Pioglitazone-Glimepiride (pioglitazone HCl/glimepiride)

Dosage of pioglitazone hydrochloride is expressed in terms of pioglitazone.

Glimepiride is administered orally once daily. Glimepiride should be administered with breakfast or with the first main meal of the day. The fixed combination of glimepiride and pioglitazone is administered orally once daily with the first main meal of the day. See the full prescribing information for additional administration instructions for the combination product. Although food slightly decreases the extent and slightly delays absorption of glimepiride, the manufacturer recommends that the drug be taken with the first meal of the day. Once-daily dosing of glimepiride provides adequate control of blood glucose concentration throughout the day.

Dosage of glimepiride must be individualized carefully based on patient response and tolerance. The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A1c (HbA1c)) values to normal or near normal using the lowest effective dosage of glimepiride, when used either as monotherapy or in combination with other antidiabetic agents.

Store glimepiride tablets at 20-25degreesC in well-closed containers with safety closures.

Pioglitazone hydrochloride is administered orally once daily and can be taken without regard to meals. The fixed combination of pioglitazone and immediate-release metformin hydrochloride should be administered orally with meals to reduce the GI effects of the metformin component. The fixed combination of pioglitazone and glimepiride is administered once daily with the first main meal. See full prescribing for additional administration instructions for these fixed-combination products.

If a dose of pioglitazone is missed on one day, the dose should not be doubled the following day.

Store pioglitazone tablets at 25oC; excursions permitted to 15--30oC. Keep container closed and protect from light, moisture, and humidity.

Glimepiride is metabolized by cytochrome P-450 (CYP) isoenzyme 2C9.

Pioglitazone is metabolized principally by cytochrome P-450 (CYP) 2C8, and to a lesser degree, by CYP3A4, with additional contributions from a variety of isoforms including the mainly extrahepatic CYP1A1.

Pioglitazone is a weak inducer of CYP3A4.

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

Cyp3a4 Inducers/Lumateperone

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: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)

Cyp3a4 Inducers/Zuranolone

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: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Pioglitazone (> 15 MG)/Strong Cyp2c8 Inhibitors

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: Strong inhibitors of CYP2C8 may inhibit the metabolism of pioglitazone.(1-5)

CLINICAL EFFECTS: Concurrent use of strong CYP2C8 inhibitors may result in elevated levels of and clinical effects, including severe hypoglycemia, from pioglitazone.(1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dosage of pioglitazone is 15 mg daily when used concurrently with strong CYP2C8 inhibitors.(2)

DISCUSSION: In a randomized, cross-over study in 10 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold. The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2) In a randomized, double-blind, cross-over study in 12 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold (range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively. There was no significant effect on pioglitazone maximum concentration (Cmax). The 0-48 hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%, respectively; however, there was no significant effect on their 0-infinity AUC.(3) In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4 days) increased the AUC of a single dose of pioglitazone (15 mg) by 4.3-fold. The increase was variable between CYP2C8 genotypes. Individuals who were CYP2C8*3 carriers had a 5.2-fold increase in pioglitazone, while CYP2C8*1 homozygotes had a 3.3-fold increase in pioglitazone.(5) Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

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)

Cyp3a4 Inducers/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

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)

Selected Cyp2c9 Substrates/Asciminib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Asciminib is a moderate inhibitor of CYP2C9.(1) Asciminib may decrease the metabolism of drugs that are CYP2C9 substrates.

CLINICAL EFFECTS: Decreased clearance may increase systemic concentrations of drugs primarily metabolized by CYP2C9, leading to toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of asciminib states coadministration of the CYP2C9 substrate drug with asciminib should be avoided. Consider an alternative agent that does not depend on CYP2C9 for metabolism. If a patient is taking asciminib 80 mg total daily dose and coadministration of the CYP2C9 substrate is unavoidable, reduce the dosage of the CYP2C9 substrate according to its product labeling.(1) Closely monitor patients stable on CYP2C9 substrates for altered therapeutic effect or toxicity when asciminib therapy is started, adjusted, or stopped.(1)

DISCUSSION: In clinical studies, coadministration of asciminib 40 mg twice daily, 80 mg once daily, and 200 mg twice daily, the area-under-the-curve (AUC) of S-warfarin increased by 41%, 52%, and 314%, respectively. Additionally, the maximum concentration (Cmax) of S-warfarin increased by 8%, 4%, and 7%, respectively.(1) Medications linked to this interaction include fluvastatin, fosphenytoin, glimepiride, glipizide, phenytoin, and tolbutamide. These drugs have a narrow therapeutic range or are designated as CYP2C9 Sensitive Substrates (i.e. moderate 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold).(2,3)

