Empagliflozin/ Metformin

Registered South African indications:

• Improve glycaemic control in patients with type 2 diabetes mellitus who have been stabilised on coadministration of the two-component medicines (as an adjunct to diet and exercise)
• Prevention of cardiovascular events in patients with type 2 diabetes mellitus and high cardiovascular risk to reduce the risk of cardiovascular death or hospitalisation for heart failure

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Severe renal impairment (GFR <30ml/min)
• Hepatic impairment
• Acute conditions with the potential to alter renal function:
  - Dehydration
  - Severe infection
  - Shock
• Type 1 diabetes mellitus
• Any type of acute metabolic acidosis (such as lactic acidosis or diabetic ketoacidosis)
• Diabetic pre-coma
• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease):
  - Decompensated heart failure
  - Respiratory failure
  - Recent myocardial infarction
  - Shock
• Acute alcohol intoxication
• Alcoholism

Cautions

• Pregnancy
• Breastfeeding
• Moderate renal impairment (GFR ≥30-59ml/min)
  - Including coadministration with medicinal agents that can acutely impair renal function (such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs)
• Elderly (≥75 years)
  - Including coadministration with medicinal agents which may lead to volume depletion (e.g. diuretics and ACE inhibitors)
• Porphyria
• Cardiorespiratory illness
• Sepsis
• Inadequately controlled diabetes
• Ketosis
• Prolonged fasting
• Any conditions associated with hypoxia
• Patients hospitalised for major surgical procedures
• Surgery under general, spinal or epidural anaesthesia
• Acute serious medical illnesses
• Low beta-cell function reserve
  - Low C-peptide or latent autoimmune diabetes in adults (LADA)
  - History of pancreatitis
• Conditions that lead to restricted food intake
• Severe dehydration
• Patients for whom insulin doses are reduced
• Patients with increased insulin requirements due to acute medical illness
• Heart failure
• Known cardiovascular disease
• Patients on antihypertensive therapy with a history of hypotension
• Conditions that may lead to fluid loss
  - Gastrointestinal illness
• Complicated urinary tract infections
• New York Heart Association (NYHA) class I-II cardiac failure
• New York Heart Association (NYHA) class III-IV cardiac failure
• Coadministration with medicinal agents that may cause lactic acidosis
• Coadministration of iodinated contrast agents (when administered intravascularly)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Treatment of type 2 diabetes mellitus (as an adjunct to diet and exercise)
- Treatment naïve patients

Empagliflozin/ Metformin

5/500 (mg)

• Oral (tab): 1 tab, 12hrly

If additional glycaemic control is required, adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25mg empagliflozin and 2000mg metformin

- 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

Empagliflozin/ Metformin

5/850 (mg)
5/1000 (mg)
12.5/500 (mg)
12.5/850 (mg)
12.5/1000 (mg)

• Oral (tab): 1 tab, 12hrly

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

Tablets should be taken 12hrly with meals to reduce the gastrointestinal adverse reactions associated with metformin. All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy restricted diet

The tablets should be swallowed whole with water

For patients insufficiently controlled on metformin (either alone or in combination with other medicinal products for the treatment of diabetes):
- The recommended starting dose of empagliflozin/ metformin should provide empagliflozin 5mg twice daily (10mg daily dose) and the dose of metformin similar to the dose already being taken
- In patients tolerating a total daily dose of empagliflozin 10mg and who need tighter glycaemic control, the dose can be increased to a total daily dose of empagliflozin 25mg
- When empagliflozin/ metformin 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

For patients switching from separate tablets of empagliflozin and metformin:
- Patients switching from separate tablets of empagliflozin (10mg or 25mg total daily dose) and metformin to empagliflozin/ metformin should receive the same daily dose of empagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• 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
• 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

Breastfeeding

• Caution; not recommended
• 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 the 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 breastfeeding

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

Renal Impairment

• Mild (GFR ≥60ml/min): No dose adjustment recommended
• Moderate (GFR ≥30-59ml/min): Caution; dose adjustment recommended
  If no adequate strength combination is available, individual monocomponents should be used instead of the fixed dose combination
• Severe (GFR <30ml/min): Contraindicated

Hepatic Impairment

• Contraindicated

Elderly

• Caution; no dose adjustment recommended
  ≥75 years: An increased risk for volume depletion should be taken into account
  ≥85 years: Initiation of empagliflozin therapy is not recommended due to limited therapeutic experience

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders

• Volume depletion

Gastrointestinal Disorders

• Gastrointestinal symptoms
  - Nausea and vomiting
  - Diarrhoea
  - Abdominal pain
  - Loss of appetite

Hepatobiliary Disorders

• Abnormal hepatic function tests
• Hepatitis

Genitourinary Disorders

• Vaginal moniliasis
• Vulvovaginitis
• Balanitis and other genital infections
• Urinary tract infection
  - Pyelonephritis
  - Urosepsis
• Increased urination
• Dysuria
• Increased blood creatinine
• Decreased glomerular filtration rate

