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Drug overview for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
Generic name: GLYBURIDE/METFORMIN HCL (GLYE-bure-ide/met-FOR-min)
Drug class: Biguanides
Therapeutic class: Endocrine
Glyburide is a sulfonylurea antidiabetic agent. Metformin hydrochloride is a biguanide antidiabetic agent.
No enhanced Uses information available for this drug.
Generic name: GLYBURIDE/METFORMIN HCL (GLYE-bure-ide/met-FOR-min)
Drug class: Biguanides
Therapeutic class: Endocrine
Glyburide is a sulfonylurea antidiabetic agent. Metformin hydrochloride is a biguanide antidiabetic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
GLYBURID-METFORMIN 1.25-250 MG
GLYBURIDE-METFORMIN 2.5-500 MG
GLYBURIDE-METFORMIN 5-500 MG
The following indications for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl) have been approved by the FDA:
Indications:
Type 2 diabetes mellitus
Professional Synonyms:
Adult onset diabetes mellitus
Adult onset diabetes
Adult onset DM
Diabetes mellitus type 2
Diabetes mellitus type II
Ketosis-resistant diabetes mellitus
Ketosis-resistant DM
Maturity onset diabetes mellitus
Maturity onset diabetes
Non-insulin dependent diabetes mellitus
Non-insulin-dependent diabetes mellitus
Type II diabetes mellitus
Indications:
Type 2 diabetes mellitus
Professional Synonyms:
Adult onset diabetes mellitus
Adult onset diabetes
Adult onset DM
Diabetes mellitus type 2
Diabetes mellitus type II
Ketosis-resistant diabetes mellitus
Ketosis-resistant DM
Maturity onset diabetes mellitus
Maturity onset diabetes
Non-insulin dependent diabetes mellitus
Non-insulin-dependent diabetes mellitus
Type II diabetes mellitus
The following dosing information is available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
For the management of type 2 diabetes mellitus in patients not previously receiving insulin or sulfonylurea antidiabetic agents, the usual initial adult dosage of glyburide is 2.5-5 mg daily; in debilitated, malnourished, or geriatric patients, or other patients at increased risk of hypoglycemia (See Cautions: Precautions and Contraindications), the initial dosage of glyburide should be 1.25 mg daily.
The manufacturers also recommend an initial dosage of 1.25 mg daily in patients with impaired renal or hepatic function. (See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response; increases in dosage should be made in increments of no more than 2.5
mg daily at weekly intervals.
A transition period generally is not required when transferring from most other sulfonylurea antidiabetic agents to glyburide, and administration of the other agent may be abruptly discontinued. Because of the prolonged elimination half-life of chlorpropamide (no longer commercially available in the US), an exaggerated hypoglycemic response may occur in some patients during the transition from chlorpropamide to glyburide, and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 2 weeks of the transition period. A drug-free interval of 2-3 days may be advisable before glyburide therapy is initiated in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide.
An initial or loading dose of glyburide is not necessary when transferring from other sulfonylurea antidiabetic agents to glyburide. The transfer should be performed conservatively.
For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the initial dosage of glyburide should be 2.5-5 mg daily. Although patients may be transferred from the maximum dosage of other sulfonylurea antidiabetic agents, the initial dosage of glyburide should not exceed 5 mg daily.
Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response. Although an exact dosage relationship between glyburide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated. (See Pharmacology: Antidiabetic Effect.)
In general, patients who were previously maintained on insulin dosages not exceeding 40 units daily may be transferred directly to glyburide, and administration of insulin may be abruptly discontinued; the initial glyburide dosage is 2.5-5 mg daily in patients whose insulin dosage was less than 20 units daily and 5 mg daily in patients whose insulin dosage was 20-40 units daily. In patients requiring insulin dosages exceeding 40 units daily, an initial glyburide dosage of 5 mg daily should be started and insulin dosage reduced by 50%.
Subsequently, insulin is withdrawn gradually and dosage of glyburide is increased in increments of 1.25-2.5 mg daily every 2-10 days, according to the patient's tolerance and therapeutic response.
During the period of insulin withdrawal, patients should test their blood for glucose and their urine for glucose and/or ketones at least 3 times daily, and should be instructed to report the results to their physician so that appropriate adjustments in therapy may be made, if necessary. The presence of persistent ketonuria with glycosuria, ketosis, and/or inadequate lowering or persistent elevation of blood glucose concentration indicates that the patient requires insulin therapy. During the period of insulin withdrawal, hypoglycemia may rarely occur.
In some patients, hospitalization may be necessary during the transition from insulin to glyburide.
The adult maintenance dosage of glyburide for the management of type 2 diabetes mellitus ranges from 1.25-20 mg daily. Most patients require 2.5-10
mg daily and some may require up to 15 mg daily; only a few patients will benefit from dosages exceeding 15 mg daily. Maintenance dosage of glyburide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients. (See Cautions: Precautions and Contraindications.)The maximum recommended dosage is 20 mg daily.
For the management of type 2 diabetes mellitus in adults, the usual initial dosage of metformin hydrochloride as immediate-release tablets or immediate-release oral solution is 500 mg twice daily or 850 mg once daily with meals. Alternatively, an initial metformin hydrochloride dosage of 500 mg once daily has been suggested by some experts. Some manufacturers state that in general, clinically important responses are not observed at metformin hydrochloride dosages of less than 1.5
g daily.
When metformin hydrochloride is administered as an extended-release tablet preparation in adults, some manufacturers recommend an initial dosage of 500 mg once daily with the evening meal. The manufacturer of a certain extended-release tablet preparation (Fortamet(R)) recommends an initial dosage of 1 g once daily with the evening meal, although the manufacturer states that 500 mg once daily may be used when clinically appropriate. The recommended initial dosage of another extended-release preparation of metformin hydrochloride (Glumetza(R)) is 1 g once daily with the evening meal.
Subsequent dosage of metformin hydrochloride should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage. (See Dosage: Dosage Titration, under Dosage and Administration.)
Although satisfactory control of blood glucose concentrations may be achieved within a few days after dosage adjustment, the full effects of the drug may not be observed for up to 2 weeks.
Initial dosages of metformin hydrochloride in geriatric patients should be conservative (initiated at the low end of the dosage range) and should be titrated carefully; limited data suggest reducing dosage by approximately 33% in geriatric patients.
For the management of type 2 diabetes mellitus in children or adolescents 10-16 years of age, the usual initial dosage of metformin hydrochloride as immediate-release tablets or the immediate-release oral solution is 500 mg twice daily given in the morning and evening with meals. Safety and efficacy of Fortamet(R) and certain other extended-release tablet preparations of metformin hydrochloride have not been established in patients younger than 17 years of age; refer to labeling of specific preparations for details. Safety and efficacy of Glumetza(R), another extended-release tablet preparation, have not been established in patients younger than 18 years of age.
In adults receiving an initial metformin hydrochloride dosage of 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired fasting blood glucose concentration is achieved or a dosage of 2.55 g daily is reached. In adults receiving an initial dosage of 500 mg of metformin hydrochloride once or twice daily (with breakfast and/or dinner), some experts recommend increasing the dosage to 850 mg or 1 g twice daily after 5-7 days if additional glycemic control is needed and the drug is well tolerated (e.g., no adverse GI effects).
If adverse GI effects appear during dosage titration of metformin hydrochloride, some experts suggest that dosage be decreased to the previous lower dosage, and further dosage increments attempted at a later time. In adults receiving an initial metformin hydrochloride dosage of 850 mg daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 850 mg every other week (i.e., every 2 weeks) until the desired fasting blood glucose concentration is achieved or a total dosage of 2.55 g daily is reached.
For patients requiring additional glycemic control with metformin hydrochloride, a maximum daily dosage of 2.55 g as immediate-release tablets or the immediate-release oral solution may be used.
In adults (17-18 years of age or older) receiving Glumetza(R) or certain other extended-release metformin hydrochloride preparations, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily is reached. If glycemic control is not achieved with extended-release metformin hydrochloride tablets (e.g., Glumetza(R)) at a dosage of 2 g once daily, a dosage of 1 g twice daily should be considered. If a dosage exceeding 2 g daily is needed in patients receiving certain other extended-release metformin hydrochloride preparations, the manufacturers suggest that therapy be switched to immediate-release metformin hydrochloride tablets and dosage titrated up to a maximum dosage of 2.55
g daily in divided doses. Conversely, therapy with extended-release tablets may be substituted for immediate-release tablets at the same total daily dosage of immediate-release tablets, up to a dosage of 2 g once daily.
With another extended-release metformin hydrochloride preparation (Fortamet(R)), daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g once daily with the evening meal. In patients transferring from immediate-release tablets to an extended-release preparation, glycemic control should be closely monitored and dosage adjustments made accordingly.
Dosage in adults generally should not exceed 2.55 g daily when given as metformin hydrochloride immediate-release tablets or immediate-release oral solution, 2.5 g daily when given as certain extended-release tablets (e.g., Fortamet(R)), or 2 g daily when given as certain other extended-release tablet preparations.
Metformin hydrochloride dosages of up to 3 g daily have been associated with modestly greater effectiveness than 1.7 g daily. However, adverse GI effects may limit the maximum dosage that can be tolerated.
(Consult the manufacturer's labeling for product-specific details.) Dosages exceeding 2 g of metformin hydrochloride daily as immediate-release tablets or the immediate-release oral solution may be better tolerated if given in 3 divided doses daily with meals.
Metformin should be used with caution in geriatric patients since aging is associated with reduced renal function, and accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment. In addition, renal function should be monitored periodically in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.
In children or adolescents 10-16 years of age receiving metformin hydrochloride 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily given in 2 divided doses is reached.
Because of the risk of lactic acidosis, which occurs rarely but may be fatal, metformin should not be used in patients with severe renal disease or dysfunction (eGFR less than 30 mL/minute per 1.73 m2) and should be avoided in those with clinical or laboratory evidence of hepatic disease. In patients with moderate renal disease, the benefits and risks of continuing metformin therapy should be assessed. (See Cautions: Lactic Acidosis.)
An FDA review of clinical studies evaluating the safety of metformin in patients with reduced kidney function suggests that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.
The manufacturers and FDA state that renal function (eGFR) should be assessed prior to initiation of metformin and at least annually; more frequent monitoring has been recommended in patients with an increased risk of developing renal impairment (e.g., geriatric patients). The manufacturers and FDA state that initiation of metformin therapy is not recommended in patients with an eGFR between 30-45 mL/minute per 1.73 m2 and that the benefits and risks of continuing the drug should be assessed in those already receiving metformin whose eGFR falls below 45 mL/minute per 1.73
m2. The manufacturers and FDA state that metformin is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m2 and that the drug should be discontinued in patients whose eGFR falls below 30 mL/minute per 1.73 m2 who are already receiving metformin.
The manufacturers also recommend an initial dosage of 1.25 mg daily in patients with impaired renal or hepatic function. (See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response; increases in dosage should be made in increments of no more than 2.5
mg daily at weekly intervals.
A transition period generally is not required when transferring from most other sulfonylurea antidiabetic agents to glyburide, and administration of the other agent may be abruptly discontinued. Because of the prolonged elimination half-life of chlorpropamide (no longer commercially available in the US), an exaggerated hypoglycemic response may occur in some patients during the transition from chlorpropamide to glyburide, and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 2 weeks of the transition period. A drug-free interval of 2-3 days may be advisable before glyburide therapy is initiated in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide.
An initial or loading dose of glyburide is not necessary when transferring from other sulfonylurea antidiabetic agents to glyburide. The transfer should be performed conservatively.