Sulfonylureas/Miconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sulfonylureas are sensitive CYP2C9 substrates. Miconazole is a moderate CYP2C9 inhibitor and may inhibit the metabolism of sulfonylureas.(1)

CLINICAL EFFECTS: Concurrent use of miconazole may result in elevated levels and effects of the sulfonylureas, including severe hypoglycemia and coma.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian, Canadian, and UK manufacturers of gliclazide and the UK manufacturer of glipizide state that concurrent use with miconazole via systemic routes or oro-mucosal gel is contraindicated.(2-5) The manufacturers of other sulfonylureas and the Australian and UK manufacturers of miconazole advise caution when using the combination of sulfonylureas and miconazole. Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted.(6-15)

DISCUSSION: A French pharmacovigilance study found that 98 cases of sulfonylurea-induced hypoglycemia were reported between 1985-1990, mostly with gliclazide (46 cases) and glyburide (40 cases). Miconazole was one of the most frequent causes of drug interactions (8 cases).(16) Other cases of severe hypoglycemia after miconazole was started in patients on sulfonylureas have been reported.(17-18)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Antidiabetics, Oral/Aspirin (> 100 MG); Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Complex. Salicylates appear to have intrinsic glucose lowering properties via several proposed mechanisms. Also, salicylates may cause protein binding displacement of antidiabetics. Decreased renal clearance may also occur.

CLINICAL EFFECTS: Potentiation of hypoglycemic effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. Particular caution should be taken when salicylates are started or stopped in patients previously stabilized on antidiabetics.

DISCUSSION: Additional documentation is necessary to confirm this potential interaction.

Antidiabetics, Oral/Clofibrate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not defined.

CLINICAL EFFECTS: May observe enhanced hypoglycemic effects.

PREDISPOSING FACTORS: Hypoalbuminemia.

PATIENT MANAGEMENT: Monitor blood glucose and watch for signs of hypoglycemia. This is particularly important when clofibrate is started or stopped.

DISCUSSION: Additional documentation is necessary to confirm this potential interaction.

Antidiabetics, Oral/Oxy-Phenylbutazone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Phenylbutazone may displace antidiabetics from plasma protein binding sites. Renal elimination of the active metabolite of acetohexamide may be reduced. Finally, tolbutamide metabolism may be decreased.

CLINICAL EFFECTS: Potentiation of antidiabetic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed.

DISCUSSION: This interaction is well documented.

Antidiabetics, Oral/Sulfonamide Antibacterials

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. However, it is speculated that sulfonamides may inhibit hepatic metabolism and/or displace oral antidiabetics from plasma protein binding sites.

CLINICAL EFFECTS: Increased serum levels of antidiabetics with potentiation of hypoglycemic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed.

DISCUSSION: Additional documentation is necessary to confirm this interaction.

Antidiabetics/Epinephrine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gluconeogenesis, glycogenolysis, and lipolysis are increased by epinephrine. Also, insulin secretion and glucose uptake by peripheral tissues are decreased by epinephrine.

CLINICAL EFFECTS: Increased blood glucose resulting in decreased effectiveness of the antidiabetic agent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Caution when starting or stopping epinephrine in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels.

DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence.

Antidiabetics/Slt Ophth Non-Cardioselective Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.(1,2)

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(3) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(4) There have been case reports of hypoglycemia following the addition of ophthalmic timolol to a diabetic regimen.(5-7) Studies have shown that ophthalmic beta-blockers, especially the aqueous solution, have significant systemic absorption and do not undergo first-pass metabolism.(8,9)

Glimepiride; Glipizide; Glyburide/Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colesevelam may bind to glimepiride, glipizide, and glyburide in the gastrointestinal track, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of colesevelam may result in decreased levels and effectiveness of glimepiride,(1) glipizide,(1) or glyburide.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Glyburide,(1) glipizide,(3) and glimepiride(4) should be administered four hours before colesevelam.

