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Liraglutide

Indications/Dosage

Labeled

  • obesity
  • reduction of cardiovascular mortality
  • type 2 diabetes mellitus
  • weight management

Off-Label

    † Off-label indication

    For the treatment of type 2 diabetes mellitus uncontrolled by diet and exercise

    Subcutaneous dosage (Victoza)

    Adults

    Initially, 0.6 mg subcutaneously once daily for 1 week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal (GI) symptoms during initial titration and is not effective for glycemic control. After 1 week, increase the dose to 1.2 mg subcutaneously once daily. If acceptable glycemic control not achieved, the dose can be increased to 1.8 mg subcutaneously once daily. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg in order to alleviate any GI symptoms associated with reinitiation of treatment. The dose should then be retitrated appropriately. The concurrent use of liraglutide and prandial insulin has not been studied.[38653] When liraglutide is added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist.[22300] When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia.[38653]

    Children and Adolescents 10 to 17 years

    Initially, 0.6 mg subcutaneously once daily for 1 week. If additional glycemic control is required, the dose may be increased to 1.2 mg subcutaneously once daily. If acceptable glycemic control is not achieved, the dose can be increased to 1.8 mg subcutaneously once daily after at least 1 week of 1.2 mg. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg in order to alleviate any GI symptoms associated with reinitiation of treatment. The dose should then be retitrated appropriately.[38653]

    For the reduction of cardiovascular mortality and CV events (e.g., non-fatal myocardial infarction or non-fatal stroke) in type 2 diabetes mellitus patients who also have established CV disease

    Subcutaneous dosage (Victoza)

    Adults

    Initially, 0.6 mg subcutaneously once daily for 1 week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal (GI) symptoms during initial titration and is not effective for glycemic control. After 1 week, increase the dose to 1.2 mg subcutaneously once daily. If acceptable glycemic control not achieved, the dose can be increased to 1.8 mg subcutaneously once daily. If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at 0.6 mg in order to alleviate any GI symptoms associated with reinitiation of treatment. The dose should then be retitrated appropriately. The concurrent use of liraglutide and prandial insulin has not been studied.[38653] When liraglutide is added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist.[22300] When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia.[38653] In addition to improving glycemic control a long-term, multicenter, randomized, double-blind, placebo-controlled trial (LEADER) of 9,340 patients with inadequately controlled type 2 DM and established, stable atherosclerotic cardiovascular disease reported that the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) was significantly reduced in the liraglutide group (13%) compared to the placebo group (14.9%) (HR 0.87; 95% CI 0.78 to 0.97; p less than 0.001 for noninferiority; p = 0.01 for superiority).[61921]

    For the treatment of obesity and for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity

    Subcutaneous dosage (Saxenda)

    Adults

    0.6 mg subcutaneously once daily for 1 week to reduce gastrointestinal (GI) symptoms associated with initial therapy. Increase the daily dose by 0.6 mg at weekly intervals until the target dose of 3 mg subcutaneously once daily is attained. If patients do not tolerate a dose increase, consider delaying dose escalation for 1 additional week. The manufacturer recommends discontinuation if the 3 mg dose is not tolerated; efficacy has not been established at lower doses.[58673] The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Practice Guidelines state that data are available for post-bariatric surgery use of liraglutide within a dose range of 1.8 to 3 mg/day.[62881] MISSED DOSE: If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, reinitiate at the 0.6 mg dose and re-titrate appropriately. PATIENT SELECTION: Liraglutide is indicated for patients with an initial body mass index (BMI) of 30 kg/m2 or more or in those with a BMI of 27 kg/m2 or more in the presence of at least 1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes).[58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, pharmacotherapy should be offered as chronic treatment along with lifestyle modifications to patients with obesity when the potential benefits outweigh the risks. Short-term pharmacotherapy has not been shown to produce longer-term health benefits and cannot be generally recommended. A generalized hierarchy for medication preferences that would be applicable to all patients cannot currently be scientifically justified. Individualized weight loss pharmacotherapy is recommended, based upon factors such as the specific characteristics of each weight loss medication, the presence of weight-related complications, and the medical history of the patient. Combination therapy should only occur when such therapy is approved by the governing agency or when sufficient safety and efficacy data assure a favorable benefit-to-risk ratio.[62881]

    Children† and Adolescents† 12 to 17 years

    0.6 mg subcutaneously once daily for 1 week to reduce gastrointestinal (GI) symptoms associated with initial therapy. Increase by 0.6 mg at weekly intervals until the target dose of 3 mg subcutaneously once daily is attained. In a small trial, pediatric patients (n = 21, age 12 to 17 years) at Tanner stage 2 to 5 with obesity were randomized (2:1) to receive 5 weeks of treatment with liraglutide (n = 14) or placebo (n = 7). Pharmacodynamic endpoints such as BMI, body weight, fasting glucose, and A1C were improved, but this study had a short duration of treatment and a small number of participants.[62544]

    Children 7 to 11 years†

    0.3 mg subcutaneously once daily for 1 week to reduce gastrointestinal (GI) symptoms associated with initial therapy. Increase the daily dose by 0.3 mg at weekly intervals until 1.2 mg is reached and then follow with 0.6 mg weekly increments to a maximum dose of 3 mg. In a small trial, pediatric patients (n = 24, age 7 to 11 years) at Tanner stage 1 with obesity were randomized (2:1) to receive 7 to 13 weeks of treatment with liraglutide (n = 16) or placebo (n = 8). A significant decrease in BMI Z score from baseline to end of treatment (estimated treatment difference: -0.28; p = 0.0062) was reported. Body weight was not significantly decreased and may be due to the short duration of treatment.[64813]

    Therapeutic Drug Monitoring

    • Individualize glycemic goals based on a risk-benefit assessment.
    • Use higher goals in patients with persistent hypoglycemia.
    • Monitor post-prandial glucose concentrations if there is any inconsistency between pre-prandial glucose and A1C concentrations and to help assess basal-bolus regimens.[64926]

     

    Blood glucose goals for adults with type 1 or type 2 diabetes [64926]:

    • Pre-prandial = 80 to 130 mg/dL
    • Peak post-prandial = less than 180 mg/dL

     

    A1C goals for adults with type 1 or type 2 diabetes [64926]:

    • Assess A1C at least 2 times a year in patients who are meeting treatment goals (and who have stable glycemic control). Perform A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals.
    • In general, an A1C target is less than 7% in nonpregnant adults.[50321][64926]
      • A more stringent goal of less than 6.5% may be appropriate for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects.[60608]
      • Less stringent goals (e.g., A1C less than 8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular/macrovascular complications, or extensive comorbid conditions.[64926]

     

    A1C goals for children and adolescents with type 2 diabetes [64926]

    • Assess A1C every 3 months in most patients or more frequently as clinically indicated.
    • In general, the A1C target is less than 7% when treatment is with oral agents alone. A lower goal of less than 6.5% is reasonable if it can be achieved without excessive hypoglycemia or adverse effects of treatment. A less stringent A1C goal of less than 7.5% may be appropriate for patients with an increased risk of hypoglycemia.

    Maximum Dosage Limits

    • Adults <p>1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.</p>
    • Geriatric <p>1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; 3 mg/day subcutaneously for the treatment of obesity.</p>
    • Adolescents <p>1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; safety and efficacy for the treatment of obesity have not been established.</p>
    • Children <p><em>10 to 12 years old:</em> 1.8 mg/day subcutaneously for the treatment of type 2 diabetes mellitus; safety and efficacy for the treatment of obesity have not been established.</p> <p><em>1 to 9 years old:</em> Safety and efficacy have not been established.</p>
    • Infants <p>Not indicated.</p>

    Patients with Hepatic Impairment Dosing

    No dosage adjustment is required.  

    Patients with Renal Impairment Dosing

    No dosage adjustment is required.

    † Off-label indication
    Revision Date: 01/29/2020, 02:27:38 PM

    References

    22300 - Levemir (insulin detemir [rDNA origin]) injection package insert. Princeton, NJ: Novo Nordisk, Inc; 2019 Dec.38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.50321 - Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-2701.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.60608 - Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. Endocrine Pract 2019;25:69-100.61921 - Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.62544 - Danne T, Biester T, Kapitzke K, et al. Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years. J Pediatr. 2017;181:146-153. Epub 2016 Dec 13.62881 - Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22 Suppl 3:1-203.64813 - Mastrandrea LD, Witten L, Carlsson Petri KC, Hale PM, Hedman HK, Riesenberg RA. Liraglutide effects in a paediatric (7-11 y) population with obesity: a randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Pediatric Obesity. 2019;14:e12495.64926 - American Diabetes Association. Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl 1):S1.

