Repaglinide

Drug overview for REPAGLINIDE (repaglinide):

Generic name: repaglinide (reh-PAGG-lin-ide)
Drug class: Hypoglycemics - Sulfonylureas and Related Non-Sulfonylureas
Therapeutic class: Endocrine

Repaglinide, a meglitinide (glinide) derivative, is a short-acting, insulinotropic antidiabetic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

REPAGLINIDE 2 MG TABLET
REPAGLINIDE 0.5 MG TABLET
REPAGLINIDE 1 MG TABLET

The following indications for REPAGLINIDE (repaglinide) 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 REPAGLINIDE (repaglinide):

Dosing
Administration
REPAGLINIDE
REPAGLINIDE

Dosage adjustments are recommended when repaglinide is administered with strong inhibitors or inducers of cytochrome P-450 (CYP) 2C8 or 3A4 isoenzymes; concomitant administration of repaglinide and gemfibrozil is contraindicated.

Concomitant use of repaglinide and clopidogrel may substantially increase repaglinide exposure and should be avoided. If concomitant use cannot be avoided, the initial dosage of repaglinide should be 0.5 mg before each meal and the total daily dosage of repaglinide should not exceed 4 mg.

The maximum daily dosage of repaglinide in patients receiving concomitant cyclosporine should not exceed 6 mg.

Repaglinide is administered orally. The manufacturer recommends that patients be instructed to take the drug within 30 minutes before meals. Depending on the patient's meal patterns, repaglinide should be given prior to each meal, with a total dosing frequency of 2-4 times daily; patients who skip a meal or add an extra meal should be instructed to skip or add a dose, respectively, for that meal.

Meal-related dosing of repaglinide allows patients to maintain glycemic control and to avoid hypoglycemic episodes even when eating patterns are varied (e.g., skipped meals). Store repaglinide tablets at 20--25degreesC. Keep bottle tightly closed and protect from moisture.

Dosing information for REPAGLINIDE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
REPAGLINIDE 0.5 MG TABLET	Maintenance	Adults take 1 tablet (0.5 mg) by oral route 3 times per day 15 to 30 minutes before meals
REPAGLINIDE 1 MG TABLET	Maintenance	Adults take 1 tablet (1 mg) by oral route 3 times per day 15 to 30 minutes before meals
REPAGLINIDE 2 MG TABLET	Maintenance	Adults take 1 tablet (2 mg) by oral route 3 times per day 15 to 30 minutes before meals

Generic dosing information for REPAGLINIDE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
REPAGLINIDE 0.5 MG TABLET	Maintenance	Adults take 1 tablet (0.5 mg) by oral route 3 times per day 15 to 30 minutesbefore meals
REPAGLINIDE 1 MG TABLET	Maintenance	Adults take 1 tablet (1 mg) by oral route 3 times per day 15 to 30 minutes before meals
REPAGLINIDE 2 MG TABLET	Maintenance	Adults take 1 tablet (2 mg) by oral route 3 times per day 15 to 30 minutes before meals

The following drug interaction information is available for REPAGLINIDE (repaglinide):

