Summary

• The INVOKANA^® Medication Guide specifically instructs patients to stay on their prescribed diet and exercise program while taking INVOKANA^®, and to check their blood sugar as their doctor instructs.¹
• Safety and efficacy of INVOKANA was not systematically evaluated in patients on special diets, including ketogenic, high-protein, low-protein, high-carbohydrate, low carbohydrate, no carbohydrate, high-fiber, high-fat, low-fat, low-calorie, high-calorie, or low sodium.
• In INVOKANA phase 3 studies, patients were counseled to maintain a diet consistent with those outlined in treatment guidelines for type 2 diabetes mellitus (T2DM) for their native country or region.²

PRODUCT LABELING AND MEDICATION GUIDE

Please refer to the following sections of the Full Prescribing Information that are relevant to your inquiry: INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS, PATIENT COUNSELING INFORMATION, and MEDICATION GUIDE.

• The INVOKANA^® Medication Guide informs patients that INVOKANA^® is a prescription medicine used along with diet and exercise.¹
• The INVOKANA^® Medication Guide specifically instructs patients to stay on their prescribed diet and exercise program while taking INVOKANA^®, and to check their blood sugar as their doctor instructs.¹
• The INVOKANA^® Medication Guide cautions patients on a low sodium (salt) diet may be at higher risk of dehydration.¹
• Before initiating INVOKANA^®, consider factors in the patient history that may predispose to ketoacidosis, including caloric restriction.¹

CLINICAL STUDIES

• INVOKANA safety and efficacy were not systematically evaluated in patients on special diets.
• In INVOKANA phase 3 studies, subjects were counseled to maintain a diet consistent with those outlined in T2DM treatment guidelines for their native country or region. For example, study subjects in the United States were counseled to follow nutrition recommendations of American Diabetes Association. Since these were multinational studies, diets reflected local food supply and eating patterns of local culture.²
• Subjects were discouraged from starting a new weight management program other than those recommended during the studies.²

ramadan studies

• Bashier et al (2018)³ conducted a multicenter, prospective study in adults with T2DM who fasted during the month of Ramadan, to assess the safety of SGLT2 inhibitors (INVOKANA 100 mg or dapagliflozin 10 mg), including hypoglycemia and dehydration (N=417). Secondary outcomes include: change in body weight, A1c, lipid profile, and creatinine.
• Laboratory data were collected before and after Ramadan.
• Hypoglycemic events occurred in 27% of patients (n=113).
  • These were confirmed via glucometer test in 78 patients.
  • Hypoglycemic events were significantly more frequent in patients on concomitant insulin than those on other oral antihyperglycemic agents (AHAs).
• Symptoms of dehydration occurred in 9.3% of patients and occurred more frequently in patients on concomitant insulin than those on other oral AHAs (39 vs. 25 patients, respectively).
• Reductions in A1c and weight were statistically significant by the end of Ramadan. There were no significant changes in lipids or creatinine levels by the end of the study.

Hassanein M et al (2017)⁴ conducted a multicenter, open-label, observational study of patients who fasted during the month of Ramadan in the Middle East (Kuwait, Lebanon, and United Arab Emirates [UAE]) to evaluate tolerability of INVOKANA in combination with metformin and with or without a dipeptidyl peptidase-4 (DPP-4) inhibitor compared to a sulfonylurea in T2DM patients (N=321).

• The primary endpoint was the proportion of patients with ≥1 hypoglycemia episode (including dizziness, visual blurring, palpitations, nausea, sweating, confusion, tremor, or intense hunger) as reported in the patient diary.
• Treatment adherence in both groups was high with no missed doses reported in 98.8% of the INVOKANA group and 96.2% of the sulfonylurea group. The number of missed fasting days was low in both groups with no missed fasting days being reported in 82.1% of the INVOKANA group and 78% of the sulfonylurea group.
• Symptomatic hypoglycemia was noted in 3.7% (n=6) of INVOKANA-treated patients versus 13.2% (n=21) of sulfonylurea-treated patients.
• Volume depletion events occurred more often in the INVOKANA-treated patients (16.1%, n=26) versus sulfonylurea-treated patients (5%, n=8) with the majority of events reported as symptoms of dehydration.
• The osmotic diuresis-related event of thirst was reported in 6.2% (n=10) of the INVOKANA-treated patients. No other osmotic diuresis-related events were reported (including pollakiuria, polyuria, or polydipsia).
• Adverse events (AE) were similar in both groups and no serious AEs were reported.

ADDITIONAL INFORMATION

• The INVOKANA^® PI warns prescribers to consider factors in the patient history that may predispose to ketoacidosis including caloric restriction, before initiating INVOKANA^®.
• It has been reported that use of an SGLT2 inhibitor in conjunction with a very lowcarbohydrate diet may exacerbate ketone body production up to levels which may lead to acidosis.⁵ Several published articles describe cases of ketoacidosis associated with the use of INVOKANA^6-8 or another SGLT2 inhibitor^{9,10, 11} during a low-carbohydrate diet or carbohydrate restriction. The authors of a case series suggested that use of an SGLT2 inhibitor with bariatric diets may increase risk of ketoacidosis.¹² In a Position Statement, the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) issued a joint recommendation that patients taking SGLT-2 inhibitors should avoid very-low carbohydrate/ketogenic diets (e.g., Atkins diet) in order to prevent or minimize risk of developing ketoacidosis.¹³
• A 2018 AACE/ACE Consensus Statement on the Comprehensive T2D Management Algorithm emphasizes more specifically that patients taking SGLT2 inhibitors with insulin should avoid very low carbohydrate meal plans.¹⁴
• The 2019 American Diabetes Association Standards of Medical Care in Diabetes advises low-carbohydrate eating plans should be used with caution for those taking SGLT2 inhibitors due to potential risk of ketoacidosis.¹⁵
• A published case report described the use of INVOKANA by a single patient on a lowcalorie, high-protein, low-fat, and low-carbohydrate diet.¹⁶
• The decision to prescribe INVOKANA together with specific dietary programs/products is up to the healthcare professional's clinical discretion in consultation with the patient.
• Janssen is aware that some manufacturers or providers of diet products, including high-protein, low-carbohydrate diet products/programs may issue restrictions and/or warnings about taking INVOKANA while on specific diet programs. If you have questions or concerns about such restrictions and/or warnings, please consult the respective manufacturer or provider who issued the restriction and/or warning for an explanation of risks associated with their diet products or programs.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 March 2023.