2016年7月25日,降糖新药Qtern(dapagliflozin and saxagliptin,沙格列汀/达帕格列津)是获欧盟首个获批的DPP-4抑制剂+SGLT2抑制剂组合疗法,对2型糖尿病患者有效控制血糖水平。
B Frequencies of all uncommon adverse reactions were based on the individual mono-components data. C Adverse reaction originates from saxagliptin or dapagliflozin post-marketing surveillance data. D Adverse reactions were reported in ≥ 2% of subjects with either mono-component and ≥ 1% more than placebo, but not in the pooled analysis. E Haematocrit values > 55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects. F See corresponding subsections below for events in the dapagliflozin programme. 1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upper respiratory tract infection, pharyngitis, rhinitis, sinusitis, pharyngitis bacterial, tonsillitis, acute tonsillitis, laryngitis, viral pharyngitis, and viral upper respiratory tract infection. 2 Urinary tract infection includes the following preferred terms: urinary tract infection, Escherichia urinary tract infection, pyelonephritis, and prostatitis. 3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginal mycotic infection, balanoposthitis, genital infection fungal, vaginal infection, and vulvovaginitis. 4 Dyslipidaemia includes the following preferred terms: dyslipidaemia, hyperlipidaemia, hypercholesterolaemia, and hypertriglyceridaemia. 5 Polyuria includes the following preferred terms: polyuria, and pollakiuria. SU = sulphonylurea Description of selected adverse reactions Hypoglycaemia Saxagliptin/dapagliflozin combination: The incidence of hypoglycaemia was low (1.4%) in the saxagliptin plus dapagliflozin plus metformin group, 0.3% in the saxagliptin plus metformin group, and 1.8% in the dapagliflozin plus metformin group. No episodes of major hypoglycaemia were reported, and no subject discontinued the study treatment due to hypoglycaemia (see sections 4.4 and 4.5). Volume depletion Saxagliptin/dapagliflozin combination: Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reflective of the adverse events with dapagliflozin and were reported in two subjects (0.4%) in the saxagliptin plus dapagliflozin plus metformin group (serious adverse event [SAE] of syncope and an AE of urine output decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 AEs of syncope and 1 of hypotension). Events related to decreased renal function Saxagliptin/dapagliflozin combination: In the pooled safety analysis, the incidence of adverse events related to decreased renal function was 2.0% subjects in the saxagliptin plus dapagliflozin plus metformin group, 1.8% subjects in the saxagliptin plus metformin group, and 0.6% subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower mean eGFR values at baseline of 61.8 ml/min/1.73m2 compared to 93.6 ml/min/1.73m2 in the overall population. The majority of events were considered non-serious, mild or moderate in intensity, and resolved. The change in mean eGFR from baseline at Week 24 was -1.17 ml/min/1.73m2 in the saxagliptin plus dapagliflozin plus metformin group, -0.46 ml/min/1.73 m2 in saxagliptin plus metformin, and 0.81 ml/min/1.73m2 in dapagliflozin plus metformin. Dapagliflozin: In the 13-study, short-term, placebo-controlled pool, reported terms referring to events related to decreased renal function were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). This group of events was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 ml/min/1.73m2), events related to decreased renal function were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with baseline eGFR ≥ 30 and < 60 ml/min/1.73m2 these events were reported in 18.5% and 9.3% of patients with dapagliflozin 10 mg or placebo. Serum creatinine was further evaluated in those patients with events related to decreased renal function, and most observed increases in creatinine were ≤ 0.5 mg/dl from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment. Vulvovaginitis, balanitis and related genital infections Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. Adverse events of genital infection were reported in 3.0% in the saxagliptin plus dapagliflozin plus metformin group, 0.9% of saxagliptin plus metformin group and 5.9% of subjects in the dapagliflozin plus metformin group. The majority of the genital infection adverse events were reported in females (84% of subjects with a genital infection), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy. Urinary tract infections Saxagliptin/dapagliflozin combination: In the pooled safety analysis, urinary tract infections (UTIs) were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group. One patient in the saxagliptin plus dapagliflozin plus metformin group experienced an SAE of pyelonephritis and discontinued treatment. The majority of the urinary tract infection adverse events were reported in females (81% of subjects with UTI), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy. Cardiovascular safety Saxagliptin/dapagliflozin combination: Cardiovascular (CV) events that were adjudicated and confirmed as CV events were reported in a total of 1.0% of subjects in the saxagliptin plus dapagliflozin plus metformin group, 0.6% in the saxagliptin plus metformin group, and 0.9% in the dapagliflozin plus metformin group. Malignancies Saxagliptin/dapagliflozin combination: Malignant and unspecified neoplasms were reported in 3 subjects included in the pooled safety data. They included adverse events of gastric neoplasm, pancreatic cancer with hepatic metastases, and invasive ductal breast carcinoma in the saxagliptin plus dapagliflozin plus metformin group. Considering the short latency between first drug exposure and tumour diagnosis, a causal relationship to any specific tumour type is considered unlikely. Dapagliflozin: In the 21-study active- and placebo-controlled pool, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50%) and placebo/comparator (1.50%), and there was no carcinogenicity or mutagenicity signal in animal data (see section 5.3). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non-clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. The numerical imbalance of breast, bladder and prostate tumours must be considered with caution; it will be further investigated in post-authorisation studies. Laboratory findings Decrease in lymphocyte counts Saxagliptin: In a pool of 5 placebo-controlled studies, a small decrease in absolute lymphocyte count was observed, approximately 100 cells/microl relative to placebo. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. This decrease in mean absolute lymphocyte count was not associated with clinically relevant adverse reactions. Lipids Saxagliptin/dapagliflozin combination: Data from the saxagliptin plus dapagliflozin plus metformin treatment arms of 3 Phase 3 trials, demonstrated trends of mean percent increases from baseline (rounded to the nearest tenth) in total cholesterol (Total C), (ranging from 0.4% to 3.8%), LDL-C (ranging from 2.1% to 6.9%) and HDL-C (ranging 2.3% to 5.2%) along with mean percent decreases from baseline in triglycerides (ranging from -3.0% to -10.8%). Special populations Elderly Saxagliptin/dapagliflozin combination: Of the 1169 subjects treated in the pooled safety data from the 3 clinical trials, 1007 subjects (86.1%) were aged < 65 years, 162 subjects (13.9%) were aged ≥ 65 years, and 9 subjects (0.8%) were aged ≥ 75 years. Generally, the most common adverse events reported in ≥ 65 years old were similar to < 65 years old. Therapeutic experience in patients 65 years and older is limited, and very limited in patients 75 years and older. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose Saxagliptin/dapagliflozin combination: There is no information available on overdose with Qtern. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its major metabolite are removed by haemodialysis (23% of dose over four hours). The removal of dapagliflozin by haemodialysis has not been studied. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD21 Mechanism of action for Qtern Qtern combines saxagliptin and dapagliflozin with complementary mechanisms of action to improve glycaemic control. Saxagliptin, through the selective inhibition of dipeptidyl peptidase-4 (DPP-4), enhances glucose-mediated insulin secretion (incretin effect). Dapagliflozin, a selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), inhibits renal glucose reabsorption independently of insulin. Actions of both medicinal products are regulated by the plasma glucose level. Mechanism of action for saxagliptin Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible and competitive inhibitor of DPP-4, an enzyme responsible for the breakdown of incretin hormones. This results in a glucose-dependent increase in insulin secretion, thus reducing fasting and post-prandial blood glucose concentrations. Mechanism of action for dapagliflozin Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2). Dapagliflozin blocks reabsorption of filtered glucose from the S1 segment of the renal tubule, effectively lowering blood glucose in a glucose dependent and insulin-independent manner. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. The increased urinary glucose excretion with SGLT2 inhibition produces an osmotic diuresis, and can result in a reduction in systolic BP. Pharmacodynamic effects In patients with type 2 diabetes, administration of saxagliptin inhibited DPP-4 enzyme activity throughout a 24-hour period. The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extended binding to the active site. After an oral glucose load, this produced in a 2- to 3-fold increase in circulating levels glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations, and increased beta-cell responsiveness, resulting in higher insulin and C-peptide concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Dapagliflozin's glucuretic effect is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years. Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from –48.3 to –18.3 micromoles/l (–0.87 to –0.33 mg/dl). Clinical efficacy and safety The safety and efficacy of the 5 mg saxagliptin/10 mg dapagliflozin fixed-dose combination was evaluated in three phase 3, randomised, double-blind, active/placebo-controlled clinical trials in 1169 adult subjects with type 2 diabetes mellitus. One trial with saxagliptin and dapagliflozin added concomitantly to metformin was conducted for 24 weeks. Two add-on therapy trials, which added either dapagliflozin to saxagliptin plus metformin or saxagliptin to dapagliflozin plus metformin, were also conducted for 24 weeks followed by a 28 week extension treatment period. The safety profile of the combined use of saxagliptin plus dapagliflozin in these trials for up to 52 weeks was comparable to the safety profiles for the mono-components. Glycaemic control Concomitant therapy with saxagliptin and dapagliflozin in patients inadequately controlled on metformin A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone (HbA1c ≥ 8% and ≤ 12%), participated in this 