QTERN should not be used in patients with type 1 diabetes (see Indications) or for the treatment of diabetic ketoacidosis (see Ketoacidosis as follows).
Use in patients at risk for volume depletion, hypotension and/or electrolyte imbalances: The diuretic effect of dapagliflozin is a potential concern for volume depleted patients. QTERN is not recommended for use in patients receiving loop diuretics or who are volume depleted.
When considering initiating QTERN, there may be patients for whom the additional diuretic effect of dapagliflozin is a potential concern either due to acute illness (such as gastrointestinal illness) or a history of hypotension or dehydration with diuretic therapy for patients who may become volume depleted. Initiation of therapy with QTERN is therefore not recommended in these patients.
For patients 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) and electrolytes is recommended. Temporary interruption of QTERN is recommended for patients who develop volume depletion until the depletion is corrected (see Adverse Reactions).
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on antihypertensive therapy with a history of hypotension or elderly patients.
Use with medications known to cause hypoglycaemia: Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycaemia if used in combination with QTERN (see Adverse Reactions).
Hypersensitivity reactions: During postmarketing 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 QTERN, assess for other potential causes for the event, and institute alternative treatment for diabetes (see Contraindications and Adverse Reactions).
Pancreatitis: During postmarketing experience with saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, QTERN should be discontinued (see Adverse Reactions).
In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and placebo-treated patients in the intent-to-treat population (see Adverse Reactions).
Ketoacidosis: QTERN should not be used for the treatment of diabetic ketoacidosis (DKA).
There have been reports of ketoacidosis, including diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent hospitalisation, in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2 inhibitors. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERN is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients treated with QTERN 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 (250 mg/dL). If ketoacidosis is suspected, QTERN should be suspended, the patient should be evaluated and prompt treatment initiated.
Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved. Before initiating QTERN, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include insulin deficiency from any cause (including insulin pump failure, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse. QTERN should be used with caution in these patients. Consider monitoring patients for ketoacidosis and temporarily discontinuing QTERN in clinical situations known to predispose to ketoacidosis.
Urinary tract infections: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including dapagliflozin. Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to control in a placebo‐pooled analysis up to 24 weeks (4.7% vs. 3.5%, respectively). Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Adverse Reactions). Temporary interruption of QTERN should be considered when treating pyelonephritis or urosepsis. Discontinuation of QTERN may be considered in cases of recurrent urinary tract infections; see Adverse Reactions
Necrotising fasciitis of the perineum (Fournier's gangrene): Postmarketing 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 female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death.
Patients treated with QTERN who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, QTERN should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
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 patients with diabetic skin complications. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event for saxagliptin (see Adverse Reactions). Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.
Bullous pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving QTERN and bullous pemphigoid is suspected, QTERN should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see Adverse Reactions).
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 patients compared to placebo, although a causal relationship has not been established. Additional analysis did not indicate a differential effect among NYHA classes (see Adverse Reactions - Cardiovascular safety). Caution is warranted if QTERN is used in patients who have known risk factors for hospitalisation for heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.
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 postmarketing reports for DPP4 inhibitors. Patients 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 a patient presents with severe joint pain, continuation of drug therapy should be individually assessed (see Adverse Reactions).
Combinations not studied: QTERN has not been studied in combination with glucagon like peptide 1 (GLP-1) analogues, insulin and insulin secretagogues, such as sulfonylureas.
Use in patients treated with pioglitazone: While a causal relationship between dapagliflozin and bladder cancer is unlikely (see Adverse Reactions), as a precautionary measure, QTERN is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.
Immunocompromised patients: Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome have not been studied in the saxagliptin clinical program. The efficacy and safety profile of QTERN in these patients has not been established.
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 diabetic patients on routine preventative footcare.
Genotoxicity: Saxagliptin: The mutagenic and clastogenic potential of saxagliptin was tested at high concentrations and exposures in a battery of genetic toxicity studies including an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. Saxagliptin was not mutagenic or clastogenic based on the combined outcomes of these studies. The major metabolite was not mutagenic in an in vitro Ames bacterial assay.
Dapagliflozin: Dapagliflozin was positive in an in vitro clastogenicity assay in the presence of metabolic activation. However, dapagliflozin was negative in the Ames mutagenicity assay and in a series of in vivo clastogenicity studies evaluating micronuclei or DNA repair in rats at exposure multiples at least 2100 times the human exposure at the MRHD. The weight of evidence from these studies, along with the absence of tumour findings in the rat and mouse carcinogenicity studies, support that dapagliflozin is not genotoxic.
Carcinogenicity: No carcinogenicity studies have been conducted with saxagliptin and dapagliflozin in combination.
