Summary

• INVOKANA can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter-2 inhibitors, including INVOKANA. Patients with impaired renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.¹
• Phase 3 clinical studies permitted the concomitant use of diuretics with INVOKANA.^2-9
• Use with thiazide diuretics: In a phase 1 study, coadministration of canagliflozin (CANA) and hydrochlorothiazide (HCTZ) was well tolerated. The 24-hour urine volume with HCTZ and CANA was not greater than the urine volume seen with each individual agent. Treatment with CANA alone or in combination with HCTZ did not have a clinically meaningful effect on the steady-state pharmacokinetics (PK) of either drug.¹⁰
• Use with loop diuretics: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. Use of a loop diuretic was one factor associated with the largest increase in volume depletion-related adverse reactions.¹ In the CANVAS program, comprised of two large cardiovascular outcomes trials, 13% and 31.4% of patients were utilizing loop and non-loop diuretics, respectively. In a secondary analysis of the CANVAS Program, there was no difference in renal-related efficacy or renal-related safety outcomes by baseline diuretic use.¹¹ In the CREDENCE trial, nearly 47% of all patients were utilizing a diuretic at baseline.¹² In a secondary analysis of the CREDENCE trial, there was no difference in renal, cardiovascular, and select-safety outcomes by baseline loop diuretic use.¹³
• Use with potassium-sparing diuretics: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.¹
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^14-16

PK CONSIDERATIONS

CANA is extensively bound to proteins in plasma (99%), mainly to albumin. O-glucuronidation is the major metabolic elimination pathway for CANA, which is mainly glucuronidated by UDP-glucuronyl transferase (UGT) 1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites. Cytochrome P450 (CYP) 3A4-mediated (oxidative) metabolism of CANA is minimal (approximately 7% in humans).¹

Because CANA undergoes glucuronidation by 2 different UGT enzymes and glucuronidation is a high-capacity/low-affinity system, clinically relevant interactions of other drugs on CANA PK via inhibition of glucuronidation are unlikely to occur. Coadministration of drugs that are specific CYP inhibitors or inducers is not likely to affect the PK of CANA. In addition, due to minimal oxidative metabolism, clinically relevant effects of other drugs on CANA PK via the CYP system are unlikely to occur.¹⁷

Please refer to the INVOKANA full Prescribing Information for FDA-approved diuretics and PK/pharmacodynamic (PD) and drug interaction information.

CLINICAL STUDIES

Drug Interaction Studies with Thiazide Diuretics

Devineni (2014)¹⁰ was a phase 1, single-center, open-label, fixed-sequence study evaluating the effects of HCTZ on the PK, PD, and safety of CANA (n=30; median age: 45.5 years; mean body mass index [BMI]: 25.7 kg/m²). The study consisted of 2 periods: during period 1, patients received CANA 300 mg/day for days 1-7; during period 2, patients received HCTZ 25 mg/day for days 1-28 followed by CANA 300 mg/day + HCTZ 25 mg/day for days 29-35.

The coadministration of HCTZ with CANA did not result in clinically meaningful changes in the steady-state PK for both CANA and HCTZ. The mean 24-hour area the under curve (AUC₂₄) was 25112 ng*h/mL for CANA alone and 28552 ng*h/mL for CANA + HCTZ, while the mean peak plasma concentration (C_max) was 3820 ng/mL for CANA alone and 4490 ng/mL for CANA + HCTZ. The mean AUC₂₄ was 1056 ng*h/mL for HCTZ alone and 1068 ng*h/mL for HCTZ + CANA, while the mean C_max was 154 ng/mL for HCTZ alone 144 ng/mL for HCTZ + CANA. The mean time to reach peak plasma concentration (T_max) was similar between both CANA and HCTZ alone and the combined CANA + HCTZ group.

CANA 300 mg/day administered alone for 7 days and in combination with HCTZ 25 mg/day for 7 days was generally well tolerated in healthy normal subjects. Treatment-emergent adverse events were reported in 23 (76.7%) out of 30 subjects. The most common treatment-emergent adverse event with co-administration were gastrointestinal. The principal investigator considered these events to be of mild severity and as either doubtfully related or not related to the study drugs.  No hypoglycemic events were reported.

Drug-drug interaction studies were not conducted between CANA and other thiazide diuretics (indapamide, metolazone) or thiazide-like diuretics (chlorthalidone).

Drug Interaction Studies with Loop Diuretics

INVOKANA results in osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. Use of a loop diuretic was one factor associated with the largest increase in volume depletion-related adverse reactions.¹

Drug-drug interaction studies were not conducted between CANA and loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid).

Drug Interaction Studies with Potassium-Sparing Diuretics

INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.¹

Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (ie, within 3 weeks) in a trial of patients with moderate renal impairment. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (ie, equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics.¹

Drug-drug interaction studies were not conducted between CANA and potassium-sparing diuretics (spironolactone, amiloride, triamterene, eplerenone).

Drug Interaction Studies with Other Diuretics

Drug-drug interaction studies were not conducted between CANA and carbonic anhydrase inhibitors (acetazolamide) or osmotic diuretics (isosorbide, mannitol).

Concomitant Use with Diuretics

Phase 3 studies permitted the concomitant use of diuretics with INVOKANA.^2-9  In the CANVAS program, comprised of two large cardiovascular outcomes trials, CANVAS (phase 3) and CANVAS-R (phase 4), 1308 (13%) were receiving loop diuretics and 3182 (31.4%) were receiving non-loop diuretics at baseline.^11,18 Neuen et al (2019)¹¹ conducted a secondary analysis to examine the efficacy and safety of INVOKANA by baseline medication use on the renal composite outcome, comprised of a sustained 40% reduction in eGFR, renal-replacement therapy, defined as the need for dialysis or at least 30 days or renal transplantation, or renal death. Baseline medications of interest included renin-angiontensin system blockade drugs, loop diuretics, and non-loop diuretics. For both loop and non-loop diuretics, there was no heterogeneity identified for the renal-composite endpoint (P=0.93 & P=0.13, respectively) or serious renal-related adverse events (P=0.79 & P=0.85, respectively).

The effects of INVOKANA on renal and cardiovascular outcomes was investigated in the CREDENCE trial, a phase 4, multicenter, randomized, double-blind, event-driven, placebo-controlled study in patients with diabetic nephropathy.¹² At baseline, roughly 47% of patients were using a diuretic.¹⁹ Neuen et al (2020)¹³ conducted a secondary analysis of cardiovascular, renal and safety outcomes by baseline loop diuretic use in the CREDENCE trial population. At baseline, 479 patients in the INVOKANA group were on a loop diuretic and 476 patients in the placebo group. At baseline, both INVOKANA and placebo groups had 1723 patients not on a loop diuretic. The effect of INVOKANA on the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death was consistent across the overall, non-loop, and loop diuretic population (interaction, P=0.18). The effect of INVOKANA on safety outcomes, including all serious adverse events, volume depletion, renal-related adverse events, acute kidney injury, hyperkalemia, and amputation, was consistent among all subgroups.

CASE REPORT

One case reported on a 44-year-old male patient who experienced acute renal failure while taking concomitant INVOKANA and chlorthalidone.²⁰

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 October 2024.