4.1. Therapeutic indications

Synjardy is indicated in adults and children aged 10 years and above for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise:

• in patients insufficiently controlled on their maximally tolerated dose of metformin alone

• in combination with other medicinal products for the treatment of diabetes, in patients insufficiently controlled with metformin and these medicinal products

• in patients already being treated with the combination of empagliflozin and metformin as separate tablets.

For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the population studied, see sections 4.4, 4.5 and 5.1.

4.2. Posology and method of administration

Posology

Adults with normal renal function (eGFR ≥90 ml/min/1.73 m2)

The recommended dose is one tablet twice daily. The dosage should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability using the recommended daily dose of 10 mg or 25 mg of empagliflozin, while not exceeding the maximum recommended daily dose of metformin.

For patients insufficiently controlled on metformin (either alone or in combination with other medicinal products for the treatment of diabetes)

In patients insufficiently controlled on metformin alone or in combination with other medicinal products for the treatment of diabetes, the recommended starting dose of Synjardy should provide empagliflozin 5 mg twice daily (10 mg daily dose) and the dose of metformin similar to the dose already being taken. In patients tolerating a total daily dose of empagliflozin 10 mg and who need tighter glycaemic control, the dose can be increased to a total daily dose of empagliflozin 25 mg. When Synjardy is used in combination with a sulphonylurea and/or insulin, a lower dose of sulphonylurea and/or insulin may be required to reduce the risk of hypoglycemia (see sections 4.5 and 4.8).

For patients switching from separate tablets of empagliflozin and metformin

Patients switching from separate tablets of empagliflozin (10 mg or 25 mg total daily dose) and metformin to Synjardy should receive the same daily dose of empagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin (for available strengths see section 2).

Missed dose

If a dose is missed, it should be taken as soon as the patient remembers; however, a double dose should not be taken on the same time. In that case, the missed dose should be skipped.

Special populations

Renal impairment

The glycaemic efficacy of empagliflozin is dependent on renal function. For cardiovascular risk reduction as add on to standard of care, a dose of 10 mg empagliflozin daily should be used in patients with an eGFR below 60 ml/min/1.73 m2 (see Table 1). Because the glycaemic lowering efficacy of empagliflozin is reduced in patients with moderate renal impairment and likely absent in patients with severe renal impairment, if further glycaemic control is needed, the addition of other anti-hyperglycaemic agents should be considered.

For dose adjustment recommendations according to eGFR or CrCL refer to Table 1.

A eGFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

If no adequate strength of Synjardy is available, individual monocomponents should be used instead of the fixed dose combination.

For dosing recommendations in the paediatric population see subsection paediatric patients below.

Table 1: Posology for renally impaired adult patientsa

eGFR [ml/min/1.73 m²] or CrCL [ml/min]

Metformin

Empagliflozin

≥60

Maximum daily dose is 3000 mg.

Dose reduction may be considered in relation to declining renal function.

Initiate with 10 mg.

In patients tolerating 10 mg and requiring additional glycaemic control, the dose can be increased to 25 mg.

45 to <60

Maximum daily dose is 2000 mg.

The starting dose is at most half of the maximum dose.

Initiate with 10 mg.b

Continue with 10 mg in patients already taking empagliflozin.

30 to <45

Maximum daily dose is 1000 mg.

The starting dose is at most half of the maximum dose.

Initiate with 10 mg.b

Continue with 10 mg in patients already taking empagliflozin.b

<30

Metformin is contraindicated.

Empagliflozin is not recommended.

a See sections 4.4, 4.8, 5.1 and 5.2

b patients with type 2 diabetes mellitus and established cardiovascular disease

Hepatic impairment

This medicinal product must not be used in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).

Elderly

Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy of empagliflozin. Because metformin is excreted by the kidney and elderly patients are more likely to have decreased renal function, Synjardy should be used with caution in these patients. Monitoring of renal function is necessary to aid in prevention of metformin‑associated lactic acidosis, particularly in elderly patients (see sections 4.3 and 4.4). In patients 75 years and older, an increased risk for volume depletion should be taken into account (see sections 4.4 and 4.8).

Paediatric population

The dosage should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability.