    How Supplied

    Liraglutide Solution for injection

    Victoza 18mg/3mL Pre-Filled Pen Solution for Injection (00169-4060) (Novo Nordisk Inc.) nullVictoza 18mg/3mL Pre-Filled Pen Solution for Injection package photo

    Liraglutide Solution for injection [Weight Management]

    Saxenda 18mg/3mL Pre-Filled Pen Solution for Injection (00169-2800) (Novo Nordisk Inc.) nullSaxenda 18mg/3mL Pre-Filled Pen Solution for Injection package photo

    Description/Classification

    Description

    Liraglutide is a synthetic glucagon-like peptide-1 receptor agonist (GLP-1 RA) and belongs to a class of antidiabetic agents called incretin mimetics. Incretins are endogenous compounds that improve glycemic control once released into the circulation via the gut. Liraglutide subcutaneous injection (Victoza) is used as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years and older and adults with type 2 diabetes mellitus (DM). It is also used to reduce the risk of non-fatal cardiovascular (CV) events and CV mortality in type 2 DM adult patients who also have CV disease.[38653][61921] Liraglutide monotherapy reduces A1C by an average of 0.84% to 1.14%. The addition of liraglutide as add-on therapy to other antidiabetic agents has resulted in statistically significant improvements in A1C and fasting plasma glucose. As with other agents in this class, liraglutide has a boxed warning regarding rodent C-cell tumor findings and the uncertain relevance to humans.[38653][38654][38655][38656][38657][38658][40249] Metformin is first-line in the treatment of type 2 DM. Additional therapy with a GLP-1 RA that has proven cardiovascular (CV) benefit should be considered in patients with indicators of high-risk or established CV disease, independent of baseline A1C or individualized A1C target. Among the GLP-1 RAs, evidence of CV benefit is strongest for liraglutide, favorable for semaglutide, and less certain for exenatide; there is no evidence of CV benefit with lixisenatide. GLP-1 RAs have high glucose-lowering efficacy, but with variation within the drug class. Evidence suggests that the effect may be greatest for semaglutide once weekly, followed by dulaglutide and liraglutide, closely followed by exenatide once weekly, and then exenatide twice daily and lixisenatide. GLP-1 RAs improve CV outcomes, as well as secondary outcomes such as heart failure (HF) and progression of renal disease, in patients with established CV disease or chronic kidney disease (CKD); this makes them an alternative treatment option in patients with indicators of high-risk or established heart failure HF or CKD who cannot tolerate a sodium-glucose cotransporter 2 inhibitor (SGLT2i). For patients requiring an injectable medication, GLP-1 RAs are preferred to insulin due to similar or even better efficacy in A1C reduction, lower risk of hypoglycemia, and reductions in body weight.[50321][64933][64926][60608] Low-dose liraglutide (Saxenda) is used as an adjunct to lifestyle modifications for weight loss and chronic weight management in obese adults or overweight adults with at least 1 weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).[58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be offered as chronic treatment along with lifestyle modifications to patients with obesity when the potential benefits outweigh the risks. Short-term pharmacotherapy has not been shown to produce longer-term health benefits and cannot be generally recommended. A generalized hierarchy for medication preferences that would apply to all overweight patients cannot currently be scientifically justified. Individualized weight loss pharmacotherapy is recommended, based upon factors such as the specific characteristics of each weight loss medication, the presence of weight-related complications, and the medical history of the patient.[62881]

    Classifications

    • Alimentary Tract and Metabolism
      • Antidiabetic Agents
        • Blood Glucose Lowering Agents, excluding Insulins
          • Incretin mimetics Antidiabetics
      • Antiobesity Agents, Excluding Dietetics
        • Other Antiobesity Agents
    Revision Date: 01/24/2020, 05:56:13 PM

    References

    38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.38654 - Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic control and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268—78.38655 - Nauck MA, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84—90.38656 - Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373:473—81.38657 - Zinman B, Gerich J, Buse J, et al. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care 2009;32:1224—30.38658 - Russell -Jones D, Vaag A, Schmidtz O, et al. Liraglutide vs. insulin glargine and placebo in combination with metformin andsulphonylurea therapy in type 2 diabetes mellitus: a randomised controlled trial (LEAD-5 met + SU). Diabetologia 2009;52:2046-55.40249 - Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010;375:1447-1456.50321 - Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-2701.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.60608 - Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. Endocrine Pract 2019;25:69-100.61921 - Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.62881 - Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22 Suppl 3:1-203.64926 - American Diabetes Association. Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl 1):S1.64933 - Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2019. Epub ahead of print, doi: 10.2337/dci19-0066.

    Administration Information

    General Administration Information

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

    Route-Specific Administration

    Injectable Administration

    • Administer by subcutaneous injection only. Do not administer by intravenous or intramuscular injection.
    • Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually viscous, cloudy, discolored, or if particles are present.
    • Do NOT mix liraglutide with insulin. When using liraglutide (Victoza) concomitantly with insulin, administer as separate injections. The two injections may be injected in the same body region, but the injections should not be adjacent to each other.[38653]
    • Liraglutide (Saxenda) for the treatment of obesity is not recommended in combination with insulin.[58673]
    • Diabetic medication or other medication pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials, if available, or reserve the use of any pen to 1 patient only.[54923][58866]

    Subcutaneous Administration

    • Liraglutide is available as a pre-filled pen.
    • For patients who are self-administering liraglutide, adequate oral, as well as written instructions on the use of the injector pen, should be supplied before they self-administer a dose.
    • Administer once daily at any time of day, independently of meals.
    • Pen needles are not included and must be purchased separately. Make sure the correct pen needles are used.
    • The liraglutide pen must be primed prior to the first use. See the pen user manual for directions.[38653][58673]

     

    Subcutaneous injection:

    • Inject subcutaneously into the thigh, abdomen, or upper arm.
    • Double-check dosage prior to administration.
    • Press down on the center of the dose button to inject until "0-mg" lines up with the pointer. Inject over 6 seconds to ensure the full dose is injected. Keep thumb on the injection button until the needle is removed from the skin.
    • Rotate administration sites with each injection to prevent lipodystrophy.
    • Storage of pens in use: Use a Saxenda or Victoza pen for only 30 days. Throw away a used pen 30 days after it has been in use, even if some medicine is left in the pen. Store pens that are in use at 59 to 86 degrees F (15 to 30 degrees C), or in a refrigerator at 36 to 46 degrees F (2 to 8 degrees C). Protect from heat and light. If exposed to temperatures above 86 degrees F (30 degrees C), throw the pen away. Keep the pen cap on when the pen is not in use. Always remove the needle after each injection. This reduces the risk of contamination, infection, leakage, and inaccurate dosing.[38653][58673]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 08/06/2020, 03:36:05 PM

      References

      38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.54923 - Institute for Safe Medication Practices. Ongoing concern about insulin pen reuse shows hospitals need to consider transitioning away from the pen. ISMP Medication Safety Alert. Retrieved from the World Wide Web June 4, 2013. http://www.ismp.org/newsletters/acutecare/showarticle.asp?id=41.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.58866 - Food and Drug Administration Drug Safety Communication: FDA requires label warnings to prohibit sharing of multi-dose diabetes pen devices among patients. Retrieved February 26, 2015. Available on the World Wide Web at: http://fda.gov/Drugs/DrugSafety/ucm43571.htm.

      Adverse Reactions

      Mild

      • abdominal pain
      • anorexia
      • anxiety
      • asthenia
      • back pain
      • diarrhea
      • dizziness
      • dysgeusia
      • dyspepsia
      • eructation
      • fatigue
      • flatulence
      • gastroesophageal reflux
      • headache
      • infection
      • influenza
      • injection site reaction
      • insomnia
      • malaise
      • nausea
      • pruritus
      • rash
      • sinusitis
      • urticaria
      • vomiting
      • xerostomia

      Moderate

      • antibody formation
      • bundle-branch block
      • cholelithiasis
      • cholestasis
      • constipation
      • dyspnea
      • edema
      • elevated hepatic enzymes
      • erythema
      • gastritis
      • hepatitis
      • hyperamylasemia
      • hyperbilirubinemia
      • hypertension
      • hypoglycemia
      • hypotension
      • orthostatic hypotension
      • palpitations
      • sinus tachycardia

      Severe

      • anaphylactoid reactions
      • angioedema
      • AV block
      • bronchospasm
      • cholecystitis
      • new primary malignancy
      • pancreatitis
      • renal failure (unspecified)
      • suicidal ideation

      Hypoglycemia in adult patients that were able to self-treat for type 2 diabetes occurred in 9.7% of patients taking liraglutide monotherapy, in 7.5% of patients taking liraglutide plus glimepiride, and in 27.4% of patients taking liraglutide in combination with glimepiride and metformin. Hypoglycemia requiring the assistance of another person for treatment occurred in 11 patients treated with liraglutide and in 2 comparator-treated patients. Of these 11 patients treated with liraglutide, 6 patients were concomitantly using metformin and a sulfonylurea, 1 was concomitantly using a sulfonylurea, 2 were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL), and 2 were using liraglutide as monotherapy (1 of these patients was undergoing an intravenous glucose tolerance test, and the other was receiving insulin as treatment during a hospital stay). For these 2 patients on liraglutide monotherapy, the insulin treatment was the likely explanation for the hypoglycemia. In the 26-week open-label trial comparing liraglutide to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose less than 56 mg/dL was comparable among the treatment groups (approximately 5%).[38653] Hypoglycemia (blood glucose less than 54 mg/dL) was reported in 24.2% of pediatric patients with type 2 diabetes receiving liraglutide vs. 10.3% of patients receiving placebo during a 52 week trial period. There were no severe hypoglycemic episodes (defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) with liraglutide and 1 severe episode in the placebo group in an insulin-treated patient.[38653] [64323] Hypoglycemia was reported in 23% of patients with type 2 diabetes receiving liraglutide for weight management (Saxenda). In a clinical trial involving patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 liraglutide-treated patients and in none of the 212 placebo-treated patients. Each of these 3 liraglutide-treated patients was also taking a sulfonylurea. In the same trial, among patients taking a sulfonylurea, documented symptomatic hypoglycemia (defined as documented symptoms of hypoglycemia in combination with a plasma glucose 70 mg/dL or less) occurred in 48 (43.6%) of 110 liraglutide-treated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia occurred in 49 (15.7%) of 312 liraglutide-treated patients and 12 (7.6%) of 157 placebo-treated patients. In clinical trials involving patients without type 2 diabetes receiving liraglutide for weight management (Saxenda), there was no systematic capturing or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2,962 liraglutide-treated patients and 19 (1.1%) of 1,729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits of 70 mg/dL or less, irrespective of hypoglycemic symptoms, were reported as hypoglycemia in 92 (3.1%) liraglutide-treated patients and 13 (0.8%) placebo-treated patients. The presence of anti-liraglutide antibodies may be associated with a higher incidence of hypoglycemia. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. When initiating liraglutide in patients taking insulin secretagogues (such as sulfonylureas), consider reducing the dose of the insulin secretagogue to reduce the risk for hypoglycemia, and monitor blood glucose. In order to decrease the risk of hypoglycemia, the manufacturer of Saxenda (liraglutide for weight management) also recommends reducing the dose of the insulin secretagogue (for example, by one-half) to reduce the risk for hypoglycemia. Conversely, if discontinuing liraglutide in patients with type 2 diabetes, monitor for an increase in blood glucose.[58673]