Saxagliptin: Two-year carcinogenicity studies were conducted in mice and rats. Saxagliptin did not induce tumours in mice treated at up to 600 mg/kg/day, producing exposure 1123-times that of humans at the recommended clinical dose. In rats, no increase in tumours was observed in males treated with saxagliptin at up to 150 mg/kg/day and females at up to 300 mg/kg/day (relative exposure at the highest doses, approximately 400 and 2465, respectively.
Dapagliflozin: Dapagliflozin did not induce tumours in two-year carcinogenicity studies in mice or rats at oral doses up to 40 mg/kg/day and 10 mg/kg/day respectively. These doses correspond to AUC exposure levels at least 78 times the human AUC at the MRHD of 10 mg/day.
Effect on laboratory tests: Saxagliptin: Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with saxagliptin 5 mg alone or in combination compared to patients treated with placebo.
A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2.2 x 109 c/L, a mean decrease of approximately 0.1 x 109 c/L relative to placebo was observed in a pooled analysis of five placebo-controlled clinical studies. Mean absolute lymphocyte counts remained stable and within the normal limits with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions.
In the SAVOR trial, decreased lymphocyte counts were reported in 0.5% of saxagliptin-treated patients and 0.4% of placebo-treated patients.
Dapagliflozin: 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 alternative methods to monitor glycaemic control.
Haematocrit: In the short-term placebo-controlled studies, at Week 24, marked laboratory abnormalities of increased haematocrit values >55% were reported at in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients. In placebo-controlled studies with long-term data, at Week 102, results for haematocrit values >55% were similar to Week 24. Most patients with marked abnormalities of elevated haematocrit or haemoglobin had elevations measured a single time that resolved at subsequent visits.
Serum Inorganic Phosphorus: In short-term placebo-controlled studies, higher proportions of patients with marked laboratory abnormalities of hyperphosphataemia were reported on dapagliflozin at Week-24 (0.9% versus 1.7% for placebo and dapagliflozin 10 mg, respectively).
In placebo-controlled studies with long-term data, at Week-102, hyperphosphataemia were reported in a higher proportion of patients in the dapagliflozin group compared to placebo (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In short-term placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week-24 in dapagliflozin 10 mg treated patients compared with placebo. Mean percent change from baseline at Week-24 for dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.5% vs. 0.0%; HDL cholesterol 6.0% vs. 2.7%; LDL cholesterol 2.9% vs. -1.0%; triglycerides -2.7% vs. -0.7%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at week 24.
In the placebo-controlled studies with short-term and long-term data, the mean percent change from baseline at Week-102 were of a similar magnitude as at week 24.
Liver Function Tests: In the 21-study active and placebo-controlled pool (see Adverse Reactions), there was no imbalance across treatment groups in the incidence of elevations of ALT or AST. ALT >3 x ULN was reported in 1.2% of patients treated with dapagliflozin 10 mg and 1.6% treated with comparator. ALT or AST >3 x ULN and bilirubin >2 x ULN was reported in 0.1% of patients on any dose of dapagliflozin, 0.2% of patients on dapagliflozin 10 mg, and 0.1% of patients on comparator.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, when driving or operating machines, it should be taken into account that dizziness has been reported with saxagliptin. Patients should be alerted to the risk of hypoglycaemia when QTERN is used in combination with a sulphonylurea or insulin.
Use in renal impairment: The glycaemic efficacy of dapagliflozin is dependent on renal function.
QTERN should not be used in patients with an eGFR persistently < 45 ml/min/1.73 m2 by MDRD or end-stage renal disease (ESRD). QTERN has not been studied in patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2 by MDRD) or end-stage renal disease (ESRD) and, therefore, should not be used in these populations. Renal function should be evaluated prior to initiation of QTERN and periodically thereafter (see Dosage & Administration).
Use in hepatic impairment: Dapagliflozin exposure is increased in patients with severe hepatic impairment. Due to limited clinical experience in patients with hepatic impairment, QTERN should not be used in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology under Actions).
Effects on fertility: No studies on the effect on fertility have been conducted with saxagliptin and dapagliflozin in combination
Saxagliptin: In a rat fertility study, males were treated with oral gavage doses of 100, 200, and 400 mg/kg/day for two weeks prior to mating, during mating, and up to scheduled termination (approximately four weeks total) and females were treated with oral gavage doses of 125, 300, and 750 mg/kg/day for two weeks prior to mating through gestation day 7. No adverse effects on fertility were observed at 200 mg/kg/day (males) or 125 mg/kg/day (females) resulting in respective exposures (AUC) of approximately 670 (males) and 865 (females) times human exposure at the recommended clinical dose. At higher, maternally toxic doses (300 and 750 mg/kg/day), increased foetal resorptions were observed (approximately 2300 and 6810 times the recommended clinical dose). Additional effects on oestrous cycling, fertility, ovulation, and implantation were observed at 750 mg/kg/day (approximately 6810 times the recommended clinical dose).