Contraindicated
Severe
Moderate

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Repaglinide/Gemfibrozil SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Gemfibrozil inhibits the OATP1B1 transporter and is a strong inhibitor of CYP2C8, leading to inhibition of repaglinide transport and metabolism by these pathways.(1,6) CLINICAL EFFECTS: Concurrent use of gemfibrozil and repaglinide may result in elevated levels and clinical effects of repaglinide.(1) PREDISPOSING FACTORS: Concurrent administration of itraconazole may further increase repaglinide levels.(1,3) PATIENT MANAGEMENT: The US manufacturers of gemfibrozil(2) and repaglinide,(3) and the Canadian manufacturer of repaglinide(4) state that concurrent use of gemfibrozil and repaglinide is contraindicated. Consider the use of fenofibrate in patients treated with repaglinide who require fibrate therapy. DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, gemfibrozil (600 mg twice daily) increased the area-under-curve (AUC) and half-life of repaglinide by 8.1-fold and 1.8-fold, respectively.(1,3) At seven hours post dose, gemfibrozil increased plasma repaglinide levels by 28.6-fold. The blood-glucose lowering effects of repaglinide were also increased by gemfibrozil.(1) In a study, concurrent administration of gemfibrozil (600 mg twice daily) and itraconazole (100 mg twice daily) for three days increased repaglinide AUC and Cmax by 19-fold and 2.8-fold, respectively.(2) In a randomized, cross-over study in 9 healthy subjects, concurrent gemfibrozil (600 mg twice daily) and itraconazole (200 mg once, then 100 mg twice daily) increased the AUC and maximum concentration (Cmax) of nateglinide (30 mg) by 47% and 30%, respectively. The AUC and Cmax of a nateglinide metabolite were also increased by 166% and 92%, respectively. However, the blood-glucose lowering effects of nateglinide were not significantly altered.(5) An in vitro study used human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes to study repaglinide metabolism. This study concluded that repaglinide undergoes direct glucuronidation and that gemfibrozil inhibited both glucuronide and M4 formation with minor M2 inhibition. This resulted in a 80% decrease in turnover of repaglinide.(8) In a randomized crossover study, ten healthy volunteers were given 0.25 mg orally of repaglinide then, 1 hour later, a single oral 30 mg, 100 mg, 300 mg, or 900 mg dose of gemfibrozil or placebo. The mean AUC of repaglinide was increased 1.9-fold,4.5-fold, 6.7-fold, or 8.3-fold after a single dose of gemfibrozil 30 mg, 100 mg, 300 mg, or 900 mg, respectively (p<0.001). The Cmax of repaglinide increased 1.4-fold, 1.7-fold, 2.1-fold, and 2.4-fold, respectively, after the single oral dose of gemfibrozil (p<0.05).(8) In a randomized cross-over study, 12 healthy patients received bezafibrate (400 mg daily), fenofibrate (200 mg daily), or placebo (once daily) for 5 days. On day 5, the patient also took a single dose of repaglinide (0.25 mg) one hour after the fibrate dose. Bezafibrate and fenofibrate had no statistically significant effects on the Cmax, Tmax, AUC, or T1/2 of repaglinide, nor did it affect blood glucose concentrations.(9)	GEMFIBROZIL, LOPID
Repaglinide/Clopidogrel SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Repaglinide is primarily metabolized by CYP2C8, and its elimination is facilitated by OATP1B1 transport. A clopidogrel metabolite inhibits both of these pathways.(1) CLINICAL EFFECTS: Concurrent use of clopidogrel and repaglinide is expected to increase systemic exposure (AUC, area-under-curve) to repaglinide and may result in hypoglycemia. PREDISPOSING FACTORS: Patients who achieve tight control of blood sugars, or have a history of multiple hypoglycemic episodes may be at greater risk for hypoglycemia with this combination. PATIENT MANAGEMENT: Based upon results of a published clinical trial, Health Canada and the Canadian manufacturer of repaglinide state that concurrent use of clopidogrel and repaglinide is contraindicated due to the risk for hypoglycemia from unanticipated lowering of serum glucose concentrations.(2) Alternative antiplatelet agents (e.g. prasugrel, ticagrelor) and antidiabetic agents are not known to inhibit CYP2C8 or OATP1B1.(3) The manufacturer of clopidogrel states that when concomitant use is required in a patient maintained on clopidogrel, initiate repaglinide at 0.5 mg with each meal and titrate based on blood glucose levels. Do not exceed a total daily dose of 4 mg. If concomitant use of clopidogrel is required in a patient stabilized on repaglinide, down titrate the dose of repaglinide based on blood glucose levels to not exceed a total daily dose of 4 mg.(4) If concomitant use is deemed medically necessary: - Hypoglycemic risk is greatest when clopidogrel is added to existing repaglinide therapy. Frequent monitoring of serum/blood glucose is needed to monitor patient response as the magnitude of glucose lowering varies between patients. - In patients stabilized on clopidogrel when repaglinide is initiated, increased sensitivity to the hypoglycemic effect of repaglinide would be expected. In addition, because repaglinide half-life is prolonged in the presence of clopidogrel, maximal effects of repaglinide may be delayed - slower than usual dose titration would be prudent. Separating the timing of drug administration would not be expected to decrease interaction risk as the clopidogrel metabolite (clopidogrel acyl-beta-D-glucuronide) is an irreversible inhibitor of CYP2C8.(1) DISCUSSION: In a drug interaction trial conducted in healthy non-diabetic adults, a clopidogrel 300 mg loading dose increased repaglinide exposure 5.1-fold and a 75 mg maintenance dose increased repaglinide exposure 3.9-fold. Corresponding serum glucose changes: - Clopidogrel 300 mg plus repaglinide decreased minimum glucose concentrations an average of 20 mg/dL (1.1 mmol/L) more than repaglinide alone. - Clopidogrel 300mg X1 dose, followed by 75 mg daily dosing for two days with daily repaglinide resulted in an average decrease in minimum glucose concentrations of 9 mg/dL lower than patients on repaglinide alone.(1)	CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX

Drug Interaction

Drug Names

Repaglinide/Gemfibrozil

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Gemfibrozil inhibits the OATP1B1 transporter and is a strong inhibitor of CYP2C8, leading to inhibition of repaglinide transport and metabolism by these pathways.(1,6)

CLINICAL EFFECTS: Concurrent use of gemfibrozil and repaglinide may result in elevated levels and clinical effects of repaglinide.(1)

PREDISPOSING FACTORS: Concurrent administration of itraconazole may further increase repaglinide levels.(1,3)

PATIENT MANAGEMENT: The US manufacturers of gemfibrozil(2) and repaglinide,(3) and the Canadian manufacturer of repaglinide(4) state that concurrent use of gemfibrozil and repaglinide is contraindicated. Consider the use of fenofibrate in patients treated with repaglinide who require fibrate therapy.

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, gemfibrozil (600 mg twice daily) increased the area-under-curve (AUC) and half-life of repaglinide by 8.1-fold and 1.8-fold, respectively.(1,3)

At seven hours post dose, gemfibrozil increased plasma repaglinide levels by 28.6-fold. The blood-glucose lowering effects of repaglinide were also increased by gemfibrozil.(1)

In a study, concurrent administration of gemfibrozil (600 mg twice daily) and itraconazole (100 mg twice daily) for three days increased repaglinide AUC and Cmax by 19-fold and 2.8-fold, respectively.(2) In a randomized, cross-over study in 9 healthy subjects, concurrent gemfibrozil (600 mg twice daily) and itraconazole (200 mg once, then 100 mg twice daily) increased the AUC and maximum concentration (Cmax) of nateglinide (30 mg) by 47% and 30%, respectively.

The AUC and Cmax of a nateglinide metabolite were also increased by 166% and 92%, respectively. However, the blood-glucose lowering effects of nateglinide were not significantly altered.(5) An in vitro study used human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes to study repaglinide metabolism.

This study concluded that repaglinide undergoes direct glucuronidation and that gemfibrozil inhibited both glucuronide and M4 formation with minor M2 inhibition. This resulted in a 80% decrease in turnover of repaglinide.(8) In a randomized crossover study, ten healthy volunteers were given 0.25

mg orally of repaglinide then, 1 hour later, a single oral 30 mg, 100 mg, 300 mg, or 900 mg dose of gemfibrozil or placebo. The mean AUC of repaglinide was increased 1.9-fold,4.5-fold,

6.7-fold, or 8.3-fold after a single dose of gemfibrozil 30 mg, 100 mg, 300 mg, or 900 mg, respectively (p<0.001).

The Cmax of repaglinide increased 1.4-fold, 1.7-fold, 2.1-fold,

and 2.4-fold, respectively, after the single oral dose of gemfibrozil (p<0.05).(8) In a randomized cross-over study, 12 healthy patients received bezafibrate (400 mg daily), fenofibrate (200 mg daily), or placebo (once daily) for 5 days.

On day 5, the patient also took a single dose of repaglinide (0.25 mg) one hour after the fibrate dose. Bezafibrate and fenofibrate had no statistically significant effects on the Cmax, Tmax, AUC, or T1/2 of repaglinide, nor did it affect blood glucose concentrations.(9)

GEMFIBROZIL, LOPID

Repaglinide/Clopidogrel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Repaglinide is primarily metabolized by CYP2C8, and its elimination is facilitated by OATP1B1 transport. A clopidogrel metabolite inhibits both of these pathways.(1)

CLINICAL EFFECTS: Concurrent use of clopidogrel and repaglinide is expected to increase systemic exposure (AUC, area-under-curve) to repaglinide and may result in hypoglycemia.