      In the controlled clinical trials of at least 26 weeks duration in patients with diabetes, gastrointestinal events were the most common category of adverse events among liraglutide-treated antibody-negative patients (43%, 18%, and 19% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). The most common reasons for withdrawal in the patients treated with liraglutide for diabetes were nausea (2.8%) and vomiting (1.5%); the comparator group had no patients withdraw due to nausea and 0.1% due to vomiting. Withdrawal due to gastrointestinal adverse events mostly occurred during the first 2 to 3 months of treatment for diabetes; the percentage of patients who reported nausea declined over time. In the 52-week monotherapy trial for diabetes, nausea and vomiting occurred at a high rate overall in the liraglutide treated adult patients (28.4% and 10.9%, respectively) compared to glimepiride-treated patients (8.5% and 3.6%, respectively); nausea and vomiting were among the most common adverse events associated with liraglutide.[38656] In a 52-week trial for diabetes, nausea (28.8% vs. 13.2% placebo), vomiting (25.8% vs. 8.8% placebo), and diarrhea (22.7% vs. 16.2% placebo) were the most commonly reported adverse events in pediatric patients ages 10 to 17 treated with liraglutide.[64323] Gastrointestinal events from liraglutide in patients with diabetes were dose-dependent and also included diarrhea (17.1% vs. 8.9% glimepiride) and constipation (9.9% vs. 4.8% glimepiride).[38656] In 26-week combination therapy trials (i.e., liraglutide used with metformin, glimepiride, metformin plus rosiglitazone, and metformin plus glimepiride) in patients with diabetes, nausea occurred in 7.5% to 34.6% of patients and vomiting occurred in 6.6% to 12.4% of patients. Other gastrointestinal adverse events that were seen during the 26-week combination therapy trials in patients with diabetes were dyspepsia, anorexia, and decreased appetite.[38655] [38657] [38658] [38654] In a 26-week trial comparing liraglutide and sitagliptin in patients with diabetes, both in combination with metformin, the following gastrointestinal events were reported at a higher incidence with liraglutide compared to sitagliptin: nausea (23.9% vs. 4.6%), diarrhea (9.3% vs. 4.6%), and vomiting (8.7% vs. 4.1%).[38653] In the clinical trials of liraglutide for weight management, approximately 68% of patients receiving liraglutide and 39% of patients receiving placebo reported gastrointestinal disorders; the most frequently reported was nausea (39% vs. 14% placebo). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among patients receiving liraglutide for weight management included diarrhea (20.9%), constipation (19.4%), vomiting (15.7%), dyspepsia (9.6%), xerostomia (2.3%), gastritis, gastroesophageal reflux disease (4.7%), flatulence (4%), eructation (4.5%), abdominal pain (5.4%), upper abdominal pain (5.1%), abdominal distension (4.5%), and anorexia (10%). In patients receiving liraglutide for weight management, most gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy; 6.2% of patients receiving liraglutide discontinued treatment as a result of gastrointestinal adverse reactions compared to 0.8% of patients receiving placebo. The most common adverse reactions leading to discontinuation were nausea (2.9%), vomiting (1.7%), and diarrhea (1.4%). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with dehydration, volume depletion, and renal impairment in patients receiving liraglutide for weight management. Dysgeusia was mainly reported within the first 12 weeks of treatment with liraglutide for weight management and was often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea.[58673]

      Hepatic adverse reactions and adverse reactions of the gallbladder have been reported with liraglutide. Elevated hepatic enzymes were reported in patients treated with liraglutide for weight management. Increases in alanine aminotransferase (ALT) 10 times or more the upper limit of normal (ULN) were observed in 5 (0.15%) liraglutide-treated patients (two of whom had ALT more than 20- and 40-times the ULN) compared with 1 (0.05%) placebo-treated patient during the liraglutide clinical trials. Clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases; therefore, the relationship to liraglutide is uncertain. Some increases in ALT and AST were associated with other confounding factors (such as gallstones). In 5 clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (defined as elevations to no more than twice the upper limit of the reference range) occurred in 4% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients; other hepatic function tests were not found to be abnormal. During postmarketing experience with liraglutide elevated hepatic enzymes, hyperbilirubinemia, cholestasis, and hepatitis have been reported. In clinical trials of patients receiving liraglutide for weight management (doses up to 3 mg), 2.2% of patients receiving liraglutide reported adverse events of cholelithiasis versus 0.8% of patients receiving placebo. The incidence of cholecystitis was 0.8% in liraglutide-treated patients versus 0.4% in placebo-treated patients. The majority of liraglutide-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in liraglutide-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. In clinical trials of liraglutide for diabetes management, the incidence of cholelithiasis (0.3%) and cholecystitis (0.2%) was the same in both liraglutide-treated and placebo-treated patients. In the LEADER trial, 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute gallbladder disease event, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy.[38653] [61921] Patients should be informed that substantial or rapid weight loss can increase the risk of cholelithiasis. Cholelithiasis may also occur in the absence of substantial or rapid weight loss. Patients should be instructed to contact their physician if cholelithiasis is suspected for appropriate clinical follow-up. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.[38653] [58673]

      In clinical trials in patients receiving liraglutide for diabetes, there were 13 cases (9 acute and 4 chronic) of pancreatitis in patients treated with liraglutide and 1 case among comparator-treated patients (2.7 vs. 0.5 cases per 1,000 patient-years). In one case of a patient treated with liraglutide for diabetes, the patient experienced pancreatitis with necrosis and eventually died; clinical causality could not be established. In some of these patients other risk factors for pancreatitis were present, such as cholelithiasis or alcoholism. Conclusive data to establish a risk of pancreatitis with liraglutide is lacking. Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with liraglutide for diabetes.[38653] In clinical trials of patients receiving liraglutide for weight management, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3,291 patients compared to 2 (0.1%) of 1,843 patients receiving placebo. In addition, there were 2 cases of acute pancreatitis in patients receiving liraglutide who prematurely withdrew from these trials, occurring 74 and 124 days after the last dose, 1 case in a liraglutide-treated patient during an off-treatment follow-up period within 2 weeks of discontinuing liraglutide, and 1 case that occurred in a patient who completed treatment and was off-treatment for 106 days. In addition, in patients receiving liraglutide for weight management, 2.1% had a lipase value at anytime during treatment of 3 times or more the upper limit of normal (ULN) compared with 1% of placebo-treated patients. Hyperamylasemia (defined as an amylase value at anytime in the trial of 3 times or more the ULN) was reported in 0.1% of patients receiving liraglutide versus 0.1% of patients receiving placebo. In a placebo-controlled trial in renal impairment patients receiving liraglutide for diabetes management, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among liraglutide-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the ULN compared with 4.5% of placebo-treated patients, and 1% of liraglutide-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the ULN versus 0.7% of placebo-treated patients.[61921] The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis.[38653] [58673] The FDA has evaluated 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.[53573] The FDA and the EMA have stated that after review, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Pancreatitis will continue to be a risk associated with incretin mimetics until more data are available; recommendations will be communicated once the review is complete.[56778] Patients should be instructed to seek prompt medical attention if they experience unexplained persistent severe abdominal pain, which may or may not be accompanied by vomiting. If pancreatitis is suspected, liraglutide should be discontinued. If pancreatitis is confirmed, liraglutide should not be restarted.[38653]

      In patients receiving liraglutide for weight management, mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed during routine clinical monitoring. More patients treated with liraglutide, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). In 6% of patients receiving liraglutide, at least one resting heart rate > 100 bpm was recorded compared with 4% of placebo-treated patients; this occurred at two consecutive study visits for 0.9% of liraglutide-treated patients and 0.3% of patients receiving placebo. Sinus tachycardia was reported in 0.6% of patients receiving liraglutide and in 0.1% of patients receiving placebo. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo; the clinical significance is unclear, especially for patients with cardiac and cerebrovascular disease as a result of limited exposure in these patients in clinical trials. In clinical trials, 11 (0.3%) of 3384 liraglutide-treated patients compared with none of the 1941 placebo-treated patients had a cardiac conduction disorder, reported as first degree atrioventricular block (AV block), right bundle-branch block, or left bundle-branch block. Adverse reactions related to hypotension (that is, reports of hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with liraglutide (1.1%) compared with placebo (0.5%). Systolic blood pressure decreases to < 80 mmHg were observed in 4 (0.1%) of liraglutide-treated patients compared with no placebo-treated patients. One patient receiving liraglutide had hypotension associated with gastrointestinal adverse reactions and renal failure. In addition, hypotension and palpitations have been associated with anaphylactic reactions in patients receiving liraglutide. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients receiving liraglutide should inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate, discontinue treatment with liraglutide.[58673]