Dapagliflozin: In a study of fertility in rats, no effects on mating, fertility, or early embryonic development were seen when males received oral doses up to 210 mg/kg/day or when females received oral doses up to 75 mg/kg/day (yielding plasma AUC values at least 1000 times the clinical exposure at the maximum recommended human dose [MRHD] of 10 mg/day). However, at 210 mg/kg/day, a dose associated with profound toxicity (including mortality), seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were increased numbers of morphologically abnormal sperm. No adverse effects on sperm or male reproductive organs were seen at 75 mg/kg/day (700 times the clinical exposure at the MRHD).
Use in pregnancy - Category D: Saxagliptin/dapagliflozin combination: There are no adequate and well-controlled studies of QTERN or its mono-components in pregnant women. Animal studies with the individual active components have identified adverse effects on embryofoetal development, most particularly with regard to dapagliflozin on the kidney. No animal developmental studies with saxagliptin and dapagliflozin in combination have been conducted. QTERN should not be used during pregnancy. If pregnancy is detected, treatment with QTERN should be discontinued.
Saxagliptin: Saxagliptin was not teratogenic at any dose evaluated in rats or rabbits. At high doses in rats, saxagliptin caused a minor developmental delay in ossification of the foetal pelvis at ≥240 mg/kg/day (≥1670 times the human exposure [AUC] at the recommended clinical dose). Maternal toxicity and reduced foetal body weights were observed at 900 mg/kg/day (>8860 times the recommended clinical dose). In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (200 mg/kg/day, exposures 1520 times the recommended clinical dose).
Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (≥250 mg/kg/day, exposures ≥1810 times the recommended clinical dose). No functional or behavioural toxicity was observed in the offspring of rats administered saxagliptin at any dose.
Saxagliptin and/or its metabolites cross the placenta into the foetus following dosing in pregnant rats.
Dapagliflozin: 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 (see Precautions). Therefore, dapagliflozin must not be used during the second and third trimesters of pregnancy. When pregnancy is detected, treatment with dapagliflozin should be discontinued.
In conventional studies of embryofoetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the period of organogenesis in humans. An increased incidence of embryofoetal lethality, decreased foetal weight and an increased incidence of foetal visceral and skeletal anomalies were seen in rats at maternotoxic doses (oral doses greater than or equal to 150 mg/kg/day). The no observed effect level for embryofoetal effects in rats was an oral dose of 75 mg/kg/day (1530 times the exposure in patients at the maximum recommended human dose [MRHD]).
No developmental toxicities were observed in rabbits at oral doses up to 180 mg/kg/day (1265 times the exposure in patients at the MRHD).
Use in lactation: Saxagliptin/dapagliflozin combination: It is not known whether QTERN or its mono-components and/or their metabolites are excreted in human milk. QTERN must not be used by a breastfeeding woman.
Saxagliptin: Saxagliptin and/or its metabolites are secreted in the milk of lactating rats.
Dapagliflozin: Studies in rats have shown excretion of dapagliflozin in milk. 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.
Use in Children: Safety and effectiveness of QTERN in paediatric patients have not been established. Delayed growth and metabolic acidosis in rats were observed in both sexes at higher doses of dapagliflozin (greater than or equal to 15 mg/kg/day). The developmental age of animals in this study approximately correlates to 2 to 16 years in humans.
Use in elderly: Elderly patients are more likely to have impaired renal function, and/or to be treated with anti hypertensive medicinal products that may cause changes in renal function such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients (see Use in Patients with Renal Impairment as previously mentioned and Dosage & Administration).
Due to limited therapeutic experience with dapagliflozin in patients 75 years and older, the initiation of QTERN therapy in this population is not recommended (see Adverse Reactions, Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Saxagliptin: Of the 16,492 patients randomised in the SAVOR trial, 8561 (51.9%) patients were ≥65 years and 2330 (14.1%) were ≥75 years.
Of the 4148 subjects in 6, double-blind, controlled clinical safety and efficacy studies of saxagliptin, (15.3%) patients were ≥65 years, (1.4%) patients were ≥75 years.
No overall differences in safety profile or efficacy were observed between subjects ≥65 years of age and younger subjects.
Saxagliptin and its major metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in the elderly based on renal function (see Dosage & Administration).
Dapagliflozin: In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin had events related to renal impairment or failure compared with placebo. The most commonly reported adverse events related to function was increased blood serum creatinine increases, the majority of which were transient and reversible (See Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. In subjects ≥65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions events related to volume depletion (see Adverse Reactions).