Empagliflozin

Registered South African indications:

• Type 2 diabetes mellitus
  - As an adjunct to diet and exercise to improve glycaemic control
  - As add-on combination therapy, with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonylurea, a DPP4 inhibitor, or insulin, when these together with diet and exercise, do not provide adequate glycaemic control
• Type 2 diabetes mellitus and high cardiovascular risk
  - To reduce the risk of cardiovascular death due to myocardial infarction
  - To reduce the risk of cardiovascular death or hospitalisation for heart failure
• Heart failure (NYHA class II-IV) independent of left ventricular ejection fraction, with or without type 2 diabetes mellitus
  - To reduce the risk of cardiovascular death and hospitalisation for heart failure
  - To slow kidney function decline

Contraindications

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients
• Type 1 diabetes mellitus
• Treatment of ketoacidosis
• Severe renal impairment (creatinine clearance <30ml/min), end stage renal disease or dialysis (for the type 2 diabetes mellitus indications)
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients

Cautions

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment (for the heart failure indication) (South African recommendations)
• Renal impairment (eGFR<60ml/min/1.73m²) (for the type 2 diabetes mellitus indications) (Recommendations in other jurisdictions)
• Renal impairment (for the heart failure indication) (Recommendations in other jurisdictions)
• Severe hepatic impairment
• Elderly (≥75 years) (Recommendations in other jurisdictions)
• Suspected diabetic ketoacidosis
• Major surgical procedures
• Acute serious medical illnesses
• Risk factors for ketoacidosis
  - Low beta-cell function reserve
  - Type 2 diabetes patients with low C-peptide
  - Latent autoimmune diabetes in adults
  - History of pancreatitis
  - Conditions leading to restricted food intake or severe dehydration
  - Patients for whom insulin doses are reduced
  - Patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse
• Known cardiovascular disease
• Patients on antihypertensive therapy with a history of hypotension
• Type 1 diabetes (Recommendations in other jurisdictions)
• Conditions leading to fluid loss e.g. gastrointestinal illness
• Cardiac failure (NYHA class I-IV)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Type 2 diabetes mellitus
- As an adjunct to diet and exercise to improve glycaemic control
- As add-on combination therapy, with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonylurea, a DPP4 inhibitor, or insulin, when these together with diet and exercise, do not provide adequate glycaemic control
Type 2 diabetes mellitus and high cardiovascular risk
- To reduce the risk of cardiovascular death due to myocardial infarction
- To reduce the risk of cardiovascular death or hospitalisation for heart failure (e.g. previous myocardial infarction, multi vessel coronary artery disease, previous coronary revitalisation, single vessel coronary disease, at least 50% narrowing of coronary artery lumen)

• Oral (fct): Initial: 10mg, dly; Maintenance: 10-25mg, dly

In patients tolerating empagliflozin 10mg, dly and requiring additional glycaemic control, the dose may be increased to 25mg once daily

Heart failure (NYHA class II-IV) independent of left ventricular ejection fraction, with or without type 2 diabetes mellitus
- To reduce the risk of cardiovascular death and hospitalisation for heart failure
- To slow kidney function decline

• Oral (fct): 10mg, dly

Empagliflozin can be taken with or without food

Assess hydration status and renal function before initiating treatment with empagliflozin. Do not initiate treatment in patients who are volume-depleted or acidotic

When empagliflozin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin should be considered to reduce the risk of hypoglycaemia

If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Empagliflozin is contraindicated in pregnancy
• Animal studies showed that empagliflozin crosses the placenta

Recommendations in other jurisdictions

• Caution; not recommended 
• There is 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 
• As a precautionary measure, it is preferable to avoid the use of empagliflozin during pregnancy 

Breastfeeding

South African recommendations

• Contraindicated
• Mothers should not breastfeed their infants while taking empagliflozin
• Animal studies have shown excretion of empagliflozin, in the milk of animals
• A risk to human newborns/infants cannot be excluded

