Dapagliflozin Propanediol

Registered South African indications:

• Type 2 diabetes mellitus
  - As monotherapy 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 sulfonylurea a DPP4 inhibitor, or insulin, when these, together with diet and exercise, do not provide adequate glycaemic control
  - To reduce the risk of developing new or worsening existing heart failure or cardiovascular death in patients with established cardiovascular (CV) disease or multiple CV risk factors
• To reduce the risk of worsening heart failure or cardiovascular death
  - In patients with heart failure (NYHA class II-IV), and with a left ventricular ejection fraction (LVEF) ≤40%
• Chronic kidney disease

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy 
• Breastfeeding 
• Type 1 diabetes mellitus 
• Patients with history of pancreatitis or pancreatic surgery

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

• Renal impairment (for the indication of heart failure and chronic kidney disease)
• Renal impairment (eGFR<45ml/min) (for the indication of diabetes mellitus)
• Severe hepatic impairment
• Suspected or diagnosed diabetic ketoacidosis (DKA)
• Predisposing factors for ketoacidosis:
  - Low beta-cell function reserve resulting from pancreatic disorders, e.g. history of pancreatitis or pancreatic surgery
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair the ability to drive and operate heavy machinery (due to hypoglycaemia, especially when in combination with sulphonylurea or insulin)

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (GFR<60ml/min) in patients with diabetes mellitus
• Severe renal impairment (GFR<30ml/min) in patients with heart failure
• Severe hepatic impairment
• Patients treated for both heart failure and type 2 diabetes mellitus where GFR falls persistently <45ml/min 
• Elderly
• Porphyria
• Very high blood glucose concentration
• Patients for whom a drop in blood pressure could pose a risk:
  - Patients on antihypertensive therapy
  - History of hypotension
• Intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness)
• Suspected or diagnosed diabetic ketoacidosis (DKA)
• Patients with increased risk of DKA:
  - Low beta-cell function reserve (e.g. type 1 diabetes patients, type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis or pancreatic surgery)
  - Conditions that lead 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
• History that may predispose a patient to ketoacidosis
• Type 1 diabetes mellitus (10mg)
• Hospitalisation for major surgical procedures or acute serious medical illnesses
• Restarting SGLT2 inhibitor treatment in patients experiencing DKA while on SGLT2 inhibitor treatment (unless another clear precipitating factor is identified and resolved)
• Pyelonephritis
• Urosepsis
• Cardiac failure NYHA class IV
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair the ability to drive and operate heavy machinery (due to hypoglycaemia, especially when in combination with sulphonylurea or insulin)

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

South African registered indications and dosages

Type 2 diabetes mellitus 
- As monotherapy 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 sulfonylurea a DPP4 inhibitor, or insulin, when these, together with diet and exercise, do not provide adequate glycaemic control
- To reduce the risk of developing new or worsening existing heart failure or cardiovascular death in patients with established cardiovascular (CV) disease or multiple CV risk factors
To reduce the risk of worsening heart failure or cardiovascular death
- In patients with heart failure (NYHA class II-IV), and with a left ventricular ejection fraction (LVEF) ≤40%
Chronic kidney disease

• Oral (fct, tab): 10mg, dly

Type 2 diabetes mellitus: The recommended dose is for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin, a thiazolidinedione, a sulfonylurea, a DPP4 inhibitor, or insulin

When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia

Heart failure: The recommended dose can be used in conjunction with other heart failure therapies

For the indication of heart failure and chronic kidney disease, dapagliflozin propanediol can be taken at any time of the day regardless of meals

Registered South African recommendations:
- The use of dapagliflozin is contraindicated for use in patients with type 1 diabetes mellitus
- The use of dapagliflozin is not indicated for use in weight control programmes

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Maternal exposure to dapagliflozin in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, dapagliflozin should be discontinued

Recommendations in other jurisdictions

• Caution; not recommended
• There are no data from the use of dapagliflozin in pregnant women. Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Therefore, the use of dapagliflozin is not recommended during the second and third trimesters of pregnancy. When pregnancy is detected, treatment with dapagliflozin should be discontinued