      In the controlled clinical trials of at least 26 weeks duration in patients with diabetes, approximately 50% to 70% of liraglutide-treated patients were tested for antibody formation at the end of treatment; low titers of antibodies were detected in 8.6% of these patients. This percentage may be an underestimation due to non-standardized sampling. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1,505 patients receiving liraglutide for weight loss. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1,505 patients receiving liraglutide for weight loss.[58673] In patients receiving liraglutide for diabetes management, cross-reacting anti-liraglutide antibodies to native glucagon-like peptide (GLP-1) occurred in 6.9% of patients in the double-blind 52 week monotherapy trial and in 4.8% of patients in the double-blind 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1. Therefore the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% (double-blind 52 week monotherapy trial) and 1% (double-blind 26-week add-on combination therapy trials) of patients receiving liraglutide for diabetes management. In pediatric patients 10 to 17 years, anti-liraglutide antibodies were detected in 1 (1.5%) liraglutide-treated patient at week 26 and 5 (8.5%) liraglutide-treated patients at week 53. None of the 5 patients had antibodies cross reactive to native GLP-1 or had neutralizing antibodies. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment.[38653] Infection was the most common adverse event in patients with diabetes who developed anti-liraglutide antibodies (40% compared to 36%, 34%, and 35% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). The specific infections which occurred with greater frequency among liraglutide-treated antibody-positive patients were primarily nonserious upper respiratory tract infections (11% antibody-positive patients and among 7%, 7%, and 5% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively). Among liraglutide-treated antibody-negative patients with diabetes, the most common category of adverse events was that of gastrointestinal (GI) events, which occurred in 43%, 18%, and 19% of antibody-negative liraglutide-treated, placebo-treated, and active-control-treated patients, respectively. When comparing mean A1C of all antibody-positive and antibody-negative patients, the results indicate that antibody formation was not associated with reduced efficacy of liraglutide; however, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in A1C with liraglutide treatment. In the LEADER trial, anti-liraglutide antibodies were detected in 11 out of the 1,247 (0.9%) liraglutide-treated patients with antibody measurements. Of the 11 liraglutide-treated patients who developed anti-liraglutide antibodies, none were observed to develop neutralizing antibodies to liraglutide, and 5 patients (0.4%) developed cross-reacting antibodies against native GLP-1.[38653] [61921] In clinical trials of liraglutide in patients with diabetes, events from an aggregate of adverse events potentially related to immunogenicity (e.g., urticaria, angioedema) occurred among 0.8% of the entire cohort of liraglutide-treated patients and among 0.4% of comparator-treated patients. About one-half of the events in this composite for liraglutide-treated patients were reported as urticaria. It should be noted that patients with anti-liraglutide antibodies were not more likely to develop this type of adverse events compared to patients who did not develop anti-liraglutide antibodies. Postmarketing reports of serious hypersensitivity reactions, including anaphylactoid reactions, rash, pruritus, and angioedema have been reported in patients receiving liraglutide for diabetes.[38653] Urticaria was reported in 0.7% of patients receiving liraglutide for weight loss. Asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, pharyngeal edema, and type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide.[58673]

      In pre-marketing trials of at least 26 weeks duration in patients with diabetes, the incidence of injection site reaction (e.g., injection site rash, erythema) in patients treated with liraglutide was approximately 2%; withdrawal rates due to injection site reactions were less than 0.2% in liraglutide-treated patients.[38653] In patients receiving liraglutide for weight management, injection site erythema (2.5%) and injection site reaction (2.5%—13.9%) were reported. The most common reactions, each reported by 1%—2.5% of liraglutide-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. Injection site reaction was the cause for discontinuation of treatment in 0.6% of  liraglutide-treated patients and 0.5% of placebo-treated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment.[58673]

      In the controlled clinical trials of at least 26 weeks duration in patients with diabetes, infection was the most common adverse event in patients who developed anti-liraglutide antibodies (40% compared to 36%, 34% and 35% of antibody-negative liraglutide-treated, placebo-treated and active-control-treated patients, respectively); the most common infection in these patients was nonserious upper respiratory infections. In the entire cohort of patients receiving liraglutide for weight management, influenza (7.4% vs. 3.6% glimepiride), sinusitis (5.6% vs. 6.0% glimepiride), and nasopharyngitis (5.2% vs. 5.2% glimepiride) were reported. Urinary tract infection was also reported in 4.3—6% of patients taking liraglutide.[38653][58673] In patients receiving liraglutide for weight management, gastroenteritis (4.7%) and viral gastroenteritis (2.8%) were reported.[58673]

      Other notable adverse events that occurred in patients with diabetes receiving liraglutide were headache (9.1% vs. 9.3% glimepiride), dizziness (5.8% vs. 5.2% glimepiride), back pain (5% vs. 4.4% glimepiride), and hypertension (3% vs. 6% glimepiride).[38653] In patients receiving liraglutide for weight management, asthenia (2.1%), fatigue (7.5%), malaise, and dizziness (6.0%) were mainly reported within the first 12 weeks of treatment and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Headache was reported in 13.6% of patients receiving liraglutide for weight management.[58673]

      New primary malignancy has been reported in patients receiving liraglutide; however, causality has not been established.[38653] [58673] In clinical trials of patients receiving liraglutide for diabetes mellitus, there were 7 reported cases of papillary thyroid carcinoma in liraglutide-treated patients; there was 1 case in patients treated with placebo (1.5 vs 0.5 cases per 1,000 patient-years). Most were less than 1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol specified screening with serum calcitonin or thyroid ultrasound. In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for new primary malignancy was 10.9 for liraglutide, 6.3 for placebo, and 7.2 for active comparator. No particular cancer cell type predominated after excluding papillary thyroid carcinoma events. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication; 6 events among liraglutide-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo, and 1 event with active comparator (colon). Causality has not been established.[38653] In patients receiving liraglutide for weight management, papillary thyroid carcinoma confirmed by adjudication was reported in 7 (0.2%) of 3,291 patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and four patients were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Calcitonin, a biological marker of medullary thyroid carcinoma (MTC), was measured throughout the clinical development program. More patients treated with liraglutide in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin 2 times or greater the upper limit of normal (ULN) at the end of the trial was 1.2% in liraglutide-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of liraglutide-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to more than 50 ng/L at the end of the trial. In clinical trials of patients receiving liraglutide for weight management, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 17 (0.5%) of 3,291 patients compared with 4 (0.2%) of 1,843 placebo-treated patients. Two positively adjudicated cases of malignant colorectal carcinoma were reported in liraglutide-treated patients (0.1%) and none in placebo-treated patients. In clinical trials of patients receiving liraglutide for weight management, breast cancer confirmed by adjudication was reported in 14 (0.6%) of 2379 women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (11 liraglutide- and 2 placebo-treated women) and ductal carcinoma in situ (3 liraglutide- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to liraglutide. In addition, there are insufficient data to determine whether liraglutide has an effect on pre-existing breast neoplasia.[58673]

      Acute renal failure (unspecified) and worsening of chronic renal failure, sometimes leading to required hemodialysis, have been reported in patients taking liraglutide. Some of these events were reported in patients without known underlying renal disease; a majority if the events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In addition, some of the affected patients were receiving one or more medications known to affect renal function or hydration status. Renal function was reversible in many of the cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide.[38653][58673]

      In clinical trials of liraglutide for weight management, 0.3% of patients receiving liraglutide reported suicidal ideation compared to 0.1% of the patients receiving placebo; one of the liraglutide-treated patients attempted suicide. Monitor patients receiving liraglutide for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue liraglutide in patients who develop suicidal thoughts or behaviors. Other psychiatric adverse reactions reported in clinical trials of patients receiving liraglutide (Saxenda) for the treatment of obesity included insomnia (2.4%) and anxiety (2%).[58673]

      Revision Date: 06/20/2019, 01:36:23 PM

      References

      38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.38654 - Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic control and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268—78.38655 - Nauck MA, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84—90.38656 - Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373:473—81.38657 - Zinman B, Gerich J, Buse J, et al. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care 2009;32:1224—30.38658 - Russell -Jones D, Vaag A, Schmidtz O, et al. Liraglutide vs. insulin glargine and placebo in combination with metformin andsulphonylurea therapy in type 2 diabetes mellitus: a randomised controlled trial (LEAD-5 met + SU). Diabetologia 2009;52:2046-55.53573 - Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Retrieved Mar. 14, 2013. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm.56778 - Egan AG, Blind E, Dunder K, , et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370:794—7.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.61921 - Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.64323 - Tamborlane WV, Barrientos-Perez M, Fainberg U, et al. Liraglutide in children and adolescents with type 2 diabetes. New England Journal of Medicine 2019;10.1056/NEJMoa1903822

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • history of angioedema
      • medullary thyroid carcinoma (MTC)
      • multiple endocrine neoplasia syndrome type 2 (MEN 2)
      • pregnancy
      • serious hypersensitivity reactions or anaphylaxis
      • thyroid C-cell tumors
      • alcoholism
      • breast-feeding
      • burns
      • cardiac arrhythmias
      • children
      • cholelithiasis
      • contraception requirements
      • depression
      • diabetic ketoacidosis
      • diarrhea
      • fever
      • gallbladder disease
      • gastroparesis
      • geriatric
      • heart failure
      • hepatic disease
      • hypoglycemia
      • hypovolemia
      • infants
      • infection
      • pancreatitis
      • renal disease
      • renal failure
      • renal impairment
      • schizophrenia
      • suicidal ideation
      • surgery
      • tachycardia
      • thyroid cancer
      • thyroid disease
      • trauma
      • type 1 diabetes mellitus
      • vomiting

      Liraglutide is contraindicated in patients with a history of a serious hypersensitivity reaction to liraglutide. There is a risk of serious hypersensitivity reactions or anaphylaxis with liraglutide use. Serious hypersensitivity reactions have been reported during postmarketing use with liraglutide, such as anaphylaxis or angioedema. Use caution in patients with a history of angioedema or anaphylaxis to other GLP-1 receptor agonists because it is unknown whether such patients will be predisposed to serious reactions with liraglutide. If a serious hypersensitivity reaction is suspected, discontinue liraglutide and consider other potential causes for the event, then initiate alternative therapy.[38653] [58673]

      Liraglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Liraglutide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Cases of MTC in patients treated with liraglutide for diabetes have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. In clinical trials, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and were diagnosed after thyroidectomy, which was prompted by finding on protocol-specified screening with serum calcitonin or thyroid ultrasound. Patients should be counseled on the potential risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with liraglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.[38653]

      Liraglutide is not a substitute for insulin in patients who require insulin. Liraglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Liraglutide has not been evaluated for use in combination with prandial insulin.[38653]

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

      Liraglutide may slow gastric emptying. Liraglutide has not been studied in patients with gastroparesis, and should be used cautiously in this population. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea.[38653]

      Hypoglycemia should be monitored for by the patient and clinician when liraglutide treatment is initiated and continued for type 2 diabetes mellitus (DM). In clinical trials, hypoglycemia was increased when liraglutide was used in combination with a sulfonylurea for type 2 DM. Although specific dose recommendations are not available, the clinician should consider a dose reduction of the sulfonylurea when used in combination with liraglutide.[38653] In addition, when liraglutide is used in combination with insulin detemir, the dose of insulin should be evaluated; in patients at increased risk of hypoglycemia consider reducing the dose of insulin at initiation of liraglutide, followed by careful titration.[22300] In pediatric patients 10 years of age and older, the risk of hypoglycemia is higher with liraglutide treatment regardless of concomitant antidiabetic therapies.[38653] 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 mellitus (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.[61491] Liraglutide may have particular benefits when used in patients with type 2 DM who are overweight or obese. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be considered as an adjunct to lifestyle therapy in all patients with type 2 DM as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. During controlled trial evaluation of liraglutide 3 mg as an adjunct to lifestyle therapy versus lifestyle therapy alone for diabetes prevention, a greater weight loss and more profound reductions in incident diabetes occurred with liraglutide plus lifestyle therapy than lifestyle therapy alone.[62881]

