Invokamet Xr (canagliflozin/metformin HCl)

Dosage of canagliflozin is expressed in terms of anhydrous canagliflozin.

Available as metformin hydrochloride; dosage expressed in terms of the salt.

Canagliflozin is administered orally once daily. Canagliflozin is commercially available as single-entity tablets that should be administered before the first meal of the day. Canagliflozin is also available in fixed combination with immediate- or extended-release metformin hydrochloride (Invokamet(R), Invokamet XR(R)). The fixed combination of canagliflozin and immediate-release metformin hydrochloride should be administered twice daily with meals. The fixed combination of canagliflozin and extended-release metformin hydrochloride should be administered once daily with the morning meal; the tablet should be swallowed whole and should not be crushed, chewed, or cut. See the full prescribing information for additional administration instructions for the combination products.

If a dose of canagliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

Store canagliflozin tablets (single-entity and fixed combinations with metformin hydrochloride) at 20degreesC to 25degreesC; excursions permitted between 15degreesC and 30degreesC. Fixed combination tablets with immediate- or extended-release metformin hydrochloride should be stored and dispensed in the original container; however, the tablets may be stored in a pill box or pill organizer for <=30 days.

Metformin hydrochloride is administered orally. In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the medication can usually be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the medication may be better tolerated if administered in 3 divided doses daily. Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the medication be taken with meals to decrease adverse GI effects. Immediate-release metformin hydrochloride in fixed combination with alogliptin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, linagliptin, pioglitazone, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component. See the full prescribing information for additional administration instructions for the combination products.

Metformin hydrochloride oral solution is administered either once or twice daily with meals. Dosages above 2 g daily may be better tolerated if administered in 3 divided doses daily. Each dose should be measured using a metformin hydrochloride oral solution specific dosing cup.

Metformin hydrochloride extended-release tablets usually are taken with the evening meal. Extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin is administered once daily with the morning meal. The fixed combination of extended-release metformin hydrochloride and linagliptin should be administered once daily with a meal. The fixed combination of extended-release metformin hydrochloride and sitagliptin should be administered once daily with a meal, preferably with the evening meal. Extended-release metformin hydrochloride in fixed combination with saxagliptin should be administered once daily with the evening meal. Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the medication must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet. See the full prescribing information for additional administration instructions for the combination products.

Store metformin hydrochloride immediate- and extended-release tablets at 20--25degreesC in light-resistant containers; excursions permitted to 15--30degreesC. Store metformin hydrochloride oral solution at 15--30degreesC.

No dosing information is available for this tab.

The major metabolic elimination pathway for canagliflozin is O-glucuronidation; the drug is mainly glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.

Canagliflozin is a P-glycoprotein substrate and weakly inhibits P-glycoprotein. Canagliflozin also is a substrate of multidrug resistance-associated protein 2 (MRP2).

There are no contraindication interactions for this drug.

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)

Canagliflozin/Ugt Inducers

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

MECHANISM OF ACTION: UGT inducers may induce the metabolism of canagliflozin, which is glucuronidated by UGT1A9 and UGT2B4.(1)

CLINICAL EFFECTS: Concurrent use of an inducer of UGT may result in decreased levels and effectiveness of canagliflozin.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2.(1)

PATIENT MANAGEMENT: In patients with a eGFR of 60 ml/min/1.73m2 or more who are currently tolerating canagliflozin 100 mg daily and require therapy with an inducer of UGT, the manufacturer of canagliflozin recommends increasing the dose of canagliflozin to 200 mg daily. Patients currently tolerating canagliflozin 200 mg daily and require additional glycemic control may have their dose increased to 300 mg daily.(1) In patients with a eGFR of less than 60 ml/min/1.73m2 who are currently tolerating canagliflozin 100 mg daily and receiving therapy with a UGT inducer, increase the dose of canagliflozin to 200 mg daily. Consider other antihyperglycemic agents in patients who require additional glycemic control.(1)

DISCUSSION: Pretreatment with rifampin (600 mg daily for 8 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of canagliflozin (300 mg) by 51% and 28%, respectively.(1) Inducers of UGT include: carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.(1)