For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the initial dosage of glyburide should be 2.5-5 mg daily. Although patients may be transferred from the maximum dosage of other sulfonylurea antidiabetic agents, the initial dosage of glyburide should not exceed 5 mg daily.
Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response. Although an exact dosage relationship between glyburide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated. (See Pharmacology: Antidiabetic Effect.)
In general, patients who were previously maintained on insulin dosages not exceeding 40 units daily may be transferred directly to glyburide, and administration of insulin may be abruptly discontinued; the initial glyburide dosage is 2.5-5 mg daily in patients whose insulin dosage was less than 20 units daily and 5 mg daily in patients whose insulin dosage was 20-40 units daily. In patients requiring insulin dosages exceeding 40 units daily, an initial glyburide dosage of 5 mg daily should be started and insulin dosage reduced by 50%.
Subsequently, insulin is withdrawn gradually and dosage of glyburide is increased in increments of 1.25-2.5 mg daily every 2-10 days, according to the patient's tolerance and therapeutic response.
During the period of insulin withdrawal, patients should test their blood for glucose and their urine for glucose and/or ketones at least 3 times daily, and should be instructed to report the results to their physician so that appropriate adjustments in therapy may be made, if necessary. The presence of persistent ketonuria with glycosuria, ketosis, and/or inadequate lowering or persistent elevation of blood glucose concentration indicates that the patient requires insulin therapy. During the period of insulin withdrawal, hypoglycemia may rarely occur.
In some patients, hospitalization may be necessary during the transition from insulin to glyburide.
The adult maintenance dosage of glyburide for the management of type 2 diabetes mellitus ranges from 1.25-20 mg daily. Most patients require 2.5-10
mg daily and some may require up to 15 mg daily; only a few patients will benefit from dosages exceeding 15 mg daily. Maintenance dosage of glyburide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients. (See Cautions: Precautions and Contraindications.)The maximum recommended dosage is 20 mg daily.
For the management of type 2 diabetes mellitus in adults, the usual initial dosage of metformin hydrochloride as immediate-release tablets or immediate-release oral solution is 500 mg twice daily or 850 mg once daily with meals. Alternatively, an initial metformin hydrochloride dosage of 500 mg once daily has been suggested by some experts. Some manufacturers state that in general, clinically important responses are not observed at metformin hydrochloride dosages of less than 1.5
g daily.
When metformin hydrochloride is administered as an extended-release tablet preparation in adults, some manufacturers recommend an initial dosage of 500 mg once daily with the evening meal. The manufacturer of a certain extended-release tablet preparation (Fortamet(R)) recommends an initial dosage of 1 g once daily with the evening meal, although the manufacturer states that 500 mg once daily may be used when clinically appropriate. The recommended initial dosage of another extended-release preparation of metformin hydrochloride (Glumetza(R)) is 1 g once daily with the evening meal.
Subsequent dosage of metformin hydrochloride should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage. (See Dosage: Dosage Titration, under Dosage and Administration.)
Although satisfactory control of blood glucose concentrations may be achieved within a few days after dosage adjustment, the full effects of the drug may not be observed for up to 2 weeks.
Initial dosages of metformin hydrochloride in geriatric patients should be conservative (initiated at the low end of the dosage range) and should be titrated carefully; limited data suggest reducing dosage by approximately 33% in geriatric patients.
For the management of type 2 diabetes mellitus in children or adolescents 10-16 years of age, the usual initial dosage of metformin hydrochloride as immediate-release tablets or the immediate-release oral solution is 500 mg twice daily given in the morning and evening with meals. Safety and efficacy of Fortamet(R) and certain other extended-release tablet preparations of metformin hydrochloride have not been established in patients younger than 17 years of age; refer to labeling of specific preparations for details. Safety and efficacy of Glumetza(R), another extended-release tablet preparation, have not been established in patients younger than 18 years of age.
In adults receiving an initial metformin hydrochloride dosage of 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired fasting blood glucose concentration is achieved or a dosage of 2.55 g daily is reached. In adults receiving an initial dosage of 500 mg of metformin hydrochloride once or twice daily (with breakfast and/or dinner), some experts recommend increasing the dosage to 850 mg or 1 g twice daily after 5-7 days if additional glycemic control is needed and the drug is well tolerated (e.g., no adverse GI effects).
If adverse GI effects appear during dosage titration of metformin hydrochloride, some experts suggest that dosage be decreased to the previous lower dosage, and further dosage increments attempted at a later time. In adults receiving an initial metformin hydrochloride dosage of 850 mg daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 850 mg every other week (i.e., every 2 weeks) until the desired fasting blood glucose concentration is achieved or a total dosage of 2.55 g daily is reached.
For patients requiring additional glycemic control with metformin hydrochloride, a maximum daily dosage of 2.55 g as immediate-release tablets or the immediate-release oral solution may be used.
In adults (17-18 years of age or older) receiving Glumetza(R) or certain other extended-release metformin hydrochloride preparations, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily is reached. If glycemic control is not achieved with extended-release metformin hydrochloride tablets (e.g., Glumetza(R)) at a dosage of 2 g once daily, a dosage of 1 g twice daily should be considered. If a dosage exceeding 2 g daily is needed in patients receiving certain other extended-release metformin hydrochloride preparations, the manufacturers suggest that therapy be switched to immediate-release metformin hydrochloride tablets and dosage titrated up to a maximum dosage of 2.55
g daily in divided doses. Conversely, therapy with extended-release tablets may be substituted for immediate-release tablets at the same total daily dosage of immediate-release tablets, up to a dosage of 2 g once daily.
With another extended-release metformin hydrochloride preparation (Fortamet(R)), daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g once daily with the evening meal. In patients transferring from immediate-release tablets to an extended-release preparation, glycemic control should be closely monitored and dosage adjustments made accordingly.
Dosage in adults generally should not exceed 2.55 g daily when given as metformin hydrochloride immediate-release tablets or immediate-release oral solution, 2.5 g daily when given as certain extended-release tablets (e.g., Fortamet(R)), or 2 g daily when given as certain other extended-release tablet preparations.
Metformin hydrochloride dosages of up to 3 g daily have been associated with modestly greater effectiveness than 1.7 g daily. However, adverse GI effects may limit the maximum dosage that can be tolerated.
(Consult the manufacturer's labeling for product-specific details.) Dosages exceeding 2 g of metformin hydrochloride daily as immediate-release tablets or the immediate-release oral solution may be better tolerated if given in 3 divided doses daily with meals.
Metformin should be used with caution in geriatric patients since aging is associated with reduced renal function, and accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment. In addition, renal function should be monitored periodically in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.
In children or adolescents 10-16 years of age receiving metformin hydrochloride 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily given in 2 divided doses is reached.
Because of the risk of lactic acidosis, which occurs rarely but may be fatal, metformin should not be used in patients with severe renal disease or dysfunction (eGFR less than 30 mL/minute per 1.73 m2) and should be avoided in those with clinical or laboratory evidence of hepatic disease. In patients with moderate renal disease, the benefits and risks of continuing metformin therapy should be assessed. (See Cautions: Lactic Acidosis.)
An FDA review of clinical studies evaluating the safety of metformin in patients with reduced kidney function suggests that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.
The manufacturers and FDA state that renal function (eGFR) should be assessed prior to initiation of metformin and at least annually; more frequent monitoring has been recommended in patients with an increased risk of developing renal impairment (e.g., geriatric patients). The manufacturers and FDA state that initiation of metformin therapy is not recommended in patients with an eGFR between 30-45 mL/minute per 1.73 m2 and that the benefits and risks of continuing the drug should be assessed in those already receiving metformin whose eGFR falls below 45 mL/minute per 1.73
m2. The manufacturers and FDA state that metformin is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m2 and that the drug should be discontinued in patients whose eGFR falls below 30 mL/minute per 1.73 m2 who are already receiving metformin.
Glyburide is administered orally. The drug (as conventional or micronized formulations; see Dosage: Type 2 Diabetes Mellitus, under Dosage and Administration) is usually administered as a single daily dose given each morning with breakfast, or with the first main meal. Once-daily dosing of glyburide provides adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns; however, some patients, particularly those who require more than 10 mg of the drug daily (as conventional formulations) or more than 6 mg daily (as micronized glyburide), may have a more satisfactory response when glyburide is administered in 2 divided doses daily.
When a twice-daily dosing regimen is employed in patients receiving more than 10 mg of glyburide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response. There is some evidence that, when a divided-dosing regimen is used, blood glucose concentration following breakfast may be better controlled when the morning dose is administered 30 minutes before rather than with the meal; a similar tendency has been observed following the midday meal, but not the evening meal, when the remaining portions of the equally divided daily dose were administered 30 minutes before rather than with these meals. When given concomitantly with colesevelam, glyburide should be administered at least 4 hours prior to colesevelam.
(See Drug Interactions: Colesevelam.) Metformin hydrochloride is administered orally. In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the drug usually can be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the drug may be better tolerated if administered in 3 divided doses daily. Immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, alogliptin, linagliptin, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.
Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the drug be taken with meals to decrease adverse GI effects. Metformin hydrochloride extended-release tablets usually are taken with the evening meal. The manufacturer of Fortamet(R) (metformin hydrochloride extended-release tablets) states that each dose of the drug should be taken with a full glass of water.
The matrix core of some extended-release tablet preparations (e.g., Glumetza(R)) usually is broken up in the GI tract, but patients should be advised that occasionally the biologically inert components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass. Occasionally, Glumetza(R) may be eliminated in the feces as a soft, hydrated mass or an insoluble shell. The membrane coating surrounding the core of another extended-release tablet (Fortamet(R)) remains intact through the GI tract and is excreted in feces as a soft mass that may resemble the original tablet.
(See Chemistry and Stability: Stability.) Extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin is administered once daily with the morning meal. The fixed combination of extended-release metformin hydrochloride and linagliptin should be administered once daily with a meal. The fixed combination of extended-release metformin hydrochloride and sitagliptin should be administered once daily with a meal, preferably with the evening meal.
Extended-release metformin hydrochloride in fixed combination with saxagliptin should be administered once daily with the evening meal. Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the drug must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet.
When a twice-daily dosing regimen is employed in patients receiving more than 10 mg of glyburide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response. There is some evidence that, when a divided-dosing regimen is used, blood glucose concentration following breakfast may be better controlled when the morning dose is administered 30 minutes before rather than with the meal; a similar tendency has been observed following the midday meal, but not the evening meal, when the remaining portions of the equally divided daily dose were administered 30 minutes before rather than with these meals. When given concomitantly with colesevelam, glyburide should be administered at least 4 hours prior to colesevelam.
(See Drug Interactions: Colesevelam.) Metformin hydrochloride is administered orally. In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the drug usually can be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the drug may be better tolerated if administered in 3 divided doses daily. Immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, alogliptin, linagliptin, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.
Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the drug be taken with meals to decrease adverse GI effects. Metformin hydrochloride extended-release tablets usually are taken with the evening meal. The manufacturer of Fortamet(R) (metformin hydrochloride extended-release tablets) states that each dose of the drug should be taken with a full glass of water.
The matrix core of some extended-release tablet preparations (e.g., Glumetza(R)) usually is broken up in the GI tract, but patients should be advised that occasionally the biologically inert components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass. Occasionally, Glumetza(R) may be eliminated in the feces as a soft, hydrated mass or an insoluble shell. The membrane coating surrounding the core of another extended-release tablet (Fortamet(R)) remains intact through the GI tract and is excreted in feces as a soft mass that may resemble the original tablet.