      Use caution when initiating or increasing doses of liraglutide for type 2 diabetes mellitus (DM) or weight loss in patients with renal impairment. There are limited data available regarding the use of liraglutide in patients with end-stage renal disease (renal failure). There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which sometimes has required hemodialysis in patients treated with liraglutide; in many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents, including liraglutide.[38653] [58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide for weight loss can be used in obese patients with mild to moderate renal impairment (i.e., CrCl 30 to 79 mL/minute). Liraglutide can be considered in selected obese patients with end-stage renal failure with a high level of caution. The AACE/ACE Obesity Guidelines recommend discontinuation of liraglutide in obese patients with severe renal disease or impairment (CrCl less than 30 mL/minute) who develop volume depletion (hypovolemia), such as may occur from nausea, vomiting, or diarrhea. Liraglutide is considered a preferred weight loss medication in patients with a history of or at risk for nephrolithiasis.[62881]

      Use liraglutide with caution in patients with risk factors for pancreatitis. After initiation and dose increases, patients should be closely observed for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue liraglutide; if pancreatitis is confirmed do not resume liraglutide.[38653] [58673] Liraglutide has been studied in a limited number of patients with a history of pancreatitis; it is unknown if these patients are at increased risk for the development of pancreatitis while using liraglutide. There have been reports of acute and chronic pancreatitis in patients taking liraglutide during premarketing clinical trials. In some of these patients, other risk factors for pancreatitis were present, such as gallstones or alcoholism. Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has also been reported postmarketing in patients treated with liraglutide. Liraglutide has been studied in a limited number of patients with a history of pancreatitis; it is unknown if these patients are at increased risk for the development of pancreatitis while using liraglutide. The FDA and the EMA have stated that after review of published and unpublished reports, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Continue to consider precautions related to pancreatic risk until more data are available.[53573] [56778] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, obese patients receiving liraglutide for weight loss should be monitored for the development of pancreatitis. Liraglutide should be avoided in patients with prior or current pancreatitis; otherwise, there are insufficient data to recommend withholding liraglutide for weight loss due to concerns of pancreatitis. According to the AACE/ACE Obesity Guidelines, either liraglutide or orlistat may be considered in obese patients with a substance abuse disorder, including alcoholism, who require treatment with a weight loss medication; many other agents have abuse potential.[62881]

      Use liraglutide with caution in patients with known gallbladder disease or a history of cholelithiasis (gallstones).[38653] [58673] In the LEADER trial, 3.1% of liraglutide-treated patients versus 1.9% of placebo-treated patients reported an acute gallbladder disease events, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy.[61921] In patients for whom cholelithiasis is suspected, consider evaluation for an acute gallbladder disease event and perform gallbladder studies and appropriate clinical follow-up.[38653] [58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, close monitoring for cholelithiasis is recommended in patients undergoing weight loss therapy, regardless of modality. In high-risk patients, liraglutide should be used with caution. Effective preventative measures for obese patients at risk for cholelithiasis include a slower rate of weight loss, increasing/including some dietary fat in the diet (assuming the patient has been on a very low-calorie diet containing little or no fat), or administration of ursodeoxycholic acid.[62881]

      There are limited data available on the use of liraglutide for type 2 diabetes mellitus (DM) or for weight loss in patients with hepatic disease. Liraglutide should be used with caution in patients with hepatic disease; however, no dosage adjustment is recommended.[38653] [58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all weight loss medications, including liraglutide, should be used cautiously in obese patients with hepatic impairment and should be avoided in patients with severe hepatic impairment (i.e., Child-Pugh score greater than 9).[62881]

      No particular cautions are recommended by the manufacturer when using liraglutide for the treatment of type 2 diabetes mellitus (DM) in patients with heart disease; liraglutide is indicated to reduce the risk of major adverse cardiovascular events (MACE), such as reduced risk for cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke in adults with type 2 DM and established cardiovascular disease.[38653] In a clinical trial evaluating cardiovascular outcomes with liraglutide in patients with type 2 DM, the primary endpoint of MI, stroke, or cardiovascular death was significantly reduced in the liraglutide group (13%) compared to the placebo group (14.9%) (HR 0.87; 95% CI 0.78 to 0.97; p < 0.001 for noninferiority; p = 0.01 for superiority).[38653] Similar data regarding MACE for obese patients with cardiac disease using liraglutide for weight loss are not available. Sinus tachycardia was observed during clinical studies. Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were seen with routine clinical monitoring in liraglutide-treated patients vs. placebo in clinical trials for weight loss. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. Tachycardia was reported as an adverse reaction in 0.6% of liraglutide-treated patients and in 0.1% of placebo-treated patients. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during liraglutide treatment for weight loss. For patients who experience a sustained increase in resting heart rate while taking liraglutide for weight loss, the drug should be discontinued.[58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide is a preferred weight loss medication in obese patients with existing hypertension and may be considered as an alternative agent in patients with established coronary artery disease (CAD) with appropriate monitoring of heart rate. Liraglutide is not a preferred weight loss medication in patients with a history or risk of cardiac arrhythmias but is reasonable to use with caution if weight loss goals are met, with careful monitoring of heart rate and rhythm. Data are insufficient regarding the benefits of the use of liraglutide in obese patients with heart failure; the AACE/ACE Obesity Guidelines recommend caution.[62881]

      When liraglutide is used for weight management, administer with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation: monitor patients receiving liraglutide for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in mood or behavior. Discontinue liraglutide in patients who develop suicidal thoughts or behaviors. In clinical trials of liraglutide for weight loss, 0.3% of obese patients receiving liraglutide reported suicidal ideation vs. 0.1% of the patients receiving placebo; one of these liraglutide-treated patients attempted suicide.[58673] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, liraglutide may be considered for patients with obesity and depression; however, monitor all patients undergoing weight loss therapy for mood disorders, depression, and suicidal ideation. Evidence assessing safety and efficacy of weight loss medications in patients with a psychotic disorder (e.g., schizophrenia) is insufficient, and the AACE/ACE Obesity Guidelines recommend caution. Patients receiving an antipsychotic should be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; the AACE/ACE Obesity Guidelines suggest that metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]

      Liraglutide (Saxenda) for the treatment of obesity or weight management is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus.[58673] According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy. The AACE/ACE ObesityGuidelines recommend contraception requirements for women of childbearing potential; those receiving liraglutide for weight reduction should use adequate contraception and discontinue liraglutide if pregnancy occurs.[62881] There are no adequate data or clinical studies of liraglutide (Victoza) use for the treatment of type 2 diabetes mellitus in pregnant women; use in pregnancy only if the potential benefit justifies the potential risk to the fetus.[38653] Because of the toxicities found in animal studies, it may be prudent to avoid liraglutide until data in human pregnancy are available.[38653] Rat studies have noted abnormalities and variations in the kidneys, and irregular skeletal ossification effects when liraglutide was given at or above 0.8 times the human systemic exposures, based on the maximum recommended human dose (MRHD) of 1.8 mg/day (determined from AUC). Reduced growth and increased total major abnormalities occurred in rabbits at systemic exposures below human exposure at the MRHD (determined from AUC).[38653] 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 mellitus or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.[64926] [62358]

      Liraglutide excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure to liraglutide, and the risk of an untreated or inadequately treated condition.[38653] [58673] In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations; the human relevance of thyroid C-cell tumors observed in mice and rats is unknown.[38653] [58673] If liraglutide is discontinued in a lactating woman with type 2 diabetes mellitus (DM) 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.[46303] 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.[31407] [31408] [31409] Tolbutamide is regarded as usually compatible with breast-feeding.[27500] Although other sulfonylureas have not been evaluated, 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.[31568] 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.[46104] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of liraglutide for weight reduction is not recommended in breast-feeding women.[62881]

      Liraglutide is approved for use in pediatric patients 10 years and older for type 2 diabetes mellitus; safety and efficacy have not been established in pediatric patients (children, infants) less than 10 years of age.[38653] The safe and effective use of liraglutide for the treatment of obesity has not been established in pediatric patients.[58673] Limited off-label use in pediatric patients 12 years and older has occurred in the context of clinical trials for weight loss.[62544] In pediatric patients 12 years and older, pharmacotherapy is usually reserved for patients with a BMI at the 95th percentile or more or meeting the adult BMI recommendations for use. Reserve medication therapy for overweight children (BMI 85th to 94th percentile) in those with significant, severe comorbidities who have not responded to lifestyle modification. Guidelines recommend the use of those medications with established benefit to risk ratios in this population; growth and weight should be routinely monitored.[58571] [63035]

      Liraglutide has been studied in patients 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric patients versus younger adult patients when the drug is used for type 2 diabetes mellitus (DM) or weight reduction.[38653] [58673] In general, however, geriatric patients with diabetes mellitus 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.[64926] 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.[60742] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, there are limited data on the use of liraglutide for weight reduction in the elderly and extra caution is advisable in this population. Geriatric patients selected for weight loss therapy should have structured lifestyle interventions including reduced calorie meal plans and exercise, clear health-related goals including blood pressure reduction, diabetes prevention in high-risk patients with pre-diabetes, and improvements in osteoarthritis, mobility, and physical functioning. Overweight or obese elderly patients being considered for a weight loss medication should be evaluated for osteopenia and sarcopenia.[62881]

      Revision Date: 01/16/2020, 03:06:38 PM

      References

      22300 - Levemir (insulin detemir [rDNA origin]) injection package insert. Princeton, NJ: Novo Nordisk, Inc; 2019 Dec.27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.31407 - Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.31408 - Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.31409 - Briggs GG, Ambrose PJ, Nageotte MP, et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol 2005;105:1437-41.31568 - Feig DS, Donat DJ, Briggs GG, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851-5.38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.46104 - Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Physician 2001; 64:119-126.46303 - Everett J. Use of oral antidiabetic agents during breastfeeding. J Hum Lact 1997;13:319-21.53573 - Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Retrieved Mar. 14, 2013. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm.56778 - Egan AG, Blind E, Dunder K, , et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370:794—7.58571 - Styne DM, Arslanian SA, Connor EL, et al. Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102:709-757.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.60742 - Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.61491 - Xultophy (insulin degludec; liraglutide) package insert. Plainsboro, NJ: Novo Nordisk, Inc.; 2019 Nov.61921 - Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.62358 - The American College of Obstetricians and Gynecologists (ACOG). Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131:e49-e64.62544 - Danne T, Biester T, Kapitzke K, et al. Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years. J Pediatr. 2017;181:146-153. Epub 2016 Dec 13.62881 - Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22 Suppl 3:1-203.63035 - Greydanus DE, Agana M, Kamboj MK, et al. Pediatric obesity: Current concepts. Dis Mon. 2018;64:98-156. Foreword on p. 97 by Leikin JB.64926 - American Diabetes Association. Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl 1):S1.

