Fixed_Dose-Saxagliptin /metformin XR

• Saxagliptin /dapagliflozin is indicated as an adjunct to healthy eating and physical activity, in combination with metformin, to improve glycaemic management in adults with type 2 diabetes mellitus when treatment with both saxagliptin and dapagliflozin is appropriate.

For the latest PBS indications for saxagliptin /dapagliflozin please see

https://www.pbs.gov.au/medicine/item/11286B-11305B

• The recommended dose of saxagliptin /dapagliflozin is one 5 mg/10 mg tablet taken once daily at any time of the day, with or without food.
• Tablet is to be swallowed whole.
• Optimal medical management of individuals with diabetes also involves attention to healthy eating, physical activity, blood glucose monitoring, assessment of complications and co-morbidities.
• Regular assessment and review of adherence and benefit/risk of all therapies is recommended.
• Renal impairment:

Assess renal function prior to initiation of dapagliflozin and periodically thereafter. The 5 mg/10 mg dosage can be used in those with mild renal impairment. Saxagliptin /dapagliflozin should not be used in those with moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] persistently <60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease [MDRD] formula, or creatinine clearance [CrCl] persistently <45 mL/min as calculated by Cockcroft-Gault formula) or in end-stage renal disease (ESRD)

• Hepatic impairment:

Saxagliptin /dapagliflozin may be used in individuals with mild or moderate hepatic impairment. Saxagliptin /dapagliflozin should not be used in those severe hepatic impairment.

 Elderly:

• In general, no dosage adjustment is recommended based on age. Renal function and risk of volume depletion should be considered due to the limited therapeutic experience in those 75 years and older, initiation of saxagliptin /dapagliflozin therapy is not recommended in this group.
•  

Paediatric and adolescent

Safety and effectiveness of saxagliptin /dapagliflozin in individuals under the age of 18 have not been established.

• The safety and efficacy of Humalog Mix50 in individuals less than 18 years of age has not been established.

• Saxagliptin /dapagliflozin is contraindicated in those with a history of any serious hypersensitivity reaction to the active substances or to any of the excipients, including anaphylaxis or angioedema following exposure to any DPP4 inhibitor. Saxagliptin /dapagliflozin is contraindicated in individuals with a history of any serious hypersensitivity to dapagliflozin or to any of the excipients.
• Moderate-Severe Renal Impairment: As the efficacy of dapagliflozin is dependent on renal function, saxagliptin /dapagliflozin should not be used with an eGFR persistently <45 mL/min/1.73m2 or those on dialysis.

• Individuals at risk for volume depletion
• In individuals with volume depletion, correcting this condition prior to initiation of saxagliptin /dapagliflozin is recommended.
• Saxagliptin /dapagliflozin should not be used in those with type 1 diabetes or for the treatment of diabetic ketoacidosis.
• Use in renal impairment:

Dapagliflozin increases serum creatinine and decreases eGFR. Renal function abnormalities can occur after initiating dapagliflozin. People with diabetes with hypovolaemia may be more susceptible to these changes. There have been post-marketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in people with diabetes receiving SGLT2 inhibitors, including dapagliflozin; some reports involved individuals younger than 65 years of age.

Monitoring of renal function is recommended as follows:

• prior to initiation of QTERN and at least yearly thereafter;
• prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter;
• for renal function where eGFR is between 45 and 60 mL/min/1.73 m2, at least 2 to 4 times per year.
• If renal function falls persistently below eGFR <45 mL/min/1.73 m2, treatment with saxagliptin /dapagliflozin should be discontinued
• Individuals with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73m2. The safety profile in individuals with mild renal impairment is similar to that in the overall population.

 Note: Diabetes MedsCheck with referral to healthcare team for annual cycle of care.

• Use in individuals at risk for volume depletion, hypotension and/or electrolyte imbalances.