(See Chemistry and Stability: Stability.) Extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin is administered once daily with the morning meal. The fixed combination of extended-release metformin hydrochloride and linagliptin should be administered once daily with a meal. The fixed combination of extended-release metformin hydrochloride and sitagliptin should be administered once daily with a meal, preferably with the evening meal.
Extended-release metformin hydrochloride in fixed combination with saxagliptin should be administered once daily with the evening meal. Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the drug must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| GLYBURID-METFORMIN 1.25-250 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
| GLYBURIDE-METFORMIN 2.5-500 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
| GLYBURIDE-METFORMIN 5-500 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| GLYBURID-METFORMIN 1.25-250 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
| GLYBURIDE-METFORMIN 2.5-500 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
| GLYBURIDE-METFORMIN 5-500 MG | Maintenance | Adults take 1 tablet by oral route 2 times per day with meals |
The following drug interaction information is available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Bosentan/Glyburide SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The mechanism behind the increased risk of elevated liver aminotransferases is unknown. CLINICAL EFFECTS: Concurrent use of bosentan and glyburide may increase the risk of liver enzyme elevations.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturers of bosentan and glyburide state that the concurrent use of these agents is contraindicated(1,2) and that alternative hypoglycemic agents should be considered.(1) DISCUSSION: An increased risk of liver enzyme elevation was seen in patients receiving concurrent bosentan and glyburide.(1,2) |
BOSENTAN, TRACLEER |
There are 6 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Metformin/Iodinated Contrast Materials SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Use of iodinated contrast materials may result in acute changes in renal function, resulting in a decrease in metformin clearance.(1-3) CLINICAL EFFECTS: Use of iodinated contrast materials may increase levels of metformin, which may result in lactic acidosis.(1-3) PREDISPOSING FACTORS: Pre-existing renal dysfunction may contribute to decreased clearance of metformin. Other factors which may increase the risk for lactic acidosis include age greater than 65 years, dehydration, metabolic acidosis, sepsis, a history of hepatic impairment, alcoholism, or heart failure.(1-4) PATIENT MANAGEMENT: Evaluate renal function prior to contrast procedure. According to manufacturer recommendations, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with a history of liver disease, alcoholism, heart failure, or if contrast is to be administered intra-arterially. When contrast is to be administered by other routes, discontinue metformin at the time of, or prior to, the procedure for patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is stable. Discontinuation of metformin is not required if eGFR is > 60 mL/min/1.73 m2.(4) According to American College of Radiology guidelines, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with acute kidney injury or chronic kidney disease (Stage IV or V or eGFR < 30 mL/min/1.73 m2), or who are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteries. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is normal. Discontinuation of metformin is not required in patients with no evidence of acute kidney injury and with eGFR >= 30 mL/min/m2.(5) DISCUSSION: An FDA review of the medical literature showed that metformin may be safely used in patients with mild or moderate renal impairment, resulting in modifications of prescribing recommendations and method for evaluation of renal function.(4) A clinical review of 33 patients on metformin who had received contrast media showed elevations in serum creatinine of the four patients with baseline elevations. The 29 patients with normal baseline renal function showed no elevations after administration of contrast media. The authors recommend that a baseline serum creatinine is obtained for all patients and that metformin should only be discontinued in patients with baseline elevations.(6) A retrospective study of ninety-seven patients currently taking metformin underwent a radiologic procedure with contrast media. Of these patients, 4 developed contrast material associated nephropathy and eight patients had an increased risk of lactic acidosis, with a baseline serum creatinine <1.5mg/dl.(7) A prospective clinical trial with 50 diabetic patients on metformin with baseline serum creatinine <1.47mg/dl showed no statistical difference in renal function before and 48 hours after administration of contrast media. The authors recommend a baseline serum creatinine for all patients and suggest that temporary discontinuation of metformin may not be necessary when baseline renal function is <1.47mg/dl.(8) A systematic review of the literature reveals that 17 of 18 case reports of metformin-induced lactic acidosis involved patients with renal dysfunction prior to administration of contrast media. The authors recommend a baseline serum creatinine in all patients and if renal dysfunction is present, metformin should be discontinued for 48 hours before and after administration of contrast media. The authors recommend follow-up creatinine measurement in patients with prior renal impairment or known comorbidities affecting lactate levels.(9) |
CONRAY, CONRAY-30, CONRAY-43, CYSTO-CONRAY II, CYSTOGRAFIN, CYSTOGRAFIN-DILUTE, IODIXANOL, IODOQUINOL, IOHEXOL, IOMERON 350, IOPAMIDOL, IOPANOIC ACID, ISOVUE-200, ISOVUE-250, ISOVUE-300, ISOVUE-370, ISOVUE-M 200, ISOVUE-M 300, LIPIODOL, OMNIPAQUE, OPTIRAY 240, OPTIRAY 300, OPTIRAY 320, OPTIRAY 350, SINOGRAFIN, ULTRAVIST, VISIPAQUE |
| Antidiabetic Agents/Gatifloxacin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of gatifloxacin may result in hypoglycemia and/or hyperglycemia.(1-4) Hypoglycemia is more common during the first three days of concurrent therapy. Hyperglycemia is more common after the first three days of concurrent therapy.(2) PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(2) PATIENT MANAGEMENT: Patients receiving concurrent gatifloxacin should be closely monitored for hypoglycemia during the first three days of concurrent therapy and for hyperglycemia after the first three days of concurrent therapy. Patients should be instructed to discontinue gatifloxacin if hypoglycemia or hyperglycemia occur.(2) DISCUSSION: Hypoglycemia has been reported with gatifloxacin and glyburide(1,5,6) or glimepiride.(7) In a study in patients with type 2 diabetes mellitus, concurrent gatifloxacin (400 mg daily for 10 days) had no effect on the pharmacokinetics of glyburide (steady state daily regimen); however, pharmacodynamic interactions have been reported.(2) Health Canada has received 19 reports of hypoglycemia in patients taking gatifloxacin. Seventeen of these involved concurrent hypoglycemic agents. Health Canada has received 2 reports of hyperglycemia in patients taking gatifloxacin and hypoglycemic agents. Health Canada has received 2 reports of patients experiencing hypoglycemia and hyperglycemia during concurrent gatifloxacin and hypoglycemic agents.(3) In a study, 13 reports of dysglycemia were reported in patients taking gatifloxacin. Ten of these patients had diabetes mellitus and were on concurrent hypoglycemic agents. Of these ten patients, nine patients experienced hypoglycemia, while one patient experienced hyperglycemia.(8) |
GATIFLOXACIN SESQUIHYDRATE |
| Metformin/Tafenoquine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine inhibits elimination by these pathways.(2) CLINICAL EFFECTS: Use of tafenoquine may increase levels of metformin, which may result in lactic acidosis. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with OCT2 and MATE1 substrates, such as metformin, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(2) Evaluate patient's renal function and consider discontinuation in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio. DISCUSSION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine is believed to inhibit the OCT2 and MATE1 pathways.(2) |
ARAKODA, KRINTAFEL |
| Selected BCRP Substrates/Darolutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible. DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3) |
NUBEQA |
| Selected BCRP Substrates/Capmatinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Capmatinib inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of capmatinib with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of capmatinib states that the concurrent use of narrow therapeutic index BCRP substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index BCRP substrate should be decreased according to the substrate prescribing information.(1) DISCUSSION: In a study, capmatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax) by 204%.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, and mitoxantrone.(1-2) |
TABRECTA |
| Selected BCRP Substrates/Oteseconazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oteseconazole is an inhibitor of the BCRP transporter, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of oteseconazole with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of oteseconazole states that the lowest possible starting dose of the BCRP substrate should be used and to consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1) DISCUSSION: Oteseconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, and sulfasalazine.(1-2) |
VIVJOA |
There are 32 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Sulfonylureas/Systemic Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and sulfonylureas. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2) |
BETAPACE, BETAPACE AF, CARVEDILOL, CARVEDILOL ER, COREG, COREG CR, CORGARD, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, LABETALOL HCL, LABETALOL HCL-WATER, NADOLOL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TIMOLOL MALEATE |
| Antidiabetics/Epinephrine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Gluconeogenesis, glycogenolysis, and lipolysis are increased by epinephrine. Also, insulin secretion and glucose uptake by peripheral tissues are decreased by epinephrine. CLINICAL EFFECTS: Increased blood glucose resulting in decreased effectiveness of the antidiabetic agent. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Caution when starting or stopping epinephrine in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels. DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence. |
ADRENALIN, ARTICADENT DENTAL, ARTICAINE-EPINEPHRINE, ARTICAINE-EPINEPHRINE BIT, BUFFERED LIDOCAINE-EPINEPHRINE, BUPIVACAINE HCL-EPINEPHRINE, BUPIVACAINE-DEXAMETH-EPINEPHRN, CITANEST FORTE DENTAL, EPINEPHRINE, EPINEPHRINE BITARTR-0.9% NACL, EPINEPHRINE BITARTRATE, EPINEPHRINE BITARTRATE-NACL, EPINEPHRINE CONVENIENCE KIT, EPINEPHRINE HCL-0.9% NACL, EPINEPHRINE HCL-D5W, EPINEPHRINE-0.9% NACL, EPINEPHRINE-D5W, EPINEPHRINE-NACL, LIDOCAINE HCL-EPINEPHRINE, LIDOCAINE HCL-EPINEPHRINE-NACL, LIDOCAINE-EPINEPHRINE, LIGNOSPAN STANDARD, MARCAINE-EPINEPHRINE, ORABLOC, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RACEPINEPHRINE HCL, SENSORCAINE-EPINEPHRINE, SENSORCAINE-MPF EPINEPHRINE, SEPTOCAINE, VIVACAINE, XYLOCAINE DENTAL-EPINEPHRINE, XYLOCAINE WITH EPINEPHRINE, XYLOCAINE-MPF WITH EPINEPHRINE |
| Selected Antidiabetics/MAOIs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs. CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia. DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI. Furazolidone is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO. |
AZILECT, EMSAM, FURAZOLIDONE, LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, ZELAPAR, ZYVOX |
| Antidiabetics, Oral/Oxy-Phenylbutazone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Phenylbutazone may displace antidiabetics from plasma protein binding sites. Renal elimination of the active metabolite of acetohexamide may be reduced. Finally, tolbutamide metabolism may be decreased. CLINICAL EFFECTS: Potentiation of antidiabetic effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. DISCUSSION: This interaction is well documented. |
PHENYLBUTAZONE |
| Antidiabetics, Oral/Sulfonamide Antibacterials SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. However, it is speculated that sulfonamides may inhibit hepatic metabolism and/or displace oral antidiabetics from plasma protein binding sites. CLINICAL EFFECTS: Increased serum levels of antidiabetics with potentiation of hypoglycemic effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. DISCUSSION: Additional documentation is necessary to confirm this interaction. |
BACTRIM, BACTRIM DS, SULFAMETHOXAZOLE, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, SULFISOXAZOLE |
| Antidiabetics, Oral/Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Complex. Salicylates appear to have intrinsic glucose lowering properties via several proposed mechanisms. Also, salicylates may cause protein binding displacement of antidiabetics. Decreased renal clearance may also occur. CLINICAL EFFECTS: Potentiation of hypoglycemic effects may be observed. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. Particular caution should be taken when salicylates are started or stopped in patients previously stabilized on antidiabetics. DISCUSSION: Additional documentation is necessary to confirm this potential interaction. |