PREDISPOSING FACTORS: Patients who achieve tight control of blood sugars, or have a history of multiple hypoglycemic episodes may be at greater risk for hypoglycemia with this combination.

PATIENT MANAGEMENT: Based upon results of a published clinical trial, Health Canada and the Canadian manufacturer of repaglinide state that concurrent use of clopidogrel and repaglinide is contraindicated due to the risk for hypoglycemia from unanticipated lowering of serum glucose concentrations.(2) Alternative antiplatelet agents (e.g. prasugrel, ticagrelor) and antidiabetic agents are not known to inhibit CYP2C8 or OATP1B1.(3) The manufacturer of clopidogrel states that when concomitant use is required in a patient maintained on clopidogrel, initiate repaglinide at 0.5

mg with each meal and titrate based on blood glucose levels. Do not exceed a total daily dose of 4 mg. If concomitant use of clopidogrel is required in a patient stabilized on repaglinide, down titrate the dose of repaglinide based on blood glucose levels to not exceed a total daily dose of 4 mg.(4)

If concomitant use is deemed medically necessary: - Hypoglycemic risk is greatest when clopidogrel is added to existing repaglinide therapy. Frequent monitoring of serum/blood glucose is needed to monitor patient response as the magnitude of glucose lowering varies between patients. - In patients stabilized on clopidogrel when repaglinide is initiated, increased sensitivity to the hypoglycemic effect of repaglinide would be expected.

In addition, because repaglinide half-life is prolonged in the presence of clopidogrel, maximal effects of repaglinide may be delayed - slower than usual dose titration would be prudent. Separating the timing of drug administration would not be expected to decrease interaction risk as the clopidogrel metabolite (clopidogrel acyl-beta-D-glucuronide) is an irreversible inhibitor of CYP2C8.(1)

DISCUSSION: In a drug interaction trial conducted in healthy non-diabetic adults, a clopidogrel 300 mg loading dose increased repaglinide exposure 5.1-fold and a 75 mg maintenance dose increased repaglinide exposure 3.9-fold.

Corresponding serum glucose changes: - Clopidogrel 300 mg plus repaglinide decreased minimum glucose concentrations an average of 20 mg/dL (1.1 mmol/L) more than repaglinide alone. - Clopidogrel 300mg X1 dose, followed by 75 mg daily dosing for two days with daily repaglinide resulted in an average decrease in minimum glucose concentrations of 9 mg/dL lower than patients on repaglinide alone.(1)

CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX

There are 6 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
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
Select CYP2C8; 2C9 Substrates/Mifepristone (Chronic therapy) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Mifepristone is a moderate inhibitor of CYP2C8 and CYP2C9.(1) CLINICAL EFFECTS: Decreased clearance may increase systemic concentrations of drugs primarily metabolized by CYP2C8 or CYP2C9, leading to toxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Closely monitor patients stable on CYP2C8/2C9 substrates for increased therapeutic effect or toxicity when chronic mifepristone therapy is started or adjusted. Adjust dosage of the 2C8/2C9 substrate drug accordingly. Because of the long half-life of mifepristone, the effect of changes in mifepristone therapy may not be seen for 2 weeks. For patients on chronic mifepristone and newly started on a CYP2C8/2C9 substrate, the smallest recommended dose of the CYP2C8/2C9 substrate is suggested by the manufacturer of mifepristone.(1) If chronic mifepristone therapy is discontinued, the manufacturer of mifepristone recommends waiting at least 2 weeks before increasing the dose of a concomitant interacting medication.(1) DISCUSSION: Mifepristone 1200 mg was given daily for 7 days, followed by a single dose of fluvastatin (40 mg), a CYP 2C8/2C9 substrate. The area-under-curve (AUC) of fluvastatin was increased 3.57 fold. The manufacturer notes this result could be representative of other oral drugs with CYP2C8/2C9 metabolism.(1) Mifepristone has a long elimination half-life of approximately 85 hours and so full effects of a mifepristone dose change on CYP2C8/2C9 substrates may not be seen for two weeks. Extended monitoring for this interaction may be required when mifepristone is started, stopped or if dose is changed.(1) Medications linked to this interaction are celecoxib, dasabuvir, fluvastatin, and repaglinide. These drugs have a narrow therapeutic range or are designated as CYP2C8 or CYP2C9 Sensitive Substrates(2,3), i.e. moderate CYP2C8 or 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold.	KORLYM, MIFEPRISTONE
Aminolevulinic Acid/Selected Photosensitizers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1) CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1) DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)	AMINOLEVULINIC ACID HCL, GLEOLAN
Porfimer/Selected Photosensitizers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1) CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1) PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1) PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer. DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)	PHOTOFRIN
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
Methoxsalen/Selected Photosensitizers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1) CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)	METHOXSALEN, UVADEX

