Actoplus Met

Drug overview for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Generic name: PIOGLITAZONE HCL/METFORMIN HCL (PYE-oh-GLI-ta-zone/met-FOR-min)
Drug class: Biguanides
Therapeutic class: Endocrine

Metformin hydrochloride is a biguanide antidiabetic agent. Pioglitazone, a thiazolidinedione (glitazone), is an antidiabetic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

ACTOPLUS MET 15 MG-850 MG TAB

The following indications for ACTOPLUS MET (pioglitazone hcl/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

The following dosing information is available for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Dosing
Administration
ACTOPLUS MET
PIOGLITAZONE-METFORMIN

Dosage of pioglitazone hydrochloride is expressed in terms of pioglitazone.

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.

Metformin hydrochloride is administered orally. In patients receiving Pioglitazone hydrochloride is administered orally once daily and can be metformin hydrochloride immediate-release tablets at a dosage of 2 g or taken without regard to meals. The fixed combination of pioglitazone and immediate-release metformin hydrochloride is administered orally once 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 twice daily with meals to reduce the GI effects of the metformin component.

better tolerated if administered in 3 divided doses daily. The fixed combination of pioglitazone and glimepiride is administered once daily with the first main meal. See full prescribing for additional Immediate-release metformin hydrochloride in fixed combination with administration instructions for these fixed-combination products.

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 If a dose of pioglitazone is missed on one day, the dose should not be component. Although food decreases the extent and slightly delays doubled the following day. absorption of metformin immediate-release tablets, the manufacturer recommends that the drug be taken with meals to decrease adverse GI Store pioglitazone tablets at 25oC; excursions permitted to 15--30oC.

Keep container closed and protect from light, moisture, and humidity. 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.

Dosing information for ACTOPLUS MET
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ACTOPLUS MET 15 MG-850 MG TAB	Maintenance	Adults take 1 tablet by oral route once daily

Generic dosing information for PIOGLITAZONE-METFORMIN
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
PIOGLITAZONE-METFORMIN 15-850	Maintenance	Adults take 1 tablet by oral route once daily

The following drug interaction information is available for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 9 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
Pioglitazone (Less Than or Equal To 15 mg); Rosiglitazone/Strong CYP2C8 Inhibitor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of pioglitazone(1-5) and rosiglitazone.(6) CLINICAL EFFECTS: Concurrent use of strong CYP2C8 inhibitors may result in elevated levels of and clinical effects, including severe hypoglycemia, from pioglitazone(1-5) or rosiglitazone.(6,7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider avoiding strong inhibitors of CYP2C8 in patients maintained on pioglitazone or rosiglitazone. The maximum recommended dosage of pioglitazone is 15 mg daily when used concurrently with gemfibrozil or other strong CYP2C8 inhibitors.(2) The dosage of pioglitazone(2) or rosiglitazone(7) may need to be adjusted if gemfibrozil is initiated or discontinued. If concurrent therapy is warranted, patients should be closely monitored for increased response to pioglitazone or rosiglitazone. DISCUSSION: In a randomized, cross-over study in 10 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold. The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2) In a randomized, double-blind, cross-over study in 12 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold (range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively. There was no significant effect on pioglitazone maximum concentration (Cmax). The 0-48 hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%, respectively; however, there was no significant effect on their 0-infinity AUC.(3) In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4 days) increased the AUC of a single dose of pioglitazone (15 mg) by 4.3-fold. The increase was variable between CYP2C8 genotypes. Individuals who were CYP2C83 carriers had a 5.2-fold increase in pioglitazone, while CYP2C81 homozygotes had a 3.3-fold increase in pioglitazone.(5) In a randomized crossover study in 10 subjects, gemfibrozil (600 mg twice daily) increased the rosiglitazone (4 mg single dose) AUC by 2.3-fold and increased rosiglitazone T1/2 from 3.6 hours to 7.6 hours. Rosiglitazone Cmax increased 1.2-fold. At 24 hours post dose, the rosiglitazone concentration was 9.8-fold greater when it was taken with gemfibrozil. Gemfibrozil increased the time to Cmax (Tmax) of N-desmethylrosiglitazone from 7 hours to 12 hours and decreased its AUC by 38%.(6) Concurrent use of gemfibrozil (600 mg twice daily) with rosiglitazone (4 mg daily) increased rosiglitazone AUC by 127%.(7) Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)	GEMFIBROZIL, LOPID
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
Lumateperone/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1) CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1) DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)	CAPLYTA
Pioglitazone; Repaglinide/Abiraterone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The mechanism of interaction is not fully understood but may at least partially involve CYP2C8 inhibition by abiraterone, resulting in decreased metabolism of pioglitazone and repaglinide.(1,2) CLINICAL EFFECTS: Concurrent use of pioglitazone or repaglinide with abiraterone may result in elevated levels and clinical effects of the anti-diabetic agents, including severe hypoglycemia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone. Consider dosage adjustment of pioglitazone or repaglinide to minimize the risk of hypoglycemia.(1) DISCUSSION: Severe hypoglycemia has been reported in diabetic patients receiving pioglitazone or repaglinide concurrently with abiraterone. A review of the FDA Adverse Events Reporting database found 2 reports of hypoglycemia in patients receiving concurrent abiraterone and repaglinide. One patient was hospitalized with life-threatening outcomes, and the other died, though he also had sepsis and cardiac failure. In a study of 16 healthy volunteers, single-dose abiraterone 1,000 mg increased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose pioglitazone 15 mg by 23% and 46%.(3)	ABIRATERONE ACETATE, ABIRTEGA, AKEEGA, YONSA, ZYTIGA
Atogepant/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong, moderate, and weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1) CLINICAL EFFECTS: The concurrent use of strong, moderate, or weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant strong, moderate, or weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and avoid use of atogepant for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness. DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)	QULIPTA
Erlotinib/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1) DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)	ERLOTINIB HCL, TARCEVA
Zuranolone/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1) DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)	ZURZUVAE