      Mechanism of Action

      Liraglutide is an incretin mimetic; specifically, liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous GLP-1 (7—37). GLP-1 (7—37) represents < 20% of total circulating endogenous GLP-1. Liraglutide binds and activates the GLP-1 receptor.[38653] 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.[38658] Liraglutide does not increase insulin secretion or suppress glucagon secretion at normal or low glucose concentrations.

       

      GLP-1 is also a physiological regulator of appetite and caloric intake and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Liraglutide acts to reduce body weight through decreased caloric intake; it does not increase 24-hour energy expenditure.[58673]

      Revision Date: 12/29/2014, 08:02:45 PM

      References

      38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.38658 - Russell -Jones D, Vaag A, Schmidtz O, et al. Liraglutide vs. insulin glargine and placebo in combination with metformin andsulphonylurea therapy in type 2 diabetes mellitus: a randomised controlled trial (LEAD-5 met + SU). Diabetologia 2009;52:2046-55.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.

      Pharmacokinetics

      Liraglutide is given via subcutaneous administration. Liraglutide is more than 98% bound to plasma protein. After a single radioactive liraglutide dose was administered to healthy subjects, the major component in plasma was intact liraglutide for the initial 24 hours. The mean apparent volume of distribution following subcutaneous administration of a 0.6 mg and 3 mg dose of liraglutide is approximately 13 L and 20 to 25 L, respectively. The metabolism of liraglutide mirrors that of large proteins without a specific organ as a major route of elimination. Following a radioactive liraglutide dose, intact liraglutide was not detected in urine or feces; only a minor part of the administered dose was excreted as metabolites in the urine (6%) or feces (5%). The mean apparent clearance following subcutaneous injection of a single dose of liraglutide is approximately 0.9 to 1.4 L/hour. Liraglutide is resistant to dipeptidyl peptidase-4 (DDP-4), the endogenous enzyme responsible for the degradation of GLP-1; this allows for a long half-life (13 hours) and once daily dosing.[38653][58673]

       

      Affected cytochrome P450 (CYP450) enzymes and drug transporters: None

      Route-Specific Pharmacokinetics

      Intravenous Route

      The mean volume of distribution after IV administration is 0.07 L/kg.[38653][58673]

      Subcutaneous Route

      Following subcutaneous injection, liraglutide binds to albumin at the injection site, and after that is released slowly into circulation. Peak plasma concentrations are achieved in roughly 8 to 12 hours; after a 0.6 mg subcutaneous dose, mean peak concentration was 35 ng/mL and total area under the curve (AUC) was 960 ng x hour/mL. Liraglutide Cmax and AUC increased proportionally over the therapeutic dose range of 0.6 to 1.8 mg. At a dose of 1.8 mg, the average steady-state concentration over 24 hours was approximately 128 ng/mL. In obese patients (BMI 30 to 40 kg/m2), the average steady-state concentration over 24 hours was approximately 116 ng/mL. Similar absorption is achieved with subcutaneous administration of liraglutide in the abdomen, thigh, or arm. The absolute bioavailability of liraglutide following subcutaneous injection is approximately 55%.[38653] [58673]

      Special Populations

      Hepatic Impairment

      The pharmacokinetics of a single dose of liraglutide were evaluated in patients with varying degrees of hepatic impairment. Compared to healthy subjects, the AUC in patients with mild (Child-Pugh score 5 to 6) to severe hepatic impairment (Child-Pugh score more than 9) was on average 11%, 14%, and 42% lower, respectively. Liraglutide should be used with caution in patients with hepatic impairment.[38653] [58673]

      Renal Impairment

      The pharmacokinetics of a single dose of liraglutide were evaluated in patients with varying degrees of renal impairment. Compared to healthy subjects, the AUC in patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 31 to 49 mL/minute), severe renal impairment (CrCl less than 30 mL/minute), and end-stage renal disease (ESRD) requiring dialysis was on average 35%, 19%, 29%, and 30% lower, respectively. Liraglutide should be used with caution in patients with renal impairment.[38653] [58673]

      Pediatrics

      A population pharmacokinetic analysis conducted in 72 pediatric patients (10 to 17 years of age) with type 2 diabetes found the pharmacokinetic profile of liraglutide to be consistent with that in adults.[38653]

      Geriatric

      Age had no effect on the pharmacokinetics of liraglutide based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age.[38653]

      Gender Differences

      Based on the results of population pharmacokinetic analyses, females have 25% lower weight-adjusted clearance of liraglutide compared to males. Based on the exposure response data, no dose adjustment is necessary based on gender.[38653]

      Ethnic Differences

      Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian, and Hispanic/Non-Hispanic subjects.[38653]

      Obesity

      Body weight significantly affects the pharmacokinetics of liraglutide based on results of population pharmacokinetic analyses conducted in patients 60 to 234 kg. The exposure of liraglutide decreases with an increase in baseline body weight. At a dose of 1.8 mg, the average steady state concentration over 24 hours was approximately 128 ng/mL. In obese patients (BMI 30 to 40 kg/m2), the average steady state concentration over 24 hours was approximately 116 ng/mL. However, in type 2 diabetes patients with a body weight of 40 to 160 kg, daily doses of 1.2 mg and 1.8 mg provided adequate systemic exposures.[38653][58673]

      Revision Date: 06/20/2019, 04:19:10 PM

      References

      38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.

      Pregnancy/Breast-feeding

      contraception requirements, pregnancy

      Liraglutide (Saxenda) for the treatment of obesity or weight management is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus.[58673] According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy. The AACE/ACE ObesityGuidelines recommend contraception requirements for women of childbearing potential; those receiving liraglutide for weight reduction should use adequate contraception and discontinue liraglutide if pregnancy occurs.[62881] There are no adequate data or clinical studies of liraglutide (Victoza) use for the treatment of type 2 diabetes mellitus in pregnant women; use in pregnancy only if the potential benefit justifies the potential risk to the fetus.[38653] Because of the toxicities found in animal studies, it may be prudent to avoid liraglutide until data in human pregnancy are available.[38653] Rat studies have noted abnormalities and variations in the kidneys, and irregular skeletal ossification effects when liraglutide was given at or above 0.8 times the human systemic exposures, based on the maximum recommended human dose (MRHD) of 1.8 mg/day (determined from AUC). Reduced growth and increased total major abnormalities occurred in rabbits at systemic exposures below human exposure at the MRHD (determined from AUC).[38653] 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 mellitus or gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.[64926] [62358]

      breast-feeding

      Liraglutide excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure to liraglutide, and the risk of an untreated or inadequately treated condition.[38653] [58673] In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations; the human relevance of thyroid C-cell tumors observed in mice and rats is unknown.[38653] [58673] If liraglutide is discontinued in a lactating woman with type 2 diabetes mellitus (DM) 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.[46303] 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.[31407] [31408] [31409] Tolbutamide is regarded as usually compatible with breast-feeding.[27500] Although other sulfonylureas have not been evaluated, 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.[31568] 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.[46104] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of liraglutide for weight reduction is not recommended in breast-feeding women.[62881]

      Revision Date: 01/16/2020, 03:05:20 PM

      References

      27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.31407 - Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.31408 - Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.31409 - Briggs GG, Ambrose PJ, Nageotte MP, et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol 2005;105:1437-41.31568 - Feig DS, Donat DJ, Briggs GG, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851-5.38653 - Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2020 Aug.46104 - Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Physician 2001; 64:119-126.46303 - Everett J. Use of oral antidiabetic agents during breastfeeding. J Hum Lact 1997;13:319-21.58673 - Saxenda (liraglutide) injection package insert. Plainsboro, NJ: Novo Nordisk Inc; 2017 May.62358 - The American College of Obstetricians and Gynecologists (ACOG). Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131:e49-e64.62881 - Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22 Suppl 3:1-203.64926 - American Diabetes Association. Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl 1):S1.