There are 14 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Bupropion/Hypoglycemics; Insulin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bupropion can lower the seizure threshold and when given concurrently with other medications that also lower the threshold there is an increased risk of seizure.(1,2) CLINICAL EFFECTS: Concurrent use of bupropion and hypoglycemics or insulin may increase the risk of seizure.(1,2) PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids, theophylline).(1,2) PATIENT MANAGEMENT: The use of bupropion in patients treated with oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1) DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and oral hypoglycemic agents or insulin should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2)	APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, WELLBUTRIN SR, WELLBUTRIN XL
Glinides; Sulfonylureas/Ethyl Alcohol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Alcohol can induce hypoglycemia and interfere with gluconeogenesis in the liver by means of intrinsic hypoglycemic activity.(1-3) Some alcoholic beverages may increase serum glucose levels from their high carbohydrate content.(4) Chronic alcohol intake may decrease half-life of sulfonylureas by increasing liver metabolism.(1, 5-8) CLINICAL EFFECTS: Alcohol consumption while on a glinide or sulfonylureas may result in unpredictable and varied reactions, ranging from mild flushing to severe hypoglycemic reactions. Alcohol consumption during chlorpropamide therapy has resulted in a disulfiram-like reaction. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Diabetics should be cautioned about the effects of alcohol consumption on diabetic control, possible flushing with concurrent use, and about unsuspected sources of alcohol such as medications. Patients on chlorpropamide therapy should be counseled about the possibility of a disulfiram-like reaction to alcohol consumption. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (21): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation DISCUSSION: Chlorpropamide has been reported to induce facial flushing (5,9-18) and a disulfiram-like reaction(4,9,10,18,19) following alcohol consumption. Tolbutamide has been shown to interact with alcohol in nonalcoholic diabetic patients, alcoholics, and normal subjects.(2,3,6-8,16,17) There is one report of reduced tolerance for alcohol in a patient on tolazamide therapy.(20) In a study in 10 normal subjects, administration of ethanol with glipizide resulted in a delay in return to fasting glucose levels. The time of onset and the extent of hypoglycemia were not altered.(21) Glipizide and glyburide have been reported to have a very low incidence of disulfiram-like reactions with concurrent alcohol; however, in one study, 5 of 11 patients taking glyburide developed flushing after a test dose of alcohol.(18)	ALCOHOL,DEHYDRATED
Selected Antidiabetic Agents/Selected Quinolones SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of quinolones and antidiabetic agents may result in severe hypoglycemia.(1-7) Hypoglycemia can lead to coma. PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction.(5) PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with a quinolone should be closely monitored for hypoglycemia.(1-4) Patients should be instructed to discontinue quinolone use and contact their doctor if hypoglycemia occurs.(2,4) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety. DISCUSSION: Hypoglycemia has been reported with concurrent ciprofloxacin and glyburide,(1,8,9) levofloxacin and glyburide,(2,10,11) norfloxacin and glyburide,(3) levofloxacin and glipizide (12) as well as levofloxacin and metformin-glibenclamide.(14) There has been one report of fatal hypoglycemia with concurrent levofloxacin and glyburide(9) and one of the above reports of hypoglycemia with concurrent levofloxacin and glyburide resulted in hypoxic brain injury.(11) A review of postmarketing adverse event data for the fluoroquinolones and hypoglycemic coma identified 56 reports in FAERS search from October 1987- April 2017 and 11 additional cases in the medical literature. Most patients had risk factors for hypoglycemia. 41 patients were taking one or more hypoglycemic drugs. 13 deaths occurred (some of these patients had renal insufficiency). 9 patients did not fully recover and had resultant disability.(13)	AVELOX IV, BAXDELA, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, LEVOFLOXACIN, LEVOFLOXACIN HEMIHYDRATE, LEVOFLOXACIN-D5W, MOXIFLOXACIN, MOXIFLOXACIN HCL, OFLOXACIN
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