Recommendations in other jurisdictions

• Caution; not recommended
• No data in humans is available on excretion of empagliflozin into milk 
• Available toxicological data in animals have shown excretion of empagliflozin in milk 
• A risk to the newborn/infant cannot be excluded. Empagliflozin should not be used during breastfeeding 

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• No studies on the effect on human fertility have been conducted for empagliflozin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility 

South African recommendations

Type 2 diabetes mellitus indications

• eGFR≥30ml/min/1.73m²: No dose adjustment recommended
• eGFR<30ml/min/1.73m², end-stage renal disease (ESRD) or dialysis: Contraindicated

Heart failure (with or without type 2 diabetes mellitus) indication

• eGFR≥20ml/min/1.73m²: Caution; no information available
• eGFR<20ml/min/1.73m²: Caution; not recommended
  There are insufficient data to support use in these patients

Recommendations in other jurisdictions

Type 2 diabetes mellitus indications

• eGFR≥60ml/min/1.73m²: No dose adjustment recommended
• eGFR≥30-<60ml/min/1.73m²: Caution; dose adjustment recommended
  Initiate therapy with 10mg daily. Continue with 10mg empagliflozin in patients already taking empagliflozin
• eGFR<30ml/min/1.73m², ESRD or dialysis: Caution; not recommended

Heart failure (with or without type 2 diabetes mellitus) indication

• eGFR≥20ml/min/1.73m²: Caution; dose adjustment recommended
  Recommended dose: 10mg daily
• eGFR<20ml/min/1.73m²: Caution; not recommended
  Due to limited experience, empagliflozin is not recommended

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  Dose adjustment may be necessary for patients with severe hepatic impairment

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; not recommended
  Empagliflozin exposure is increased in patients with severe hepatic impairment
  Therapeutic experience in patients with severe hepatic impairment is limited and therefore not recommended for use in this population

South African recommendations

• No dose adjustment recommended

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  ≥75 years: An increased risk for volume depletion should be taken into account

Cardiovascular Disorders

• Volume depletion

Genitourinary Disorders

• Increased urination
• Dysuria
• Increased blood creatinine
• Decreased glomerular filtration rate

Endocrine and Metabolic Disorders

• Hypoglycaemia (when used with sulphonylurea or insulin)
• Thirst
• Diabetic ketoacidosis
• Increased serum lipids

Skin and Subcutaneous Tissue Disorders

• Pruritus (generalised)
• Rash
• Urticaria
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Increased haematocrit
• Vaginal moniliasis
• Vulvovaginitis
• Balanitis
• Other genital infections
• Urinary tract infection
• Pyelonephritis
• Urosepsis
• Necrotising fasciitis of the perineum (Fournier's gangrene) (see additional prescribing points)

• Thiazide diuretics
• Loop diuretics
• Insulin
• Insulin secretagogues
• Sulphonylureas
• UGT enzyme inducers
• UGT enzyme inhibitor
• Gemfibrozil
• Probenecid
• Rifampicin
• Phenytoin

• Blood glucose
• HbA1C
• Blood Pressure
• Haematocrit levels
• Electrolytes
• Renal function
• Volume status

None routine. Specific cases may require

• Blood ketone levels
• Arterial pH levels

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

• Monitoring of glycaemic control cannot be done by urine glucose monitoring or with a 1,5 AG blood assay, as SGLT2 inhibitors interfere with the assay

Necrotising fasciitis of the perineum (Fournier’s gangrene)

• Cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene), a rare, but serious and life threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin
• Serious outcomes have included hospitalisation, multiple surgeries, and death
• Patients treated with empagliflozin who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis
• If suspected, empagliflozin should be discontinued, and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary)

Pharmacokinetics

• Elimination half-life (t_1/2): 12.4 hours

Empagliflozin is a reversible, highly potent and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000 times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin improves both fasting and postprandial 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. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction.

Tablet 10mg

• Jardiance (Boehringer)

Tablet 25mg

• Jardiance (Boehringer)