There are 19 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
Pioglitazone/Insulin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown, but may be the result of additive fluid retention.(1,2) CLINICAL EFFECTS: The concurrent use of pioglitazone with insulin may increase the risk of edema and heart failure.(1,2) PREDISPOSING FACTORS: Specific risk factors for heart failure could not be determined. Patients with ongoing edema are more likely to have edema-associated adverse effects with combination therapy.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for cardiovascular adverse events. If signs and symptoms of congestive heart failure develop, patients should be treated according to current standards of care. Consideration should be given to lowering the dosage of or discontinuing pioglitazone.(1,2) DISCUSSION: In a clinical trial, two of 191 (1.1%) of patients receiving pioglitazone (15 mg) and insulin and two of 188 (1.1%) of patients receiving pioglitazone (30 mg) and insulin developed congestive heart failure. None of the patients receiving insulin alone developed congestive heart failure.(1)	ADMELOG, ADMELOG SOLOSTAR, AFREZZA, APIDRA, APIDRA SOLOSTAR, BASAGLAR KWIKPEN U-100, BASAGLAR TEMPO PEN U-100, FIASP, FIASP FLEXTOUCH, FIASP PENFILL, FIASP PUMPCART, HUMALOG, HUMALOG JUNIOR KWIKPEN, HUMALOG KWIKPEN U-100, HUMALOG KWIKPEN U-200, HUMALOG MIX 50-50 KWIKPEN, HUMALOG MIX 75-25, HUMALOG MIX 75-25 KWIKPEN, HUMALOG TEMPO PEN U-100, HUMULIN R U-500, HUMULIN R U-500 KWIKPEN, INSULIN ASPART, INSULIN ASPART FLEXPEN, INSULIN ASPART PENFILL, INSULIN ASPART PROT MIX 70-30, INSULIN DEGLUDEC, INSULIN DEGLUDEC PEN (U-100), INSULIN DEGLUDEC PEN (U-200), INSULIN GLARGINE MAX SOLOSTAR, INSULIN GLARGINE SOLOSTAR, INSULIN GLARGINE-YFGN, INSULIN LISPRO, INSULIN LISPRO JUNIOR KWIKPEN, INSULIN LISPRO KWIKPEN U-100, INSULIN LISPRO PROTAMINE MIX, LANTUS, LANTUS SOLOSTAR, LYUMJEV, LYUMJEV KWIKPEN U-100, LYUMJEV KWIKPEN U-200, LYUMJEV TEMPO PEN U-100, MYXREDLIN, NOVOLOG, NOVOLOG FLEXPEN, NOVOLOG MIX 70-30, NOVOLOG MIX 70-30 FLEXPEN, NOVOLOG PENFILL, REZVOGLAR KWIKPEN, SEMGLEE (YFGN), SEMGLEE (YFGN) PEN, SOLIQUA 100-33, TOUJEO MAX SOLOSTAR, TOUJEO SOLOSTAR, TRESIBA, TRESIBA FLEXTOUCH U-100, TRESIBA FLEXTOUCH U-200, XULTOPHY 100-3.6
Selected Antidiabetic Agents/Selected Quinolones SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma. PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5) PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety. DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13)	AVELOX IV, BAXDELA, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, LEVOFLOXACIN, LEVOFLOXACIN HEMIHYDRATE, LEVOFLOXACIN-D5W, MOXIFLOXACIN, MOXIFLOXACIN HCL, OFLOXACIN
Metformin/MATE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal tubular secretion of metformin.(1) CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent. PATIENT MANAGEMENT: Use an alternative agent if possible. If both drugs are given, monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Dosage of either agent may need to be adjusted.(1) DISCUSSION: In a study of normal healthy volunteers, concurrent metformin and oral cimetidine increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) MATE inhibitors include: cimetidine, pyrimethamine, and risdiplam.(3)	CIMETIDINE, DARAPRIM, EVRYSDI, PYRIMETHAMINE
Metformin/Cephalexin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cephalexin may inhibit the renal tubular secretion of metformin.(1,2) CLINICAL EFFECTS: Concurrent use of cephalexin may result in increased levels and clinical effects of metformin,(1,2) as well as an increased risk of lactic acidosis. PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: Patients maintained on metformin should be closely monitored when cephalexin is initiated and discontinued. The dosage of metformin may need to be adjusted.(1) DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, concurrent metformin (500 mg) and cephalexin (500 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metformin by 34% and 24%, respectively. Metformin renal clearance decreased by 14%.(1,2)	CEPHALEXIN
Pregabalin/Thiazolidinedione Antidiabetics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both pregabalin and thiazolidinedione antidiabetics may cause weight gain and/or fluid retention.(1) CLINICAL EFFECTS: Concurrent use of pregabalin and thiazolidinedione antidiabetics may result in weight gain and/or fluid retention, which may increase the risk of heart failure in patients with preexisting cardiac conditions.(1) PREDISPOSING FACTORS: Preexisting cardiac conditions may increase the risk of heart failure.(1) PATIENT MANAGEMENT: Patients should be monitored for weight gain and/or fluid retention when taking pregabalin with the thiazolidinedione antidiabetics agents together. Congestive heart failure or worsening of existing congestive heart failure may occur. DISCUSSION: In clinical trials, the incidence of peripheral edema was 3% of patients receiving a thiazolidinedione antidiabetic alone, 8% of patients receiving pregabalin alone, and 19% of patients on combination therapy. The incidence of weight gain was 0% of patients receiving a thiazolidinedione antidiabetic alone, 4% of patients receiving pregabalin alone, and 7.5% of patients on combination therapy.(1)	LYRICA, LYRICA CR, PREGABALIN, PREGABALIN ER