Repaglinide/Deferasirox SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Deferasirox may inhibit the metabolism of repaglinide by CYP2C8.(1) CLINICAL EFFECTS: Concurrent use of deferasirox may result in elevated levels of and increased effects of repaglinide.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with deferasirox and repaglinide closely. Consider decreasing the dosage of repaglinide.(1) DISCUSSION: In a study in healthy subjects, administration of deferasirox (30 mg/kg/day for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.5 mg) by 2.3-fold and 62%, respectively.(1)	DEFERASIROX, EXJADE, JADENU, JADENU SPRINKLE
Repaglinide/Cyclosporine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cyclosporine may inhibit the metabolism of repaglinide by CYP3A4 and OATP-mediated hepatic uptake of repaglinide.(1) CLINICAL EFFECTS: Concurrent use with cyclosporine may result in increased levels of and effects from repaglinide, including hypoglycemia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use caution when initiating repaglinide in patients maintained on cyclosporine.(1,2) Lower starting doses and careful titration may be required.(3) Monitor patients receiving concurrent therapy for signs of hypoglycemia.(1,2) The dose of repaglinide may need to be adjusted. The US manufacturer of repaglinide recommends the daily maximum dose should be limited to 6 mg and increased frequency of glucose monitoring may be required with concurrent therapy.(4) DISCUSSION: In a study in 12 healthy males, cyclosporine (100 mg every 12 hours for 2 doses) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of repaglinide (0.25 mg) by 1.8-fold (range 0.6-3.7-fold, p<0.001) and by 2.4-fold (range 1.2-5.3-fold, p<0.001).(1,2) The amount of unchanged repaglinide, its M2 metabolite, and its M4 metabolite excreted in the urine 2.7-fold, 7.5-fold, 5.0-fold, respectively. No statistically significant changes in blood glucose response were noted; however, individual responses correlated with the degree of increased repaglinide levels.(1)	CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE
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
Repaglinide/Letermovir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Letermovir may inhibit the metabolism of repaglinide by CYP3A4, CYP2C8, and OATP-mediated hepatic uptake of repaglinide.(1) CLINICAL EFFECTS: Concurrent use with letermovir may result in increased levels of and effects from repaglinide, including hypoglycemia.(1,2) PREDISPOSING FACTORS: Concurrent administration with cyclosporine. Patients who achieve tight control of blood sugars, or have a history of hypoglycemic episodes may be at greater risk for hypoglycemia with this combination. PATIENT MANAGEMENT: The US manufacturer of letermovir recommends that when letermovir is coadministered with repaglinide that glucose concentrations are frequently monitored. If letermovir is coadministered with cyclosporine, use of repaglinide is not recommended.(1) When letermovir is coadministered with cyclosporine, the combined effect on repaglinide may be similar to a strong CYP3A4 inhibitor.(1) DISCUSSION: Letermovir is a moderate inhibitor of CYP3A4 and a OATP1B1/3 inhibitor. In a study, concomitant administration of letermovir (480 mg once daily) administered with the CYP3A4 substrate midazolam (1 mg single dose intravenous) increased the midazolam area-under-the-curve (AUC) and C24hr by 1.47-fold and 2.74 fold, respectively. Concomitant administration of letermovir (480 mg once daily) with midazolam (2 mg single dose oral) increased the midazolam AUC and maximum concentration (Cmax) by 2.25-fold and 1.72-fold.(1)	PREVYMIS
Repaglinide/Tecovirimat SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tecovirimat may inhibit the metabolism of repaglinide by CYP2C8. Repaglinide is also metabolized by CYP3A4 and tecovirimat is a weak inducer of CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of tecovirimat may result in elevated levels of repaglinide and may result in mild to moderate hypoglycemia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with tecovirimat and repaglinide closely for hypoglycemic symptoms.(1) DISCUSSION: In a study in healthy subjects, concurrent administration of tecovirimat and repaglinide (2 mg) resulted in 10 of 30 subjects experiencing mild (6 subjects) and moderate hypoglycemia (4 subjects).(1) In a study in healthy subjects, administration of tecovirimat (600 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (2 mg) by 29% and 27%, respectively.(1)	TPOXX (NATIONAL STOCKPILE)
Nateglinide; Repaglinide/Slt Non-Cardioselective B-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. CLINICAL EFFECTS: Diminished response to nateglinide and repaglinide may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)	BETAPACE, BETAPACE AF, CARVEDILOL, CARVEDILOL ER, COREG, COREG CR, CORGARD, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, LABETALOL HCL, LABETALOL HCL-WATER, NADOLOL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TIMOLOL MALEATE
