sofosbuvir: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Levothyroxine: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Levothyroxine; Liothyronine (Porcine): (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Levothyroxine; Liothyronine (Synthetic): (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    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) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Lisinopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lonapegsomatropin: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
    Loop diuretics: (Minor) Loop diuretics, such as bumetanide, furosemide, and torsemide, may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents, including incretin mimetics. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
    Lopinavir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
    Losartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Mecasermin rinfabate: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
    Meglitinides: (Moderate) The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues such as meglitinides. Although specific dose recommendations are not available, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Meperidine; Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Metformin; Repaglinide: (Moderate) The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues such as meglitinides. Although specific dose recommendations are not available, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    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.
    Methenamine; Sodium Salicylate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
    Moexipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Monoamine oxidase inhibitors: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Nandrolone Decanoate: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Nateglinide: (Moderate) The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues such as meglitinides. Although specific dose recommendations are not available, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Nebivolol; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Nelfinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary.
    Nicotine: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Nirmatrelvir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Octreotide: (Moderate) Monitor patients receiving octreotide concomitantly with insulin or other antidiabetic agents for changes in glycemic control and adjust doses of these medications accordingly. Octreotide alters the balance between the counter-regulatory hormones of insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. In patients with concomitant type1 diabetes mellitus, octreotide is likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in type 1 diabetic patients. In Type 2 diabetes patients with partially intact insulin reserves, octreotide administration may result in decreases in plasma insulin levels and hyperglycemia.
    Olanzapine; Fluoxetine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Minor) Weight-loss may affect glycemic control in patients with diabetes mellitus. In many patients, glycemic control may improve. A reduction in dose of oral hypoglycemic medications may be required in some patients taking orlistat. Monitor blood glucose and glycemic control and adjust therapy as clinically indicated.
    Oxandrolone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Oxymetholone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Pasireotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pasireotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pasireotide inhibits the secretion of insulin and glucagon. Patients treated with pasireotide may experience either hypoglycemia or hyperglycemia.
    Pegvisomant: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pegvisomant treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pegvisomant increases sensitivity to insulin by lowering the activity of growth hormone, and in some patients glucose tolerance improves with treatment. Patients with diabetes treated with pegvisomant and antidiabetic agents may be more likely to experience hypoglycemia.
    Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
    Pentoxifylline: (Moderate) Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
    Perindopril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Perindopril; Amlodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Perphenazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Perphenazine; Amitriptyline: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenelzine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Phenothiazines: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Phenytoin: (Minor) Phenytoin can decrease the hypoglycemic effects of dulaglutide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
    Pioglitazone; Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Prochlorperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine; Dextromethorphan: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Promethazine; Phenylephrine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Quinapril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Quinolones: (Moderate) Monitor blood glucose during concomitant incretin mimetic and quinolone use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ramipril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Regular Insulin: (Moderate) Monitor blood glucose during concomitant regular insulin and dulaglutide use; consider decreasing the regular insulin dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor blood glucose during concomitant insulin NPH and dulaglutide use; consider decreasing the insulin NPH dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant regular insulin and dulaglutide use; consider decreasing the regular insulin dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Repaglinide: (Moderate) The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues such as meglitinides. Although specific dose recommendations are not available, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia in this setting. Adequate blood glucose monitoring should be continued and followed.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving reserpine concomitantly with antidiabetic agents, such as incretin mimetics, should be monitored for changes in glycemic control.
    Ritonavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Salicylates: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Salsalate: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Saquinavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sofosbuvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
    Sofosbuvir; Velpatasvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir. (Moderate) Closely monitor blood glucose levels if voxilaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as voxilaprevir.
    Somatropin, rh-GH: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
    Sulfonamides: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sulfonylureas: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sympathomimetics: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Tacrolimus: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including dulaglutide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
    Tegaserod: (Moderate) Tegaserod can enhance gastric emptying in patients with diabetes. Typically, blood glucose could be affected, which, in turn, may affect the clinical response to antidiabetic agents. However, incretin mimetics have been shown to slow gastric emptying. The clinical effects of these competing mechanisms is not known. The dosing of antidiabetic agents may require adjustment and blood glucose should be closely monitored when coadministered with tegaserod.
    Telmisartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Telmisartan; Amlodipine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Testosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
    Thiazide diuretics: (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
    Thiethylperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thioridazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Thyroid hormones: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
    Tipranavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tolazamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Tolbutamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and dulaglutide use; consider decreasing the sulfonylurea dose when starting dulaglutide. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Trandolapril: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Trandolapril; Verapamil: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Tranylcypromine: (Moderate) Monitor blood glucose during concomitant incretin mimetic and monoamine oxidase inhibitor (MAOI) use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary.
    Trifluoperazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted.
    Valsartan: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood glucose during concomitant incretin mimetic and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well-controlled studies have been conducted with dulaglutide during pregnancy; use only if clearly needed and the benefit justifies the potential risk to the fetus. A drug-associated risk for major birth defects or miscarriage cannot be determined. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy. In rats and rabbits, dulaglutide administered during the major period of organogenesis produced fetal growth reductions and/or skeletal anomalies and ossification deficits in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide. Increases in post-implantation loss also were observed in pregnant rats given dulaglutide. Female offspring of maternal rats who were given dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. The human relevance of these memory deficits in female rats is not known. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.

    It is not known if dulaglutide is excreted into human milk. Decreased body weight in offspring was observed in rats treated with dulaglutide during gestation and lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure including the potential for tumorigenicity, and the risk of an untreated or inadequately treated condition. If dulaglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breast-feeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected. Also, while the manufacturers of metformin recommend against breast-feeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    MECHANISM OF ACTION

    Dulaglutide is an incretin mimetic; specifically, dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with 90% amino acid sequence homology to endogenous GLP-1 (7—37). GLP-1 (7—37) represents < 20% of total circulating endogenous GLP-1. Dulaglutide binds and activates the GLP-1 receptor. GLP-1 is an important, gut-derived, glucose homeostasis regulator that is released after the oral ingestion of carbohydrates or fats. In patients with type 2 diabetes, GLP-1 concentrations are decreased in response to an oral glucose load. GLP-1 enhances insulin secretion; it increases glucose-dependent insulin synthesis and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. In addition to increases in insulin secretion and synthesis, GLP-1 suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta-cell proliferation.

    PHARMACOKINETICS

    Dulaglutide is given via subcutaneous injection. The apparent population mean central volume of distribution was 3.09 L and the apparent population mean peripheral volume of distribution was 5.98 L. Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. The apparent population mean clearance of dulaglutide was 0.142 L/hour. The elimination half-life of dulaglutide was approximately 5 days.
     
    Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: None

    Subcutaneous Route

    The mean absolute bioavailability of dulaglutide following subcutaneous administration of a single 0.75 mg or 1.5 mg dose was 65% and 47%, respectively. Absolute subcutaneous bioavailability for 3 mg and 4.5 mg doses were estimated to be similar to 1.5 mg although this has not been specifically studied. Dulaglutide concentrations increased approximately proportional to dose from 0.75 mg to 4.5 mg. Following subcutaneous administration, the time to maximum plasma concentration (Tmax) of dulaglutide at steady-state ranges from 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady-state, the mean peak plasma concentration (Cmax) was 114 ng/mL (range 56 to 231 ng/mL) and the total systemic exposure (AUC) of dulaglutide was 14,000 ng x hour/mL (range 6,940 to 26,000 ng x hour/mL); accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once-weekly administration. The site of subcutaneous administration (i.e., abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.