Dapagliflozin/ Metformin Hydrochloride

Registered South African indications:

• Type 2 diabetes mellitus when therapy with both dapagliflozin and metformin is appropriate
  - Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise
  - To reduce the risk of developing new or worsening existing heart failure or cardiovascular death in type 2 diabetic mellitus patients with established cardiovascular (CV) disease or multiple CV risk factors

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients in this combination product
• Pregnancy
• Breastfeeding
• Severe renal impairment [(metformin component)] (eGFR<30ml/min/1,73m²)
• Acute or chronic metabolic acidosis including diabetic ketoacidosis
• Type 1 diabetes mellitus

Cautions

• Moderate renal impairment (eGFR≥30-59ml/min/1,73m²)
  - Including coadministration with medicinal agents that can acutely impair renal function (such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs)
• Hepatic impairment
• Elderly
• Risk for volume depletion
• Acute conditions associated with hypoxia or impacting renal function (See additional prescribing points)
  - Cardiovascular collapse (shock)
  - Acute congestive heart failure
  - Acute myocardial infarction
  - Dehydration
  - Severe infections
  - Hypoperfusion
• Risk factors associated with lactic acidosis
  - Poorly controlled diabetes
  - Ketosis
  - Prolonged fasting
  - Excessive alcohol intake
  - Hepatic insufficiency
  - Dehydration
  - Acute conditions associated with hypoxia or impacting renal function
• Predisposing factors for metabolic acidosis
  - Insulin dose reduction
  - Reduced caloric intake
  - Reduced fluid intake
  - Increased insulin requirements due to infection
  - Illness
  - Surgery
  - Alcohol abuse
• Predisposing factors for ketoacidosis
  - Low beta-cell function reserve
  - Pancreatic disorders (e.g history of pancreatitis or pancreatic surgery)
• Surgical procedures
  (See additional prescribing points)
• Debilitated or malnourished patients
• Coadministration with intravascular iodinated contrast materials
  (See additional prescribing points)
• Coadministration with hypoglycaemic agents
• Coadministration with alcohol
• Galactose intolerance, e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: extended-release tab (XR tab)

Type 2 diabetes mellitus when therapy with both dapagliflozin and metformin is appropriate
- Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise
- To reduce the risk of developing new or worsening existing heart failure or cardiovascular death in type 2 diabetic mellitus patients with established cardiovascular (CV) disease or multiple CV risk factors

Dapagliflozin/ Metformin hydrochloride
5/500 (mg)
5/1000 (mg)
10/500 (mg)
10/1000 (mg)

• Oral (XR tab): 1 tab, dly at night; Titrate up to 2 tab (5/1000 (mg)), dly; Max: 10mg dapagliflozin (2 tab (5/500 (mg)) OR 2 tab (5/1000 (mg))/24hrs

The recommended dose of dapagliflozin is 10mg, dly. The recommended starting dose of metformin is 500mg, dly; which can be titrated to 2000mg, dly; with gradual dose escalation to reduce the gastrointestinal side effects due to metformin

In patients treated with metformin, the dose of dapagliflozin/ metformin hydrochloride XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose

Dapagliflozin/ metformin hydrochloride XR should be taken with the evening meal

Dapagliflozin/ metformin hydrochloride XR tablets must be swallowed whole and never crushed, cut, or chewed

Occasionally, the inactive ingredients of dapagliflozin/ metformin hydrochloride XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet

If no adequate strength of dapagliflozin/ metformin hydrochloride XR is available, individual mono-components should be used instead of the fixed dose combination

Max dose: It is recommended to not exceed a dose of dapagliflozin 10mg daily (two tablets of 5mg dapagliflozin / 500mg metformin or two tablets of 5mg dapagliflozin / 1000mg metformin)