DISCUSSION: When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of glimepiride (4 mg) decreased by 18% and by 8%, respectively. When administered 4 hours prior to colesevelam, the AUC of glimepiride decreased by 6% and the Cmax increased 3%.(1) When administered with colesevelam (3.75 g), the AUC and Cmax of glipizide (20 mg) decreased by 12% and by 13%, respectively. When administered 4 hours prior to colesevelam, the AUC of glipizide decreased by 4%. There was no effect on glipizide Cmax when glipizide and colesevelam were separated by 4 hours.(1) When administered with colesevelam (3.75 g), AUC and Cmax of glyburide (3 mg) decreased by 32% and by 47%, respectively. When administered 1 hour prior to colesevelam, the AUC and Cmax of glyburide decreased by 20% and 15%, respectively. When administered 4 hours prior to colesevelam, the AUC and Cmax of glyburide decreased by 7% and 4%, respectively.(1,2)

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 a range of reactions, 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)

Hypoglycemics; Insulin/Bupropion

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. Concurrent use of hypoglycemics or insulin increases the risk of hypoglycemia which can result in seizures.(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)

Moderate And Weak Cyp3a4 Inducers/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)

DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Pioglitazone/Insulin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may be the result of additive fluid retention.(1,2)

CLINICAL EFFECTS: The concurrent use of pioglitazone with insulin may increase the risk of edema and heart failure.(1,2)

PREDISPOSING FACTORS: Specific risk factors for heart failure could not be determined. Patients with ongoing edema are more likely to have edema-associated adverse effects with combination therapy.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for cardiovascular adverse events. If signs and symptoms of congestive heart failure develop, patients should be treated according to current standards of care. Consideration should be given to lowering the dosage of or discontinuing pioglitazone.(1,2)

DISCUSSION: In a clinical trial, two of 191 (1.1%) of patients receiving pioglitazone (15 mg) and insulin and two of 188 (1.1%) of patients receiving pioglitazone (30 mg) and insulin developed congestive heart failure. None of the patients receiving insulin alone developed congestive heart failure.(1)

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)

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)

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)

Selected Antidiabetics/Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI. Furazolidone is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Selected Antidiabetics/Safinamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism by which MAO inhibitors such as safinamide affect carbohydrate metabolism and subsequent enhancement of the hypoglycemic action of insulin is not clear. The adrenergic response to hypoglycemia may be blocked by insulin release caused by MAOI's. In vitro studies have shown that MAO inhibitors are capable of both potentiating and inhibiting insulin release, depending on their concentrations. Stimulation of glucose-mediated insulin secretion is believed to be related to the MAO inhibitory effects of the drugs.

CLINICAL EFFECTS: The hypoglycemic response to both insulin and glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylurea may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent MAO inhibitor therapy for depression in a diabetic patient will often require reduction in dosage of the hypoglycemic agent because of enhanced hypoglycemic effects. Since the extent of the reaction is highly unpredictable, any diabetic patients receiving MAO inhibitors should be monitored for possible excessive hypoglycemia.

DISCUSSION: This interaction is likely to occur. The interaction between MAOIs and insulin is well documented. Additional documentation is necessary to confirm the potential interaction of MAOI's with other glucose lowering agents including alpha glucosidase inhibitors, meglitinides, and sulfonylureas but is expected to occur based on pharmacologic similarity. It may take several weeks for the full hypoglycemic effect of the MAOI to occur. Conversely, it may take several weeks for the effect to dissipate after stopping the MAOI.

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 substrate may need to be adjusted if leflunomide or teriflunomide are initiated.(1) Because of teriflunomide's slow elimination, the effects of teriflunomide on these CYP2C8 substrates 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)

Selected Cyp2c9 Substrates/Nitisinone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nitisinone is a moderate inhibitor of CYP2C9.(1,2)

CLINICAL EFFECTS: Decreased clearance may increase systemic concentrations of drugs primarily metabolized by CYP2C9, leading to toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Decrease the dosage of the CYP2C9 substrate drug by one-half. Additional dose adjustments may be necessary. Closely monitor patients stable on CYP2C9 substrates for altered therapeutic effect or toxicity when nitisinone therapy is started or adjusted.(1)

DISCUSSION: In a study, 16 healthy subjects who were pre-treated with nitisinone (80 mg daily) for 14 days and received a single dose of tolbutamide (500 mg) had an increase in tolbutamide area-under-curve (AUC) and maximum concentration (Cmax) of 131 % and 16 %, respectively, compared to tolbutamide administered alone.(1,2) Medications linked to this interaction include fluvastatin, fosphenytoin, glimepiride, glipizide, phenytoin, tolbutamide, and warfarin. These drugs have a narrow therapeutic range or are designated as CYP2C9 Sensitive Substrates(3,4) (i.e. moderate 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold).

Selected Moderate-Weak Cyp3a4 Inducers/Exemestane

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.

DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Sulfonylureas/Amiodarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amiodarone may decrease the metabolism of sulfonylureas by inhibiting CYP2C9. Amiodarone is a moderate CYP2C9 inhibitor.(1-5)

CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia.