ACETYL SALICYLIC ACID, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BALSALAZIDE DISODIUM, BISMUTH SUBSALICYLATE, BUTALBITAL-ASPIRIN-CAFFEINE, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHOLINE MAGNESIUM TRISALICYLAT, COLAZAL, DISALCID, DURLAZA, MB CAPS, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, PHENYL SALICYLATE, SALSALATE, SODIUM SALICYLATE, URELLE, URETRON D-S, URIBEL TABS, URIMAR-T, URNEVA, URO-MP, URO-SP, YOSPRALA |
| Thiazides/Antidiabetics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Thiazides antagonize hypoglycemic effects of antidiabetics due to intrinsic hyperglycemic activity. CLINICAL EFFECTS: Impaired glucose tolerance and diminished hypoglycemic effects of antidiabetics may occur. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Caution when starting or stopping thiazides in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels. DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence. A cross-sectional study of 425 outpatients found 46 patients with 86 suspected drug interactions resulting in uncontrolled glycemia. Recorded drug interactions included hydrochlorothiazide-gliclazide (22.1%), hydrochlorothiazide-insulins (2.3%), and chlorothiazide-gliclazide (1.2%). Using the drug interaction probability scale (DIPS), these drug interactions were categorized as possible.(2) |
ACCURETIC, AMILORIDE-HYDROCHLOROTHIAZIDE, AMLODIPINE-VALSARTAN-HCTZ, ATACAND HCT, ATENOLOL-CHLORTHALIDONE, AVALIDE, BENAZEPRIL-HYDROCHLOROTHIAZIDE, BENICAR HCT, BISOPROLOL-HYDROCHLOROTHIAZIDE, CANDESARTAN-HYDROCHLOROTHIAZID, CAPTOPRIL-HYDROCHLOROTHIAZIDE, CHLOROTHIAZIDE, CHLOROTHIAZIDE SODIUM, CHLORTHALIDONE, DIOVAN HCT, DIURIL, EDARBYCLOR, ENALAPRIL-HYDROCHLOROTHIAZIDE, EXFORGE HCT, FOSINOPRIL-HYDROCHLOROTHIAZIDE, HEMICLOR, HYDROCHLOROTHIAZIDE, HYZAAR, INDAPAMIDE, INZIRQO, IRBESARTAN-HYDROCHLOROTHIAZIDE, LISINOPRIL-HYDROCHLOROTHIAZIDE, LOSARTAN-HYDROCHLOROTHIAZIDE, LOTENSIN HCT, METHYLDOPA-HYDROCHLOROTHIAZIDE, METOLAZONE, METOPROLOL-HYDROCHLOROTHIAZIDE, MICARDIS HCT, OLMESARTAN-AMLODIPINE-HCTZ, OLMESARTAN-HYDROCHLOROTHIAZIDE, PROPRANOLOL-HYDROCHLOROTHIAZID, QUINAPRIL-HYDROCHLOROTHIAZIDE, SPIRONOLACTONE-HCTZ, TELMISARTAN-HYDROCHLOROTHIAZID, TENORETIC 100, TENORETIC 50, THALITONE, TRIAMTERENE-HYDROCHLOROTHIAZID, TRIBENZOR, TRICHLORMETHIAZIDE, VALSARTAN-HYDROCHLOROTHIAZIDE, VASERETIC, ZESTORETIC |
| Sulfonylureas/Diazoxide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: In a patient stabilized on a sulfonylurea hypoglycemic agent, hyperglycemia may occur following the addition of diazoxide to the treatment. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood glucose and adjust the dose of the sulfonylurea hypoglycemic agent as needed. DISCUSSION: The concurrent administration of a sulfonylurea hypoglycemic agent and diazoxide has been beneficial in treating chlorpropamide-induced hypoglycemia and diazoxide-induced hyperglycemia. These reports indicate a potential problem if these agents are administered without proper monitoring of the patient's blood glucose. |
DIAZOXIDE, PROGLYCEM |
| Azole Antifungals/Sulfonylureas SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Azole antifungals inhibit the metabolism of sulfonylureas. CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted. DISCUSSION: Prospective and retrospective studies in healthy subjects have documented an interaction between the sulfonylureas and fluconazole, ketoconazole, and miconazole. In vitro studies have shown the metabolism of sulfonylureas to be inhibited by ketoconazole, clotrimazole, and miconazole. In 13 healthy males, fluconazole increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by 19% and 49%, respectively. In 20 healthy males, fluconazole increased the Cmax and AUC of a single dose of glyburide (5 mg) by 19% and 44%, respectively. In 13 healthy males, fluconazole increased the Cmax and AUC of a single dose of tolbutamide (500 mg) by 11% and 26%, respectively. Although itraconazole was found to have no effect on tolbutamide clearance in a study in rats, additional information is needed to determine if an interaction occurs. In healthy subjects, glucose concentrations decreased during concurrent therapy with glipizide and posaconazole. Voriconazole has been shown to inhibit CYP2C9. |
CLOTRIMAZOLE, DIFLUCAN, FLUCONAZOLE, FLUCONAZOLE-NACL, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, MICONAZOLE, MICONAZOLE 3, MICONAZOLE NITRATE, NOXAFIL, ORAVIG, POSACONAZOLE, SPORANOX, TOLSURA, VFEND, VFEND IV, VORICONAZOLE |
| Selected Antidiabetic Agents/Clarithromycin; Telithromycin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Clarithromycin and telithromycin may inhibit the metabolism of glipizide(1) and glyburide(1,2) by CYP3A4. CLINICAL EFFECTS: Concurrent use of glipizide or glyburide and clarithromycin or telithromycin may result in elevated levels of and effects from glipizide and glyburide, including hypoglycemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on glipizide or glyburide should be closely monitored if clarithromycin or telithromycin is added to or withdrawn from concurrent therapy. A dosage adjustment of the antidiabetic agent may be required during macrolide therapy. DISCUSSION: In a study in 12 healthy subjects, clarithromycin (250 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of glyburide (0.875 mg) by 1.35-fold and 1.25-fold, respectively.(2) Severe hypoglycemia has been reported in patients following the addition of clarithromycin to glipizide and glyburide therapy.(1) |
CLARITHROMYCIN, CLARITHROMYCIN ER, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK |
| Bupropion/Hypoglycemics; Insulin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bupropion can lower the seizure threshold and when given concurrently with other medications that also lower the threshold there is an increased risk of seizure.(1,2) CLINICAL EFFECTS: Concurrent use of bupropion and hypoglycemics or insulin may increase the risk of seizure.(1,2) PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids, theophylline).(1,2) PATIENT MANAGEMENT: The use of bupropion in patients treated with oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) |
APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL |
| Glinides; Sulfonylureas/Ethyl Alcohol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Alcohol can induce hypoglycemia and interfere with gluconeogenesis in the liver by means of intrinsic hypoglycemic activity.(1-3) Some alcoholic beverages may increase serum glucose levels from their high carbohydrate content.(4) Chronic alcohol intake may decrease half-life of sulfonylureas by increasing liver metabolism.(1, 5-8) CLINICAL EFFECTS: Alcohol consumption while on a glinide or sulfonylureas may result in unpredictable and varied reactions, ranging from mild flushing to severe hypoglycemic reactions. Alcohol consumption during chlorpropamide therapy has resulted in a disulfiram-like reaction. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Diabetics should be cautioned about the effects of alcohol consumption on diabetic control, possible flushing with concurrent use, and about unsuspected sources of alcohol such as medications. Patients on chlorpropamide therapy should be counseled about the possibility of a disulfiram-like reaction to alcohol consumption. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (21): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation DISCUSSION: Chlorpropamide has been reported to induce facial flushing (5,9-18) and a disulfiram-like reaction(4,9,10,18,19) following alcohol consumption. Tolbutamide has been shown to interact with alcohol in nonalcoholic diabetic patients, alcoholics, and normal subjects.(2,3,6-8,16,17) There is one report of reduced tolerance for alcohol in a patient on tolazamide therapy.(20) In a study in 10 normal subjects, administration of ethanol with glipizide resulted in a delay in return to fasting glucose levels. The time of onset and the extent of hypoglycemia were not altered.(21) Glipizide and glyburide have been reported to have a very low incidence of disulfiram-like reactions with concurrent alcohol; however, in one study, 5 of 11 patients taking glyburide developed flushing after a test dose of alcohol.(18) |
ALCOHOL,DEHYDRATED |
| Selected Antidiabetic Agents/Selected Quinolones SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma. PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5) PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety. DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13) |
AVELOX IV, BAXDELA, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, LEVOFLOXACIN, LEVOFLOXACIN HEMIHYDRATE, LEVOFLOXACIN-D5W, MOXIFLOXACIN, MOXIFLOXACIN HCL, OFLOXACIN |
| Metformin/MATE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal tubular secretion of metformin.(1) CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent. PATIENT MANAGEMENT: Use an alternative agent if possible. If both drugs are given, monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Dosage of either agent may need to be adjusted.(1) DISCUSSION: In a study of normal healthy volunteers, concurrent metformin and oral cimetidine increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) MATE inhibitors include: cimetidine, pyrimethamine, and risdiplam.(3) |
CIMETIDINE, DARAPRIM, EVRYSDI, PYRIMETHAMINE |
| Metformin/Cephalexin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cephalexin may inhibit the renal tubular secretion of metformin.(1,2) CLINICAL EFFECTS: Concurrent use of cephalexin may result in increased levels and clinical effects of metformin,(1,2) as well as an increased risk of lactic acidosis. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: Patients maintained on metformin should be closely monitored when cephalexin is initiated and discontinued. The dosage of metformin may need to be adjusted.(1) DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, concurrent metformin (500 mg) and cephalexin (500 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metformin by 34% and 24%, respectively. Metformin renal clearance decreased by 14%.(1,2) |
CEPHALEXIN |
| Glimepiride; Glipizide; Glyburide/Colesevelam SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Colesevelam may bind to glimepiride, glipizide, and glyburide in the gastrointestinal track, preventing their absorption.(1,2) CLINICAL EFFECTS: Simultaneous administration of colesevelam may result in decreased levels and effectiveness of glimepiride,(1) glipizide,(1) or glyburide.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Glyburide,(1) glipizide,(3) and glimepiride(4) should be administered four hours before colesevelam. DISCUSSION: When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of glimepiride (4 mg) decreased by 18% and by 8%, respectively. When administered 4 hours prior to colesevelam, the AUC of glimepiride decreased by 6% and the Cmax increased 3%.(1) When administered with colesevelam (3.75 g), the AUC and Cmax of glipizide (20 mg) decreased by 12% and by 13%, respectively. When administered 4 hours prior to colesevelam, the AUC of glipizide decreased by 4%. There was no effect on glipizide Cmax when glipizide and colesevelam were separated by 4 hours.(1) When administered with colesevelam (3.75 g), AUC and Cmax of glyburide (3 mg) decreased by 32% and by 47%, respectively. When administered 1 hour prior to colesevelam, the AUC and Cmax of glyburide decreased by 20% and 15%, respectively. When administered 4 hours prior to colesevelam, the AUC and Cmax of glyburide decreased by 7% and 4%, respectively.(1,2) |
COLESEVELAM HCL, WELCHOL |
| Metformin/Ranolazine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ranolazine may decrease renal elimination of metformin by inhibiting OCT-2.(1) CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of and toxicity from metformin.(1) PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metformin and ranolazine. In patients receiving 1000 mg ranolazine twice daily, limit the dose of metformin to 1700 mg daily.(1) DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased exposure of metformin by 80%. Ranolazine (500 mg BID) increased metformin exposure by 40%.(1) |
ASPRUZYO SPRINKLE, RANOLAZINE ER |
| Metformin/Carbonic Anhydrase Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1) CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent. PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1) DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1) |
ACETAZOLAMIDE, ACETAZOLAMIDE ER, ACETAZOLAMIDE SODIUM, DICHLORPHENAMIDE, EPRONTIA, KEVEYIS, METHAZOLAMIDE, ORMALVI, QSYMIA, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TOPIRAMATE ER SPRINKLE, TROKENDI XR, ZONEGRAN, ZONISADE, ZONISAMIDE |
| Metformin/Dolutegravir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dolutegravir may inhibit the renal organic cation transporter, OCT2, responsible for the elimination of metformin.(1) CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: With concomitant use, assess the benefit and risk of metformin in patients on dolutegravir. When starting or stopping dolutegravir, the metformin dose may require an adjustment. Monitor blood glucose when initiating concomitant use and after stopping dolutegravir.(1) Monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio.(1) DISCUSSION: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of metformin.(1) In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of metformin by 66% and 79%, respectively. In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg twice daily) increased the Cmax and AUC of metformin by 111% and 145%, respectively.(1) |