Selected Antidiabetic Agents/Chloroquine; Hydroxychloroquine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Chloroquine and hydroxychloroquine may increase insulin sensitivity by inhibiting insulin metabolism and inflammation and increasing cellular uptake of glucose and glycogen synthesis.(1,2) These effects may result in additive hypoglycemia with anti-diabetic agents. CLINICAL EFFECTS: Concurrent use of chloroquine or hydroxychloroquine and antidiabetic agents may result in severe hypoglycemia.(3) Hypoglycemia can lead to coma. PREDISPOSING FACTORS: Elderly patients, especially those with decreased renal function may be predisposed to this interaction. PATIENT MANAGEMENT: Patients maintained on antidiabetic agents who require concurrent therapy with chloroquine or hydroxychloroquine should be closely monitored for hypoglycemia. A decrease in the dose of insulin or other anti-diabetic medications may be required. Patients should be advised of the risk and symptoms of hypoglycemia and to contact their doctor if hypoglycemia occurs.(3) Signs of hypoglycemia may include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, or unusual anxiety. DISCUSSION: Hydroxychloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening.(3) Concomitant hypoglycemic agents may increase the risk and/or severity of this effect. A 77 year old man who was stable on twice daily insulin suffered two episodes of hypoglycemic coma 2 weeks after starting prednisone 5 mg daily and hydroxychloroquine 400 mg daily for rheumatoid arthritis. His insulin dosage required a decrease of 37%.(4) Many studies have investigated the glucose-lowering effect of hydroxychloroquine. In a clinical trial of type II diabetics on maximal doses of sulfonylureas, addition of hydroxychloroquine lowered hemoglobin A1C (HbA1C) up to 1% more than placebo.(5) Another clinical trial of type II diabetics on metformin and glimepiride or gliclazide found that hydroxychloroquine 400 mg daily reduced fasting blood glucose (FBG), post-prandial glucose (PPG), and HbA1C to a similar degree as pioglitazone 15 mg daily at 24 weeks.(6) In a prospective observational study, 250 uncontrolled type II diabetics on metformin, glimepiride, pioglitazone, sitagliptin, and a SGLT-2 inhibitor received hydroxychloroquine 400 mg daily for 48 weeks. HbA1C decreased from 8.83% to 6.44%, FBG decreased by 40.78%, and PPG decreased by 58.95%. The doses of metformin were reduced by 50%, glimepiride and sitagliptin by 75%, and SGLT-2 inhibitors were discontinued in most patients.(7)	CHLOROQUINE PHOSPHATE, HYDROXYCHLOROQUINE SULFATE, PLAQUENIL, SOVUNA
BCRP or OATP1B1 Substrates/Eltrombopag SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1) DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: ciprofloxacin, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1)	ALVAIZ, PROMACTA
Repaglinide/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of repaglinide by CYP3A4.(1-3) CLINICAL EFFECTS: Concurrent use of repaglinide and strong CYP3A4 inhibitors may result in elevated levels of and effects from repaglinide, including hypoglycemia. PREDISPOSING FACTORS: Concurrent administration with a CYP2C8 inhibitor. PATIENT MANAGEMENT: Patients maintained on repaglinide should be closely monitored if a strong CYP3A4 inhibitor is added to or withdrawn from concurrent therapy. A dosage adjustment of the antidiabetic agent may be required during therapy with a strong CYP3A4 inhibitor. DISCUSSION: In a study, concurrent administration of itraconazole (100 mg twice daily for 3 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 1.4 fold and 1.5 fold, respectively. Concurrent administration of itraconazole (100 mg twice daily for 3 days) and gemfibrozil (600 mg twice daily for 3 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 19 fold and 2.8 fold, respectively.(1,5) In a randomized, double-blind, crossover study in nine healthy subjects, clarithromycin (250 mg daily for 5 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 40% and 67%, respectively. The AUC and Cmax of insulin increased by 51% and 61%, respectively.(2) In a randomized, cross-over study of 12 healthy volunteers, telithromycin (800 mg for 3 days) raised the mean Cmax and AUC of repaglinide (0.25 mg single dose on day 3) to 138% and 177% respectively. Telithromycin did not effect the elimination half-life of repaglinide. Telithromycin increased the urinary excretion of unchanged repaglinide to 229%. The renal clearance of repaglinide was increased by telithromycin to 138%. Telithromycin also lowered the Cmax of blood glucose by 10% and mean concentration of blood glucose by as much as 12% after repaglinide intake.(3) Severe hypoglycemia has been reported in patients following the addition of clarithromycin to repaglinide therapy.(4)	APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA
OATP1B1 Substrates/Midostaurin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1) DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin.	RYDAPT

