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Drug overview for KAZANO (alogliptin benzoate/metformin hcl):
Generic name: ALOGLIPTIN BENZOATE/METFORMIN HCL (AL-oh-GLIP-tin/met-FOR-min)
Drug class: Biguanides
Therapeutic class: Endocrine
Alogliptin benzoate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an Metformin hydrochloride is a biguanide antidiabetic agent. antidiabetic agent.
No enhanced Uses information available for this drug.
Generic name: ALOGLIPTIN BENZOATE/METFORMIN HCL (AL-oh-GLIP-tin/met-FOR-min)
Drug class: Biguanides
Therapeutic class: Endocrine
Alogliptin benzoate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an Metformin hydrochloride is a biguanide antidiabetic agent. antidiabetic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
KAZANO 12.5-500 MG TABLET
KAZANO 12.5-1,000 MG TABLET
The following indications for KAZANO (alogliptin benzoate/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 KAZANO (alogliptin benzoate/metformin hcl):
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.
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.
When administered as monotherapy, alogliptin may be administered orally once daily without regard to meals. When alogliptin is administered in fixed combination with metformin hydrochloride, the combination should be administered twice daily with food; dosage should be titrated gradually to minimize adverse GI effects of the metformin component. Fixed-combination tablets should be swallowed whole and should not be split before swallowing.
When alogliptin is administered in fixed combination with pioglitazone, the combination should be administered once daily without regard to meals. Fixed-combination tablets should be swallowed whole and should not be split before swallowing. If a dose of alogliptin alone or in combination with metformin or pioglitazone is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.
If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose. 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 alogliptin is administered in fixed combination with pioglitazone, the combination should be administered once daily without regard to meals. Fixed-combination tablets should be swallowed whole and should not be split before swallowing. If a dose of alogliptin alone or in combination with metformin or pioglitazone is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.
If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose. 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 |
|---|---|---|
| KAZANO 12.5-500 MG TABLET | Maintenance | Adults take 1 tablet by oral route 2 times per day with food, swallowing whole. Do not break, crush, chew and/or divide. |
| KAZANO 12.5-1,000 MG TABLET | Maintenance | Adults take 1 tablet by oral route 2 times per day with food, swallowing whole. Do not break, crush, chew and/or divide. |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ALOGLIPTIN-METFORMIN 12.5-500 | Maintenance | Adults take 1 tablet by oral route 2 times per day with food, swallowing whole. Do not break, crush, chew and/or divide. |
| ALOGLIPTIN-METFORMIN 12.5-1000 | Maintenance | Adults take 1 tablet by oral route 2 times per day with food, swallowing whole. Do not break, crush, chew and/or divide. |
The following drug interaction information is available for KAZANO (alogliptin benzoate/metformin hcl):
There are 0 contraindications.
There are 3 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 |
There are 14 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 |
|---|---|
| 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 |
| Tamoxifen/Selected Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5) CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence. PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(16) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(17-18) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(19-21) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(22-26) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, cimetidine, clobazam, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sertraline, verapamil and viloxazine.(27) |
SOLTAMOX, TAMOXIFEN CITRATE |
| 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 |
| 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 |
| Eliglustat/Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The dosage of eliglustat with weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, clobazam, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sertraline, vemurafenib, and venlafaxine.(3,4) |
CERDELGA |
| 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 |
| 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 |
| ACE Inhibitors/Dipeptidyl Peptidase-IV Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bradykinin can cause vasodilation and increase vascular permeability both directly and by stimulating release of substance P, which also increases vascular permeability.(1) Bradykinin is primarily metabolized by angiotensin-1 converting enzyme (ACE). If ACE is inhibited by ACE inhibitors, other metabolic enzymes become more significant in bradykinin metabolism, including dipeptidyl peptidase-IV (DPP-IV). DPP-IV inhibitors can inhibit both bradykinin and substance P metabolism.(2) CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.(1-3) PREDISPOSING FACTORS: History of previous angioedema. PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and DPP-IV inhibitor. Consider switching the patient to an angiotensin receptor blocker or a different anti-diabetic medication. Use caution in patients receiving concurrent therapy.(3) Monitor closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately. DISCUSSION: A pre-marketing surveillance compared incidence of angioedema in patients on vildagliptin versus a comparator. In all patients combined regardless of ACE inhibitor therapy, there was no association between vildagliptin and angioedema. However among patients taking an ACE inhibitor, vildagliptin was associated with an increased risk of angioedema (odds ratio 9.29 (95% CI 1.22-70.70) from pooled data; odds ratio of 4.57 (95% CI 1.57-13.28) in the meta-analysis). This interaction may be dose-related.(4) In a pooled analysis of data from 19 clinical trials of patients on sitagliptin versus a comparator, there was no difference in the incidence of angioedema between patients on ACE inhibitors and sitagliptin compared to patients on ACE inhibitors alone or patients not on ACE inhibitors.(5) However, events were not adjudicated and encompassed urticaria, anaphylaxis, and hypersensitivity reactions, which may have confounded the results.(6) A disproportionality analysis of the WHO pharmacovigilance database found 340,686 reports of bradykinin-mediated angioedema. Of those, 345 reports involved patients on concomitant ACE inhibitor and DPP-IV inhibitor, with a reporting odds ratio of 42.77 (95% CI 36.93-49.53). There was no association between use of a DPP-IV inhibitor without an ACE inhibitor and angioedema.(7) |
ACCUPRIL, ACCURETIC, ALTACE, CAPTOPRIL, CAPTOPRIL-HYDROCHLOROTHIAZIDE, ENALAPRIL MALEATE, ENALAPRIL-HYDROCHLOROTHIAZIDE, ENALAPRILAT, EPANED, FOSINOPRIL SODIUM, FOSINOPRIL-HYDROCHLOROTHIAZIDE, LISINOPRIL, LISINOPRIL-HYDROCHLOROTHIAZIDE, MOEXIPRIL HCL, PERINDOPRIL ERBUMINE, PRESTALIA, QBRELIS, QUINAPRIL HCL, QUINAPRIL-HYDROCHLOROTHIAZIDE, RAMIPRIL, TRANDOLAPRIL, TRANDOLAPRIL-VERAPAMIL ER, VASERETIC, VASOTEC, ZESTORETIC, ZESTRIL |
The following contraindication information is available for KAZANO (alogliptin benzoate/metformin hcl):
Drug contraindication overview.
Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions) to alogliptin.
Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions) to alogliptin.
There are 9 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute pancreatitis |
| 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 13 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute decompensated heart failure |
| Acute myocardial infarction |
| Chronic heart failure |
| Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min |
| 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 |
| Disease of liver |
| Hypoglycemic disorder |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Severe diarrhea |
| Severe hypoxemia |
| Severe vomiting |
There are 7 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Debilitation |
| Disease of liver |
| Fever |
| Hypothyroidism |
| Infection |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Vitamin b12 deficiency |
The following adverse reaction information is available for KAZANO (alogliptin benzoate/metformin hcl):
Adverse reaction overview.
Adverse effects reported in at least 4% of patients receiving alogliptin monotherapy and more commonly than with placebo include nasopharyngitis, headache, and upper respiratory tract infection. Adverse effects reported in at least 4% of patients receiving alogliptin in combination with metformin and more commonly than with placebo include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infection. Adverse effects reported in at least 4% of patients receiving alogliptin in combination with pioglitazone and more commonly than with placebo include nasopharyngitis, back pain, and upper respiratory tract infection.
Adverse effects reported in at least 4% of patients receiving alogliptin monotherapy and more commonly than with placebo include nasopharyngitis, headache, and upper respiratory tract infection. Adverse effects reported in at least 4% of patients receiving alogliptin in combination with metformin and more commonly than with placebo include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infection. Adverse effects reported in at least 4% of patients receiving alogliptin in combination with pioglitazone and more commonly than with placebo include nasopharyngitis, back pain, and upper respiratory tract infection.
There are 23 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Dyspnea Heart failure Kidney disease with reduction in glomerular filtration rate (GFr) |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute pancreatitis Acute respiratory distress syndrome Anaphylaxis Angioedema Autoimmune hemolytic anemia Autoimmune hepatitis Bullous pemphigoid Cholestatic hepatitis Hepatic failure Hepatocellular damage Hypersensitivity drug reaction Hypoglycemic disorder Ileus Lactic acidosis Megaloblastic anemia Pancreatitis Rhabdomyolysis Skin rash Stevens-johnson syndrome |
There are 35 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Diarrhea Dysgeusia Flatulence Headache disorder Nausea Pharyngitis Upper respiratory infection Vitamin b12 deficiency Vomiting Weight loss |
Acute abdominal pain Chills Constipation Dizziness Dyspepsia Flu-like symptoms Flushing General weakness Hyperhidrosis Interstitial nephritis Myalgia Nail disorders Palpitations Rhinitis |
| Rare/Very Rare |
|---|
|
Anticholinergic toxicity Arthralgia Constipation Diarrhea Drowsy Hypoglycemic disorder Nausea Pruritus of skin Skin rash Urticaria |
The following precautions are available for KAZANO (alogliptin benzoate/metformin hcl):
Safety and efficacy of alogliptin alone, in fixed combination with metformin, or in fixed combination with pioglitazone have not been established in pediatric patients younger than 18 years of age.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category B. (See Users Guide.) 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.
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.
Alogliptin is distributed into milk in lactating rats at a milk-to-plasma ratio of 2:1; it is not known whether the drug is distributed into human milk. Caution is advised if alogliptin is administered in nursing women. 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).
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).
Of 8507 patients in clinical trials of alogliptin, 24.3% were 65 years of age and older; 4% were 75 years of age and older. No substantial differences in safety and efficacy relative to younger adults were observed, but increased sensitivity cannot be ruled out.
The following prioritized warning is available for KAZANO (alogliptin benzoate/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 KAZANO (alogliptin benzoate/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