Not established for use in children and adolescents

Pregnancy

• Contraindicated
• Dapagliflozin/ metformin hydrochloride XR is contraindicated in pregnancy
• When pregnancy is detected, dapagliflozin/ metformin hydrochloride XR should be discontinued
• In the time period corresponding to second and third trimester of pregnancy with respect to human renal maturation, maternal exposure to dapagliflozin in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny
• There are no adequate and well-controlled studies of dapagliflozin/ metformin hydrochloride XR in pregnant women

Breastfeeding

• Contraindicated 
• Dapagliflozin/ metformin hydrochloride XR must not be used by a breastfeeding woman
• No studies in lactating animals have been conducted with the combined components of dapagliflozin/ metformin hydrochloride XR
• In studies performed with the individual components, both dapagliflozin and metformin are excreted in the milk of lactating rats
• Direct and indirect exposure of dapagliflozin to weanling juvenile rats and during late pregnancy are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny, although the long-term functional consequences of these effects are unknown. These periods of exposure coincide with a critical window of renal maturation in rats
• As functional maturation of the kidneys in humans continues in the first 2 years of life, dapagliflozin-associated dilated renal pelvis and tubules noted in juvenile rats could constitute potential risk for human renal maturation during the first 2 years of life
• Additionally, the negative effects on body-weight gain associated with lactational exposure in weanling juvenile rats suggest that dapagliflozin must be avoided during the first 2 years of life

Fertility

• The effect of dapagliflozin/ metformin hydrochloride XR on human fertility has not been studied
• Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively
• Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body-surface-area comparisons

Renal Impairment

• Mild (eGFR≥60-89ml/min/1.73m²): No dose adjustment recommended 
• Moderate (eGFR≥45-59ml/min/1.73m²): Caution; no dose adjustment recommended 
• Moderate (eGFR≥30-44ml/min/1.73m²): Caution; dose adjustment recommended 
  Dapagliflozin/ metformin hydrochloride XR is not recommended for the treatment of diabetes in patients with eGFR persistently <45mL/min/1,73m²
• Severe (eGFR<30ml/min/1.73m²): Contraindicated 

Hepatic Impairment

• Caution: no dose adjustment recommended 
  Since impaired hepatic function has been associated with some cases of lactic acidosis in patients taking metformin, dapagliflozin/ metformin hydrochloride XR should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment

Elderly

• Caution; no dose adjustment recommended 
  Dose dapagliflozin/ metformin hydrochloride XR according to renal function

Risk for volume depletion

• For patients at risk for volume depletion due to co-existing conditions, a 5mg starting dose of dapagliflozin may be appropriate

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Taste disturbance

Cardiovascular Disorders

• Decrease in blood pressure

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Loss of appetite

Hepatobiliary Disorders

• Hepatic function disorders
• Hepatitis

Genitourinary Disorders

• Genital infection
  - Vulvovaginal infections
  - Vulvovaginal mycotic infections
  - Candidiasis
  - Bacterial vaginitis
  - Vulval abscess
  - Balanoposthitis
  - Balanitis
  - Candida balanitis
  - Penile abscess
  - Penile infection
• Urinary tract infection
  - Genitourinary tract infection
  - Cystitis
  - Pyelonephritis
  - Trigonitis
  - Urethritis
  - Prostatitis
• Pollakiuria
• Polyuria
  - Increased urine output

Endocrine and Metabolic Disorders

• Hypoglycaemia (when used with sulphonylurea or insulin)
• Diabetic ketoacidosis
• Atypical ketoacidosis
• Lactic acidosis
  - Acidotic dyspnoea
  - Abdominal pain
  - Muscle cramps
  - Asthenia
  - Hypothermia
  - Coma
• Vitamin B₁₂ deficiency

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Generalised rash
  - Pruritic rash
  - Macular rash
  - Maculo-papular rash
  - Pustular rash
  - Vesicular rash
  - Erythematous rash
• Urticaria
• Erythema
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Megaloblastic anaemia

Dapagliflozin

• Insulin
• Insulin secretagogues
• Sulphonylureas
  (See additional prescribing points)