DOVATO, JULUCA, TIVICAY, TIVICAY PD, TRIUMEQ, TRIUMEQ PD |
| Metformin/Trimethoprim SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Trimethoprim inhibits elimination by these pathways. CLINICAL EFFECTS: Use of trimethoprim may increase levels of metformin, which may result in lactic acidosis. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin and/or trimethoprim be adjusted as needed. Consider the benefits and risks of concomitant use.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio. DISCUSSION: Trimethoprim was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney). (2) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area under the curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%. (3) 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (4) |
BACTRIM, BACTRIM DS, PRIMSOL, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED |
| Metformin/Vandetanib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Renal tubular secretion of metformin is mediated by organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein (MATE) transporter. Vandetanib inhibits elimination by the OCT2 and MATE pathways.(1) CLINICAL EFFECTS: Use of vandetanib may increase levels of metformin. Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.(1) PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent. PATIENT MANAGEMENT: Use an alternative agent if possible. The US labeling for vandetanib recommends caution with concomitant use of metformin and close monitoring for metformin toxicity.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio. DISCUSSION: A study in 13 healthy subjects receiving a single 1,000 mg dose of metformin 3 hours after a single 800 mg dose of vandetanib resulted in increases in metformin area-under-curve (AUC) of 74% and maximum concentration (Cmax) of 50% with coadministration compared to metformin alone.(1) In a study of normal healthy volunteers, concurrent metformin and oral cimetidine (MATE inhibitor) increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) |
CAPRELSA |
| Patiromer/Metformin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Patiromer may bind to metformin.(1) CLINICAL EFFECTS: Concurrent use may result in decreased gastrointestinal absorption and loss of efficacy of metformin.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of patiromer recommends that you administer patiromer at least 3 hours before or 3 hours after metformin.(1) DISCUSSION: A study in healthy volunteers showed that patiromer decreased the systemic exposure of coadministered metformin. No interaction was seen when these drugs were taken 3 hours apart.(1) |
VELTASSA |
| Antidiabetics/Selected Ophthalmic Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.(1,2) CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(3) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(4) There have been case reports of hypoglycemia following the addition of ophthalmic timolol to a diabetic regimen.(5-7) Studies have shown that ophthalmic beta-blockers, especially the aqueous solution, have significant systemic absorption and do not undergo first-pass metabolism.(8,9) |
BETIMOL, BRIMONIDINE TARTRATE-TIMOLOL, CARTEOLOL HCL, COMBIGAN, COSOPT, COSOPT PF, DORZOLAMIDE-TIMOLOL, ISTALOL, LEVOBUNOLOL HCL, TIMOLOL, TIMOLOL MALEATE, TIMOLOL-BIMATOPROST, TIMOLOL-BRIMONI-DORZOL-BIMATOP, TIMOLOL-BRIMONIDIN-DORZOLAMIDE, TIMOLOL-DORZOLAMIDE-BIMATOPRST, TIMOPTIC OCUDOSE |
| Metformin/Bictegravir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Bictegravir inhibits elimination by these pathways.(1,2) CLINICAL EFFECTS: Use of bictegravir may increase levels of metformin, which may result in lactic acidosis. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio. DISCUSSION: Bictegravir is an inhibitor of OCT2 and MATE1.(2) Trimethoprim, an inhibitor of OCT2 and MATE1, was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney).(3) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area-under-curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%.(4) In a study in 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (5) |
BIKTARVY |
| Lacosamide/Sodium Channel Blockers; Potassium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1) DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2) |
LACOSAMIDE, MOTPOLY XR, VIMPAT |
| Selected Antidiabetic Agents/Chloroquine; Hydroxychloroquine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Chloroquine and hydroxychloroquine may increase insulin sensitivity by inhibiting insulin metabolism and inflammation and increasing cellular uptake of glucose and glycogen synthesis.(1,2) These effects may result in additive hypoglycemia with anti-diabetic agents. CLINICAL EFFECTS: Concurrent use of chloroquine or hydroxychloroquine and antidiabetic agents may result in severe hypoglycemia.(3) Hypoglycemia can lead to coma. PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction. PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with chloroquine or hydroxychloroquine should be closely monitored for hypoglycemia. A decrease in the dose of insulin or other anti-diabetic medications may be required. Patients should be advised of the risk and symptoms of hypoglycemia and to contact their doctor if hypoglycemia occurs.(3) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety. DISCUSSION: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening.(3) Concomitant hypoglycemic agents may increase the risk and/or severity of this effect. A 77 year old man who was stable on twice daily insulin suffered two episodes of hypoglycemic coma 2 weeks after starting prednisone 5 mg daily and hydroxychloroquine 400 mg daily for rheumatoid arthritis. His insulin dosage required a decrease of 37%.(4) Many studies have investigated the glucose-lowering effect of hydroxychloroquine. In a clinical trial of type II diabetics on maximal doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin A1C (HbA1C) up to 1% more than placebo.(5) Another clinical trial of type II diabetics on metformin and glimepiride or gliclazide found that hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG), post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone 15 mg daily at 24 weeks.(6) In a prospective observational study, 250 uncontrolled type II diabetics on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from 8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%, and SGLT-2 inhibitors were discontinued in most patients.(7) |
CHLOROQUINE PHOSPHATE, HYDROXYCHLOROQUINE SULFATE, PLAQUENIL, SOVUNA |
| BCRP or OATP1B1 Substrates/Eltrombopag SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1) DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: ciprofloxacin, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1) |
ALVAIZ, PROMACTA |
| OATP1B1 Substrates/Midostaurin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1) DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin. |
RYDAPT |
| Glyburide/Safinamide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates such as glyburide.(1) The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs. CLINICAL EFFECTS: Administration of safinamide with glyburide may result in elevated levels of and toxicity from glyburide, including additive hypoglycemia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The EMA and UK manufacturer of safinamide recommend monitoring patients who are on concomitant drugs that are substrates of BCRP, including glyburide. Dose adjustment of glyburide should be performed according to the prescribing information for glyburide.(1) Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.(1) DISCUSSION: Safinamide transiently inhibits BCRP in the small intestine, which may result in increased absorption of BCRP substrates.(1) In a clinical study, safinamide increased the AUC of rosuvastatin, a BCRP substrate, by 1.25- to 2-fold.(1,3) |
XADAGO |
| Selected BCRP Substrates/Momelotinib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Momelotinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of BCRP substrates.(1) CLINICAL EFFECTS: Administration of momelotinib with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of momelotinib states concurrent use with BCRP substrates should be approached with caution. If concurrent use is warranted, consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1) DISCUSSION: Momelotinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%, respectively.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-2) |
OJJAARA |
| Sulfonylureas/Amiodarone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Amiodarone may decrease the metabolism of sulfonylureas by inhibiting CYP2C9. Amiodarone is a moderate CYP2C9 inhibitor.(1-5) CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia. PREDISPOSING FACTORS: This interaction may be more likely in patients using higher doses of amiodarone and who use amiodarone for greater than 180 days.(6) PATIENT MANAGEMENT: Closely monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted when initiating or discontinuing amiodarone therapy. DISCUSSION: In a nested case control study, concurrent use of amiodarone and sulfonylureas increased the risk of severe hypoglycemia by 56% (95% CI:0.98-2.46). In patients on sulfonylureas, amiodarone use greater than 180 days and at higher daily doses was associated with a 2.08-fold and a 2.21-fold increase in severe hypoglycemia, respectively, which was statistically significant.(6) |
AMIODARONE HCL, AMIODARONE HCL-D5W, NEXTERONE, PACERONE |
| Metformin/OCT2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of metformin by OCT2 in the kidneys.(1) CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from metformin.(1) PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels higher than 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of metformin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of metformin and consider dosage reduction of metformin.(1) DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) OCT2 inhibitors linked to this monograph include: arimoclomol, givinostat, trilaciclib, and vimseltinib.(2) |
DUVYZAT, MIPLYFFA, ROMVIMZA |
The following contraindication information is available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 8 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Alcohol intoxication |
| Alcohol use disorder |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Dehydration |
| Metabolic acidosis |
| Sepsis |
| Shock |
There are 14 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute decompensated heart failure |
| Acute myocardial infarction |
| Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Debilitation |
| Disease of liver |
| Hepatic porphyria |
| High fever >101 degrees fahrenheit |
| Hypoglycemic disorder |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Severe diarrhea |
| Severe hypoxemia |
| Severe vomiting |
There are 13 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Alcohol use disorder |
| Debilitation |
| Disease of liver |
| Fever |
| Glucose-6-phosphate dehydrogenase (g6Pd) deficiency |
| Hemolytic anemia |
| Hypothyroidism |
| Infection |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Pituitary insufficiency |
| Primary adrenocortical insufficiency |
| Severe hepatic disease |
| Vitamin b12 deficiency |
The following adverse reaction information is available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 34 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Hypoglycemic disorder Weight gain |
Dyspnea Erythema multiforme Exfoliative dermatitis |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Accommodation disorder Acute respiratory distress syndrome Agranulocytosis Angioedema Aplastic anemia Autoimmune hemolytic anemia Autoimmune hepatitis Bullous dermatitis Cholestasis Cholestatic hepatitis Eosinophilia Hemolytic anemia Hepatic failure Hepatic porphyria Hepatitis Hepatocellular damage Hypoglycemic disorder Hyponatremia Lactic acidosis Leukopenia Maculopapular rash Megaloblastic anemia Obstructive hyperbilirubinemia Pancreatitis Pancytopenia Porphyria cutanea tarda Thrombocytopenic disorder Vasculitis |
There are 35 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Constipation Diarrhea Dysgeusia Epigastric fullness Flatulence Headache disorder Heartburn Nausea Upper respiratory infection Vitamin b12 deficiency Vomiting Weight loss |
Acute abdominal pain Chills Constipation Dizziness Dyspepsia Flu-like symptoms Flushing General weakness Hyperhidrosis Myalgia Nail disorders Palpitations Rhinitis |
| Rare/Very Rare |
|---|
|
Anticholinergic toxicity Arthralgia Drowsy Myalgia Pruritus of skin Skin photosensitivity Skin rash Urticaria Visual changes |
The following precautions are available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
When a glyburide dosage 6250 times the maximum recommended human dosage was given to rats, a shortening of long bones (humerus and femur) in rat pups was noted. These effects were observed during the period of lactation and not during organogenesis. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.