PREDISPOSING FACTORS: This interaction may be more likely in patients using higher doses of amiodarone and who use amiodarone for greater than 180 days.(6)

PATIENT MANAGEMENT: Closely monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted when initiating or discontinuing amiodarone therapy.

DISCUSSION: In a nested case control study, concurrent use of amiodarone and sulfonylureas increased the risk of severe hypoglycemia by 56% (95% CI:0.98-2.46). In patients on sulfonylureas, amiodarone use greater than 180 days and at higher daily doses was associated with a 2.08-fold and a 2.21-fold increase in severe hypoglycemia, respectively, which was statistically significant.(6)

Sulfonylureas/Azole Antifungals

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Azole antifungals inhibit the metabolism of sulfonylureas.

CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted.

DISCUSSION: Prospective and retrospective studies in healthy subjects have documented an interaction between the sulfonylureas and fluconazole and ketoconazole. In vitro studies have shown the metabolism of sulfonylureas to be inhibited by ketoconazole and clotrimazole. In 13 healthy males, fluconazole increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by 19% and 49%, respectively. In 20 healthy males, fluconazole increased the Cmax and AUC of a single dose of glyburide (5 mg) by 19% and 44%, respectively. In 13 healthy males, fluconazole increased the Cmax and AUC of a single dose of tolbutamide (500 mg) by 11% and 26%, respectively. Although itraconazole was found to have no effect on tolbutamide clearance in a study in rats, additional information is needed to determine if an interaction occurs. In healthy subjects, glucose concentrations decreased during concurrent therapy with glipizide and posaconazole. Voriconazole has been shown to inhibit CYP2C9.

Sulfonylureas/Diazoxide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: In a patient stabilized on a sulfonylurea hypoglycemic agent, hyperglycemia may occur following the addition of diazoxide to the treatment.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood glucose and adjust the dose of the sulfonylurea hypoglycemic agent as needed.

DISCUSSION: The concurrent administration of a sulfonylurea hypoglycemic agent and diazoxide has been beneficial in treating chlorpropamide-induced hypoglycemia and diazoxide-induced hyperglycemia. These reports indicate a potential problem if these agents are administered without proper monitoring of the patient's blood glucose.

Sulfonylureas/Systemic Non-Cardioselective Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and sulfonylureas. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

Thiazolidinedione Antidiabetics/Pregabalin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both pregabalin and thiazolidinedione antidiabetics may cause weight gain and/or fluid retention.(1)

CLINICAL EFFECTS: Concurrent use of pregabalin and thiazolidinedione antidiabetics may result in weight gain and/or fluid retention, which may increase the risk of heart failure in patients with preexisting cardiac conditions.(1)

PREDISPOSING FACTORS: Preexisting cardiac conditions may increase the risk of heart failure.(1)

PATIENT MANAGEMENT: Patients should be monitored for weight gain and/or fluid retention when taking pregabalin with the thiazolidinedione antidiabetics agents together. Congestive heart failure or worsening of existing congestive heart failure may occur.

DISCUSSION: In clinical trials, the incidence of peripheral edema was 3% of patients receiving a thiazolidinedione antidiabetic alone, 8% of patients receiving pregabalin alone, and 19% of patients on combination therapy. The incidence of weight gain was 0% of patients receiving a thiazolidinedione antidiabetic alone, 4% of patients receiving pregabalin alone, and 7.5% of patients on combination therapy.(1)

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

*Hypersensitivity to glimepiride or any ingredient in the formulation.

*Hypersensitivity to sulfonamide derivatives.

*Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure (HF).

*Known serious hypersensitivity reaction to pioglitazone or any ingredient in the formulation.

• Acute decompensated heart failure
• Lactation
• Malignant tumor of urinary bladder

• Chronic heart failure
• Hematuria
• Hypoglycemic disorder

• Alcohol use disorder
• Autonomic dysreflexia
• Debilitation
• Disease of liver
• Edema
• Fever
• Fracture
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemolytic anemia
• Hypoglycemic disorder
• Infection
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Macular retinal edema
• Pituitary insufficiency
• Primary adrenocortical insufficiency

The most common adverse effects of glimepiride (>=5% of patients and more common than placebo) reported in clinical trials were hypoglycemia, headache, nausea, and dizziness.