The diuretic effect of dapagliflozin is a potential concern for volume depleted individuals. Saxagliptin /dapagliflozin is not recommended for use in those receiving loop diuretics or who are volume depleted. For those receiving saxagliptin /dapagliflozin, in case of intercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) electrolytes is recommended.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annual cycle of care.

• Surgery:

Treatment with saxagliptin /dapagliflozin should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time. Those scheduled for non-urgent surgery who have not ceased dapagliflozin should be assessed and consideration should be given to postponing the procedure. Treatment with saxagliptin /dapagliflozin may be restarted once the individual’s condition has stabilised and oral intake is normal.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Hypersensitivity reactions

During post marketing experience the following adverse reactions have been reported with use of saxagliptin: serious hypersensitivity reactions, including anaphylaxis and angioedema. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue saxagliptin /dapagliflozin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Pancreatitis

During post marketing experience with saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis. Individuals should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, saxagliptin /dapagliflozin should be discontinued.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Ketoacidosis

Saxagliptin /dapagliflozin should not be used for the treatment of ketoacidosis.

There have been reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, in those taking dapagliflozin and other SGLT2 inhibitors. Fatal cases of ketoacidosis have been reported in hose taking dapagliflozin.

Individuals treated with saxagliptin /dapagliflozin who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L. If ketoacidosis is suspected, saxagliptin /dapagliflozin should be suspended, the person should be evaluated, and prompt treatment initiated. Treatment of ketoacidosis generally requires insulin, fluid, potassium, and carbohydrate replacement. Restarting SGLT2 inhibitor treatment in a person with previous ketoacidosis while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.

Note: Diabetes MedsCheck with counselling on side effect profile. 

• Urinary tract infections

There have been post marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in those receiving SGLT2 inhibitors, including dapagliflozin.  Evaluate individuals for signs and symptoms of urinary tract infections and treat promptly, if indicated Temporary interruption of saxagliptin /dapagliflozin should be considered when treating pyelonephritis or urosepsis. Discontinuation of saxagliptin /dapagliflozin may be considered in cases of recurrent urinary tract infections. 

Note: Diabetes MedsCheck with counselling on side effect profile.

• Necrotising fasciitis of the perineum (Fournier’s gangrene)

Post marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene), a rare, but serious and potentially life-threatening necrotising infection, have been reported in females and males with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death. individuals treated with saxagliptin /dapagliflozin who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, saxagliptin /dapagliflozin should be discontinued, and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Note: Diabetes MedsCheck with counselling on side effect profile.

• Skin disorders

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies with saxagliptin. Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in those with diabetic skin complications. Post marketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event for saxagliptin Therefore, in keeping with routine care of someone with diabetes, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended. Note: Diabetes MedsCheck with counselling on side effect profile.  

• Bullous pemphigoid

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, individuals typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell individuals to report development of blisters or erosions while receiving saxagliptin /dapagliflozin. If bullous pemphigoid is suspected, saxagliptin /dapagliflozin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Note: Diabetes Medscheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.

• Cardiac failure
• Saxagliptin

Experience in NYHA class III-IV is still limited. In the SAVOR trial a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin treated individuals compared to placebo, although a causal relationship has not been established. Additional analysis did not indicate a differential effect among NYHA classes.  Caution is warranted if saxagliptin /dapagliflozin is used in those who have known risk factors for hospitalisation for heart failure or moderate to severe renal impairment. Individuals should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.

• Dapagliflozin

Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV.

• Arthralgia

Joint pain, which may be severe, has been reported in post marketing reports for DPP4 inhibitors. Individuals experienced relief of symptoms after discontinuation of the medication and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. If an individual presents with severe joint pain, continuation of drug therapy should be individually assessed.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Combinations not studied.

Saxagliptin /dapagliflozin has not been studied in combination with glucagon like peptide 1 (GLP-1) analogues, insulin, and insulin secretagogues, such as sulfonylureas.

• Lower limb amputations
• Dapagliflozin

In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all those with diabetes on routine preventative footcare.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.

