|
英文药名：Xigduo(dapagliflozin+metformin)Tablet 中文药名：达格列净/盐酸二甲双胍复方片 生产厂家：阿斯利康和百时美施贵宝
bSee corresponding subsection below for additional information. cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess. dPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased. eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension. fMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 1.4% versus -0.4%; HDL cholesterol 5.5% versus 3.8%; LDL cholesterol 2.7% versus -1.9%; triglycerides -5.4% versus -0.7%. gMean changes from baseline in haematocrit were 2.15% for dapagliflozin 10 mg versus -0.40% for placebo. hLong-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia). iGastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases. *Reported in ≥ 2% of subjects treated with dapagliflozin 10 mg and ≥ 1% more frequently than placebo. **Reported in ≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg regardless of glycaemic rescue compared to placebo. Description of selected adverse reactions Dapagliflozin plus metformin Hypoglycaemia In studies with dapagliflozin in add-on combination with metformin, minor episodes of hypoglycaemia were reported at similar frequencies in the group treated with dapagliflozin 10 mg plus metformin (6.9%) and in the placebo plus metformin group (5.5%). No major events of hypoglycaemia were reported. In an add-on to metformin and a sulphonylurea study, up to 24 weeks, minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. No major events of hypoglycaemia were reported. Dapagliflozin Hypoglycaemia The frequency of hypoglycaemia depended on the type of background therapy used in each study. For studies of dapagliflozin as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. In a study with add-on insulin therapy, higher rates of hypoglycaemia were observed (see section 4.5). In an add-on to insulin study up to 104 weeks, episodes of major hypoglycaemia were reported in0.5% and 1.0% of subjects in dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin. Volume depletion Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 0.8% and 0.4% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo (see section 4.4). Vulvovaginitis, balanitis and related genital infections Vulvovaginitis, balanitis and related genital infections were reported in 4.8% and 0.9% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (6.9% and 1.5% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection. Urinary tract infections Urinary tract infections were more frequently reported for dapagliflozin compared with placebo (4.3% versus 3.7%, respectively; see section 4.4). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. Parathyroid hormone (PTH) Small increases in serum PTH levels were observed with increases being larger in subjects with higher baseline PTH concentrations. Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of one year. Malignancies During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.47%) and placebo/comparator (1.35%), 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. Since the numerical imbalance of breast, bladder and prostate tumours must be considered with caution, it will be further investigated in post-authorisation studies. Special populations Elderly patients (≥ 65 years) In subjects ≥ 65 years of age, adverse reactions related to renal impairment or failure were reported in 2.5% of subjects treated with dapagliflozin and 1.1% of subjects treated with placebo (see section 4.4). The most commonly reported adverse reaction related to renal function was increased serum creatinine. The majority of these reactions were transient and reversible. In subjects ≥ 65 years of age, adverse reactions of volume depletion, most commonly reported as hypotension, were reported in 1.5% and 0.4% of dapagliflozin-treated subjects and placebo-treated subjects, respectively (see section 4.4). 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 IMB Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt 4.9 Overdose Removal of dapagliflozin by haemodialysis has not been studied. The most effective method to remove metformin and lactate is haemodialysis. Dapagliflozin Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Metformin High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose-lowering drugs, ATC code: A10BD15 Mechanism of action Xigduo combines two anti-hyperglycaemic medicinal products with different and complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a member of the biguanide class. Dapagliflozin Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2). The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, reabsorption of filtered glucose continues. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin. Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption. Metformin Metformin is a biguanide with anti-hyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin may act via three mechanisms: - by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; - by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation in muscle; - by delaying intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4). Pharmacodynamic effects Dapagliflozin 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. This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 ml/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations. 