Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Boehringer Ingelheim International GmbH, Binger Str. 173, 55216 Ingelheim am Rhein, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Cases of ketoacidosis, including life-threatening and fatal cases, have been reported in patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is not known if ketoacidosis is more likely to occur with higher doses of empagliflozin. Although ketoacidosis is less likely to occur in patients without diabetes mellitus, cases have also been reported in these patients.
The risk of ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where ketoacidosis is suspected or diagnosed, treatment with empagliflozin should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with empagliflozin may be restarted when the ketone values are normal and the patient’s condition has stabilised.
Before initiating empagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of ketoacidosis include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous ketoacidosis while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
Jardiance should not be used in patients with type 1 diabetes. Data from a clinical trial program in patients with type 1 diabetes showed increased ketoacidosis occurrence with common frequency in patients treated with empagliflozin 10 mg and 25 mg as an adjunct to insulin compared to placebo.
Due to limited experience, it is not recommended to initiate treatment with empagliflozin in patients with an eGFR <20 ml/min/1.73 m².
In patients with an eGFR <60 ml/min/1.73 m² the daily dose of empagliflozin is 10 mg (see section 4.2).
The glucose lowering efficacy of empagliflozin is dependent on renal function, and is reduced in patients with an eGFR <45 ml/min/1.73 m² and is likely absent in patients with an eGFR <30 ml/min/1.73 m² (see section 4.2, 5.1 and 5.2).
Assessment of renal function is recommended as follows:
Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying glucosuria may lead to a modest decrease in blood pressure (see section 5.1). Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older.
In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with empagliflozin should be considered until the fluid loss is corrected.
The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status. Patients aged 75 years and older may be at an increased risk of volume depletion. A higher number of these patients treated with empagliflozin had adverse reactions related to volume depletion as compared to placebo (see section 4.8). Therefore, special attention should be given to their volume intake in case of co-administered medicinal products which may lead to volume depletion (e.g. diuretics, ACE inhibitors).
Cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with empagliflozin (see section 4.8). Temporary interruption of empagliflozin should be considered in patients with complicated urinary tract infections.
Cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have been reported in female and male patients with diabetes mellitus taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier´s gangrene is suspected, Jardiance should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot-care.
Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established.
Haematocrit increase was observed with empagliflozin treatment (see section 4.8).
Patients with albuminuria may benefit more from treatment with empagliflozin.
Patients with infiltrative disease or with Takotsubo cardiomyopathy have not been specifically studied. Therefore, efficacy in these patients has not been established.
Due to its mechanism of action, patients taking Jardiance will test positive for glucose in their urine.
Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycaemic control is advised.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Each tablet contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’.
Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with empagliflozin (see sections 4.2 and 4.8).
In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak empagliflozin plasma concentrations (Cmax) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.
The effect of UGT induction (e.g. induction by rifampicin or phenytoin) on empagliflozin has not been studied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potential risk of decreased efficacy. If an inducer of these UGT enzymes must be co-administered, monitoring of glycaemic control to assess response to Jardiance is appropriate.
An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin Cmax increased by 15% and AUC increased by 59% following co-administration. These changes were not considered to be clinically meaningful.
Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% increase in Cmax and a 35% increase in AUC of empagliflozin. These changes were not considered to be clinically meaningful.
Empagliflozin exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on empagliflozin.
Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.
Empagliflozin may increase renal lithium excretion and the blood lithium levels may be decreased. Serum concentration of lithium should be monitored more frequently after empagliflozin initiation and dose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serum concentration of lithium.
Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-drug interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely.
Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with active substances that are P-gp substrates. Coadministration of digoxin, a P-gp substrate, with empagliflozin resulted in a 6% increase in AUC and 14% increase in Cmax of digoxin. These changes were not considered to be clinically meaningful.
Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as such, drug-drug interactions with substrates of these uptake transporters are considered unlikely.
Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives.
There are no data from the use of empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Jardiance during pregnancy.
No data in humans are available on excretion of empagliflozin into milk. Available toxicological data in animals have shown excretion of empagliflozin in milk. A risk to the newborns/infants cannot be excluded. Jardiance should not be used during breast-feeding.
No studies on the effect on human fertility have been conducted for Jardiance. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
Jardiance has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Jardiance is used in combination with a sulphonylurea and/or insulin.
A total of 15 582 patients with type 2 diabetes were included in clinical studies to evaluate the safety of empagliflozin, of which 10 004 patients received empagliflozin, either alone or in combination with metformin, a sulphonylurea, pioglitazone, DPP-4 inhibitors, or insulin.
In 6 placebo-controlled trials of 18 to 24 weeks duration, 3 534 patients were included of which 1 183 were treated with placebo and 2 351 with empagliflozin. The overall incidence of adverse events in patients treated with empagliflozin was similar to placebo. The most frequently reported adverse reaction was hypoglycaemia when used with sulphonylurea or insulin (see description of selected adverse reactions).
The EMPEROR studies included patients with heart failure and either reduced ejection fraction (N=3 726) or preserved ejection fraction (N=5 985) treated with empagliflozin 10 mg or placebo. Approximately half of the patients had type 2 diabetes mellitus. The most frequent adverse reaction of the pooled EMPEROR-Reduced and EMPEROR-Preserved studies was volume depletion (empagliflozin 10 mg: 11.4%. placebo: 9.7%).
The EMPA-KIDNEY study included patients with chronic kidney disease (N = 6 609) treated with 10 mg empagliflozin or placebo. About 44% of the patients had type 2 diabetes mellitus. The most frequent adverse events in the EMPA-KIDNEY study were gout (empagliflozin 7.0% vs placebo 8.0%), and acute kidney injury (empagliflozin 2.8% vs placebo 3.5%) which were more frequently reported in patients on placebo.