Breastfeeding

South African recommendations

• Contraindicated
• Mothers on dapagliflozin should not breastfeed their infants. Alternatively, mothers breastfeeding their infants must not use dapagliflozin. Studies in rats have shown excretion of dapagliflozin in milk. Exposure to dapagliflozin must be avoided during the first 2 years of life

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/ toxicological data in animals have shown excretion of dapagliflozin/ metabolites in milk, as well as pharmacologically mediated effects in nursing offspring. A risk to the newborns/ infants cannot be excluded. Dapagliflozin should not be used while breastfeeding

Fertility

South African recommendations

• The effect of dapagliflozin on fertility in humans has not been studied

Recommendations in other jurisdictions

• The effect of dapagliflozin on fertility in humans has not been studied
• In male and female rats, dapagliflozin showed no effects on fertility at any dose tested

South African recommendations

- Treatment of diabetes mellitus

• GFR≥45ml/min: No dose adjustment recommended
• eGFR<45ml/min/1.73 m²: Caution; not recommended
  As the glycaemic efficacy of dapagliflozin is dependent on renal function, it is not recommended to improve glycaemic control in the treatment of diabetes when eGFR is persistently below 45ml/min/1.73 m²
  Therefore, if eGFR falls below 45ml/min/1,73 m², additional glucose lowering treatment should be considered in patients with type 2 diabetes mellitus if further glycaemic control is needed

- Treatment of heart failure and chronic kidney disease

• Caution; no dose adjustment recommended
  Treatment with dapagliflozin should be continued for the management of renal and cardiovascular comorbidities
  There is limited experience with initiating dapagliflozin in patients with eGFR<25ml/min/1.73m²

Recommendations in other jurisdictions

- Treatment of diabetes mellitus

• Mild (GFR≥60ml/min): No dose adjustment recommended
• Moderate (GFR≥45-<60ml/min): Caution; no dose adjustment recommended
  The glycaemic efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment
  In subjects with moderate renal impairment (GFR<60ml/min), a higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo
  To improve glycaemic control in the treatment of diabetes mellitus, dapagliflozin should not be initiated in patients with a GFR<60ml/min
• Moderate (GFR≥30-<45ml/min): Caution; not recommended for use
  To improve glycaemic control in the treatment of diabetes mellitus, dapagliflozin should be discontinued at GFR persistently<45ml/min
• Severe (GFR<30ml/min): Caution; no information available
  Dapagliflozin has not been studied in severe renal impairment or end-stage renal disease (ESRD)

- Treatment of heart failure

• Mild to moderate (GFR≥30ml/min): No dose adjustment recommended
• Severe (GFR<30ml/min): Caution; no dose adjustment recommended
  There is limited experience with dapagliflozin for the treatment of heart failure in patients with severe renal impairment

In patients treated with dapagliflozin for both heart failure and type 2 diabetes mellitus, additional glucose-lowering treatment should be considered if GFR falls persistently below 45ml/min

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; not recommended for use
  Dapagliflozin is not recommended for patients with severe hepatic impairment as efficacy has not been established

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
  There is limited experience in clinical studies in patients with hepatic impairment
• Severe: Caution; dose adjustment recommended
  Initial: 5mg, dly; if well tolerated, the dose may be increased to 10mg
  There is limited experience in clinical studies in patients with hepatic impairment

South African recommendations

• No dose adjustment recommended

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended

Central Nervous System Disorders

• Dizziness

Gastrointestinal Disorders

• Constipation
• Dry mouth

Genitourinary Disorders

• Vulvovaginitis, balanitis and related genital infections
  - Vulvovaginal mycotic infection
  - Vaginal infection
  - Fungal genital infection
  - Vulvovaginal candidiasis
  - Balanitis candida
  - Genital candidiasis
  - Male genital infection
  - Penile infection
  - Vulvitis
  - Bacterial vaginitis
  - Vulval abscess
• Urinary tract infection
  - Cystitis
  - Escherichia urinary tract infection
  - Genitourinary tract infection
  - Pyelonephritis
  - Trigonitis
  - Urethritis
  - Kidney infection
  - Prostatitis
• Necrotising fasciitis of the perineum (Fournier's gangrene)
• Dysuria
• Polyuria
  - Pollakiuria
  - Increased urine output
• Nocturia
• Vulvovaginal pruritus
• Genital pruritus
• Decreased creatinine renal clearance
• Increased blood creatinine
• Increased blood urea