Use of glyburide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible) or when the potential benefit justifies the possible risks to the fetus. Glyburide has been used in some pregnant women without unusual adverse effects. In a prospective, comparative clinical trial in women with gestational diabetes, treatment with glyburide (mean daily dosage 9 mg, range 2.5-20 mg) initiated in the second trimester (11-33 weeks gestation) and continued until delivery resulted in similar degrees of glycemic control and perinatal outcomes as treatment with insulin human (mean daily dosage: 85 units).
The incidence of hypoglycemia in neonates whose mothers received either insulin or glyburide therapy also was similar. Additional studies in a larger number of patients are needed to establish the safety of glyburide in gestational diabetes. In a retrospective study, hypoglycemia occurred and persisted for up to 2 days or longer in a few neonates whose mothers had received glyburide up to the time of delivery.
Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives. To minimize the risk of neonatal hypoglycemia if glyburide is used during pregnancy, the manufacturers recommend that the drug be discontinued at least 2 weeks before the expected delivery date. Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus.
Determination of fetal concentrations of metformin suggest that a partial placental barrier to the drug exists. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus who have an HbA1c exceeding 7 and has been reported to be as high as 20-25% in women with a HbA1c exceeding 10.
The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Available studies on the use of metformin in pregnant women have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Metformin should be used during pregnancy only when clearly needed.
Use of glyburide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible) or when the potential benefit justifies the possible risks to the fetus. Glyburide has been used in some pregnant women without unusual adverse effects. In a prospective, comparative clinical trial in women with gestational diabetes, treatment with glyburide (mean daily dosage 9 mg, range 2.5-20 mg) initiated in the second trimester (11-33 weeks gestation) and continued until delivery resulted in similar degrees of glycemic control and perinatal outcomes as treatment with insulin human (mean daily dosage: 85 units).
The incidence of hypoglycemia in neonates whose mothers received either insulin or glyburide therapy also was similar. Additional studies in a larger number of patients are needed to establish the safety of glyburide in gestational diabetes. In a retrospective study, hypoglycemia occurred and persisted for up to 2 days or longer in a few neonates whose mothers had received glyburide up to the time of delivery.
Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives. To minimize the risk of neonatal hypoglycemia if glyburide is used during pregnancy, the manufacturers recommend that the drug be discontinued at least 2 weeks before the expected delivery date. Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus.
Determination of fetal concentrations of metformin suggest that a partial placental barrier to the drug exists. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus who have an HbA1c exceeding 7 and has been reported to be as high as 20-25% in women with a HbA1c exceeding 10.
The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Available studies on the use of metformin in pregnant women have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Metformin should be used during pregnancy only when clearly needed.
Although it is not known whether glyburide is distributed into milk, some sulfonylurea antidiabetic agents are distributed into milk. Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If glyburide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.
Metformin is distributed into milk in lactating rats. Limited data indicate that small amounts of metformin also are distributed into breast milk in humans. In a study in 7 nursing women who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35
and the overall average concentration in milk over the dosing interval was 0.27 mg/L. Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated.
In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42
and 0.39 mcg/mL, respectively, in breast milk. The mean milk-to-serum ratio was 0.63
and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%. Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL).
The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the drug and potential adverse effects on the breastfed child (e.g., hypoglycemia). Breastfed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).
Metformin is distributed into milk in lactating rats. Limited data indicate that small amounts of metformin also are distributed into breast milk in humans. In a study in 7 nursing women who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35
and the overall average concentration in milk over the dosing interval was 0.27 mg/L. Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated.
In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42
and 0.39 mcg/mL, respectively, in breast milk. The mean milk-to-serum ratio was 0.63
and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%. Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL).
The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the drug and potential adverse effects on the breastfed child (e.g., hypoglycemia). Breastfed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl):
WARNING: Rarely, too much metformin can build up in the body and cause a serious (sometimes fatal) condition called lactic acidosis. Lactic acidosis is more likely if you are an older adult, if you have kidney or liver disease, dehydration, heart failure, heavy alcohol use, if you have surgery, if you have X-ray or scanning procedures that use iodinated contrast, or if you are using certain drugs. For some conditions, your doctor may tell you to stop taking this medication for a short time.
Ask your doctor or pharmacist for more details. Stop taking this medication and get medical help right away if you have any symptoms of lactic acidosis, such as unusual tiredness, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, or stomach pain with nausea/vomiting/diarrhea.
WARNING: Rarely, too much metformin can build up in the body and cause a serious (sometimes fatal) condition called lactic acidosis. Lactic acidosis is more likely if you are an older adult, if you have kidney or liver disease, dehydration, heart failure, heavy alcohol use, if you have surgery, if you have X-ray or scanning procedures that use iodinated contrast, or if you are using certain drugs. For some conditions, your doctor may tell you to stop taking this medication for a short time.
Ask your doctor or pharmacist for more details. Stop taking this medication and get medical help right away if you have any symptoms of lactic acidosis, such as unusual tiredness, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, or stomach pain with nausea/vomiting/diarrhea.
The following icd codes are available for GLYBURIDE-METFORMIN HCL (glyburide/metformin hcl)'s list of indications:
| Type 2 diabetes mellitus | |
| E08 | Diabetes mellitus due to underlying condition |
| E08.0 | Diabetes mellitus due to underlying condition with hyperosmolarity |
| E08.00 | Diabetes mellitus due to underlying condition with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHc) |
| E08.01 | Diabetes mellitus due to underlying condition with hyperosmolarity with coma |
| E08.1 | Diabetes mellitus due to underlying condition with ketoacidosis |
| E08.10 | Diabetes mellitus due to underlying condition with ketoacidosis without coma |
| E08.11 | Diabetes mellitus due to underlying condition with ketoacidosis with coma |
| E08.2 | Diabetes mellitus due to underlying condition with kidney complications |
| E08.21 | Diabetes mellitus due to underlying condition with diabetic nephropathy |
| E08.22 | Diabetes mellitus due to underlying condition with diabetic chronic kidney disease |
| E08.29 | Diabetes mellitus due to underlying condition with other diabetic kidney complication |
| E08.3 | Diabetes mellitus due to underlying condition with ophthalmic complications |
| E08.31 | Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy |
| E08.311 | Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy with macular edema |
| E08.319 | Diabetes mellitus due to underlying condition with unspecified diabetic retinopathy without macular edema |
| E08.32 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy |
| E08.321 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy with macular edema |
| E08.3211 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy with macular edema, right eye |
| E08.3212 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy with macular edema, left eye |
| E08.3213 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy with macular edema, bilateral |
| E08.3219 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E08.329 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy without macular edema |
| E08.3291 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy without macular edema, right eye |
| E08.3292 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy without macular edema, left eye |
| E08.3293 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy without macular edema, bilateral |
| E08.3299 | Diabetes mellitus due to underlying condition with mild nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E08.33 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy |
| E08.331 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy with macular edema |
| E08.3311 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy with macular edema, right eye |
| E08.3312 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy with macular edema, left eye |
| E08.3313 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy with macular edema, bilateral |
| E08.3319 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E08.339 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy without macular edema |
| E08.3391 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy without macular edema, right eye |
| E08.3392 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy without macular edema, left eye |
| E08.3393 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy without macular edema, bilateral |
| E08.3399 | Diabetes mellitus due to underlying condition with moderate nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E08.34 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy |
| E08.341 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy with macular edema |
| E08.3411 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy with macular edema, right eye |
| E08.3412 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy with macular edema, left eye |
| E08.3413 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy with macular edema, bilateral |
| E08.3419 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E08.349 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy without macular edema |
| E08.3491 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy without macular edema, right eye |
| E08.3492 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy without macular edema, left eye |
| E08.3493 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy without macular edema, bilateral |
| E08.3499 | Diabetes mellitus due to underlying condition with severe nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E08.35 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy |
| E08.351 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with macular edema |
| E08.3511 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with macular edema, right eye |
| E08.3512 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with macular edema, left eye |
| E08.3513 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with macular edema, bilateral |
| E08.3519 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with macular edema, unspecified eye |
| E08.352 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment involving the macula |
| E08.3521 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment involving the macula, right eye |
| E08.3522 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment involving the macula, left eye |
| E08.3523 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment involving the macula, bilateral |
| E08.3529 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment involving the macula, unspecified eye |
| E08.353 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment not involving the macula |
| E08.3531 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, right eye |
| E08.3532 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, left eye |
| E08.3533 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, bilateral |
| E08.3539 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, unspecified eye |
| E08.354 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment |
| E08.3541 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, right eye |
| E08.3542 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, left eye |
| E08.3543 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, bilateral |
| E08.3549 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, unspecified eye |
| E08.355 | Diabetes mellitus due to underlying condition with stable proliferative diabetic retinopathy |
| E08.3551 | Diabetes mellitus due to underlying condition with stable proliferative diabetic retinopathy, right eye |
| E08.3552 | Diabetes mellitus due to underlying condition with stable proliferative diabetic retinopathy, left eye |
| E08.3553 | Diabetes mellitus due to underlying condition with stable proliferative diabetic retinopathy, bilateral |
| E08.3559 | Diabetes mellitus due to underlying condition with stable proliferative diabetic retinopathy, unspecified eye |
| E08.359 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy without macular edema |
| E08.3591 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy without macular edema, right eye |
| E08.3592 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy without macular edema, left eye |
| E08.3593 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy without macular edema, bilateral |
| E08.3599 | Diabetes mellitus due to underlying condition with proliferative diabetic retinopathy without macular edema, unspecified eye |
| E08.36 | Diabetes mellitus due to underlying condition with diabetic cataract |
| E08.37 | Diabetes mellitus due to underlying condition with diabetic macular edema, resolved following treatment |
| E08.37x1 | Diabetes mellitus due to underlying condition with diabetic macular edema, resolved following treatment, right eye |
| E08.37x2 | Diabetes mellitus due to underlying condition with diabetic macular edema, resolved following treatment, left eye |
| E08.37x3 | Diabetes mellitus due to underlying condition with diabetic macular edema, resolved following treatment, bilateral |
| E08.37x9 | Diabetes mellitus due to underlying condition with diabetic macular edema, resolved following treatment, unspecified eye |
| E08.39 | Diabetes mellitus due to underlying condition with other diabetic ophthalmic complication |
| E08.4 | Diabetes mellitus due to underlying condition with neurological complications |
| E08.40 | Diabetes mellitus due to underlying condition with diabetic neuropathy, unspecified |