• Saxagliptin /dapagliflozin is indicated as an adjunct to healthy eating and physical activity, in combination with metformin, to improve glycaemic management in adults with type 2 diabetes mellitus when treatment with both saxagliptin and dapagliflozin is appropriate.

For the latest PBS indications for saxagliptin /dapagliflozin please see

https://www.pbs.gov.au/medicine/item/11286B-11305B

• The recommended dose of saxagliptin /dapagliflozin is one 5 mg/10 mg tablet taken once daily at any time of the day, with or without food.
• Tablet is to be swallowed whole.
• Optimal medical management of individuals with diabetes also involves attention to healthy eating, physical activity, blood glucose monitoring, assessment of complications and co-morbidities.
• Regular assessment and review of adherence and benefit/risk of all therapies is recommended.
• Renal impairment:

Assess renal function prior to initiation of dapagliflozin and periodically thereafter. The 5 mg/10 mg dosage can be used in those with mild renal impairment. Saxagliptin /dapagliflozin should not be used in those with moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] persistently <60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease [MDRD] formula, or creatinine clearance [CrCl] persistently <45 mL/min as calculated by Cockcroft-Gault formula) or in end-stage renal disease (ESRD)

• Hepatic impairment:

Saxagliptin /dapagliflozin may be used in individuals with mild or moderate hepatic impairment. Saxagliptin /dapagliflozin should not be used in those severe hepatic impairment.

 Elderly:

• In general, no dosage adjustment is recommended based on age. Renal function and risk of volume depletion should be considered due to the limited therapeutic experience in those 75 years and older, initiation of saxagliptin /dapagliflozin therapy is not recommended in this group.
•  

Paediatric and adolescent

Safety and effectiveness of saxagliptin /dapagliflozin in individuals under the age of 18 have not been established.

• The safety and efficacy of Humalog Mix50 in individuals less than 18 years of age has not been established.

• Saxagliptin /dapagliflozin is contraindicated in those with a history of any serious hypersensitivity reaction to the active substances or to any of the excipients, including anaphylaxis or angioedema following exposure to any DPP4 inhibitor. Saxagliptin /dapagliflozin is contraindicated in individuals with a history of any serious hypersensitivity to dapagliflozin or to any of the excipients.
• Moderate-Severe Renal Impairment: As the efficacy of dapagliflozin is dependent on renal function, saxagliptin /dapagliflozin should not be used with an eGFR persistently <45 mL/min/1.73m2 or those on dialysis.

• Individuals at risk for volume depletion
• In individuals with volume depletion, correcting this condition prior to initiation of saxagliptin /dapagliflozin is recommended.
• Saxagliptin /dapagliflozin should not be used in those with type 1 diabetes or for the treatment of diabetic ketoacidosis.
• Use in renal impairment:

Dapagliflozin increases serum creatinine and decreases eGFR. Renal function abnormalities can occur after initiating dapagliflozin. People with diabetes with hypovolaemia may be more susceptible to these changes. There have been post-marketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in people with diabetes receiving SGLT2 inhibitors, including dapagliflozin; some reports involved individuals younger than 65 years of age.

Monitoring of renal function is recommended as follows:

• prior to initiation of QTERN and at least yearly thereafter;
• prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter;
• for renal function where eGFR is between 45 and 60 mL/min/1.73 m2, at least 2 to 4 times per year.
• If renal function falls persistently below eGFR <45 mL/min/1.73 m2, treatment with saxagliptin /dapagliflozin should be discontinued
• Individuals with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73m2. The safety profile in individuals with mild renal impairment is similar to that in the overall population.

 Note: Diabetes MedsCheck with referral to healthcare team for annual cycle of care.

• Use in individuals at risk for volume depletion, hypotension and/or electrolyte imbalances.

The diuretic effect of dapagliflozin is a potential concern for volume depleted individuals. Saxagliptin /dapagliflozin is not recommended for use in those receiving loop diuretics or who are volume depleted. For those receiving saxagliptin /dapagliflozin, in case of intercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) electrolytes is recommended.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annual cycle of care.