Endocrine and Metabolic Disorders

• Hypoglycaemia (when used with sulphonylureas or insulin)
• Volume depletion
  - Dehydration
  - Hypovolaemia
  - Hypotension
• Thirst
• Diabetic ketoacidosis (when used for type 2 diabetes mellitus)
• Dyslipidaemia
• Decreased weight

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Generalised rash
  - Pruritic rash
  - Macular rash
  - Maculopapular rash
  - Pustular rash
  - Vesicular rash
  - Erythematous rash
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Fungal infection
• Increased haematocrit

• Diuretics
• Thiazide
• Loop diuretics
• Insulin
• Insulin secretagogues
• Sulphonylureas

Other interactions

• Laboratory tests and assays (See additional prescribing points)
  - 1,5-anhydroglucitol (1,5-AG) assay
  - Urine glucose test

• Renal function
• Lipid profile
• Volume status
  - Physical examination
  - Weight
  - Blood pressure
  - Haematocrit
  - Electrolytes
• Blood glucose
• HbA1c

Specific cases may require

• Blood ketones
• Arterial pH

Additional observations

• Genital mycotic infections
• Urinary tract infection
• Hypersensitivity reactions
• Signs and symptoms of ketoacidosis
  - Nausea and vomiting
  - Abdominal pain
  - Malaise
  - Shortness of breath

Lower limb amputations

• An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care

Interaction with laboratory tests and assays

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

Before initiating treatment with dapagliflozin (in type 1 diabetes mellitus) (Recommendations in other jurisdictions)

• Risk factors for diabetic ketoacidosis (DKA) should be assessed
• It should be ensured that ketone levels are normal. If ketones are elevated (blood beta-hydroxybutyrate reading greater than 0.6mmol/L or urine ketones one plus (+)), treatment with dapagliflozin should not be started until the ketone levels are normal
• It should be ensured that the patient demonstrates the ability to monitor ketone levels
• It is recommended that patients obtain several baseline ketone levels over one to two weeks prior to initiation of dapagliflozin therapy, and patients should become familiar with how their behaviours and circumstances affect their ketone levels
• Patients should be informed, in a dedicated education session, on the risk of DKA, how to recognise DKA risk factors, signs or symptoms, how and when to monitor ketone levels and what actions to take at elevated ketone readings
• Correction of volume depletion prior to initiation of dapagliflozin is recommended in patients with this condition  
• In order to avoid hypoglycaemia with the first dose of dapagliflozin, a 20% reduction in the first mealtime bolus insulin may be considered. Subsequent bolus doses should be adjusted individually based on blood glucose results. No reduction in basal insulin is recommended when initiating dapagliflozin. Subsequently, basal insulin should be adjusted based on blood glucose results. When needed, insulin dose reduction should be done cautiously to avoid ketosis and DKA

- Ketone monitoring during treatment

• During the initial 1-2 weeks of treatment with dapagliflozin, ketones should be monitored on a regular basis, then the frequency of ketone level testing should be individualised, according to the patient's lifestyle and/or risk factors
• Patients should be informed about what actions to take if ketone levels are elevated. The recommended actions are listed in the table below. Measurement of blood ketone levels is preferred to urine

Dapagliflozin is a highly potent, selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2). Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure, and lower preload and afterload, which may have beneficial effects on cardiac remodelling. Other effects include an increase in haematocrit and reduction in body weight. The cardiac benefits of dapagliflozin are not solely dependent on the blood glucose-lowering effect and not limited to patients with diabetes as demonstrated in the DAPA-HF study.

Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood glucose, dapagliflozin has a low propensity to cause hypoglycaemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin.

Tablet 5mg

• Forxiga 5 (AstraZeneca)

Tablet 10mg

• Forxiga 10 (AstraZeneca)