Metformin

• Cationic agents
• Cimetidine
• Amiloride
• Digoxin
• Morphine
• Procainamide
• Quinidine
• Quinine
• Ranitidine
• Triamterene
• Trimethoprim
• Vancomycin
• Furosemide
• Beta-adrenergic blockers
• Diuretics
• Thiazide diuretics
• Corticosteroids
• Phenothiazines
• Thyroid agents
• Oestrogens
• Oral contraceptives
• Phenytoin
• Nicotinic acid
• Sympathomimetics
• Calcium channel blockers
• Nifedipine
• Isoniazid
• Non-steroidal anti-inflammatory drugs
• Antihypertensives
• Insulin
• Sulphonylureas

Other interactions

• Alcohol
• Iodinated contrast agents
  (See additional prescribing points)
• 1,5-anhydroglucitol (1,5-AG) assay
  (See additional prescribing points)

• Blood glucose
• Glycaemic control
• Ketone levels
  - Urine and serum ketones
• Renal function
• Hepatic function

Specific cases may require

• Blood pressure
• Blood pH
• Serum electrolytes
• Lactate and pyruvate levels
  - Lactate/ pyruvate ratio
• Anion gap
• Metformin levels

Additional observations

• Signs and symptoms
  - Metabolic acidosis
  - Ketoacidosis
  - Lactic acidosis

Coadministration with iodinated contrast agents

• Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin
• Dapagliflozin/ metformin hydrochloride XR should temporarily be discontinued prior to, or at the time of the procedure and not reinstituted until 48 hours afterwards and only after renal function has been re-evaluated and found to be stable

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

Surgical procedures

• Use of dapagliflozin/ metformin hydrochloride XR should be temporarily suspended before any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as stable
• The patient should receive regular monitoring of their blood glucose with the administration of soluble insulin perioperatively as indicated

Change in clinical status of patients with previously controlled type 2 diabetes

• A patient with type 2 diabetes previously well controlled on dapagliflozin/ metformin hydrochloride XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of lactic acidosis
• Evaluation should include serum electrolytes, urine and serum ketones, blood glucose, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs, dapagliflozin/ metformin hydrochloride XR must be stopped immediately and other appropriate corrective measures initiated

Acute conditions associated with hypoxia or impacting renal function

• Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia
• Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. In these situations, metformin must be discontinued

Medications that cause hypoglycaemia

• Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia
• Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin

Dapagliflozin/ metformin hydrochloride combines two antihyperglycaemic agents with complementary mechanisms of action to improve both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in patients with type 2 diabetes mellitus: dapagliflozin, an SGLT2 inhibitor, and metformin hydrochloride, a biguanide.

Dapagliflozin

Dapagliflozin is a potent, selective, and reversible inhibitor of sodium glucose cotransporter 2 (SGLT2) that improves glycaemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis). SGLT2 is selectively expressed in the proximal renal tubules with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder, and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin reduces maximum tubular glucose transport by 55% and reduces renal glucose reabsorption such that glucose appears in the urine at normal plasma glucose levels. Thus, dapagliflozin improves both fasting and postprandial plasma glucose levels. 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 healthy subjects with normal 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. Over time, improvement in beta-cell function (HOMA-2) has been observed in clinical studies with dapagliflozin. Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. The majority of weight reduction is body fat loss, including visceral fat rather than lean tissue or fluid loss as demonstrated by dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is greater than 1400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

Metformin

Metformin is an antihyperglycaemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. 

COMBINATION PREPARATIONS

Dapagliflozin/ Metformin Hydrochloride

Film-coated tablet 5mg/500mg

• Xigduo XR (AstraZeneca) originator

Film-coated tablet 5mg/1000mg

• Xigduo XR (AstraZeneca) originator

Film-coated tablet 10mg/500mg

• Xigduo XR (AstraZeneca) originator

Film-coated tablet 10mg/1000mg

• Xigduo XR (AstraZeneca) originator