      Interactions

      Level 2 (Major)

      • Chloroquine

      Level 3 (Moderate)

      • Acetaminophen; Aspirin, ASA; Caffeine
      • Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine
      • Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide
      • Aliskiren; Valsartan
      • Aminosalicylate sodium, Aminosalicylic acid
      • Amlodipine; Benazepril
      • Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan
      • Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan
      • Amlodipine; Olmesartan
      • Amlodipine; Telmisartan
      • Amlodipine; Valsartan
      • Amoxicillin; Clarithromycin; Lansoprazole
      • Amoxicillin; Clarithromycin; Omeprazole
      • Amprenavir
      • Androgens
      • Angiotensin II receptor antagonists
      • Angiotensin-converting enzyme inhibitors
      • Aspirin, ASA
      • Aspirin, ASA; Butalbital; Caffeine
      • Aspirin, ASA; Butalbital; Caffeine; Codeine
      • Aspirin, ASA; Caffeine; Dihydrocodeine
      • Aspirin, ASA; Caffeine; Orphenadrine
      • Aspirin, ASA; Carisoprodol
      • Aspirin, ASA; Carisoprodol; Codeine
      • Aspirin, ASA; Citric Acid; Sodium Bicarbonate
      • Aspirin, ASA; Dipyridamole
      • Aspirin, ASA; Omeprazole
      • Aspirin, ASA; Oxycodone
      • Aspirin, ASA; Pravastatin
      • Atazanavir
      • Atazanavir; Cobicistat
      • Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate
      • atypical antipsychotic
      • Azilsartan
      • Azilsartan; Chlorthalidone
      • Benazepril
      • Benazepril; Hydrochlorothiazide, HCTZ
      • Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate
      • Beta-blockers
      • Bismuth Subsalicylate
      • Bismuth Subsalicylate; Metronidazole; Tetracycline
      • Bortezomib
      • Candesartan
      • Candesartan; Hydrochlorothiazide, HCTZ
      • Captopril
      • Captopril; Hydrochlorothiazide, HCTZ
      • Choline Salicylate; Magnesium Salicylate
      • Chromium
      • Clarithromycin
      • Conjugated Estrogens; Medroxyprogesterone
      • Corticosteroids
      • Cyclosporine
      • Daclatasvir
      • Danazol
      • Darunavir
      • Darunavir; Cobicistat
      • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
      • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
      • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
      • Dienogest; Estradiol valerate
      • Disopyramide
      • Drospirenone
      • Drospirenone; Estradiol
      • Drospirenone; Ethinyl Estradiol
      • Drospirenone; Ethinyl Estradiol; Levomefolate
      • Elagolix; Estradiol; Norethindrone acetate
      • Elbasvir; Grazoprevir
      • Enalapril, Enalaprilat
      • Enalapril; Felodipine
      • Enalapril; Hydrochlorothiazide, HCTZ
      • Eprosartan
      • Eprosartan; Hydrochlorothiazide, HCTZ
      • Esterified Estrogens; Methyltestosterone
      • Estradiol Cypionate; Medroxyprogesterone
      • Estradiol; Levonorgestrel
      • Estradiol; Norethindrone
      • Estradiol; Norgestimate
      • Estradiol; Progesterone
      • Estrogens
      • Ethanol
      • Ethinyl Estradiol; Desogestrel
      • Ethinyl Estradiol; Ethynodiol Diacetate
      • Ethinyl Estradiol; Etonogestrel
      • Ethinyl Estradiol; Levonorgestrel
      • Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate
      • Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate
      • Ethinyl Estradiol; Norelgestromin
      • Ethinyl Estradiol; Norethindrone
      • Ethinyl Estradiol; Norethindrone Acetate
      • Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate
      • Ethinyl Estradiol; Norethindrone; Ferrous fumarate
      • Ethinyl Estradiol; Norgestimate
      • Ethinyl Estradiol; Norgestrel
      • Etonogestrel
      • Fibric acid derivatives
      • Fluoxetine
      • Fluoxetine; Olanzapine
      • Fluoxymesterone
      • Fosamprenavir
      • Fosinopril
      • Fosinopril; Hydrochlorothiazide, HCTZ
      • Garlic, Allium sativum
      • Glecaprevir; Pibrentasvir
      • Green Tea
      • Hydrochlorothiazide, HCTZ; Irbesartan
      • Hydrochlorothiazide, HCTZ; Lisinopril
      • Hydrochlorothiazide, HCTZ; Losartan
      • Hydrochlorothiazide, HCTZ; Moexipril
      • Hydrochlorothiazide, HCTZ; Olmesartan
      • Hydrochlorothiazide, HCTZ; Quinapril
      • Hydrochlorothiazide, HCTZ; Telmisartan
      • Hydrochlorothiazide, HCTZ; Valsartan
      • Hydroxychloroquine
      • Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate
      • Indapamide
      • Indinavir
      • Insulin Aspart
      • Insulin Degludec
      • Insulin Degludec; Liraglutide
      • Insulin Detemir
      • Insulin Glargine
      • Insulin Glargine; Lixisenatide
      • Insulin Glulisine
      • Insulin Lispro
      • Insulin Lispro
      • Insulin Lispro; Insulin Lispro Protamine
      • Insulin Regular
      • Insulin, Inhaled
      • Irbesartan
      • Isocarboxazid
      • Lanreotide
      • Ledipasvir; Sofosbuvir
      • Leuprolide; Norethindrone
      • Levonorgestrel
      • Linezolid
      • Lisinopril
      • Lithium
      • Lomefloxacin
      • Lopinavir; Ritonavir
      • Lorcaserin
      • Losartan
      • Lovastatin; Niacin
      • Magnesium Salicylate
      • Mecasermin rinfabate
      • Mecasermin, Recombinant, rh-IGF-1
      • Medroxyprogesterone
      • Mestranol; Norethindrone
      • Methyltestosterone
      • Metyrapone
      • Moexipril
      • Monoamine oxidase inhibitors
      • Nandrolone Decanoate
      • Nebivolol; Valsartan
      • Nelfinavir
      • Niacin, Niacinamide
      • Niacin; Simvastatin
      • Norethindrone
      • Norgestrel
      • Octreotide
      • Olmesartan
      • Ombitasvir; Paritaprevir; Ritonavir
      • Oxandrolone
      • Oxymetholone
      • Pasireotide
      • Pegvisomant
      • Pentamidine
      • Pentoxifylline
      • Perindopril
      • Perindopril; Amlodipine
      • Phenelzine
      • Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements)
      • Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved)
      • Progesterone
      • Progestins
      • Protease inhibitors
      • Quinapril
      • Quinolones
      • Ramipril
      • Regular Insulin
      • Regular Insulin; Isophane Insulin (NPH)
      • Reserpine
      • Ritonavir
      • Sacubitril; Valsartan
      • Salicylates
      • Salsalate
      • Saquinavir
      • Segesterone Acetate; Ethinyl Estradiol
      • Sofosbuvir
      • Sofosbuvir; Velpatasvir
      • Sofosbuvir; Velpatasvir; Voxilaprevir
      • Somatropin, rh-GH
      • Sparfloxacin
      • Sulfonamides
      • Sympathomimetics
      • Tacrolimus
      • Tegaserod
      • Telmisartan
      • Testolactone
      • Testosterone
      • Thiazide diuretics
      • Tipranavir
      • Trandolapril
      • Trandolapril; Verapamil
      • Tranylcypromine
      • Valsartan

      Level 4 (Minor)