| E08.41 | Diabetes mellitus due to underlying condition with diabetic mononeuropathy |
| E08.42 | Diabetes mellitus due to underlying condition with diabetic polyneuropathy |
| E08.43 | Diabetes mellitus due to underlying condition with diabetic autonomic (poly)neuropathy |
| E08.44 | Diabetes mellitus due to underlying condition with diabetic amyotrophy |
| E08.49 | Diabetes mellitus due to underlying condition with other diabetic neurological complication |
| E08.5 | Diabetes mellitus due to underlying condition with circulatory complications |
| E08.51 | Diabetes mellitus due to underlying condition with diabetic peripheral angiopathy without gangrene |
| E08.52 | Diabetes mellitus due to underlying condition with diabetic peripheral angiopathy with gangrene |
| E08.59 | Diabetes mellitus due to underlying condition with other circulatory complications |
| E08.6 | Diabetes mellitus due to underlying condition with other specified complications |
| E08.61 | Diabetes mellitus due to underlying condition with diabetic arthropathy |
| E08.610 | Diabetes mellitus due to underlying condition with diabetic neuropathic arthropathy |
| E08.618 | Diabetes mellitus due to underlying condition with other diabetic arthropathy |
| E08.62 | Diabetes mellitus due to underlying condition with skin complications |
| E08.620 | Diabetes mellitus due to underlying condition with diabetic dermatitis |
| E08.621 | Diabetes mellitus due to underlying condition with foot ulcer |
| E08.622 | Diabetes mellitus due to underlying condition with other skin ulcer |
| E08.628 | Diabetes mellitus due to underlying condition with other skin complications |
| E08.63 | Diabetes mellitus due to underlying condition with oral complications |
| E08.630 | Diabetes mellitus due to underlying condition with periodontal disease |
| E08.638 | Diabetes mellitus due to underlying condition with other oral complications |
| E08.64 | Diabetes mellitus due to underlying condition with hypoglycemia |
| E08.641 | Diabetes mellitus due to underlying condition with hypoglycemia with coma |
| E08.649 | Diabetes mellitus due to underlying condition with hypoglycemia without coma |
| E08.65 | Diabetes mellitus due to underlying condition with hyperglycemia |
| E08.69 | Diabetes mellitus due to underlying condition with other specified complication |
| E08.8 | Diabetes mellitus due to underlying condition with unspecified complications |
| E08.9 | Diabetes mellitus due to underlying condition without complications |
| E09 | Drug or chemical induced diabetes mellitus |
| E09.0 | Drug or chemical induced diabetes mellitus with hyperosmolarity |
| E09.00 | Drug or chemical induced diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHc) |
| E09.01 | Drug or chemical induced diabetes mellitus with hyperosmolarity with coma |
| E09.1 | Drug or chemical induced diabetes mellitus with ketoacidosis |
| E09.10 | Drug or chemical induced diabetes mellitus with ketoacidosis without coma |
| E09.11 | Drug or chemical induced diabetes mellitus with ketoacidosis with coma |
| E09.2 | Drug or chemical induced diabetes mellitus with kidney complications |
| E09.21 | Drug or chemical induced diabetes mellitus with diabetic nephropathy |
| E09.22 | Drug or chemical induced diabetes mellitus with diabetic chronic kidney disease |
| E09.29 | Drug or chemical induced diabetes mellitus with other diabetic kidney complication |
| E09.3 | Drug or chemical induced diabetes mellitus with ophthalmic complications |
| E09.31 | Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy |
| E09.311 | Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy with macular edema |
| E09.319 | Drug or chemical induced diabetes mellitus with unspecified diabetic retinopathy without macular edema |
| E09.32 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy |
| E09.321 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema |
| E09.3211 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, right eye |
| E09.3212 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, left eye |
| E09.3213 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, bilateral |
| E09.3219 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E09.329 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema |
| E09.3291 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, right eye |
| E09.3292 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, left eye |
| E09.3293 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, bilateral |
| E09.3299 | Drug or chemical induced diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E09.33 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy |
| E09.331 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema |
| E09.3311 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, right eye |
| E09.3312 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, left eye |
| E09.3313 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, bilateral |
| E09.3319 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E09.339 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema |
| E09.3391 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, right eye |
| E09.3392 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, left eye |
| E09.3393 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, bilateral |
| E09.3399 | Drug or chemical induced diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E09.34 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy |
| E09.341 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema |
| E09.3411 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, right eye |
| E09.3412 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, left eye |
| E09.3413 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, bilateral |
| E09.3419 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E09.349 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema |
| E09.3491 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, right eye |
| E09.3492 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, left eye |
| E09.3493 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, bilateral |
| E09.3499 | Drug or chemical induced diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E09.35 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy |
| E09.351 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with macular edema |
| E09.3511 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with macular edema, right eye |
| E09.3512 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with macular edema, left eye |
| E09.3513 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with macular edema, bilateral |
| E09.3519 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with macular edema, unspecified eye |
| E09.352 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula |
| E09.3521 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, right eye |
| E09.3522 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, left eye |
| E09.3523 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, bilateral |
| E09.3529 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, unspecified eye |
| E09.353 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula |
| E09.3531 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, right eye |
| E09.3532 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, left eye |
| E09.3533 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, bilateral |
| E09.3539 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, unspecified eye |
| E09.354 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment |
| E09.3541 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, right eye |
| E09.3542 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, left eye |
| E09.3543 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, bilateral |
| E09.3549 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, unspecified eye |
| E09.355 | Drug or chemical induced diabetes mellitus with stable proliferative diabetic retinopathy |
| E09.3551 | Drug or chemical induced diabetes mellitus with stable proliferative diabetic retinopathy, right eye |
| E09.3552 | Drug or chemical induced diabetes mellitus with stable proliferative diabetic retinopathy, left eye |
| E09.3553 | Drug or chemical induced diabetes mellitus with stable proliferative diabetic retinopathy, bilateral |
| E09.3559 | Drug or chemical induced diabetes mellitus with stable proliferative diabetic retinopathy, unspecified eye |
| E09.359 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy without macular edema |
| E09.3591 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy without macular edema, right eye |
| E09.3592 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy without macular edema, left eye |
| E09.3593 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy without macular edema, bilateral |
| E09.3599 | Drug or chemical induced diabetes mellitus with proliferative diabetic retinopathy without macular edema, unspecified eye |
| E09.36 | Drug or chemical induced diabetes mellitus with diabetic cataract |
| E09.37 | Drug or chemical induced diabetes mellitus with diabetic macular edema, resolved following treatment |
| E09.37x1 | Drug or chemical induced diabetes mellitus with diabetic macular edema, resolved following treatment, right eye |
| E09.37x2 | Drug or chemical induced diabetes mellitus with diabetic macular edema, resolved following treatment, left eye |
| E09.37x3 | Drug or chemical induced diabetes mellitus with diabetic macular edema, resolved following treatment, bilateral |
| E09.37x9 | Drug or chemical induced diabetes mellitus with diabetic macular edema, resolved following treatment, unspecified eye |
| E09.39 | Drug or chemical induced diabetes mellitus with other diabetic ophthalmic complication |
| E09.4 | Drug or chemical induced diabetes mellitus with neurological complications |
| E09.40 | Drug or chemical induced diabetes mellitus with neurological complications with diabetic neuropathy, unspecified |
| E09.41 | Drug or chemical induced diabetes mellitus with neurological complications with diabetic mononeuropathy |
| E09.42 | Drug or chemical induced diabetes mellitus with neurological complications with diabetic polyneuropathy |
| E09.43 | Drug or chemical induced diabetes mellitus with neurological complications with diabetic autonomic (poly)neuropathy |
| E09.44 | Drug or chemical induced diabetes mellitus with neurological complications with diabetic amyotrophy |
| E09.49 | Drug or chemical induced diabetes mellitus with neurological complications with other diabetic neurological complication |
| E09.5 | Drug or chemical induced diabetes mellitus with circulatory complications |
| E09.51 | Drug or chemical induced diabetes mellitus with diabetic peripheral angiopathy without gangrene |
| E09.52 | Drug or chemical induced diabetes mellitus with diabetic peripheral angiopathy with gangrene |
| E09.59 | Drug or chemical induced diabetes mellitus with other circulatory complications |
| E09.6 | Drug or chemical induced diabetes mellitus with other specified complications |
| E09.61 | Drug or chemical induced diabetes mellitus with diabetic arthropathy |
| E09.610 | Drug or chemical induced diabetes mellitus with diabetic neuropathic arthropathy |
| E09.618 | Drug or chemical induced diabetes mellitus with other diabetic arthropathy |
| E09.62 | Drug or chemical induced diabetes mellitus with skin complications |
| E09.620 | Drug or chemical induced diabetes mellitus with diabetic dermatitis |
| E09.621 | Drug or chemical induced diabetes mellitus with foot ulcer |
| E09.622 | Drug or chemical induced diabetes mellitus with other skin ulcer |
| E09.628 | Drug or chemical induced diabetes mellitus with other skin complications |
| E09.63 | Drug or chemical induced diabetes mellitus with oral complications |
| E09.630 | Drug or chemical induced diabetes mellitus with periodontal disease |
| E09.638 | Drug or chemical induced diabetes mellitus with other oral complications |
| E09.64 | Drug or chemical induced diabetes mellitus with hypoglycemia |
| E09.641 | Drug or chemical induced diabetes mellitus with hypoglycemia with coma |
| E09.649 | Drug or chemical induced diabetes mellitus with hypoglycemia without coma |
| E09.65 | Drug or chemical induced diabetes mellitus with hyperglycemia |
| E09.69 | Drug or chemical induced diabetes mellitus with other specified complication |
| E09.8 | Drug or chemical induced diabetes mellitus with unspecified complications |
| E09.9 | Drug or chemical induced diabetes mellitus without complications |
| E11 | Type 2 diabetes mellitus |
| E11.0 | Type 2 diabetes mellitus with hyperosmolarity |
| E11.00 | Type 2 diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHc) |
| E11.01 | Type 2 diabetes mellitus with hyperosmolarity with coma |
| E11.1 | Type 2 diabetes mellitus with ketoacidosis |
| E11.10 | Type 2 diabetes mellitus with ketoacidosis without coma |
| E11.11 | Type 2 diabetes mellitus with ketoacidosis with coma |
| E11.2 | Type 2 diabetes mellitus with kidney complications |
| E11.21 | Type 2 diabetes mellitus with diabetic nephropathy |
| E11.22 | Type 2 diabetes mellitus with diabetic chronic kidney disease |
| E11.29 | Type 2 diabetes mellitus with other diabetic kidney complication |
| E11.3 | Type 2 diabetes mellitus with ophthalmic complications |
| E11.31 | Type 2 diabetes mellitus with unspecified diabetic retinopathy |
| E11.311 | Type 2 diabetes mellitus with unspecified diabetic retinopathy with macular edema |
| E11.319 | Type 2 diabetes mellitus with unspecified diabetic retinopathy without macular edema |
| E11.32 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy |
| E11.321 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema |
| E11.3211 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, right eye |
| E11.3212 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, left eye |
| E11.3213 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, bilateral |
| E11.3219 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E11.329 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema |
| E11.3291 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, right eye |
| E11.3292 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, left eye |
| E11.3293 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, bilateral |
| E11.3299 | Type 2 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E11.33 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy |
| E11.331 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema |
| E11.3311 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, right eye |
| E11.3312 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, left eye |
| E11.3313 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, bilateral |
| E11.3319 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E11.339 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema |
| E11.3391 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, right eye |
| E11.3392 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, left eye |
| E11.3393 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, bilateral |
| E11.3399 | Type 2 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E11.34 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy |
| E11.341 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema |
| E11.3411 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, right eye |
| E11.3412 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, left eye |
| E11.3413 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, bilateral |