Metformin/Iodinated Contrast Materials

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

MECHANISM OF ACTION: Use of iodinated contrast materials may result in acute changes in renal function, resulting in a decrease in metformin clearance.(1-3)

CLINICAL EFFECTS: Use of iodinated contrast materials may increase levels of metformin, which may result in lactic acidosis.(1-3)

PREDISPOSING FACTORS: Pre-existing renal dysfunction may contribute to decreased clearance of metformin. Other factors which may increase the risk for lactic acidosis include age greater than 65 years, dehydration, metabolic acidosis, sepsis, a history of hepatic impairment, alcoholism, or heart failure.(1-4)

PATIENT MANAGEMENT: Evaluate renal function prior to contrast procedure. According to manufacturer recommendations, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with a history of liver disease, alcoholism, heart failure, or if contrast is to be administered intra-arterially. When contrast is to be administered by other routes, discontinue metformin at the time of, or prior to, the procedure for patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is stable. Discontinuation of metformin is not required if eGFR is > 60 mL/min/1.73 m2.(4) According to American College of Radiology guidelines, discontinue metformin at the time of, or prior to, the contrast imaging procedure in patients with acute kidney injury or chronic kidney disease (Stage IV or V or eGFR < 30 mL/min/1.73 m2), or who are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteries. Re-evaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is normal. Discontinuation of metformin is not required in patients with no evidence of acute kidney injury and with eGFR >= 30 mL/min/m2.(5)

DISCUSSION: An FDA review of the medical literature showed that metformin may be safely used in patients with mild or moderate renal impairment, resulting in modifications of prescribing recommendations and method for evaluation of renal function.(4) A clinical review of 33 patients on metformin who had received contrast media showed elevations in serum creatinine of the four patients with baseline elevations. The 29 patients with normal baseline renal function showed no elevations after administration of contrast media. The authors recommend that a baseline serum creatinine is obtained for all patients and that metformin should only be discontinued in patients with baseline elevations.(6) A retrospective study of ninety-seven patients currently taking metformin underwent a radiologic procedure with contrast media. Of these patients, 4 developed contrast material associated nephropathy and eight patients had an increased risk of lactic acidosis, with a baseline serum creatinine <1.5mg/dl.(7) A prospective clinical trial with 50 diabetic patients on metformin with baseline serum creatinine <1.47mg/dl showed no statistical difference in renal function before and 48 hours after administration of contrast media. The authors recommend a baseline serum creatinine for all patients and suggest that temporary discontinuation of metformin may not be necessary when baseline renal function is <1.47mg/dl.(8) A systematic review of the literature reveals that 17 of 18 case reports of metformin-induced lactic acidosis involved patients with renal dysfunction prior to administration of contrast media. The authors recommend a baseline serum creatinine in all patients and if renal dysfunction is present, metformin should be discontinued for 48 hours before and after administration of contrast media. The authors recommend follow-up creatinine measurement in patients with prior renal impairment or known comorbidities affecting lactate levels.(9)

Metformin/Tafenoquine

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

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine inhibits elimination by these pathways.(2)

CLINICAL EFFECTS: Use of tafenoquine may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with OCT2 and MATE1 substrates, such as metformin, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(2) Evaluate patient's renal function and consider discontinuation in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine is believed to inhibit the OCT2 and MATE1 pathways.(2)

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)

Metformin/Bictegravir

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

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Bictegravir inhibits elimination by these pathways.(1,2)

CLINICAL EFFECTS: Use of bictegravir may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Bictegravir is an inhibitor of OCT2 and MATE1.(2) Trimethoprim, an inhibitor of OCT2 and MATE1, was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney).(3) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area-under-curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%.(4) In a study in 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (5)

Metformin/Carbonic Anhydrase Inhibitors

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

MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1)

CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1)

DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1)

Metformin/Cephalexin

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

MECHANISM OF ACTION: Cephalexin may inhibit the renal tubular secretion of metformin.(1,2)