If empagliflozin is added in patients already receiving metformin, the metformin dose should remain the same as the patient is already taking. The recommended empagliflozin starting dose is 5 mg twice daily (10 mg total daily doses). In patients tolerating empagliflozin 5 mg twice daily and requiring additional glycaemic control, the dose can be increased to 12.5 mg twice daily (25 mg total daily dose).

If patients switching from separate tablets of empagliflozin and metformin to Synjardy the same daily dose of empagliflozin and metformin should remain as already being taken or the nearest therapeutically appropriate dose of metformin.

The maximum recommended daily dose of Synjardy is 25 mg of empagliflozin and 2000 mg of metformin (see general information above in section 4.2).

No data are available for children with eGFR <60 ml/min/1.73 m² and children below 10 years of age.

Method of administration

Synjardy should be taken twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin. The tablets should be swallowed whole with water. All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy restricted diet.

4.3. Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) (see section 4.4).

• Diabetic pre-coma.

• Severe renal failure (eGFR <30 ml/min/1.73 m2) (see sections 4.2 and 4.4).

• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock (see sections 4.4 and 4.8).

• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock (see section 4.4).

• Hepatic impairment, acute alcohol intoxication, alcoholism (see sections 4.2 and 4.5).

4.4. Special warnings and precautions for use

General

Empagliflozin should not be used in patients with type 1 diabetes mellitus (see “Diabetic ketoacidosis” in section 4.4)

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients 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 DKA is more likely to occur with higher doses of empagliflozin.

The risk of diabetic 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 DKA 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.

Prolonged diabetic ketoacidosis and prolonged glucosuria have been observed with empagliflozin. Diabetic ketoacidosis may last longer after discontinuation of empagliflozin than expected from the plasma half-life (see section 5.2). Empagliflozin-independent factors, such as insulin deficiency, might be involved in prolonged periods of diabetic ketoacidosis.

Patients who may be at higher risk of DKA 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 DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

Synjardy should not be used in patients with type 1 diabetes. Data from a clinical trial program in patients with type 1 diabetes showed increased DKA occurrence with common frequency in patients treated with empagliflozin 10 mg and 25 mg as an adjunct to insulin compared to placebo.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5).

Renal impairment

Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy of empagliflozin. Empagliflozin/metformin is contraindicated in patients with eGFR<30 ml/min/1.73 m2 and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Monitoring of renal function

Assessment of renal function is recommended as follows:

- Prior to empagliflozin/metformin initiation and periodically during treatment, i.e. at least yearly (see section 4.2).

- Prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Synjardy may be used with a regular monitoring of cardiac and renal function. For patients with acute and unstable heart failure, Synjardy is contraindicated due to the metformin component (see section 4.3).

Surgery

Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

Risk for volume depletion

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure (see section 5.1). Therefore, caution should be exercised in patients for whom a 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 Synjardy. Temporary interruption of treatment with Synjardy should be considered until the fluid loss is corrected.

Elderly

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. 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).

Urinary tract infections

Post-marketing 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 treatment should be considered in patients with complicated urinary tract infections.

Necrotising fasciitis of the perineum (Fournier's gangrene)

Cases of necrotising fasciitis of the perineum, (also known as Fournier's gangrene), have been reported in female and male patients taking SGLT2 inhibitors, including empagliflozin. 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, Synjardy should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Lower limb amputations

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.

Hepatic injury

Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established.

Elevated haematocrit

Haematocrit increase was observed with empagliflozin treatment (see section 4.8). Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

Chronic kidney disease

There is experience with empagliflozin for the treatment of diabetes in patients with chronic kidney disease (eGFR ≥30 mL/min/1.73 m2) both with and without albuminuria. Patients with albuminuria may benefit more from treatment with empagliflozin.

Urine laboratory assessments

Due to its mechanism of action, patients taking Synjardy will test positive for glucose in their urine.

Interference with 1,5-anhydroglucitol (1,5-AG) assay

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.

Vitamin B12

Metformin may reduce vitamin B12 levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

Paediatric population

In the DINAMO trial (see section 5.1), the overall safety profile in children and adolescents was similar with the known safety profile seen in adult patients and there were no relevant differences between placebo and empagliflozin regarding growth assessments or concerning the sexual maturation after 26 weeks of treatment.