Endocrine and Metabolic Disorders

• Diabetic ketoacidosis
  - Nausea and vomiting
  - Anorexia
  - Abdominal pain
  - Excessive thirst
  - Difficulty breathing
  - Confusion
  - Unusual fatigue or sleepiness
• Hypoglycaemia (when used with sulphonylurea or insulin)
• Thirst
• Diabetic ketoacidosis
• Lactic acidosis
  - Acidotic dyspnea
  - Abdominal pain
  - Muscle cramps
  - Asthenia
  - Hypothermia followed by coma
• Vitamin B12 deficiency
  - Megaloblastic anaemia

Skin and Subcutaneous Tissue Disorders

• Necrotising fasciitis of the perineum (Fournier's gangrene)
  - Pain
  - Tenderness
  - Erythema
  - Swelling in the genital or perineal area
  - Fever
  - Malaise
  - Uro-genital infection
  - Perineal abscess
• Generalised pruritus
• Rash
• Urticaria
• Erythema

Immune, Blood and Lymphatic System Disorders

• Angioedema
• Increased serum lipids
• Increased haemotocrit

Sensory Disorders

• Taste disturbance

Empagliflozin

• Diuretics
• Thiazides
• Loop diuretics
• Insulin
• Insulin secretagogues
• Sulfonylureas
• UGT inducers
• Rifampicin
• Phenytoin

Metformin

• Organic cation transporters 1 (OCT1) inhibitors
• Verapamil
• Organic cation transporters 1 (OCT1) inducers
• Rifampicin
• Organic cation transporters 2 (OCT2) inhibitors
• Cimetidine
• Dolutegravir
• Ranolazine
• Trimethoprim
• Vandetanib
• Isavuconazole
• Crizotinib
• Olaparib
• Medicinal agents that can acutely impair renal function
• Antihypertensives
• Non-steroidal anti-inflammatory drugs
• Selective cyclo-oxygenase (COX) II inhibitors
• Angiotensin-converting-enzyme inhibitors
• Angiotensin II receptor antagonists
• Diuretics
• Loop diuretics
• Glucocorticoids (given by systemic and local routes)
• Beta 2 agonists
• Insulin
• Insulin secretagogues
• Sulfonylureas

Other interactions

• Alcohol
• Iodinated contrast agents (See additional prescribing points)
• Interference with 1,5-anhydroglucitol (1,5-AG) assay
  (See additional prescribing points)
• Urine laboratory assessments (See additional prescribing points)

• Blood glucose
• HbA1c
• Renal function
• Volume status
  - Haematocrit
  - Electrolytes
  - Blood pressure
  - Physical examination
• Haematologic parameters
• Blood pressure

Specific cases may require

• Vitamin B12 levels
• Folate levels
• Serum bicarbonate
• Urinary ketones
• Blood ketones
• Arterial pH
• Cardiac function

Additional observations

• Genital mycotic infections
• Urinary tract infections
• Signs and symptoms of ketoacidosis

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

Coadministration with iodinated contrast agents

• 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 48hrs after, provided that renal function has been re-evaluated and found to be stable

Interference with laboratory tests or assays

• Glucose in urine test: Due to its mechanism of action, patients taking empagliflozin/ metformin will test positive for glucose in their urine
• 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

Surgery

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

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

Important Warnings (South African manufacturer recommendations)

• Empagliflozin/ metformin is contraindicated for use in type 1 diabetes
• Empagliflozin/ metformin is not indicated for use in weight control programmes
• There have been reports of metabolic acidosis, including ketoacidosis, which were serious, life-threatening or fatal, in patients taking empagliflozin/ metformin
• Patients who present with signs and symptoms including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for metabolic acidosis, even if blood glucose levels are below 11mmol/L
• Empagliflozin/ metformin should be discontinued and the patient should be promptly evaluated and managed accordingly
• Predisposing factors for metabolic acidosis include insulin dose reduction, reduced caloric intake, reduced fluid intake or increased insulin requirements due to infections, illness, surgery or alcohol abuse
• Caution is advised in treating these patients with empagliflozin/ metformin
• Predisposing factors for ketoacidosis include low beta-cell function reserve resulting from pancreatic disorders, e.g. history of pancreatitis or pancreatic surgery. Empagliflozin/ metformin is contraindicated in these patients

Empagliflozin/ metformin combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes.

Empagliflozin

Empagliflozin is a reversible, highly potent and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation of empagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascular volume.

Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure. The glucosuria, natriuresis and osmotic diuresis observed with empagliflozin may contribute to the improvement in cardiovascular outcomes.

Metformin

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. Metformin may act via 3 mechanisms; the reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increasing insulin sensitivity in muscle, improving peripheral glucose uptake and utilization; and the delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date. In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

COMBINATION PREPARATIONS

Empagliflozin/ Metformin

Film-coated tablets 5mg/500mg

• Synjardy (Ingelheim Pharmaceuticals) originator

Film-coated tablets 5mg/850mg

• Synjardy (Ingelheim Pharmaceuticals) originator

Film-coated tablets 5mg/1000mg

• Synjardy (Ingelheim Pharmaceuticals) originator

Film-coated tablets 12.5mg/500mg

• Synjardy (Ingelheim Pharmaceuticals) originator

Film-coated tablets 12.5mg/850mg

• Synjardy (Ingelheim Pharmaceuticals) originator

Film-coated tablets 12.5mg/1000mg

• Synjardy (Ingelheim Pharmaceuticals) originator