CLINICAL EFFECTS: Concurrent use of cephalexin may result in increased levels and clinical effects of metformin,(1,2) as well as an increased risk of lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Patients maintained on metformin should be closely monitored when cephalexin is initiated and discontinued. The dosage of metformin may need to be adjusted.(1)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, concurrent metformin (500 mg) and cephalexin (500 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metformin by 34% and 24%, respectively. Metformin renal clearance decreased by 14%.(1,2)

Metformin/Dolutegravir

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

MECHANISM OF ACTION: Dolutegravir may inhibit the renal organic cation transporter, OCT2, responsible for the elimination of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: With concomitant use, assess the benefit and risk of metformin in patients on dolutegravir. When starting or stopping dolutegravir, the metformin dose may require an adjustment. Monitor blood glucose when initiating concomitant use and after stopping dolutegravir.(1) Monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio.(1)

DISCUSSION: Dolutegravir has been shown to inhibit OCT2 in vitro and in vivo and is expected to inhibit the excretion of metformin.(1) In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of metformin by 66% and 79%, respectively. In a study in 15 subjects, concomitant metformin (500 mg twice daily) with dolutegravir (50 mg twice daily) increased the Cmax and AUC of metformin by 111% and 145%, respectively.(1)

Metformin/Mate Inhibitors

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

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal tubular secretion of metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: Use an alternative agent if possible. If both drugs are given, monitor patient's renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Dosage of either agent may need to be adjusted.(1)

DISCUSSION: In a study of normal healthy volunteers, concurrent metformin and oral cimetidine increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2) MATE inhibitors include: brepocitinib, cimetidine, pyrimethamine, and risdiplam.(3)

Metformin/Oct2 Inhibitors

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

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of metformin by OCT2 in the kidneys.(1)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from metformin.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels higher than 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of metformin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of metformin and consider dosage reduction of metformin.(1)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) OCT2 inhibitors linked to this monograph include: arimoclomol, givinostat, trilaciclib, and vimseltinib.(2)

Metformin/Patiromer

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

MECHANISM OF ACTION: Patiromer may bind to metformin.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased gastrointestinal absorption and loss of efficacy of metformin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of patiromer recommends that you administer patiromer at least 3 hours before or 3 hours after metformin.(1)

DISCUSSION: A study in healthy volunteers showed that patiromer decreased the systemic exposure of coadministered metformin. No interaction was seen when these drugs were taken 3 hours apart.(1)

Metformin/Ranolazine

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

MECHANISM OF ACTION: Ranolazine may decrease renal elimination of metformin by inhibiting OCT-2.(1)

CLINICAL EFFECTS: Concurrent ranolazine may result in elevated levels of and toxicity from metformin.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metformin and ranolazine. In patients receiving 1000 mg ranolazine twice daily, limit the dose of metformin to 1700 mg daily.(1)

DISCUSSION: In healthy subjects, ranolazine (1000 mg twice daily) increased exposure of metformin by 80%. Ranolazine (500 mg BID) increased metformin exposure by 40%.(1)

Metformin/Trimethoprim

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

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Trimethoprim inhibits elimination by these pathways.

CLINICAL EFFECTS: Use of trimethoprim may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin and/or trimethoprim be adjusted as needed. Consider the benefits and risks of concomitant use.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Trimethoprim was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney). (2) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area under the curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%. (3) 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (4)

Metformin/Vandetanib

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

MECHANISM OF ACTION: Renal tubular secretion of metformin is mediated by organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein (MATE) transporter. Vandetanib inhibits elimination by the OCT2 and MATE pathways.(1)

CLINICAL EFFECTS: Use of vandetanib may increase levels of metformin. Concurrent use may result in increased plasma levels of metformin and toxicity such as lactic acidosis. Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low pH, increased anion gap and elevated blood lactate.(1)