The overall safety profile of empagliflozin was generally consistent across the studied indications.
Adverse reactions classified by system organ class and MedDRA preferred terms reported in patients who received empagliflozin in placebo-controlled studies are presented in the table below (Table 1).
The adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), or very rare (<1/10 000), and not known (cannot be estimated from the available data).
Table 1. Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled studies and from post-marketing experience:
| System organ class | Very common | Common | Uncommon | Rare | Very Rare |
|---|---|---|---|---|---|
| Infections and infestations | Vaginal moniliasis, vulvovaginitis, balanitis and other genital infectiona Urinary tract infection (including pyelonephritis and urosepsis)a | Necrotising fasciitis of the perineum (Fournier´s gangrene)* | |||
| Metabolism and nutrition disorders | Hypoglycaemia (when used with sulphonylurea or insulin)a | Thirst | Ketoacidosis* | ||
| Gastrointestinal disorders | Constipation | ||||
| Skin and subcutaneous tissue disorders | Pruritus (generalised) Rash | Urticaria Angioedema | |||
| Vascular disorders | Volume depletiona | ||||
| Renal and urinary disorders | Increased urinationa | Dysuria | Tubulo-interstitial nephritis | ||
| Investigations | Serum lipids increaseda | Blood creatinine increased/ Glomerular filtration rate decreaseda Haematocrit increaseda |
a see subsections below for additional information
* see section 4.4
The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as monotherapy, add-on to metformin, add-on to pioglitazone with or without metformin, as add-on to linagliptin and metformin, and as adjunct to standard care therapy and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components. An increased frequency was noted when given as add-on to metformin and a sulphonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5%, placebo: 8.4%), add-on to basal insulin with or without metformin and with or without a sulphonylurea (empagliflozin 10 mg: 19.5%, empagliflozin 25 mg: 28.4%, placebo: 20.6% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg and 25 mg: 36.1%, placebo 35.3% over the 78-week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 39.8%, empagliflozin 25 mg: 41.3%, placebo: 37.2% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 51.1%, empagliflozin 25 mg: 57.7%, placebo: 58% over the 52-week trial).
In the EMPEROR heart failure studies, similar frequency of hypoglycaemia was noted when used addon to sulphonylurea or insulin (empagliflozin 10 mg: 6.5%, placebo: 6.7%).
No increase in major hypoglycaemia was observed with empagliflozin compared to placebo as monotherapy, add-on to metformin, add-on to metformin and a sulphonylurea, add-on to pioglitazone with or without metformin, add-on to linagliptin and metformin, as adjunct to standard care therapy and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components. An increased frequency was noted when given as add-on to basal insulin with or without metformin and with or without a sulphonylurea (empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo: 0% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo 0% over the 78-week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 0.5%, empagliflozin 25 mg: 0.5%, placebo: 0.5% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 1.6%, empagliflozin 25 mg: 0.5%, placebo: 1.6% over the 52-week trial).
In the EMPEROR heart failure studies, major hypoglycaemia was observed at similar frequencies in patients with diabetes mellitus when treated with empagliflozin and placebo as add-on to sulphonylurea or insulin (empagliflozin 10 mg: 2.2%, placebo: 1.9%).
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in patients treated with empagliflozin (empagliflozin 10 mg: 4.0%, empagliflozin 25 mg: 3.9%) compared to placebo (1.0%). These infections were reported more frequently in females treated with empagliflozin compared to placebo, and the difference in frequency was less pronounced in males. The genital tract infections were mild or moderate in intensity.
In the EMPEROR heart failure studies, the frequency of these infections was more pronounced in patients with diabetes mellitus (empagliflozin 10 mg: 2.3%; placebo: 0.8%) than in patients without diabetes mellitus (empagliflozin 10 mg: 1.7%; placebo: 0.7%) when treated with empagliflozin compared to placebo.
Increased urination (including the predefined terms pollakiuria, polyuria, and nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.5%, empagliflozin 25 mg: 3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was similar for placebo and empagliflozin (<1%).
In the EMPEROR heart failure studies, increased urination was observed at similar frequencies in patients treated with empagliflozin and placebo (empagliflozin 10 mg: 0.9%, placebo 0.5%).
The overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo (7.0% and 7.2%) and higher in empagliflozin 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity (mild, moderate, severe) of urinary tract infection was similar in patients treated with empagliflozin and placebo. Urinary tract infection was reported more frequently in females treated with empagliflozin compared to placebo; there was no difference in males.
The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was similar in patients treated with empagliflozin (empagliflozin 10 mg: 0.6%, empagliflozin 25 mg: 0.4%) and placebo (0.3%). The frequency of volume depletion events was increased in patients 75 years and older treated with empagliflozin 10 mg (2.3%) or empagliflozin 25 mg (4.3%) compared to placebo (2.1%).
The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%). Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patients treated with empagliflozin were generally transient during continuous treatment or reversible after drug discontinuation of treatment.
Consistently, in the EMPA-REG OUTCOME study, patients treated with empagliflozin experienced an initial fall in eGFR (mean: 3 ml/min/1.73 m²). Thereafter, eGFR was maintained during continued treatment. Mean eGFR returned to baseline after treatment discontinuation suggesting acute haemodynamic changes may play a role in these renal function changes. This phenomenon is also observed in the EMPEROR heart failure studies and the EMPA-KIDNEY study.
Mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 4.9% and 5.7% versus 3.5%; HDL-cholesterol 3.3% and 3.6% versus 0.4 ; LDL-cholesterol 9.5 and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus 10.5%.
Mean changes from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg, respectively, compared to 0.1% for placebo. In the EMPA-REG Outcome study, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