Pioglitazone; Repaglinide; Rosiglitazone/Trimethoprim SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Trimethoprim, a weak CYP2C8 inhibitor, may inhibit the metabolism of pioglitazone,(1,2) repaglinide,(3) and rosiglitazone.(4,5) CLINICAL EFFECTS: Concurrent use of trimethoprim may result in increased levels of and effects from pioglitazone,(1,2) repaglinide,(3) and rosiglitazone.(4,5) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent trimethoprim and pioglitazone, repaglinide, or rosiglitazone should be monitored for signs and symptoms of hypoglycemia. The dosage of the antidiabetic agent may need to be adjusted during and following trimethoprim therapy. DISCUSSION: In a randomized, cross-over study in 16 healthy subjects, trimethoprim (160 mg twice daily for 6 days) increased the area-under-curve (AUC) of a single dose of pioglitazone (15 mg) by 42%.(1) Trimethoprim was shown to inhibit pioglitazone metabolism in vitro in human liver microsomes.(1,2) In a randomized, double-blind, cross-over study in 9 healthy subjects, trimethoprim (160 mg twice daily for 3 days) increased the AUC and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 61% and 41%, respectively. Trimethoprim also inhibited repaglinide metabolism in vitro in a concentration-dependent manner.(3) In a randomized, cross-over study in 8 healthy subjects, trimethoprim (200 mg twice daily for 5 days) increased the AUC of a single dose of rosiglitazone (8 mg) by 31%. An in vitro study in human liver microsomes showed that trimethoprim inhibited troglitazone metabolism.(4) In a randomized, cross-over study in 10 healthy subjects, trimethoprim (160 mg twice daily for 4 days) increased the AUC of a single dose of troglitazone (4 mg) by 37%.(5)	BACTRIM, BACTRIM DS, PRIMSOL, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED
Selected CYP2C8 Substrates/Leflunomide; Teriflunomide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Teriflunomide may inhibit the metabolism of agents metabolized by CYP2C8. Leflunomide is metabolized to teriflunomide and recommended dosages of both products produce similar levels of teriflunomide.(1) CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide may result in elevated levels of and toxicity from agents metabolized by CYP2C8, such as pioglitazone, repaglinide, or rosiglitazone.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy with leflunomide or teriflunomide and an agent metabolized by CYP2C8 should be closely monitored. The dosage of the CYP2C8 inhibitor may need to be adjusted if teriflunomide is initiated. Because of teriflunomide's slow elimination, the effects of teriflunomide on these agents may persist for some time without the use of cholestyramine or activated charcoal to increase teriflunomide elimination.(1) DISCUSSION: Concurrent teriflunomide increased the maximum concentration (Cmax) and area-under-curve (AUC) of repaglinide (0.25 mg single dose) by 1.7-fold and 2.4-fold, respectively.(1) Leflunomide is metabolized to teriflunomide and recommended dosages of both products produce similar levels of teriflunomide.(1) CYP2C8 substrates include pioglitazone, repaglinide, or rosiglitazone.(1,2)	ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE
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
Exemestane/Selected Moderate-Weak CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers. DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)	AROMASIN, EXEMESTANE
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
Ubrogepant/Moderate and Weak CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1) DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone,suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)	UBRELVY
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
Tacrolimus/Moderate and Weak CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1) CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1) DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)	ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL
Metformin/OCT2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of metformin by OCT2 in the kidneys.(1) CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from metformin.(1) PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels higher than 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of metformin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of metformin and consider dosage reduction of metformin.(1) DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) OCT2 inhibitors linked to this monograph include: arimoclomol, givinostat, trilaciclib, and vimseltinib.(2)	DUVYZAT, MIPLYFFA, ROMVIMZA