24-week randomised, double-blind, active comparator-controlled superiority trial to compare the combination of saxagliptin and dapagliflozin added concurrently to metformin, versus saxagliptin (DPP-4 inhibitor) or dapagliflozin (SGLT2 inhibitor) added to metformin. Patients were randomised to one of three double-blind treatment groups to receive saxagliptin 5 mg and dapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, or dapagliflozin 10 mg and placebo added to metformin. The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versus either the saxagliptin group or dapagliflozin group at 24 weeks (see table 2). Table 2. HbA1c at week 24 in active-controlled study comparing the combination of saxagliptin and dapagliflozin added concurrently to metformin with either saxagliptin or dapagliflozin added to metformin
2. Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement. 3. Least squares mean adjusted for baseline value. 4. p-value <0.0001. 5. p-value=0.0166. The majority of patients in this study had a baseline HbA1c of > 8% (see table 3). The combination of saxagliptin and dapagliflozin added to metformin consistently demonstrated greater reductions in HbA1c irrespective of baseline HbA1c compared with saxagliptin or dapagliflozin alone added to metformin. In a separate pre-specified subgroup analysis, mean reductions from baseline in HbA1c were generally greater for patients with higher baseline HbA1c values. Table 3. HbA1c subgroup analysis by baseline HbA1c at week 24 in randomised subjects
n = number of subjects with non-missing baseline and a Week 24 value. Proportion of patients achieving HbA1c < 7% Forty-one point four percent (41.4%) (95% CI [34.5, 48.2]) of patients in the saxagliptin and dapagliflozin combination group achieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) patients in the saxagliptin group and 22.2% (95% CI [16.1, 28.3]) patients in the dapagliflozin group. Add-on therapy with dapagliflozin in patients inadequately controlled on saxagliptin plus metformin A 24-week randomised, double-blind, placebo-controlled study compared the sequential addition of 10 mg dapagliflozin to 5 mg saxagliptin and metformin to the addition of placebo to 5 mg saxagliptin (DPP-4 inhibitor) and metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10.5%). Three hundred twenty (320) subjects were randomised equally into either the dapagliflozin added to saxagliptin plus metformin treatment group or placebo plus saxagliptin plus metformin treatment group. Patients who completed the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension (52 weeks). The group with dapagliflozin sequentially added to saxagliptin and metformin achieved statistically significant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentially added to saxagliptin plus metformin group at 24 weeks (see table 4). The effect in HbA1c observed at Week 24 was sustained at Week 52. Add-on therapy with saxagliptin in patients inadequately controlled on dapagliflozin plus metformin A 24-week randomised, double-blind, placebo-controlled study conducted on patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10.5%) on metformin and dapagliflozin alone, compared the sequential addition of 5 mg saxagliptin to 10 mg dapagliflozin and metformin, to the addition of placebo to 10 mg dapagliflozin and metformin, 153 patients were randomised into the saxagliptin added to dapagliflozin plus metformin treatment group, and 162 patients were randomised into the placebo added to dapagliflozin plus metformin treatment group. Patients who completed the initial 24-week study period were eligible to enter a controlled 28 week long-term study extension (52 weeks). The safety profile of saxagliptin added to dapagliflozin plus metformin in the long-term treatment period was consistent with that previously observed in the clinical trial experience for the concomitant therapy study and that observed in the 24-week treatment period in this study. The group with saxagliptin sequentially added to dapagliflozin and metformin achieved statistically significant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentially added to dapagliflozin plus metformin group at 24 weeks (see table 4). The effect in HbA1c observed at Week 24 was sustained at Week 52. Table 4. HbA1c change from baseline at week 24 excluding data after rescue for randomised subjects – studies MB102129 and CV181168
N is the number of randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement. Least squares mean adjusted for baseline value. Saxa=saxagliptin; dapa=dapagliflozin; met=metformin Proportion of patients achieving HbA1c < 7% The proportion of patients achieving HbA1c < 7.0% at Week 24 in the add-on therapy with saxagliptin to dapagliflozin plus metformin trial was higher in the saxagliptin plus dapagliflozin plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin plus metformin group 12.4% (95% CI [7.0, 17.9]). The effect in HbA1c observed at Week 24 was sustained at Week 52. The proportion of patients achieving HbA1c < 7% at week 24 for add-on therapy with dapagliflozin to saxagliptin plus metformin trial was higher in the saxagliptin plus dapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.2]) compared to the placebo plus dapagliflozin plus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at Week 24 was sustained at Week 52. Body weight In the concomitant study, the adjusted mean change from baseline in body weight at Week 24 (excluding data after rescue) was −2.05 kg (95% CI [−2.52, −1.58]) in the saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin group and −2.39 kg (95% CI [−2.87, −1.91]) in the dapagliflozin 10 mg plus metformin group, while the saxagliptin 5 mg plus metformin group had no change (0.00 kg) (95% CI [−0.48, 0.49]). Blood pressure Treatment with Qtern resulted in change from baseline for systolic blood pressure ranging from –1.3 to –2.2 mm Hg and for diastolic blood pressure ranging from –0.5 to –1.2 mm Hg caused by Qtern's mild diuretic effect. The modest lowering effects on BP were consistent over time and a similar number of subjects had systolic BP < 130 mmHg or diastolic BP < 80 mmHg at Week 24 across the treatment groups. Cardiovascular safety Dapagliflozin: A meta-analysis of cardiovascular events in the clinical program was performed. In the clinical program, 34.4% of subjects had a history of cardiovascular disease (excluding hypertension) at baseline and 67.9% had hypertension. The hazard ratio comparing dapagliflozin to comparator was 0.79 (95% CI: 0.58, 1.07), indicating that in this analysis dapagliflozin is not associated with an increase in cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovascular death, MI and stroke were observed with a hazard ratio of 0.77 (95% CI: 0.54, 1.10). Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus - thrombolysis in myocardial infarction (SAVOR) study SAVOR was a CV outcome trial in 16,492 patients with HbA1c ≥ 6.5% and < 12% (12,959 with established CV disease; 3533 with multiple risk factors only) who were randomised to saxagliptin (n=8280) or placebo (n=8212) added to regional standards of care for HbA1c and CV risk factors. The study population included those ≥ 65 years (n=8561) and ≥ 75 years (n=2330), with normal or mild renal impairment (n=13,916) as well as moderate (n=2240) or severe (n=336) renal impairment. The primary safety (non-inferiority) and efficacy (superiority) endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following major adverse CV events (MACE): CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptin does not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo when added to current background therapy. No benefit was observed for MACE or all-cause mortality. One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P=0.007]. Clinically relevant factors predictive of increased relative risk with saxagliptin treatment could not be definitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatment assignment, could be identified by known risk factors for heart failure such as baseline history of heart failure or impaired renal function. However, subjects on saxagliptin with a history of heart failure or impaired renal function at baseline were not at an increased risk relative to placebo for the primary or secondary composite endpoints or all-cause mortality. Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin group and 4.6% in the placebo group. CV deaths were balanced across the treatment groups. There was a numerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than placebo (1.4%) [HR=1.27; (95% CI 1.00, 1.62); P=0.051]. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Qtern in all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Saxagliptin/dapagliflozin combination: Overall, the pharmacokinetics of saxagliptin and dapagliflozin were not affected in clinically relevant manner when administered as Qtern compared with independent doses of saxagliptin and dapagliflozin. The following reflects the pharmacokinetic properties of Qtern unless stated that the presented data are from administration of saxagliptin or dapagliflozin. 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 subjects. The pharmacokinetics of dapagliflozin, and saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes. Administration of Qtern with a high-fat meal decreases dapagliflozin Cmax by up to 35% and prolongs Tmax by approximately 1.5 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. Drug interactions: Saxagliptin/dapagliflozin combination: No drug interaction studies have been performed with Qtern and other medicinal products. Such studies have been conducted with the individual active substances. Saxagliptin: In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. Dapagliflozin: In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes. Absorption Saxagliptin: Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng h/ml and 214 ng h/ml, respectively. The corresponding plasma Cmax values were 24 ng/ml and 47 ng/ml, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%. Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax and AUC values following once daily 10 mg doses of dapagliflozin were 158 ng/ml and 628 ng h/ml, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Distribution Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. 