| E11.3419 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E11.349 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema |
| E11.3491 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, right eye |
| E11.3492 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, left eye |
| E11.3493 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, bilateral |
| E11.3499 | Type 2 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E11.35 | Type 2 diabetes mellitus with proliferative diabetic retinopathy |
| E11.351 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema |
| E11.3511 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema, right eye |
| E11.3512 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema, left eye |
| E11.3513 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema, bilateral |
| E11.3519 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with macular edema, unspecified eye |
| E11.352 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula |
| E11.3521 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, right eye |
| E11.3522 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, left eye |
| E11.3523 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, bilateral |
| E11.3529 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, unspecified eye |
| E11.353 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula |
| E11.3531 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, right eye |
| E11.3532 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, left eye |
| E11.3533 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, bilateral |
| E11.3539 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, unspecified eye |
| E11.354 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment |
| E11.3541 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, right eye |
| E11.3542 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, left eye |
| E11.3543 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, bilateral |
| E11.3549 | Type 2 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, unspecified eye |
| E11.355 | Type 2 diabetes mellitus with stable proliferative diabetic retinopathy |
| E11.3551 | Type 2 diabetes mellitus with stable proliferative diabetic retinopathy, right eye |
| E11.3552 | Type 2 diabetes mellitus with stable proliferative diabetic retinopathy, left eye |
| E11.3553 | Type 2 diabetes mellitus with stable proliferative diabetic retinopathy, bilateral |
| E11.3559 | Type 2 diabetes mellitus with stable proliferative diabetic retinopathy, unspecified eye |
| E11.359 | Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema |
| E11.3591 | Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema, right eye |
| E11.3592 | Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema, left eye |
| E11.3593 | Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema, bilateral |
| E11.3599 | Type 2 diabetes mellitus with proliferative diabetic retinopathy without macular edema, unspecified eye |
| E11.36 | Type 2 diabetes mellitus with diabetic cataract |
| E11.37 | Type 2 diabetes mellitus with diabetic macular edema, resolved following treatment |
| E11.37x1 | Type 2 diabetes mellitus with diabetic macular edema, resolved following treatment, right eye |
| E11.37x2 | Type 2 diabetes mellitus with diabetic macular edema, resolved following treatment, left eye |
| E11.37x3 | Type 2 diabetes mellitus with diabetic macular edema, resolved following treatment, bilateral |
| E11.37x9 | Type 2 diabetes mellitus with diabetic macular edema, resolved following treatment, unspecified eye |
| E11.39 | Type 2 diabetes mellitus with other diabetic ophthalmic complication |
| E11.4 | Type 2 diabetes mellitus with neurological complications |
| E11.40 | Type 2 diabetes mellitus with diabetic neuropathy, unspecified |
| E11.41 | Type 2 diabetes mellitus with diabetic mononeuropathy |
| E11.42 | Type 2 diabetes mellitus with diabetic polyneuropathy |
| E11.43 | Type 2 diabetes mellitus with diabetic autonomic (poly)neuropathy |
| E11.44 | Type 2 diabetes mellitus with diabetic amyotrophy |
| E11.49 | Type 2 diabetes mellitus with other diabetic neurological complication |
| E11.5 | Type 2 diabetes mellitus with circulatory complications |
| E11.51 | Type 2 diabetes mellitus with diabetic peripheral angiopathy without gangrene |
| E11.52 | Type 2 diabetes mellitus with diabetic peripheral angiopathy with gangrene |
| E11.59 | Type 2 diabetes mellitus with other circulatory complications |
| E11.6 | Type 2 diabetes mellitus with other specified complications |
| E11.61 | Type 2 diabetes mellitus with diabetic arthropathy |
| E11.610 | Type 2 diabetes mellitus with diabetic neuropathic arthropathy |
| E11.618 | Type 2 diabetes mellitus with other diabetic arthropathy |
| E11.62 | Type 2 diabetes mellitus with skin complications |
| E11.620 | Type 2 diabetes mellitus with diabetic dermatitis |
| E11.621 | Type 2 diabetes mellitus with foot ulcer |
| E11.622 | Type 2 diabetes mellitus with other skin ulcer |
| E11.628 | Type 2 diabetes mellitus with other skin complications |
| E11.63 | Type 2 diabetes mellitus with oral complications |
| E11.630 | Type 2 diabetes mellitus with periodontal disease |
| E11.638 | Type 2 diabetes mellitus with other oral complications |
| E11.64 | Type 2 diabetes mellitus with hypoglycemia |
| E11.641 | Type 2 diabetes mellitus with hypoglycemia with coma |
| E11.649 | Type 2 diabetes mellitus with hypoglycemia without coma |
| E11.65 | Type 2 diabetes mellitus with hyperglycemia |
| E11.69 | Type 2 diabetes mellitus with other specified complication |
| E11.8 | Type 2 diabetes mellitus with unspecified complications |
| E11.9 | Type 2 diabetes mellitus without complications |
| E13 | Other specified diabetes mellitus |
| E13.0 | Other specified diabetes mellitus with hyperosmolarity |
| E13.00 | Other specified diabetes mellitus with hyperosmolarity without nonketotic hyperglycemic-hyperosmolar coma (NKHHc) |
| E13.01 | Other specified diabetes mellitus with hyperosmolarity with coma |
| E13.1 | Other specified diabetes mellitus with ketoacidosis |
| E13.10 | Other specified diabetes mellitus with ketoacidosis without coma |
| E13.11 | Other specified diabetes mellitus with ketoacidosis with coma |
| E13.2 | Other specified diabetes mellitus with kidney complications |
| E13.21 | Other specified diabetes mellitus with diabetic nephropathy |
| E13.22 | Other specified diabetes mellitus with diabetic chronic kidney disease |
| E13.29 | Other specified diabetes mellitus with other diabetic kidney complication |
| E13.3 | Other specified diabetes mellitus with ophthalmic complications |
| E13.31 | Other specified diabetes mellitus with unspecified diabetic retinopathy |
| E13.311 | Other specified diabetes mellitus with unspecified diabetic retinopathy with macular edema |
| E13.319 | Other specified diabetes mellitus with unspecified diabetic retinopathy without macular edema |
| E13.32 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy |
| E13.321 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema |
| E13.3211 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, right eye |
| E13.3212 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, left eye |
| E13.3213 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, bilateral |
| E13.3219 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E13.329 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema |
| E13.3291 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, right eye |
| E13.3292 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, left eye |
| E13.3293 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, bilateral |
| E13.3299 | Other specified diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E13.33 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy |
| E13.331 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema |
| E13.3311 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, right eye |
| E13.3312 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, left eye |
| E13.3313 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, bilateral |
| E13.3319 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E13.339 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema |
| E13.3391 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, right eye |
| E13.3392 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, left eye |
| E13.3393 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, bilateral |
| E13.3399 | Other specified diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E13.34 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy |
| E13.341 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema |
| E13.3411 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, right eye |
| E13.3412 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, left eye |
| E13.3413 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, bilateral |
| E13.3419 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, unspecified eye |
| E13.349 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema |
| E13.3491 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, right eye |
| E13.3492 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, left eye |
| E13.3493 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, bilateral |
| E13.3499 | Other specified diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, unspecified eye |
| E13.35 | Other specified diabetes mellitus with proliferative diabetic retinopathy |
| E13.351 | Other specified diabetes mellitus with proliferative diabetic retinopathy with macular edema |
| E13.3511 | Other specified diabetes mellitus with proliferative diabetic retinopathy with macular edema, right eye |
| E13.3512 | Other specified diabetes mellitus with proliferative diabetic retinopathy with macular edema, left eye |
| E13.3513 | Other specified diabetes mellitus with proliferative diabetic retinopathy with macular edema, bilateral |
| E13.3519 | Other specified diabetes mellitus with proliferative diabetic retinopathy with macular edema, unspecified eye |
| E13.352 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula |
| E13.3521 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, right eye |
| E13.3522 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, left eye |
| E13.3523 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, bilateral |
| E13.3529 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, unspecified eye |
| E13.353 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula |
| E13.3531 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, right eye |
| E13.3532 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, left eye |
| E13.3533 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, bilateral |
| E13.3539 | Other specified diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, unspecified eye |
| E13.354 | Other specified diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment |
| E13.3541 | Other specified diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, right eye |
| E13.3542 | Other specified diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, left eye |
| E13.3543 | Other specified diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, bilateral |
| E13.3549 | Other specified diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, unspecified eye |
| E13.355 | Other specified diabetes mellitus with stable proliferative diabetic retinopathy |
| E13.3551 | Other specified diabetes mellitus with stable proliferative diabetic retinopathy, right eye |
| E13.3552 | Other specified diabetes mellitus with stable proliferative diabetic retinopathy, left eye |
| E13.3553 | Other specified diabetes mellitus with stable proliferative diabetic retinopathy, bilateral |
| E13.3559 | Other specified diabetes mellitus with stable proliferative diabetic retinopathy, unspecified eye |
| E13.359 | Other specified diabetes mellitus with proliferative diabetic retinopathy without macular edema |
| E13.3591 | Other specified diabetes mellitus with proliferative diabetic retinopathy without macular edema, right eye |
| E13.3592 | Other specified diabetes mellitus with proliferative diabetic retinopathy without macular edema, left eye |
| E13.3593 | Other specified diabetes mellitus with proliferative diabetic retinopathy without macular edema, bilateral |
| E13.3599 | Other specified diabetes mellitus with proliferative diabetic retinopathy without macular edema, unspecified eye |
| E13.36 | Other specified diabetes mellitus with diabetic cataract |
| E13.37 | Other specified diabetes mellitus with diabetic macular edema, resolved following treatment |
| E13.37x1 | Other specified diabetes mellitus with diabetic macular edema, resolved following treatment, right eye |
| E13.37x2 | Other specified diabetes mellitus with diabetic macular edema, resolved following treatment, left eye |
| E13.37x3 | Other specified diabetes mellitus with diabetic macular edema, resolved following treatment, bilateral |
| E13.37x9 | Other specified diabetes mellitus with diabetic macular edema, resolved following treatment, unspecified eye |
| E13.39 | Other specified diabetes mellitus with other diabetic ophthalmic complication |
| E13.4 | Other specified diabetes mellitus with neurological complications |
| E13.40 | Other specified diabetes mellitus with diabetic neuropathy, unspecified |
| E13.41 | Other specified diabetes mellitus with diabetic mononeuropathy |
| E13.42 | Other specified diabetes mellitus with diabetic polyneuropathy |
| E13.43 | Other specified diabetes mellitus with diabetic autonomic (poly)neuropathy |
| E13.44 | Other specified diabetes mellitus with diabetic amyotrophy |
| E13.49 | Other specified diabetes mellitus with other diabetic neurological complication |
| E13.5 | Other specified diabetes mellitus with circulatory complications |
| E13.51 | Other specified diabetes mellitus with diabetic peripheral angiopathy without gangrene |
| E13.52 | Other specified diabetes mellitus with diabetic peripheral angiopathy with gangrene |
| E13.59 | Other specified diabetes mellitus with other circulatory complications |
| E13.6 | Other specified diabetes mellitus with other specified complications |
| E13.61 | Other specified diabetes mellitus with diabetic arthropathy |
| E13.610 | Other specified diabetes mellitus with diabetic neuropathic arthropathy |
| E13.618 | Other specified diabetes mellitus with other diabetic arthropathy |
| E13.62 | Other specified diabetes mellitus with skin complications |
| E13.620 | Other specified diabetes mellitus with diabetic dermatitis |
| E13.621 | Other specified diabetes mellitus with foot ulcer |
| E13.622 | Other specified diabetes mellitus with other skin ulcer |
| E13.628 | Other specified diabetes mellitus with other skin complications |
| E13.63 | Other specified diabetes mellitus with oral complications |
| E13.630 | Other specified diabetes mellitus with periodontal disease |
| E13.638 | Other specified diabetes mellitus with other oral complications |
| E13.64 | Other specified diabetes mellitus with hypoglycemia |
| E13.641 | Other specified diabetes mellitus with hypoglycemia with coma |
| E13.649 | Other specified diabetes mellitus with hypoglycemia without coma |
| E13.65 | Other specified diabetes mellitus with hyperglycemia |
| E13.69 | Other specified diabetes mellitus with other specified complication |
| E13.8 | Other specified diabetes mellitus with unspecified complications |
| E13.9 | Other specified diabetes mellitus without complications |
Formulary Reference Tool