SUMMARY  

• Monitoring guidance is provided in the enclosed INVOKANA full prescribing information (PI).¹
• For the various parameters listed in the INVOKANA PI, specific recommendations on the frequency, duration, or level of monitoring are not provided. These parameters should be individualized for each patient and the decision is ultimately up to the healthcare professional's clinical discretion.

BACKGROUND

The below information provides an overview of the monitoring recommendations listed in the enclosed INVOKANA PI.¹ The INVOKANA PI does not provide specific recommendations on the frequency, duration, or level of monitoring required. These parameters should be individualized for each patient and the decision is ultimately up to the healthcare professional's clinical discretion.

Prescribing information

Glucose/HbA1C Monitoring and Other Counseling Information

• Inform patients to stay on prescribed diet and exercise program while taking INVOKANA. Also inform patients that doctor will check diabetes with regular blood tests, including blood sugar levels and HbA1c. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. (Section 17: PATIENT COUNSELING INFORMATION)¹
• Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize risk of hypoglycemia when used in combination with INVOKANA. (Section 7: DRUG INTERACTIONS)¹
• Monitoring glycemic control with urine glucose tests is not recommended in patients taking sodium-glucose co-transporter 2 (SGLT2) inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control. (Section 7: DRUG INTERACTIONS)¹
• Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. (Section 7: DRUG INTERACTIONS)¹

Lower Limb Amputation

• Lower limb amputations, most frequently of the toe and midfoot, some involving the leg, have been reported in INVOKANA-treated patients with type 2 diabetes mellitus (T2DM) who had either established cardiovascular disease (CVD) or were at risk for CVD. Some patients had multiple amputations, some involving both lower limbs. The risk of lower limb amputations was seen at both the 100 mg and 300 mg once daily doses. (Section 5: WARNINGS AND PRECAUTIONS)¹
• Before initiating INVOKANA, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur. (Section 5: WARNINGS AND PRECAUTIONS)¹
• Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot, and to seek medical advice immediately if such signs or symptoms develop and discontinue INVOKANA if these complications occur. (Section 5: WARNINGS AND PRECAUTIONS)¹

Volume Status and Renal Function

• 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 T2DM receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (estimated glomerular filtration rate [eGFR] less than 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. (Section 5: WARNINGS AND PRECAUTIONS)¹
• Initiation of INVOKANA causes an increase in serum creatinine and decrease in eGFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. The acute effect on eGFR reverses after treatment discontinuation, suggesting that acute hemodynamic changes may play a role in the renal function changes observed with INVOKANA. (Section 6: ADVERSE REACTIONS)¹

Ketoacidosis

• Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 diabetes mellitus (T1DM) and T2DM receiving SGLT2 inhibitors, including INVOKANA. In placebo-controlled trials of patients with T1DM, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. Assess patients who present with signs and symptoms of severe metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue INVOKANA, evaluate, and treat promptly. Before initiating INVOKANA, consider risk factors for ketoacidosis. For patients who undergo surgery, consider temporarily discontinuing INVOKANA for at least 3 days prior to surgery. Patients on INVOKANA may require monitoring for ketoacidosis and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. Ensure risk factors for ketoacidosis are resolved prior to restarting INVOKANA. (Section 5: WARNINGS AND PRECAUTIONS)¹

Urosepsis and Pyelonephritis

• Treatment with SGLT2 inhibitors, including INVOKANA, increases the risk for urinary tract infections (UTIs) including urosepsis and pyelonephritis, some requiring hospitalization. Evaluate patients for signs and symptoms of UTIs and treat promptly if indicated. (Section 5: WARNINGS AND PRECAUTIONS)¹

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

• Reports of Fournier’s gangrene have been identified in postmarketing surveillance in patients with diabetes taking SGLT2 inhibitors, including INVOKANA. This is a rare, but serious and life-threatening necrotizing infection requiring urgent surgical intervention, and can cause hospitalization, multiple surgeries, and death. Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perianal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment with broad-spectrum antibiotics immediately and surgical debridement, if necessary. Discontinue INVOKANA and closely monitor glucose levels, providing alternative therapy for glucose control. (Section 5: WARNINGS AND PRECAUTIONS)¹

Genital Mycotic Infections

• INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. (Section 5: WARNINGS AND PRECAUTIONS)¹

Hypersensitivity Reactions

• Hypersensitivity reactions (e.g., urticaria, rash, angioedema, and anaphylaxis), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve. (Section 5: WARNINGS AND PRECAUTIONS and Section 17: PATIENT COUNSELING INFORMATION)¹

Bone Fracture

• An increased risk of bone fracture was seen as early as 12 weeks after treatment initiation in patients using INVOKANA in the CANVAS trial. Consider factors that contribute to fracture risk prior to initiating INVOKANA. (Section 5: WARNINGS AND PRECAUTIONS)¹

UGT Enzyme Inducers

• In patients with eGFR ≥60 mL/min/1.73 m², if an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, consider increasing the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA 100 mg daily. The total dose may be increased to 300 mg once daily in patients currently tolerating INVOKANA 200 mg and who require additional glycemic control. (Section 7:DRUG INTERACTIONS)¹
• In those with eGFR <60 mL/min/1.73 m², if an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, consider increasing the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA 100 mg daily. Consider adding another antihyperglycemic agent in patients who require additional glycemic control. (Section 7:DRUG INTERACTIONS)¹

Digoxin

• There was an increase in the geometric mean ratio (GMR) of area under the curve and peak drug concentration of digoxin (1.20 and 1.36, respectively) when coadministered with canagliflozin 300 mg. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately to adjust the dosage of digoxin. (Section 7: DRUG INTERACTIONS and Section 12: CLINICAL PHARMACOLOGY)¹

Lithium

• The serum concentration of lithium decreases when lithium is co-administered with an SGLT2 inhibitor. In patients taking SGLT2 inhibitors with concomitant lithium, serum lithium concentrations should be monitored more frequently during the initiation or dosage change of INVOKANA.(Section 7: DRUG INTERACTIONS)¹

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 May 2023.