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

More Frequent

• Hypoglycemic disorder

Less Frequent

• Body fluid retention
• Edema
• Weight gain

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Aplastic anemia
• Cutaneous vasculitis
• Dyspnea
• Erythema
• Fracture
• Heart failure
• Hemolytic anemia
• Hepatic failure
• Hepatitis
• Hepatitis
• Hyponatremia
• Hypotension
• Idiopathic thrombocytopenic purpura
• Leukopenia
• Macular retinal edema
• Malignant tumor of urinary bladder
• Ovulation stimulation
• Pancytopenia
• Porphyria cutanea tarda
• SIADH syndrome
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Urticaria
• Worsening of chronic heart failure

More Frequent

• Dizziness
• Dizziness
• Flatulence
• Headache disorder
• Headache disorder
• Myalgia
• Nausea
• Pharyngitis
• Sinusitis
• Upper respiratory infection
• Urinary tract infection
• Weight gain

Less Frequent

• Diarrhea
• Flu-like symptoms
• Hypoglycemic disorder

Rare or Very Rare

• Alopecia
• Dysgeusia
• Pruritus of skin
• Skin photosensitivity

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Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a single dose of glimepiride were evaluated in 30 pediatric patients (aged 10--17 years) with type 2 diabetes mellitus. The results of this study found that the maximum plasma concentration, AUC, and half-life were comparable to historical data in adults. The safety and efficacy of glimepiride in pediatric patients were evaluated in a single-blind, 24-week trial that randomized 272 patients (aged 8--17 years) with type 2 diabetes to receive either glimepiride or metformin. Treatment naive and previously treated patients were enrolled; previously treated patients were required to discontinue other oral antidiabetic agents at randomization. After 24 weeks, the overall mean treatment difference in glycosylated hemoglobin (hemoglobin A1c; HbA1c) was 0.2%, favoring metformin. Based on this result, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin. Adverse effects reported in pediatric patients treated with glimepiride were similar to those reported in adult patients. Hypoglycemic events documented by a blood glucose <36 mg/dL were observed in 4% of patients treated with glimepiride compared to 1% treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode.

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

Available data from a small number of published studies and decades of postmarketing experience with glimepiride in pregnancy have not identified any drug associated risk for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glimepiride) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Prolonged hypoglycemia, lasting 4--10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life.

In animal studies, there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times and 0.1 times the maximum recommended human dose (based on body surface area), respectively. This fetotoxicity was observed only at doses inducing maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride, as has been similarly noted with other sulfonylureas.

Poorly controlled diabetes in pregnancy is associated with risks to both the mother and fetus. Poorly controlled diabetes in pregnancy is associated with increased maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes also increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity.

Due to reports of prolonged hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glimepiride should be discontinued at least 2 weeks before expected delivery. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.

There is insufficient evidence with pioglitazone in pregnant women to evaluate a drug-associated risk for major birth defects or miscarriage. In reproduction studies in rats and rabbits, pioglitazone administered during organogenesis at exposures up to 5 and 35 times the maximum recommended human dose, respectively, was not associated with adverse developmental effects. However, delayed parturition and reduced embryofetal viability were observed with pioglitazone dosages at least 9 times the maximum recommended human dose. Offspring of pregnant rats who were administered pioglitazone at dosages at least 2 times the maximum recommended human dose during late gestation and lactation had delayed postnatal development attributed to decreased body weight.

Poorly controlled diabetes during pregnancy increases the risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth, delivery complications, major birth defects, and macrosomia related morbidity.

There is no information regarding the presence of glimepiride in human milk or the effects on milk production. Glimepiride is distributed into milk in rats. During prenatal and postnatal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformities were determined to be the result of nursing from mothers exposed to glimepiride.

The developmental and health benefits of breastfeeding should be considered along with any potential adverse effects on the breast-fed child from glimepiride or from the underlying maternal condition. Breast-fed infants of lactating women using glimepiride should be monitored for symptoms of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

There are no data on the presence of pioglitazone in human milk, the effects on the breast-fed infant, or the effects on milk production. Pioglitazone is distributed into milk in rats. The benefits of breast-feeding should be weighed against the potential risk of adverse effects on the breast-fed infant from pioglitazone.

In clinical trials of glimepiride, 1053 of 3491 patients (30%) were >65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. There were no significant differences in the pharmacokinetics of glimepiride between patients with type 2 diabetes <=65 years and those >65 years of age.

Glimepiride is substantially excreted by the kidney. Geriatric patients are more likely to have renal impairment. Additionally, hypoglycemia may be difficult to recognize in geriatric patients. Use caution when initiating glimepiride and increasing the dosage of glimepiride in geriatric patients.

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