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: Use an alternative agent if possible. The US labeling for vandetanib recommends caution with concomitant use of metformin and close monitoring for metformin toxicity.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: A study in 13 healthy subjects receiving a single 1,000 mg dose of metformin 3 hours after a single 800 mg dose of vandetanib resulted in increases in metformin area-under-curve (AUC) of 74% and maximum concentration (Cmax) of 50% with coadministration compared to metformin alone.(1) In a study of normal healthy volunteers, concurrent metformin and oral cimetidine (MATE inhibitor) increased metformin maximum concentration (Cmax) in plasma and whole blood by 60% and increased metformin area-under-curve (AUC) levels in plasma and whole blood by 40%.(1) In a study in 7 subjects, concurrent metformin (250 mg daily) with cimetidine (400 mg twice daily) increased metformin AUC by 50%. Metformin renal clearance over 24 hours was reduced by 27%.(2)

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)

Sglt2 Inhibitors/Loop Diuretics

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

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Sodium-Glucose Co-Transporter 2 (Sglt2) Inhibitors/Lithium

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

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

*History of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) to canagliflozin.

*Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

*Severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/minute per 1.73 m2).

*Known hypersensitivity to metformin hydrochloride.

• Alcohol intoxication
• Alcohol use disorder
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Dehydration
• History of diabetes-related lower-extremity amputation
• Metabolic acidosis
• Mitochondrial disease
• Sepsis
• Shock

• Acute decompensated heart failure
• Acute myocardial infarction
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Diabetic foot infection
• Disease of liver
• Hyperkalemia
• Hypoglycemic disorder
• Hypovolemia
• Invasive surgical procedure
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Necrotizing fasciitis of perineum or genital area
• Peripheral vascular disease
• Pregnancy
• Severe diarrhea
• Severe hypoxemia
• Severe vomiting
• Type 1 diabetes mellitus

• Debilitation
• Diabetic peripheral neuropathy
• Fever
• Hypothyroidism
• Infection
• Osteopenia
• Vitamin b12 deficiency

The most common adverse effects of canagliflozin (>=5% of patients) include female genital mycotic infections, urinary tract infection, and increased urination.

The most common adverse effects of immediate-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

The most common adverse effects of metformin hydrochloride oral solution are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

The most common adverse effects of extended-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

More Frequent

• Hypoglycemic disorder

Less Frequent

• Dehydration
• Dyspnea
• Hypermagnesemia
• Hypersensitivity drug reaction
• Hypotension
• Syncope

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Acute kidney injury
• Acute respiratory distress syndrome
• Anaphylaxis
• Angioedema
• Autoimmune hemolytic anemia
• Autoimmune hepatitis
• Bacterial sepsis
• Cholestatic hepatitis
• Depression
• Diabetic ketoacidosis
• Fracture
• Genitourinary tract infections
• Hepatocellular damage
• Hyperkalemia
• Hypoglycemic disorder
• Ketoacidosis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lactic acidosis
• Megaloblastic anemia
• Metabolic acidosis
• Necrotizing fasciitis of perineum or genital area
• Osteopenia
• Pancreatitis
• Pancreatitis
• Pyelonephritis
• Renal cell carcinoma
• Urosepsis

More Frequent

• Abdominal distension
• Diarrhea
• Dysgeusia
• Flatulence
• Headache disorder
• Increased urinary frequency
• Nausea
• Upper respiratory infection
• Urinary tract infection
• Vitamin b12 deficiency
• Vomiting
• Vulvovaginal candidiasis
• Weight loss

Less Frequent

• Acute abdominal pain
• Candidal balanitis
• Chills
• Constipation
• Constipation
• Dental abscess
• Dizziness
• Dyspepsia
• Fatigue
• Flu-like symptoms
• Flushing
• General weakness
• General weakness
• Genital organ pruritus
• Hypercholesterolemia
• Hyperhidrosis
• Hyperlipidemia
• Hyperphosphatemia
• Increased hemoglobin
• Myalgia
• Nail disorders
• Nausea
• Orthostatic hypotension
• Palpitations
• Polydipsia
• Rhinitis
• Xerostomia

Rare or Very Rare

• Acute abdominal pain
• Anticholinergic toxicity
• Drowsy
• Pruritus of skin
• Skin photosensitivity
• Skin rash
• Urticaria
• Urticaria

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The safety and effectiveness of canagliflozin as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of canagliflozin for this indication is supported by a 52-week, placebo-controlled trial in 171 patients 10--17 years of age with type 2 diabetes mellitus and a pediatric pharmacokinetic study. The safety, exposure, and response of canagliflozin in pediatric patients was similar to that observed in adults. Safety and efficacy of canagliflozin have not been established in pediatric patients younger than 10 years of age. Safety and efficacy of canagliflozin for other indications have not been established.

Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have been established in pediatric patients 10--16 years of age. Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have not been established in pediatric patients <10 years of age. Use of immediate-release metformin hydrochloride tablets and oral solution is supported by evidence from adequate and well-controlled studies in adults with additional data from a controlled clinical study in pediatric patients 10--16 years of age with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dosage of 2 g of immediate-release metformin hydrochloride tablets or oral solution is recommended.

Safety and effectiveness of extended-release metformin hydrochloride tablets in pediatric patients have not been established.

There is insufficient evidence with canagliflozin in pregnant women to evaluate a drug-associated risk for major birth defects or miscarriage. Based on the results of reproductive and developmental toxicity studies in animals, canagliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy. In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5 times the 300-mg clinical dosage, based on area under the concentration-time curve (AUC).

Poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus, including DKA, pre-eclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. The manufacturer states that canagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

Limited data with metformin hydrochloride in pregnant females are not sufficient to determine a medication-associated risk for major birth defects or miscarriage. Available studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality.

Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus. Determination of fetal concentrations of metformin suggest that a partial placental barrier to the medication exists.

Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.

There is no information regarding the presence of canagliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Canagliflozin is distributed into milk in rats. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be a risk to the developing human kidney. Because of the potential for serious adverse reactions in nursing infants from canagliflozin, use of the drug is not recommended while breastfeeding.

Metformin is distributed into milk in lactating rats. Limited data indicate that metformin is distributed into breast milk in humans. However, there is insufficient information to determine the effects of metformin on the breast-fed infant and no available information on the effects of metformin on milk production.

Published clinical lactation studies report that metformin present in human milk resulted in infant doses approximately 0.11--1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, these studies were not designed to establish the risk of metformin use during lactation; limited adverse event data were collected in infants. In a study in 7 nursing females who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35 and the overall average concentration in milk over the dosing interval was 0.27 mg/L. Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated. In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42 and 0.39 mcg/mL, respectively, in breast milk. The mean milk-to-serum ratio was 0.63 and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%. Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL).

The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the medication and potential adverse effects on the breast-fed child (e.g., hypoglycemia). Breast-fed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Metformin should be used with caution in geriatric patients since aging is associated with a greater frequency of reduced renal, hepatic, and cardiac function, and of concomitant disease or other therapy, resulting in a higher risk of lactic acidosis. Initial dosages of metformin hydrochloride in geriatric patients should be conservative (initiated at the low end of the dosage range) and should be titrated carefully; limited data suggest reducing dosage by approximately 33% in geriatric patients. In addition, renal function should be monitored more frequently in geriatric patients to determine the appropriate dosage of metformin hydrochloride. Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.

Among patients in 13 clinical trials, 2294 were 65 years of age or older and 351 were 75 years of age or older, including one trial in patients 55 to 80 years of age. Geriatric patients experienced reduced efficacy of canagliflozin compared with younger patients as evidenced by smaller reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c). Patients 65 years of age and older were more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration) with canagliflozin, particularly those receiving 300 mg daily; a prominent increase in the incidence of volume depletion-related adverse effects in these trials was seen in patients who were 75 years of age and older.

Controlled clinical trials evaluating metformin hydrochloride immediate-release and extended-release tablets did not include sufficient numbers of geriatric patients to determine whether geriatric patients respond differently to metformin than younger patients, although other reported clinical experience has not identified any differences in response between geriatric and younger patients.

In general, dosage selection for a geriatric patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medication therapy and the higher risk of lactic acidosis. In addition, renal function should be monitored more frequently in geriatric patients and care should be taken in dosage selection; such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.