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 was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 l. The volume of distribution of saxagliptin was 205 l. Biotransformation Saxagliptin: The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major active metabolite of saxagliptin, 5-OH-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, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do 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. Elimination Saxagliptin: The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 ml/min) was greater than the average estimated glomerular filtration rate (~120 ml/min), suggesting some active renal excretion. Dapagliflozin: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 ml/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. Linearity Saxagliptin: The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg. Dapagliflozin: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks. Special populations Renal impairment Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe renal impairment (or ESRD) classified on the basis of creatinine clearance the mean AUC values of saxagliptin were 1.2-, and up to 2.1- and 4.5- fold higher, respectively, than AUC values in subjects with normal renal function. The AUC values of 5-OH-saxagliptin were also increased. The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite. Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of hemodialysis on dapagliflozin exposure is not known. Hepatic impairment Saxagliptin: In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 (saxagliptin metabolite) were 22%, 7%, and 33% lower, respectively, than those observed in healthy subjects. Dapagliflozin: In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively. Elderly Saxagliptin: Elderly patients (65–80 years) had about 60% higher saxagliptin AUC than young patients (18–40 years). This is not considered clinically meaningful, therefore, no dose adjustment for saxagliptin is recommended on the basis of age alone. Dapagliflozin: There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients > 70 years old. Gender Saxagliptin: Females had approximately 25% higher systemic exposure values for saxagliptin. There were no clinically relevant differences observed in saxagliptin pharmacokinetics between males and females. Dapagliflozin: The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males. Race Saxagliptin: Race was not identified as a statistically significant covariate on the apparent clearance of saxagliptin and its metabolite. Dapagliflozin: There were no clinically relevant differences in systemic exposures between White, Black or Asian races. Body weight Dapagliflozin: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high-weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful. Saxagliptin: Body weight had a small and non-clinically meaningful impact on saxagliptin exposure. Females had approximately 25% higher systemic-exposure values for saxagliptin, this difference is considered not clinically relevant. 5.3 Preclinical safety data Non-clinical studies of either saxagliptin or dapagliflozin revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity or carcinogenicity. Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) in cynomolgus monkeys. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose (RHD) of 5 mg/day. The clinical relevance of the skin lesions is not known and skin lesions have not been observed in humans. Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD. Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively. Reproductive and developmental toxicity Saxagliptin has effects on fertility in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively. Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. In a juvenile study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations (with dose-related increases in kidney weight and macroscopic kidney enlargement) were reported at all dose levels; pup exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period. Dapagliflozin dosed to maternal rats from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (at maternal and pup dapagliflozin exposures of 1415 times and 137 times, respectively, the human values at the maximum recommended human dose [MRHD]). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day (pup exposures ≥ 29 times the human values at the MRHD). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The NOAEL for developmental toxicity is associated with a maternal systemic exposure 19 times the human values at the MRHD. In studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternal nor developmental toxicities at any dose tested; the highest dose tested corresponded to a systemic exposure 1191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1441 times the human values at the MRHD. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Microcrystalline cellulose (E460i) Croscarmellose sodium (E468) Lactose, anhydrous Magnesium stearate (E470b) Dental type silica (E551) Film-coating Polyvinyl alcohol (E1203) Macrogol 3350 Titanium dioxide (E171) Talc (E553b) Iron oxide yellow (E172) Iron oxide red (E172) Printing ink Shellac Indigo carmine aluminium lake (E132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PA/Alu/PVC-Alu blister Pack sizes of 14, 28, and 98 film-coated tablets in calendar blisters Pack size of 30 film-coated tablets in blisters Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder AstraZeneca AB SE-151 85 Södertälje Sweden 8. Marketing authorisation number(s) EU/1/16/1108/001 14 film-coated tablets EU/1/16/1108/002 28 film-coated tablets EU/1/16/1108/003 98 film-coated tablets EU/1/16/1108/004 30 film-coated tablets 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 15th July 2016 10. Date of revision of the text 19th January 2017 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu |
Qtern(dapagliflozin/saxagliptin filmcoated tablets)简介:
2016年7月25日,降糖新药Qtern(dapagliflozin and saxagliptin,沙格列汀/达帕格列津)是获欧盟首个获批的DPP-4抑制剂+SGLT2抑制剂组合疗法,对2型糖尿病患者有效控制血糖水平。 沙格列汀/达帕格列津的 ... 责任编辑:p53 |
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