5. Drug-Drug Interactions
Patient profiles will be reviewed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for oral antidiabetic agents are summarized in Table 13. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level* |
|---|---|---|---|---|
| acarbose | digoxin | adjunctive administration may result in decreased digoxin levels; acarbose most likely impairs digoxin absorption | avoid concurrent administration; separate administration by 6 hours to avoid interaction; monitor digoxin levels | 2-major (CP) |
| alpha-glucosidase inhibitors (AGIs) | intestinal adsorbents (e.g. charcoal) and digestive enzymes (e.g. amylase, pancreatin) | combined therapy may result in decreased AGI absorption, reduced pharmacologic effects | avoid concurrent administration; separate administration times | moderate (DrugReax) 2-major (CP) |
| antidiabetic agents (ADAs) | ACE inhibitors/ angiotensin receptor blockers (ARBs) | combined therapy may result in increased risk of hypoglycemia, most likely due to ACE inhibitor/ARB improved insulin sensitivity | monitor glycemic control when initiating or changing therapy | 3-moderate (CP) |
| ADAs | atypical antipsychotics (AAs) | combined therapy may result in loss of glycemic control; AAs may increase insulin resistance or inhibit beta cells | monitor for loss of glycemic control; adjust doses as necessary | 3-moderate (CP) |
| ADAs | beta blockers (BB) | BB may prolong hypoglycemia (interference with mobilization of glycogen stores), promote hyperglycemia (inhibit insulin secretion/decrease tissue insulin sensitivity), as well as mask signs/symptoms of hypoglycemia | administer cautiously together; consider cardioselective BB due to lesser effects on glucose metabolism, less masking of hypoglycemic signs/ symptoms | moderate (DrugReax) 3-moderate (CP) |
| ADAs | fluoroquinolones | combined administration may increase risk of hyper- or hypoglycemia; mechanism unknown | closely monitor serum glucose levels; adjust ADA doses as needed | major (DrugReax) 3-moderate (CP) |
| ADAs | MAOIs | adjunctive therapy may result in additive glucose-lowering effects; MAOIs may stimulate insulin secretion | closely monitor serum glucose levels; decrease antidiabetic agent doses as necessary | moderate (DrugReax) 3-moderate (CP) |
| ADAs | somatostatin analogues (SAs) (e.g., octreotide, pasireotide) | concurrent use may impair glucose regulation as SAs inhibit insulin and glucagon secretion; substantially increased blood glucose levels may result | monitor closely for changes in blood glucose control before and throughout SA therapy; adjust antidiabetic doses as needed | major (DrugReax) 2-major (CP) |
| ADAs | thiazide diuretics | combined therapy may antagonize hypoglycemic effects of ADAs as thiazides increase blood glucose levels in dose-related manner | utilize lower thiazide doses, if possible; monitor serum glucose levels; adjust ADA doses as needed | 3-moderate (CP) |
| bromocriptine | ergot alkaloids | combined therapy may increase risk of ergot toxicity (e.g., angina, paresthesias) as bromocriptine is ergot derivative | avoid using together | 1-severe (CP) |
| bromocriptine | metoclopramide | combined therapy may attenuate bromocriptine pharmacological effects; metoclopramide is dopamine antagonist | avoid concurrent use | 2-major (CP) |
| bromocriptine | select macrolides (e.g., clarithromycin, erythromycin) | potential for increased bromocriptine pharmacologic/ adverse effects due to decreased hepatic metabolism by macrolide | monitor patient for adverse effects; decrease bromocriptine dose as necessary | moderate (DrugReax) 3-moderate (CP) |
| bromocriptine | serotonin-receptor agonists (e.g., sumatriptan) | increased risk of serious coronary ischemia due to potential for additive vasospasm | avoid concurrent administration within 24 hours of each other | 2-major (CP) |
| bromocriptine | drugs metabolized by CYP3A4 (e.g., tacrolimus, cyclosporine, sirolimus) | potential for decreased cyclosporine/ sirolimus/ tacrolimus clearance, enhanced pharmacologic/ adverse effects; bromocriptine is CYP3A4 inhibitor | monitor for increased pharmacologic/adverse effects; consider reducing dose of CYP3A4 substrate | 2-major (CP) |
| bromocriptine | first generation antipsychotics | decreased efficacy of bromocriptine due to antagonization of prolactin-lowering effects and elevation of prolactin levels with chronic administration of these antipsychotics | avoid concurrent administration together; closely monitor for adverse events if they must be co-administered | 2-major (CP) |
| canagliflozin | UGT enzyme inducers (e.g., rifampin) | adjunctive administration may decrease canagliflozin AUC by 51% and reduce therapeutic efficacy as canagliflozin is metabolized through O-glucuronidation by several UGT enzymes (UGT1A9 and UGT2B4) | administer cautiously together; may increase canagliflozin dose to 300 mg daily during adjunctive therapy with UGT enzyme inducers or may consider alternative antidiabetic agents metabolized by different mechanisms | major (DrugReax) 2-major (CP) |
| colesevelam | cyclosporine | decreased cyclosporine peak serum concentrations and AUC with combined therapy | administer cyclosporine at least 4 hours prior to colesevelam; monitor serum cyclosporine levels | 3-moderate (CP) |
