Regulatory Decision Summary for JARDIANCE

The main objection leading to the Notice of Deficiency was that the 25 mg tablet strength was proposed as the starting dose for all indications, whereas the sponsor agreed that the 10 mg dose provided meaningful glycemic efficacy, with a good safety profile and should be the starting dose.

The non-clinical review identified that the major target organs of toxicity are the kidney and urinary tract. Sodium glucose co-transporter 2 (SGLT2) inhibitors, such as empagliflozin, have been found to affect renal development and maturation. As empagliflozin crosses the placenta and is excreted into milk at high levels in rats, there is a potential risk to the developing human kidneys if empagliflozin is used by pregnant or nursing women.

The quality review did not identify issues which affected the reliability of the clinical data.

The efficacy and safety of empagliflozin in the treatment of type 2 diabetes were assessed in 4 pivotal Phase 3 placebo-controlled double blind studies. Approximately 11,250 subjects with type 2 diabetes with inadequate glycemic control were randomized and treated with empagliflozin 10 mg, 25 mg or placebo once daily for up to 24 weeks. The primary efficacy endpoint was the placebo adjusted change from baseline in HbA1c. Secondary endpoints included changes in fasting plasma glucose, blood pressure and body weight. Superiority of both doses of empagliflozin over placebo was demonstrated as monotherapy, as add-on therapy to metformin alone or with a sulfonylurea, add-on to pioglitazone alone or with metformin (placebo-adjusted mean change in HbA1c from -0.48% to -0.73% for the 10 mg dose, and -0.59% to -0.84% for the 25 mg dose) and as add on to multiple daily injections of basal and prandial insulin alone or with metformin after 18 weeks (-0.44% for empagliflozin 10 mg and -0.52% for empagliflozin 25 mg).

Empagliflozin demonstrated statistically significant and clinically meaningful improvements on glycemic control in patients with type 2 diabetes.

Empagliflozin also demonstrated an acceptable risk profile. The most common adverse events (AEs) in the empagaliflozin arms of the trials were nausea, urinary and genital tract infections, upper respiratory tract infections, hypoglycemia, dyslipidemia, arthralgias and vulvovaginal pruritus. The most commonly reported serious adverse events across treatment groups were cardiovascular (CV) in nature, consistent with the high CV risk population. Adverse events of special interest included renal impairment, volume depletion events, genital infections, urinary tract infections, polyuria, hemoconcentration, malignancies, hepatic adverse events and dyslipidemia.

During review, post-market cases of diabetic ketoacidosis (DKA) were reported in patients taking any of the marketed SGLT2 inhibitors. An Information Update regarding this issue was released by the Marketed Health Products Directorate (MHPD), who is currently reviewing the evidence regarding an association with SGLT2 inhibitors. Although cases of DKA were rare and less common in empagliflozin treated patients than in placebo patients in the clinical trials, a warning was added to the labelling.

Risk mitigation is achieved through labelling and a risk management plan reviewed by MHPD. Labelling includes a contraindication in patients with eGFR <45 mL/min/1.73m², a statement that use is not recommended in patients with severe hepatic impairment, warnings against use in patients with volume depletion, pregnant and nursing women, statements to use with caution in the elderly, patients taking anti-hypertensives, particularly diuretics, those with a history of low blood pressure, cardiovascular disease, pre-existing elevated hematocrit or hemoglobin level or moderate renal impairment. Hepatic safety and risk of malignancy, including malignant melanoma, lung, bladder, and breast cancer, will be monitored as a post-market commitment through the Cardiovascular Outcomes Trial.