The following contraindication information is available for REPAGLINIDE (repaglinide):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Concomitant use of gemfibrozil. *Known hypersensitivity to the drug or any inactive ingredients.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Lactation

There are 3 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min

There are 12 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Alcohol intoxication
Alcohol use disorder
Debilitation
Disease of liver
Hypoglycemic disorder
Invasive surgical procedure
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Major traumatic injury
Pituitary insufficiency
Primary adrenocortical insufficiency
Severe adrenal insufficiency
Severe infection

The following adverse reaction information is available for REPAGLINIDE (repaglinide):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse effects (>=5% of patients) reported with repaglinide are hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain.

There are 18 severe adverse reactions.

More Frequent	Less Frequent
None.	Pruritus of skin Sinusitis Skin rash Tooth disorder

Rare/Very Rare
Abnormal hepatic function tests Acute myocardial infarction Acute pancreatitis Anaphylaxis Cardiac arrhythmia Chest pain Hemolytic anemia Hepatitis Hypertension Hypoglycemic disorder Jaundice Leukopenia Stevens-johnson syndrome Thrombocytopenic disorder

There are 16 less severe adverse reactions.

More Frequent	Less Frequent
Upper respiratory infection	Arthralgia Back pain Bronchitis Constipation Diarrhea Dyspepsia Headache disorder Nausea Rhinitis Urinary tract infection Vomiting

Rare/Very Rare
Alopecia Paresthesia Peripheral edema Weight gain

The following precautions are available for REPAGLINIDE (repaglinide):

Pediatric
Pregnant
Lactation
Geriatric

Safety and effectiveness of repaglinide in children younger than 18 years of age have not been established.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Limited data from case reports and case series of repaglinide use in pregnant women have not revealed a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus also increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Reproduction studies in rats and rabbits given repaglinide during organogenesis at dosages representing 60 and 1 times, respectively, the maximum daily clinical dosage based on body surface area have not revealed evidence of harm to the fetus. No adverse developmental effects were observed in offspring of rats administered repaglinide during late gestation and lactation at approximately 4 times the maximum daily dosage.

There is no information on the presence of repaglinide in human milk, the effects on the breast-fed infant, or the effects on milk production. Repaglinide is present in animal milk. Nursing pups of rat dams receiving repaglinide at 15 times the human exposure on a mg/m2 basis during days 17-22 of gestation and throughout lactation developed shortening, thickening, and bending of the humerus during the postnatal period.

Cross-fostering studies indicate that such skeletal changes could be induced in control pups nursed by treated dams, although skeletal changes occurred to a lesser degree than in pups exposed to repaglinide in utero. Because of the potential for repaglinide to cause hypoglycemia in breast-fed infants, repaglinide is not recommended for use when breastfeeding.

The safety and efficacy of repaglinide appear to be similar in geriatric and younger patients. No pharmacokinetic differences were noted in healthy geriatric individuals (65 years of age or older) versus healthy younger individuals receiving repaglinide 2 mg before each meal. Subgroup analyses of clinical trials have not revealed evidence of altered effectiveness or safety of repaglinide based on age other than the expected age-related increase in cardiovascular morbidity observed with repaglinide and other comparative oral antidiabetic agents. No increase in the frequency and severity of hypoglycemia was observed in geriatric versus younger patients receiving repaglinide.

The following icd codes are available for REPAGLINIDE (repaglinide)'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