| colesevelam | oral contraceptives (OC) | decreased peak ethinyl estradiol/ norethindrone serum levels, AUC with combined therapy | administer OC at least 4 hours before colesevelam | 3-moderate (CP) |
| colesevelam | thyroid hormones (TH) (e.g., levothyroxine, liothyronine) | combined therapy may cause reduced thyroid hormone absorption due to nonspecific binding to colesevelam | take TH at least 4 hours prior to colesevelam; monitor for adequate thyroid response; adjust TH dose as needed | moderate (DrugReax) 3-moderate (CP) |
| glimepiride | voriconazole | combined therapy may increase glimepiride levels and risk of hypoglycemia; voriconazole inhibits CYP2C9, glimepiride metabolized by CYP2C9 | monitor for hypoglycemia; consider lowering glimepiride dose | major (DrugReax) 3-moderate (CP) |
| glyburide, TZDs | bosentan | increased risk of elevated liver enzymes when used concurrently; bosentan, a CYP2C9 and CYP3A4 inducer, may decrease glyburide and TZD levels/reduce hypoglycemic effects; glyburide, rosiglitazone metabolized by CYP2C9, pioglitazone metabolized by CYP3A4 | combined therapy contraindicated; choose alternative ADA | glyburide -1-severe; TZDs - 2-major (CP) glyburide -contraindicated (DrugReax) |
| linagliptin | CYP3A4 and p-glycoprotein inducers | combined therapy may significantly decrease linagliptin concentrations decrease efficacy; linagliptin metabolized by CYP3A4 | administer cautiously together; monitor serum glucose levels | rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, St. John’s wort - major (DrugReax) others - moderate (DrugReax) |
| meglitinides, sulfonylureas, TZDs | CYP2C8 Inducers (e.g. rifamycins) | combined therapy may result in reduced ADA serum levels and loss of hypoglycemic control due to enhanced ADA hepatic metabolism by rifamycin | closely monitor serum glucose levels; adjust ADA dose as necessary | moderate (DrugReax) 4-minor (CP) |
| metformin | dofetilide | increased risk of lactic acidosis; dofetilide decreases metformin elimination by competing for renal tubular transport system; potential for increased dofetilide serum concentrations and cardiotoxicity risk | manufacturer recommends avoiding concurrent use | 1-severe (CP) major (DrugReax) |
| pioglitazone | tolvaptan | combined therapy may decreases tolvaptan concentrations; pioglitazone is CYP3A4 inducer, tolvaptan is metabolized by CYP3A4 | avoid concurrent use if possible; if combined therapy necessary, increase tolvaptan dose and monitor efficacy | major (DrugReax) |
| repaglinide, TZDs | Strong CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel) | combined therapy increases potential for elevated repaglinide or TZD levels/amplified repaglinide or TZD hypoglycemic effects due to inhibition of CYP2C8; repaglinide, TZDs metabolized by CYP2C8 | avoid concurrent administration; if combination cannot be avoided, use lower repaglinide dose | contraindicated (DrugReax) 1-severe |
| repaglinide | CYP3A4 inhibitors (e.g., rifamycins, macrolides, itraconazole) | combined therapy may significantly increase repaglinide concentrations and increase hypoglycemia risk; repaglinide metabolized by CYP3A4 | administer cautiously together; monitor for hypoglycemia; adjust repaglinide dose as necessary | itraconazole-major; others – moderate (DrugReax) 2-major (CP) |
| repaglinide | cyclosporine | cyclosporine is CYP3A4 inhibitor, also inhibits uptake of repaglinide into liver by inhibiting OATP1B1, which increases risk of elevated repaglinide levels and hypoglycemia when given concurrently | administer cautiously together; closely monitor glycemic control; adjust repaglinide dose as necessary | 2-major (CP) |
| repaglinide | isophane insulin (NPH) | combined therapy caused myocardial ischemia in clinical trials | avoid concurrent administration | 2-major (CP) |
| rosiglitazone | nitrates | in clinical trials, increased risk of myocardial ischemia in patients receiving combined therapy | avoid concurrent administration (manufacturer recommendations) | 2-major (CP) |
| saxagliptin | CYP3A4/5 inhibitors (e.g., ketoconazole, erythromycin, fluconazole) | combined therapy may increase saxagliptin levels and risk of hypoglycemia; saxagliptin metabolized by CYP3A4/5 | utilize lower saxagliptin dose (2.5 mg daily) with strong CYP3A4/5 inhibitors (e.g., ketoconazole); adjunctive therapy with moderate CYP3A4/5 inhibitors does not warrant dosage adjustments | 2-major (CP) |
| sulfonylureas | methotrexate | concurrent administration may result in methotrexate displacement from protein binding sites and increased risk of methotrexate toxicity | consider avoiding combination; watch for signs of toxicity | 2-major (CP) |
| sulfonylureas | sulfonamides | combined therapy may exaggerate sulfonylurea hypoglycemic effects; sulfonamides may inhibit sulfonylurea metabolism or displace sulfonylurea from protein binding site; glipizide, glyburide not significantly affected due to nonionic binding of these agents | use combination cautiously; closely monitor serum glucose levels, observe for signs/symptoms of hypoglycemia, reduce sulfonylurea dose as necessary | moderate (DrugReax) 3-moderate (CP) |
| TZDs | insulins | combined therapy associated with increased risk of heart failure and/or edema and myocardial ischemic events | manufacturer recommends avoiding concurrent use | 2-major (CP) |
Legend:
- *CP = Clinical Pharmacology