No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12

In metformin studies, only 15 patients aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents.

The DINAMO trial included 157 patients and 91% were on metformin as background therapy, 25 of these patients were between 10 and 12 years old.

Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

4.5. Interaction with other medicinal products and other forms of interaction

Co-administration of multiple doses of empagliflozin and metformin does not meaningfully alter the pharmacokinetics of either empagliflozin or metformin in healthy subjects.

No interaction studies have been performed for Synjardy. The following statements reflect the information available on the individual active substances.

Empagliflozin

Pharmacodynamic interactions

Diuretics

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

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).

Pharmacokinetic interactions

Effects of other medicinal products on empagliflozin

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 Synjardy 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.

Effects of empagliflozin on other medicinal products

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. Co‑administration 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.

Metformin

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin (see sections 4.2 and 4.4).

Iodinated contrast agents

Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re‑evaluated and found to be stable (see sections 4.2 and 4.4).

Combination requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Glucocorticoids (given by systemic and local routes), beta 2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Insulin and insulin secretagogues

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 metformin (see sections 4.2 and 4.8).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of this medicinal product or 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. A limited amount of data suggests that the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with the combination of empagliflozin and metformin or with metformin alone have shown reproductive toxicity at higher doses of metformin only (see section 5.3).

When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.

Breast‑feeding

Metformin is excreted into human milk. No effects have been shown in breastfed newborns/infants of treated women. No data in humans are available on excretion of empagliflozin into milk. Available animal data have shown excretion of empagliflozin and metformin in milk. A risk to the newborns/infants cannot be excluded.

This medicinal product should not be used during breast feeding.

Fertility

No studies on the effect on human fertility have been conducted for this medicinal product or empagliflozin. Animal studies with empagliflozin and metformin do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Synjardy 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 Synjardy is used in combination with a sulphonylurea and/or insulin.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in clinical trials were hypoglycaemia in combination with insulin and/or sulphonylurea and gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal pain and loss of appetite). No additional adverse reactions were identified in clinical trials with empagliflozin as add‑on to metformin compared to the side effects of the single components.

Tabulated list of adverse reactions

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 2: Tabulated list of adverse reactions (MedDRA) from 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 infection1, 2

Urinary tract infection (including pyelonephritis and urosepsis)1, 2

Necrotising fasciitis of the perineum (Fournier's gangrene) a

Metabolism and nutrition disorders

Hypoglycaemia (when used with sulphonylurea or insulin)1

Thirst2

Vitamin B12 decrease/deficiency3,a

Diabetic ketoacidosisa

Lactic acidosis3

Nervous system disorders

Taste disturbance3

Vascular disorders

Volume depletion1, 2, d

Gastrointestinal disorders

Gastrointestinal symptoms3, 4

Constipation

Hepatobiliary disorders

Liver function tests abnormalities3

Hepatitis3

Skin and subcutaneous tissue disorders

Pruritus (generalised)2, 3

Rash

Urticaria

Angioedema

Erythema3

Renal and urinary disorders

Increased urination1, 2

Dysuria2

Tubulointerstitial nephritis

Investigations

Serum lipids increased2, b

Blood creatinine increased/ Glomerular filtration rate decreased1

Haematocrit increased2, c

1 See subsections below for additional information

2 Identified adverse reactions of empagliflozin monotherapy

3 Identified adverse reactions of metformin monotherapy

4 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

a See section 4.4

b Mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 5.0% and 5.2% versus 3.7%; HDL-cholesterol 4.6% and 2.7% versus -0.5%; LDL-cholesterol 9.1% and 8.7% versus 7.8%; triglycerides 5.4% and 10.8% versus 12.1%.

c Mean changes from baseline in haematocrit were 3.6% and 4.0% for empagliflozin 10 mg and 25 mg, respectively, compared to 0% 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.

d Pooled data of empagliflozin trials in patients with heart failure (where half of the patients had type 2 diabetes mellitus) showed a higher frequency of volume depletion (“very common”: 11.4% for empagliflozin versus 9.7% for placebo).