The following contraindication information is available for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure (HF). *Known serious hypersensitivity reaction to pioglitazone or any ingredient in the formulation.

There are 10 contraindications. Absolute contraindication.

Contraindication List
Acute decompensated heart failure
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
Malignant tumor of urinary bladder
Metabolic acidosis
Sepsis
Shock

There are 11 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 3B (moderate) GFR 30-44 ml/min
Disease of liver
Hematuria
Hypoglycemic disorder
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Severe diarrhea
Severe hypoxemia
Severe vomiting

There are 8 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Debilitation
Edema
Fever
Fracture
Hypothyroidism
Infection
Macular retinal edema
Vitamin b12 deficiency

The following adverse reaction information is available for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse effects of pioglitazone (>=5% of patients) reported in clinical trials were upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.

There are 22 severe adverse reactions.

More Frequent	Less Frequent
None.	Body fluid retention Dyspnea Edema Weight gain

Rare/Very Rare
Abnormal hepatic function tests Acute respiratory distress syndrome Autoimmune hemolytic anemia Autoimmune hepatitis Cholestatic hepatitis Fracture Heart failure Hepatic failure Hepatitis Hepatocellular damage Hypoglycemic disorder Lactic acidosis Macular retinal edema Malignant tumor of urinary bladder Megaloblastic anemia Ovulation stimulation Pancreatitis Worsening of chronic heart failure

There are 35 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal distension Diarrhea Dizziness Dysgeusia Flatulence Headache disorder Myalgia Nausea Pharyngitis Sinusitis Upper respiratory infection Urinary tract infection Vitamin b12 deficiency Vomiting Weight loss	Acute abdominal pain Chills Constipation Diarrhea Dizziness Dyspepsia Flu-like symptoms Flushing General weakness Hyperhidrosis Hypoglycemic disorder Myalgia Nail disorders Palpitations Rhinitis

Rare/Very Rare
Anticholinergic toxicity Drowsy Pruritus of skin Skin rash Urticaria

The following precautions are available for ACTOPLUS MET (pioglitazone hcl/metformin hcl):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of pioglitazone have not been established in children or adolescents younger than 18 years of age; use in this age group currently is not recommended by the manufacturer because of adverse effects observed in adults (e.g., fluid retention and HF, fractures, urinary bladder tumors).

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

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. There is insufficient evidence with pioglitazone in pregnant women to evaluate a drug-associated risk for major birth defects or miscarriage.

In reproduction studies in rats and rabbits, pioglitazone administered during organogenesis at exposures up to 5 and 35 times the maximum recommended human dose, respectively, was not associated with adverse developmental effects. However, delayed parturition and reduced embryofetal viability were observed with pioglitazone dosages at least 9 times the maximum recommended human dose. Offspring of pregnant rats who were administered pioglitazone at dosages at least 2 times the maximum recommended human dose during late gestation and lactation had delayed postnatal development attributed to decreased body weight. Poorly controlled diabetes during pregnancy increases the risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth, delivery complications, major birth defects, and macrosomia related morbidity.

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). There are no data on the presence of pioglitazone in human milk, the effects on the breast-fed infant, or the effects on milk production.

Pioglitazone is distributed into milk in rats. The benefits of breast-feeding should be weighed against the potential risk of adverse effects on the breast-fed infant from pioglitazone.

Pharmacokinetic, efficacy, and adverse effect profiles in geriatric patients are similar to those in younger adults, although small sample sizes in studies of patients 75 years or older limit conclusions. While pioglitazone AUC is about 21% higher in healthy geriatric individuals than in younger individuals and mean terminal half-life is also prolonged (10 versus 7 hours, respectively), these changes are not considered clinically relevant.

The following icd codes are available for ACTOPLUS MET (pioglitazone hcl/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