Saxagliptin (as hydrochloride) /dapagliflozin propanediol monohydrate
- QTERN 5/10 is available as a film-coated tablet containing 5 mg saxagliptin as saxagliptin hydrochloride and dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.
QTERN 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 QTERN please see https://www.pbs.gov.au/medicine/item/11286B-11305B
- The recommended dose of QTERN 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 the compliance 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. QTERN 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 <60 mL/min as calculated by Cockcroft-Gault formula) or in end-stage renal disease (ESRD)
- Hepatic impairment:
QTERN may be used in individuals with mild or moderate hepatic impairment. QTERN should not be used in those severe hepatic impairment.
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 QTERN therapy is not recommended in this group.
QTERN 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. QTERN 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. QTERN should not be used with CrCl persistently <60 mL/min or eGFR persistently <60 mL/min/1.73m2
- Individuals at risk for volume depletion
- In individuals with volume depletion, correcting this condition prior to initiation of QTERN is recommended.
- QTERN 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. Those 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 patients 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 approaching moderate renal impairment, at least 2 to 4 times per year. If renal function falls persistently below CrCl < 60 mL/min or eGFR <60 mL/min/1.73 m2 treatment with QTERN should be discontinued.
Note: Diabetes MedsCheck with referral to healthcare team for annual cycle of care.
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.
Individuals with moderate or severe renal impairment (eGFR <60 mL/min/1.73m2 ) or end-stage renal disease. The efficacy of dapagliflozin is dependent on renal function and efficacy is reduced in those who have moderate renal impairment and likely absent with severe renal impairment. The dose of saxagliptin 5 mg is not recommended in those with moderate or severe renal impairment or ESRD. QTERN has not been studied in individuals with severe renal impairment (eGFR <30 mL/min/1.73m2 by MDRD or CrCl <30 mL/min by Cockcroft-Gault).
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. QTERN is not recommended for use in those receiving loop diuretics or who are volume depleted. For those receiving QTERN, 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.
Treatment with QTERN 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 QTERN may be restarted once the individual’s condition has stabilised and oral intake is normal.
Note: Diabetes MedsCheck with counselling on side effect profile.
- Saxagliptin/dapagliflozin combination: Bioequivalence has been confirmed between the QTERN 5 mg/10 mg tablet and the individual saxagliptin 5 mg and dapagliflozin 10 mg tablets after single dose administration in the fasted state in healthy volunteers. Administration of QTERN with a high-fat meal decreases dapagliflozin Cmax by up to 47% and prolongs Tmax by approximately 2 hours but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. There was no food effect observed for saxagliptin. QTERN can be administered with or without food.
- Saxagliptin: The amount of saxagliptin absorbed following an oral dose is at least 75%. The absolute oral bioavailability of saxagliptin is approximately 50% (90% CI of 48-53%). Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with ahigh-fat meal resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.
- Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. The Cmax and AUC values increased proportional to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
- Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
- Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (e.g., renal, or hepatic impairment).
- Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.
- Dapagliflozin: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does not contribute to the glucose lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP mediated metabolism was a minor clearance pathway in humans.
Saxagliptin is eliminated by both renal and hepatic pathways. I don’t think we need any of this??
Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin.
The Cmax and AUC values for the major metabolite of saxagliptin increased proportionally to the increment in the saxagliptin dose. Following single oral doses of 2.5 mg to 400 mg saxagliptin in the fed or fasted states, the mean AUC values for the major metabolite ranged from 2- and 7-times higher than the parent saxagliptin exposures on a molar basis.
For more detailed information on this product please consult the product information.