• Surgery:

Treatment with saxagliptin /dapagliflozin should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time. Those scheduled for non-urgent surgery who have not ceased dapagliflozin should be assessed and consideration should be given to postponing the procedure. Treatment with saxagliptin /dapagliflozin may be restarted once the individual’s condition has stabilised and oral intake is normal.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Hypersensitivity reactions

During post marketing experience the following adverse reactions have been reported with use of saxagliptin: serious hypersensitivity reactions, including anaphylaxis and angioedema. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue saxagliptin /dapagliflozin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Pancreatitis

During post marketing experience with saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis. Individuals should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, saxagliptin /dapagliflozin should be discontinued.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Ketoacidosis

Saxagliptin /dapagliflozin should not be used for the treatment of ketoacidosis.

There have been reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, in those taking dapagliflozin and other SGLT2 inhibitors. Fatal cases of ketoacidosis have been reported in hose taking dapagliflozin.

Individuals treated with saxagliptin /dapagliflozin who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L. If ketoacidosis is suspected, saxagliptin /dapagliflozin should be suspended, the person should be evaluated, and prompt treatment initiated. Treatment of ketoacidosis generally requires insulin, fluid, potassium, and carbohydrate replacement. Restarting SGLT2 inhibitor treatment in a person with previous ketoacidosis while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.

Note: Diabetes MedsCheck with counselling on side effect profile. 

• Urinary tract infections

There have been post marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in those receiving SGLT2 inhibitors, including dapagliflozin.  Evaluate individuals for signs and symptoms of urinary tract infections and treat promptly, if indicated Temporary interruption of saxagliptin /dapagliflozin should be considered when treating pyelonephritis or urosepsis. Discontinuation of saxagliptin /dapagliflozin may be considered in cases of recurrent urinary tract infections. 

Note: Diabetes MedsCheck with counselling on side effect profile.

• Necrotising fasciitis of the perineum (Fournier’s gangrene)

Post marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene), a rare, but serious and potentially life-threatening necrotising infection, have been reported in females and males with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death. individuals treated with saxagliptin /dapagliflozin who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, saxagliptin /dapagliflozin should be discontinued, and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Note: Diabetes MedsCheck with counselling on side effect profile.

• Skin disorders

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies with saxagliptin. Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in those with diabetic skin complications. Post marketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event for saxagliptin Therefore, in keeping with routine care of someone with diabetes, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended. Note: Diabetes MedsCheck with counselling on side effect profile.  

• Bullous pemphigoid

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, individuals typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell individuals to report development of blisters or erosions while receiving saxagliptin /dapagliflozin. If bullous pemphigoid is suspected, saxagliptin /dapagliflozin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Note: Diabetes Medscheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.

• Cardiac failure
• Saxagliptin

Experience in NYHA class III-IV is still limited. In the SAVOR trial a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin treated individuals compared to placebo, although a causal relationship has not been established. Additional analysis did not indicate a differential effect among NYHA classes.  Caution is warranted if saxagliptin /dapagliflozin is used in those who have known risk factors for hospitalisation for heart failure or moderate to severe renal impairment. Individuals should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.

• Dapagliflozin

Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV.

• Arthralgia

Joint pain, which may be severe, has been reported in post marketing reports for DPP4 inhibitors. Individuals experienced relief of symptoms after discontinuation of the medication and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. If an individual presents with severe joint pain, continuation of drug therapy should be individually assessed.

Note: Diabetes MedsCheck with counselling on side effect profile.

• Combinations not studied.

Saxagliptin /dapagliflozin has not been studied in combination with glucagon like peptide 1 (GLP-1) analogues, insulin, and insulin secretagogues, such as sulfonylureas.

• Lower limb amputations
• Dapagliflozin

In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all those with diabetes on routine preventative footcare.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annal cycle of care.