      • Acetazolamide
      • Carbonic anhydrase inhibitors
      • Chlorpromazine
      • Chlorthalidone; Clonidine
      • Clonidine
      • Codeine; Phenylephrine; Promethazine
      • Codeine; Promethazine
      • Dextromethorphan; Promethazine
      • Diazoxide
      • Ethotoin
      • Fluphenazine
      • Fosphenytoin
      • Hydrochlorothiazide, HCTZ; Triamterene
      • Hydroxyprogesterone
      • Levothyroxine
      • Levothyroxine; Liothyronine (Porcine)
      • Levothyroxine; Liothyronine (Synthetic)
      • Liothyronine
      • Loop diuretics
      • Meperidine; Promethazine
      • Mesoridazine
      • Methazolamide
      • Nicotine
      • Orlistat
      • Perphenazine
      • Perphenazine; Amitriptyline
      • Phenothiazines
      • Phenylephrine; Promethazine
      • Phenytoin
      • Prochlorperazine
      • Promethazine
      • Thiethylperazine
      • Thioridazine
      • Thyroid hormones
      • tobacco
      • Triamterene
      • Trifluoperazine
      Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [28267] [28294] [57357] Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Amlodipine; Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. [28238] Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. [28238] Amprenavir: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. [30575] [50113] [50814] Androgens: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Angiotensin II receptor antagonists: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Aspirin, ASA: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Butalbital; Caffeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Carisoprodol: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Dipyridamole: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Omeprazole: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Oxycodone: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Aspirin, ASA; Pravastatin: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [30575] [50113] [50814] 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. [30575] [50113] [50814] Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] atypical antipsychotic: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. [28915] [30575] Azilsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Benazepril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [28618] [29403] [30489] [30575] [32916] [53617] [62853] Bismuth Subsalicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [28383] Candesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Captopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Captopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] 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. [28267] [28294] [57357] 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. [29758] 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. [28915] [30575] 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. [29533] [30585] [44086] Choline Salicylate; Magnesium Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [25731] [25732] Clarithromycin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. [28238] 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. [29533] [30585] [44086] 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. [28915] [30575] 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. [28915] [30575] Conjugated Estrogens; Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Corticosteroids: (Moderate) Monitor patients receiving antidiabetic agents closely for worsening glycemic control when corticosteroids are instituted and for signs of hypoglycemia when corticosteroids are discontinued. Systemic and inhaled corticosteroids are known to increase blood glucose and worsen glycemic control in patients taking antidiabetic agents. The main risk factors for impaired glucose tolerance due to corticosteroids are the dose of steroid and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. [28032] [30585] [51002] [62853] Cyclosporine: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including liraglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related. [30576] [30585] 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. [60001] Danazol: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [30575] [50113] [50814] 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. [30575] [50113] [50814] 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. [30575] [50113] [50814] 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. [58664] [60002] [61023] 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. [30575] [50113] [50814] Dextromethorphan; 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. [28915] [30575] 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. [49068] Dienogest; Estradiol valerate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving this combination should be monitored for changes in glycemic control. [28228] Drospirenone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Drospirenone; Estradiol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Drospirenone; Ethinyl Estradiol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Elagolix; Estradiol; Norethindrone acetate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [60523] Enalapril, Enalaprilat: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Enalapril; Felodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Eprosartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Esterified Estrogens; Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Estradiol Cypionate; Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Estradiol; Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Estradiol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Estradiol; Norgestimate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Estradiol; Progesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Estrogens: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as combined hormonal oral contraceptives (OCs). Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. atients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. [30585] [38653] [48491] [57014] [57946] [61024] [62853] Ethanol: (Moderate) Patients should be advised to limit alcohol (ethanol) ingestion when treated with an antidiabetic agent. Ethanol inhibits gluconeogenesis, which can contribute to or increase the risk for hypoglycemia. In some patients, hypoglycemia can be prolonged. If a patient with diabetes ingests alcohol, they should be counselled to to avoid ingestion of alcohol on an empty stomach, which increases risk for low blood sugar. Patients should also be aware of the carbohydrate intake provided by certain types of alcohol in the diet, which can contribute to poor glycemic control. If a patient chooses to ingest alcohol, they should monitor their blood glucose frequently. Many non-prescription drug products may be formulated with alcohol; instruct patients to scrutinize product labels prior to consumption. [29403] [30585] [62853] Ethinyl Estradiol; Desogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Etonogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norelgestromin: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norgestimate: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Ethinyl Estradiol; Norgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [23813] Etonogestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Fibric acid derivatives: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. [30585] [62853] Fluoxetine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued. [30585] [32127] [44058] [44059] Fluoxetine; Olanzapine: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued. [30585] [32127] [44058] [44059] Fluoxymesterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [28915] [30575] 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. [30575] [50113] [50814] Fosinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] 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. [23813] 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. [28464] [28465] [28466] [57571] [63042] [63043] 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. [62201] (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. [62201] 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. [29904] [29905] Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Triamterene can decrease the hypoglycemic effects of antidiabetic agents, such as incretin mimetics, by producing an increase in blood glucose levels. Patients on antidiabetics should be monitored for changes in blood glucose control if triamterene is added or deleted. Dosage adjustments may be necessary. [29160] [29403] [30489] Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Hydroxychloroquine: (Moderate) Careful monitoring of blood glucose is recommended when hydroxychloroquine and antidiabetic agents, including the incretin mimetics, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with hydroxychloroquine and an antidiabetic agent. [41806] 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. [30585] [43316] [62853] [62893] Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [29403] [48959] 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. [30575] [50113] [50814] Insulin Aspart: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin aspart because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [58673] Insulin Degludec: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin degludec because of the risk of hypoglycemia. When liraglutide is used with insulin for the treatment of diabetes, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [58673] Insulin Degludec; Liraglutide: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin degludec because of the risk of hypoglycemia. When liraglutide is used with insulin for the treatment of diabetes, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [58673] Insulin Detemir: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin detemir because of the risk of hypoglycemia. When liraglutide is added to insulin detemir for the treatment of diabetes, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 Units subcutaneously once daily when combining with a GLP-1 receptor agonist, such as liraglutide. Blood glucose concentrations should be closely monitored. [38653] [50277] [58673] Insulin Glargine: (Moderate) Liraglutid used for weight loss should not be given concomitantly with insulin glargine because of the risk of hypoglycemia. When liraglutide is used with insulin glargine for the treatment of diabetes, consider lowering the dose of the insulin glargine to reduce the risk of hypoglycemia and increase the frequency of blood glucose monitoring. [38653] [58673] [60453] Insulin Glargine; Lixisenatide: (Moderate) Liraglutid used for weight loss should not be given concomitantly with insulin glargine because of the risk of hypoglycemia. When liraglutide is used with insulin glargine for the treatment of diabetes, consider lowering the dose of the insulin glargine to reduce the risk of hypoglycemia and increase the frequency of blood glucose monitoring. [38653] [58673] [60453] Insulin Glulisine: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin glulisine because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [58673] Insulin Lispro: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [30510] [38653] [58673] Insulin Lispro: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [30510] [38653] [58673] Insulin Lispro; Insulin Lispro Protamine: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin lispro because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [30510] [38653] [58673] Insulin Regular: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [44405] [58673] Insulin, Inhaled: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [58673] Irbesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Isocarboxazid: (Moderate) Serum glucose should be monitored closely when monoamine oxidase inhibitors (MAOIs) are added to any regimen containing antidiabetic agents. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. [30585] [59433] 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. [33519] 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. [56528] [58167] (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. [56528] Leuprolide; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Levonorgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [43942] 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. [43942] 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. [43942] 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. [28599] 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. [43942] Lisinopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy iincluding incretin mimetics. Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments of insulin may be necessary. [29403] [30466] Lomefloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are co-administered. [28288] [28292] 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. [28429] [28620] [29353] 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. [30575] [50113] [50814] 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. [51065] Losartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Lovastatin; Niacin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted [29194] [30490] Magnesium Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [31516] [31524] [31821] 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. [31516] [31524] [31821] Medroxyprogesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [28915] [30575] Mesoridazine: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. [28915] [30575] Mestranol; Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [28267] [28294] [57357] Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [33528] Moexipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Monoamine oxidase inhibitors: (Moderate) Serum glucose should be monitored closely when monoamine oxidase inhibitors (MAOIs) are added to any regimen containing antidiabetic agents. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. [30585] [59433] Nandrolone Decanoate: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Nebivolol; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] 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. [30575] [50113] [50814] Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted [29194] [30490] Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. When used at daily doses of 750 to 2,000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen and adjust dosages as clinically warranted [29194] [30490] 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. [29535] Norethindrone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Norgestrel: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [29113] [51310] Olmesartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] 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. [30575] [50113] [50814] 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. [25616] [27971] [60877] [62881] Oxandrolone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Oxymetholone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [52611] [58639] 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. [51250] 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. [28879] 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. [6316] [7238] Perindopril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Perindopril; Amlodipine: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] 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. [28915] [30575] 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. [28915] [30575] Phenelzine: (Moderate) Serum glucose should be monitored closely when monoamine oxidase inhibitors (MAOIs) are added to any regimen containing antidiabetic agents. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. [30585] [59433] 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. [28915] [30575] 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. [28915] [30575] Phenytoin: (Minor) Phenytoin can decrease the hypoglycemic effects of liraglutide 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. [23813] Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [28915] [30575] Progesterone: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] Progestins: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [28915] [30575] 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. [30575] [50113] [50814] Quinapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Quinolones: (Moderate) Monitor blood glucose carefully when systemic quinolones and antidiabetic agents, including incretin mimetics, are coadministered. Discontinue the quinolone if a hypoglycemic reaction occurs and initiate appropriate therapy immediately. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Hypoglycemia, sometimes resulting in coma, can occur. [28423] [28424] [43411] [62028] [65562] Ramipril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Regular Insulin: (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [44405] [58673] Regular Insulin; Isophane Insulin (NPH): (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin isophane (NPH insulin) because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [29532] [38653] [58673] (Moderate) Liraglutide used for weight loss should not be given concomitantly with insulin regular because of the risk of hypoglycemia. Liraglutide for the treatment of diabetes has not been studied in combination with prandial insulin. When liraglutide is used with insulin, consider lowering the dose of the insulin to reduce the risk of hypoglycemia and monitor the blood glucose concentration more frequently. [38653] [44405] [58673] 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. [30466] 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. [30575] [50113] [50814] Sacubitril; Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Salicylates: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] Salsalate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Monitor blood glucose closely during coadministration. [29403] 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. [30575] [50113] [50814] Segesterone Acetate; Ethinyl Estradiol: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control. [30585] [38653] [48491] [57014] [57946] [61024] 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. [56528] 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. [56528] (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. [56528] [60911] 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. [56528] (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. [56528] [60911] (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. [62131] 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. [30059] [33527] [45044] [45045] [49770] [56647] [56648] [56649] [56650] [56651] [58095] [58096] [59579] [60682] Sparfloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered. [28288] [28292] Sulfonamides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. [29536] [30585] [30623] [32166] Sympathomimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. [44662] [51002] Tacrolimus: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including liraglutide. 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. [30576] [30585] 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. [28956] [61024] Telmisartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Testolactone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] Testosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together. [33919] [33920] [33921] [33922] [33923] [33924] 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. [29403] 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. [28915] [30575] 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. [28915] [30575] 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. [43942] 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. [30575] [50113] [50814] Tobacco: (Minor) Tobacco smoking is known to aggravate insulin resistance. The cessation of tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either smoking status occurs; dosage adjustments in antidiabetic agents may be needed. [29535] Trandolapril: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Trandolapril; Verapamil: (Moderate) ACE inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. [29403] [30585] Tranylcypromine: (Moderate) Serum glucose should be monitored closely when monoamine oxidase inhibitors (MAOIs) are added to any regimen containing antidiabetic agents. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and other antidiabetic agents. [30585] [59433] 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. [29160] [29403] [30489] 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. [28915] [30575] Valsartan: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591]
      Revision Date: 08/18/2020, 02:40:00 AM

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      Monitoring Parameters

      • blood glucose
      • glycosylated hemoglobin A1c (HbA1c)
      • weight

      US Drug Names

      • Saxenda
      • Victoza

      Global Drug names

      Argentina

      • Victoza - (Novo Nordisk)

      Australia

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Austria

      • Victoza - (Novo Nordisk)

      Belgium

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Brazil

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Canada

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Chile

      • Victoza - (Novo Nordisk)

      China

      • Victoza - (Novo Nordisk)

      Czech Republic

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Denmark

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Finland

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      France

      • Victoza - (Novo Nordisk)

      Germany

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Greece

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Hong Kong

      • Victoza - (Novo Nordisk)

      Hungary

      • Victoza - (Novo Nordisk)

      Indonesia

      • Victoza - (Novo Nordisk)

      Ireland

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Israel

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Japan

      • Victoza - (Novo Nordisk)

      Malaysia

      • Victoza - (Novo Nordisk)

      Mexico

      • Victoza - (Novo Nordisk)

      Netherlands

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Norway

      • Victoza - (Novo Nordisk)

      Philippines

      • Victoza - (Novo Nordisk)

      Poland

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Portugal

      • Victoza - (Novo Nordisk)

      Russian Federation

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Singapore

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      South Africa

      • Victoza - (Novo Nordisk)

      Spain

      • Victoza - (Novo Nordisk)

      Sweden

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Switzerland

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Thailand

      • Victoza - (Novo Nordisk)

      Turkey

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)

      Ukraine

      • Victoza - (Novo Nordisk)

      United Kingdom

      • Saxenda - (Novo Nordisk)
      • Victoza - (Novo Nordisk)