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). The pharmacodynamics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were compared in healthy subjects. The steady-state inhibition of renal glucose reabsorption and the amount of urinary glucose excretion over a 24-hour period was the same for both dosing regimens. Metformin In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels. In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss. Clinical efficacy and safety The coadministration of dapagliflozin and metformin has been studied in subjects with type 2 diabetes inadequately controlled on metformin alone or in combination with a DPP-4 inhibitor (sitagliptin), sulphonylurea or insulin. Treatment with dapagliflozin plus metformin at all doses produced clinically relevant and statistically significant improvements in HbA1c and fasting plasma glucose compared with placebo in combination with metformin. These clinically relevant glycaemic effects were sustained in long-term extensions up to 104 weeks. HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI). Additionally, at Week 24, clinically relevant and statistically significant improvements in mean changes from baseline in body weight were seen with dapagliflozin and metformin combination treatments compared with control. Body weight reductions were sustained in long-term extensions up to 208 weeks. Additionally, dapagliflozin twice-daily treatment added to metformin was shown to be effective and safe in type 2 diabetic subjects. Glycaemic control In a 52-week, active-controlled non-inferiority study (with 52- and 104-week extension periods), dapagliflozin 10 mg was evaluated as add-on therapy to metformin compared with a sulphonylurea (glipizide) as add-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 52, compared with glipizide, thus demonstrating non-inferiority (Table 2). At Week 104, adjusted mean change from baseline in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide, respectively. At Week 208, adjusted mean change from baseline in HbA1c was -0.10% for dapagliflozin and 0.20% for glipizide, respectively. At 52, 104 and 208 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5%, 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia compared with the group treated with glipizide (40.8%, 47% and 50.0%, respectively). The proportion of subjects remaining in the study at Week 104 and Week 208 was 56.2% and 39.7% for the group treated with dapagliflozin and 50.0% and 34.6% for the group treated with glipizide. Table 2. Results at Week 52 (LOCFa) in an active-controlled study comparing dapagliflozin with glipizide as add-on to metformin
aLOCF: Last observation carried forward
1Metformin ≥ 1500 mg/day; 2Sitagliptin 100 mg/day aLOCF: Last observation (prior to rescue for rescued subjects) carried forward bPlacebo-controlled 16-week study cAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-blind period dLeast squares mean adjusted for baseline value *p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product **p-value < 0.05 versus placebo + oral glucose-lowering medicinal product ***The percent change in body weight was analysed as a key secondary endpoint (p < 0.0001); absolute body weight change (in kg) was analysed with a nominal p-value (p < 0.0001). Table 4. Results of a 24-week placebo-controlled study of dapagliflozin in add on combination with metformin and a sulphonylurea
aRandomized and treated patients with baseline and at least 1 post-baseline efficacy measurement. bHbA1c analyzed using LRM (Longitudinal repeated measures analysis) cLeast squares mean adjusted for baseline value *p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product(s) Table 5. Results at Week 24 (LOCFa) in a placebo-controlled study of dapagliflozin in combination with insulin (alone or with oral glucose-lowering medicinal products, including metformin)
bAll randomised subjects who took at least one dose of double-blind study medicinal product during the short-term double-blind period cLeast squares mean adjusted for baseline value and presence of oral glucose-lowering medicinal product *p-value < 0.0001 versus placebo + insulin ± oral glucose-lowering medicinal product **p-value < 0.05 versus placebo + insulin ± oral glucose-lowering medicinal product 1Up-titration of insulin regimens (including short-acting, intermediate, and basal insulin) was only allowed if subjects met pre-defined FPG criteria. 2Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-lowering medicinal product(s) in addition to insulin: Of this latter group, 80% were on metformin alone, 12% were on metformin plus sulphonylurea therapy, and the rest were on other oral glucose-lowering medicinal products. Fasting plasma glucose Treatment with dapagliflozin as an add-on to either metformin alone (dapagliflozin 10 mg QD or dapagliflozin 5 mg BID) or metformin plus sitagliptin, sulphonylurea or insulin resulted in statistically significant reductions in fasting plasma glucose (-1.90 to -1.20 mmol/l [-34.2 to -21.7 mg/dl]) compared with placebo (-0.58 to 0.18 mmol/l [-10.4 to 3.3 mg/dl]) at Week 16 (5 mg BID) or Week 24. This effect was observed at Week 1 of treatment and maintained in studies extended through Week 102. Post-prandial glucose Treatment with dapagliflozin 10 mg as an add-on to sitagliptin plus metformin resulted in reductions in 2-hour post-prandial glucose at 24 weeks that were maintained up to Week 48. Body weight Dapagliflozin as an add-on to metformin alone or metformin plus sitagliptin, sulphonylurea or insulin (with or without additional oral glucose-lowering medicinal products, including metformin) resulted in statistically significant body weight reduction up to 24 weeks (p < 0.0001, Tables 3, 4 and 5). These effects were sustained in longer-term trials. At 48 weeks, the difference for dapagliflozin as add-on to metformin plus sitagliptin compared with placebo was -2.07 kg. At 102 weeks, the difference for dapagliflozin as add-on to metformin compared with placebo or as add-on to insulin compared with placebo was -2.14 and -2.88 kg, respectively. As an add-on therapy to metformin in an active-controlled non-inferiority study, dapagliflozin resulted in a statistically significant body weight change compared with glipizide of -4.65 kg at 52 weeks (p < 0.0001, Table 2) that was sustained at 104 and 208 weeks (-5.06 kg and -4.38 kg, respectively). A 24-week study in 182 diabetic subjects using dual energy X-ray absorptiometry (DXA) to evaluate body composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared with placebo plus metformin, respectively, in body weight and body fat mass as measured by DXA rather than lean tissue or fluid loss. Treatment with dapagliflozin 10 mg plus metformin showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonance imaging substudy. Blood pressure In a pre-specified pooled analysis of 12 placebo-controlled studies, treatment with dapagliflozin 10 mg resulted in a systolic blood pressure change from baseline of -4.4 mmHg and diastolic blood pressure of -2.1 mmHg versus -0.9 mmHg systolic and -0.5 mmHg diastolic blood pressure for placebo group at Week 24. Cardiovascular safety A meta-analysis of cardiovascular events in the clinical program was performed. In the clinical program, 36.6% of subjects had a history of cardiovascular disease (excluding hypertension) at baseline and 70.0% had hypertension. Cardiovascular episodes were adjudicated by an independent adjudication committee. The primary end point was the time-to-first event of one of the following outcomes: cardiovascular death, stroke, myocardial infarction (MI) or hospitalisation for unstable angina. Primary episodes occurred at a rate of 1.64% per patient-year in subjects treated with dapagliflozin and 1.99% in comparator-treatment subjects, per patient-year. The hazard ratio comparing dapagliflozin to comparator was 0.82 (95% Confidence interval [CI]: 0.58, 1.15), 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 0.79 (95% CI: 0.54, 1.17). Patients with baseline HbA1c ≥ 9% In a pre-specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment with dapagliflozin 10 mg resulted in statistically significant reductions in HbA1c at Week 24 as an add-on to metformin (adjusted mean change from baseline: -1.32% and -0.53% for dapagliflozin and placebo, respectively). Metformin The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: - a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034; - a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017; - a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021); - a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01). Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Xigduo 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 Xigduo combination tablets are considered to be bioequivalent to coadministration of corresponding doses of dapagliflozin and metformin hydrochloride administered together as individual tablets. The pharmacokinetics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were compared in healthy subjects. Administration of 5 mg dapagliflozin twice daily gave similar overall exposures (AUCss) over a 24-hour period as 10 mg dapagliflozin administered once daily. As expected, dapagliflozin 5 mg administered twice daily compared with 10 mg dapagliflozin once daily resulted in lower peak dapagliflozin plasma concentrations (Cmax) and higher trough plasma dapagliflozin concentrations (Cmin). Interaction with food The administration of this medicinal product in healthy volunteers after a high fat meal compared to after the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin. The meal resulted in a delay of 1 to 2 hours in the peak concentrations and a decrease in the maximum plasma concentration of 29% of dapagliflozin and 17% of metformin. These changes are not considered to be clinically meaningful. Paediatric population Pharmacokinetics in the paediatric population have not been studied. The following statements reflect the pharmacokinetic properties of the individual active substances of this medicinal product. Dapagliflozin Absorption 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 