Description of selected adverse reactions

Hypoglycaemia

The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as add-on to metformin, as add-on to linagliptin and metformin, for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components, and as adjunct to standard care therapy. An increased frequency was noted when empagliflozin given as add-on to metformin and a sulfonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5% and placebo: 8.4%), or as add-on to metformin and insulin (empagliflozin 10 mg: 31.3%, empagliflozin 25 mg: 36.2% and placebo: 34.7%).

Major hypoglycaemia (events requiring assistance)

The overall frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo as add-on to metformin, and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components, and as adjunct to standard care therapy. Major hypoglycaemic events occurred in 0.5%, 0% and 0.5% of patients treated with empagliflozin 10 mg, empagliflozin 25 mg and placebo when added on to metformin and insulin, respectively. No patient had a major hypoglycaemic event in the combination with metformin and a sulphonylurea and as add-on to linagliptin and metformin.

Urinary tract infection

The overall frequency of urinary tract infection adverse events was higher in metformin-treated patients who received empagliflozin 10 mg (8.8%) compared to empagliflozin 25 mg (6.6%) or placebo (7.8%). 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 of urinary tract infections (i.e. mild/moderate/severe) was similar to placebo. Urinary tract infection events were reported more frequently for empagliflozin 10 mg compared with placebo in female patients, but not for empagliflozin 25 mg. The frequencies of urinary tract infections were low for male patients and were balanced across treatment groups.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in metformin‑treated patients who received empagliflozin 10 mg (4.0%) and empagliflozin 25 mg (3.9%) compared to placebo (1.3%), and were reported more frequently for empagliflozin compared to placebo in female patients. The difference in frequency was less pronounced in male patients. Genital tract infections were mild and moderate in intensity, none was severe in intensity.

Cases of phimosis/acquired phimosis have been reported concurrent with genital infections and in some cases, circumcision was required.

Increased urination

As expected from the mechanism of action, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in metformin‑treated patients who received empagliflozin 10 mg (3.0%) and empagliflozin 25 mg (2.9%) compared to placebo (1.4%) as add‑on to metformin therapy. Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin (<1%).

Volume depletion

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) in metformin‑treated patients who received empagliflozin was low: 0.6% for empagliflozin 10 mg, 0.3% for empagliflozin 25 mg and 0.1% for placebo. The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older. In patients ≥75 years of age volume depletion events have been reported in a single patient treated with empagliflozin 25 mg as add‑on to metformin therapy.

Blood creatinine increased/Glomerular filtration rate decreased

The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo as add-on to metformin (blood creatinine increased: empagliflozin 10 mg 0.5%, empagliflozin 25 mg 0.1%, placebo 0.4%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.2%).

Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patients treated with empagliflozin as add-on to metformin therapy 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.

Paediatric population

In the DINAMO trial 157 children aged 10 years and above with type 2 diabetes were treated, in which 52 patients received empagliflozin, 52 linagliptin and 53 placebo (see section 5.1). During the placebo-controlled phase, the most frequent adverse drug reaction was hypoglycaemia (empagliflozin 10 mg and 25 mg, pooled: 23.1%, placebo: 9.4%). None of these events was severe or required assistance.

Overall, the safety profile in children was similar to the safety profile in adults with type 2 diabetes mellitus.

Reporting of suspected adverse reactions

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Symptoms

Empagliflozin

In controlled clinical studies single doses of up to 800 mg empagliflozin (equivalent to 32‑times the highest recommended daily dose) in healthy volunteers and multiple daily doses of up to 100 mg empagliflozin (equivalent to 4‑times the highest recommended daily dose) in patients with type 2 diabetes did not show any toxicity. Empagliflozin increased urine glucose excretion leading to an increase in urine volume. The observed increase in urine volume was not dose‑dependent and is not clinically meaningful. There is no experience with doses above 800 mg in humans.

Metformin

Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital (see sections 4.4 and 4.5).

Therapy

In the event of an overdose, treatment should be initiated as appropriate to the patient's clinical status. The most effective method to remove lactate and metformin is haemodialysis. The removal of empagliflozin by haemodialysis has not been studied.