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. Biotransformation 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 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. After administration of a 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in feces. In feces, approximately 15% of the dose was excreted as parent drug. Linearity 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 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 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 with 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 patients (≥ 65 years) 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 The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males. Race There were no clinically relevant differences in systemic exposures between White, Black or Asian races. Body weight 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. Paediatric population Pharmacokinetics in the paediatric population have not been studied. Metformin Absorption After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%. After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady-state plasma concentrations are reached within 24-48 hours and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 μg/ml, even at maximum doses. Distribution Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 l. Biotransformation Metformin is excreted unchanged in the urine. No metabolites have been identified in humans. Elimination Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. Special populations Renal impairment In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance, leading to increased levels of metformin in plasma. 5.3 Preclinical safety data Coadministration of dapagliflozin and metformin Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. The following statements reflect the preclinical safety data of the individual active substances of Xigduo. Dapagliflozin Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in two-year carcinogenicity studies. Reproductive and developmental toxicity Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (time periods 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 toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period. In a separate study of pre- and postnatal development, maternal rats were dosed from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and 137 times, respectively, the human values at the maximum recommended human dose). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day (associated with pup exposures that are ≥ 29 times the human values at the maximum recommended human dose). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The no observed adverse effect level (NOAEL) for developmental toxicity, the lowest dose tested, is associated with a maternal systemic exposure multiple that is approximately 19 times the human value at the maximum recommended human dose. In additional studies of embryo-foetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested; the highest dose tested is associated with a systemic exposure multiple of approximately 1,191 times the maximum recommended human dose. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1,441 times the maximum recommended human dose. Metformin Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Hydroxypropyl cellulose (E463) Microcrystalline cellulose (E460(i)) Magnesium stearate (E470b) Sodium starch glycolate type A Film-coating: Polyvinyl alcohol (E1203) Macrogol 3350 (E1520(iii)) Talc (E553b) Titanium dioxide (E171) Iron oxide yellow (E172) Iron oxide red (E172), in 5 mg/850 mg only 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 PVC/Aclar/Alu blister. Pack sizes: 14, 28, 56 and 60 film-coated tablets in non-perforated blisters. 60x1 film-coated tablets in perforated unit dose blisters. Multipack containing 196 (2 packs of 98) film-coated tablets in non-perforated blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Bristol-Myers Squibb/AstraZeneca EEIG Bristol-Myers Squibb House Uxbridge Business Park Sanderson Road Uxbridge Middlesex UB8 1DH United Kingdom 8. Marketing authorisation number(s) EU/1/13/900/003: Xigduo 5 mg/850 mg 56 tablets EU/1/13/900/009: Xigduo 5 mg/1000 mg 56 tablets 9. Date of first authorisation/renewal of the authorisation 16th January 2014 10. Date of revision of the text 22nd May 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 2014年3月11日，阿斯利康和百时美施贵宝公司宣布，欧洲药品管理局（EMA）的人用医药产品委员会（CHMP）已对批准Xigduo™（达格列净的和盐酸二甲双胍）治疗为18岁以上的成年人的2型糖尿病采取了积极的意见，CHMP建议将Xigduo™ 用于无法仅用基于二甲双胍治疗方案控制血糖或正接受dapagliflozin的和二甲双胍治疗但是分别给药的患者作为饮食和运动改善血糖控制情况外的增加辅助治疗。 Xigduo™组合钠-葡萄糖协同转运蛋白2（SGLT2）选择性可逆抑制剂达格列净（dapagliflozin，商品名Forxiga®）和盐酸二甲双胍，并制成片剂，该片剂需要每天服务两次。这是CHM认可的第一个SGLT2和盐酸二甲双胍的固定剂量组合。目前，CHMP的积极意见正由由欧洲委员会审核，该委员会有权批准药品在欧盟国家上市。最终的决定将适用于所有28个欧洲联盟会员国以及冰岛和挪威。 Xigduo™结合Forxiga和盐酸二甲双胍两种具有互补性作用机制的抗高血糖产品以改善血糖控制。Forxiga是第一个获得监管部门批准的SGLT2药物，目前已被多个国家与地区被批准用于2型糖尿病，包括欧盟、阿根廷、澳大利亚、巴西、冰岛、墨西哥、挪威和新西兰。 关于 SGLT2 抑制剂： 肾脏通过从循环中过滤和重吸引葡萄糖调节体内葡萄糖水平，在维持血糖平衡中起到重要作用。SGLT2（钠-葡萄糖协同转运蛋白）主要在肾脏上表达，负责大部的葡萄糖的重吸收。在2型糖尿病患者中，肾脏的重吸收葡萄糖的能力提高约20％，进一步加剧了与疾病相关的高血糖症。SGLT2的选择性抑制可减少过量的葡萄糖的重吸收，并通过尿清除。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
