英文药名:Trulicity(dulaglutide Solution for injection) 中文药名:度拉糖肽注射剂 生产厂家:礼来制药
Dulaglutide 1.5 mg dose only. For dulaglutide 0.75 mg, adverse reaction met frequency for next lower incidence grouping. Description of selected adverse reactions Hypoglycaemia When dulaglutide 0.75 mg and 1.5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone, the incidences of documented symptomatic hypoglycaemia were 5.9% to 10.9% and the rates were 0.14 to 0.62 events/patient/year, and no episodes of severe hypoglycaemia were reported. The incidences of documented symptomatic hypoglycaemia when dulaglutide 0.75 mg and 1.5 mg, respectively, were used in combination with a sulphonylurea (plus metformin) were 39.0% and 40.3% and the rates were 1.67 and 1.67 events/patient/year. The severe hypoglycaemia event incidences were 0% and 0.7%, and rates were 0.00 and 0.01 events/patient/year. The incidences when dulaglutide 0.75 mg and 1.5 mg, respectively, were used in combination with prandial insulin were 85.3% and 80.0% and rates were 35.66 and 31.06 events/patient/year. The severe hypoglycaemia event incidences were 2.4% and 3.4%, and rates were 0.05 and 0.06 events/patient/year. Gastrointestinal adverse reactions Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0.75mg and 1.5 mg, respectively, included nausea (12.9% and 21.2 %), diarrhoea (10.7% and 13.7 %) and vomiting (6.9% and 11.5 %). These were typically mild or moderate in severity and were reported to peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks, after which the rate remained relatively constant. In clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks, the majority of gastrointestinal events were reported during the first 2-3 days after the initial dose and declined with subsequent doses. Acute pancreatitis The incidence of acute pancreatitis in phase II and III clinical studies was 0.07% for dulaglutide compared to 0.14% for placebo and 0.19% for comparators with or without additional background antidiabetic therapy. Pancreatic enzymes Dulaglutide is associated with mean increases from baseline in pancreatic enzymes (lipase and/or pancreatic amylase) of 11 % to 21 % (see section 4.4). In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis. Heart rate increase Small mean increases in heart rate of 2 to 4 beats per minute (bpm) and a 1.3% and 1.4 % incidence of sinus tachycardia, with a concomitant increase from baseline ≥ 15 bpm, were observed with dulaglutide 0.75mg and 1.5 mg, respectively. First degree AV block/PR interval prolongation Small mean increases from baseline in PR interval of 2 to 3 msec and a 1.5% and 2.4 % incidence of first-degree AV block were observed with dulaglutide 0.75 mg and 1.5 mg, respectively. Immunogenicity In clinical studies, treatment with dulaglutide was associated with a 1.6 % incidence of treatment emergent dulaglutide anti-drug antibodies, indicating that the structural modifications in the GLP-1 and modified IgG4 parts of the dulaglutide molecule, together with high homology with native GLP-1 and native IgG4, minimise the risk of immune response against dulaglutide. Patients with dulaglutide anti-drug antibodies generally had low titres, and although the number of patients developing dulaglutide anti-drug antibodies was low, examination of the phase III data revealed no clear impact of dulaglutide anti-drug antibodies on changes in HbA1c. Hypersensitivity In the phase II and phase III clinical studies, systemic hypersensitivity events (e.g., urticaria, oedema) were reported in 0.5 % of patients receiving dulaglutide. None of the patients with systemic hypersensitivity developed dulaglutide anti-drug antibodies. Injection site reactions Injection site adverse events were reported in 1.9 % of patients receiving dulaglutide. Potentially immune-mediated injection site adverse events (e.g., rash, erythema) were reported in 0.7 % of patients and were usually mild. Discontinuation due to an adverse event In studies of 26 weeks duration, the incidence of discontinuation due to adverse events was 2.6% (0.75 mg) and 6.1% (1.5 mg) for dulaglutide versus 3.7 % for placebo. Through the full study duration (up to 104 weeks), the incidence of discontinuation due to adverse events was 5.1% (0.75 mg) and 8.4 % (1.5 mg) for dulaglutide. The most frequent adverse reactions leading to discontinuation for 0.75 mg and 1.5 mg dulaglutide, respectively, were nausea (1.0%, 1.9 %), diarrhoea (0.5%, 0.6 %), and vomiting (0.4%, 0.6 %), and were generally reported within the first 4-6 weeks. 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, or 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 4.9 Overdose Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders and hypoglycaemia. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: {not yet assigned}, ATC code: {not yet assigned}. Mechanism of action Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. The molecule consists of 2 identical disulfide-linked chains, each containing a modified human GLP-1 analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker. The GLP-1 analog portion of dulaglutide is approximately 90 % homologous to native human GLP-1 (7-37). Native GLP-1 has a half-life of 1.5-2 minutes due to degradation by DPP-4 and renal clearance. In contrast to native GLP-1, dulaglutide is resistant to degradation by DPP-4, and has a large size that slows absorption and reduces renal clearance. These engineering features result in a soluble formulation and a prolonged half-life of 4.7 days, which makes it suitable for once-weekly subcutaneous administration. In addition, the dulaglutide molecule was engineered to prevent the Fcγ receptor-dependent immune response and to reduce its immunogenic potential. Dulaglutide exhibits several antihyperglycaemic actions of GLP-1. In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. Dulaglutide also slows gastric emptying. Pharmacodynamic effects Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre-meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval. A pharmacodynamic study with dulaglutide demonstrated, in patients with type 2 diabetes, a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects on placebo, and improved second phase insulin secretion in response to an intravenous bolus of glucose. In the same study, a single 1.5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the β-cells, and to enhance β-cell function in subjects with type 2 diabetes mellitus as compared with placebo. Consistent with the pharmacokinetic profile, dulaglutide has a pharmacodynamic profile suitable for once weekly administration (see section 5.2). Clinical efficacy and safety Glycaemic control The safety and efficacy of dulaglutide was evaluated in six randomised, controlled, phase III trials involving 5,171 patients with type 2 diabetes. Of these, 958 were ≥ 65 years of which 93 were ≥ 75 years. These studies included 3,136 dulaglutide-treated patients, of whom 1,719 were treated with Trulicity 1.5 mg weekly and 1,417 were treated with Trulicity 0.75 mg weekly. In all studies, dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA1c). Monotherapy Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin. Trulicity 1.5 mg and 0.75 mg were superior to metformin (1500-2000 mg/day) in the reduction in HbA1c and a significantly greater proportion of patients reached an HbA1c target of < 7.0 % and ≤ 6.5 % with Trulicity 1.5 mg and Trulicity 0.75 mg compared to metformin at 26 weeks. Table 2: Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin
p < 0.05, ## p < 0.001 dulaglutide treatment group compared to metformin The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and metformin were 0.62, 0.15, and 0.09 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed. Combination therapy with metformin The safety and efficacy of dulaglutide was investigated in a placebo and active controlled (sitagliptin 100 mg daily) study of 104 weeks duration, all in combination with metformin. Treatment with Trulicity 1.5 mg and 0.75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at 52 weeks, accompanied by a significantly greater proportion of patients achieving HbA1c targets of < 7.0 % and ≤ 6.5 %. These effects were sustained to the end of the study (104 weeks). Table 3: Results of a 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin
multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo, assessed for HbA1c only p < 0.001 dulaglutide treatment group compared to placebo p < 0.001 dulaglutide treatment group compared to sitagliptin The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and sitagliptin were 0.19, 0.18, and 0.17 episodes/patient/year, respectively. No cases of severe hypoglycaemia with dulaglutide were observed. The safety and efficacy of dulaglutide was also investigated in an active controlled study (liraglutide 1.8 mg daily) of 26 weeks duration, both in combination with metformin. Treatment with Trulicity 1.5 mg resulted in similar lowering of HbA1c and patients achieving HbA1c targets of < 7.0 % and ≤ 6.5 % compared to liraglutide. Table 4: Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide
p < 0.05 dulaglutide treatment group compared to liraglutide. Patients randomised to liraglutide were initiated at a dose of 0.6 mg/day. After Week 1, patients were up-titrated to 1.2 mg/day and then at Week 2 to 1.8 mg/day. The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 0.12 episodes/patient/year and with liraglutide was 0.29 episodes/patient/year. No cases of severe hypoglycaemia were observed. Combination therapy with metformin and sulphonylurea In an active controlled study of 78 weeks duration, dulaglutide was compared to insulin glargine, both on a background of metformin and a sulphonylurea. At 52 weeks, Trulicity 1.5 mg demonstrated superior lowering in HbA1c to insulin glargine which was maintained at 78 weeks; whereas lowering in HbA1c with Trulicity 0.75 mg was non-inferior to insulin glargine. With Trulicity 1.5 mg a significantly higher percentage of patients reached a target HbA1c of < 7.0 % or ≤ 6.5 % at 52 and 78 weeks compared to insulin glargine. Table 5: Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine
p < 0.05, ## p < 0.001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of < 5.6 mmol/L The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and insulin glargine were 1.67, 1.67, and 3.02 episodes/patient/year, respectively. Two cases of severe hypoglycaemia were observed with Trulicity 1.5mg and two cases of severe hypoglycaemia were observed with insulin glargine. Combination therapy with metformin and pioglitazone In a placebo and active (exenatide twice daily) controlled study, both in combination with metformin and pioglitazone, Trulicity 1.5 mg and 0.75 mg demonstrated superiority for HbA1c reduction in comparison to placebo and exenatide, accompanied by a significantly greater percentage of patients achieving HbA1c targets of < 7.0 % or ≤ 6.5 %. Table 6: Results of a 52 week active controlled study with two doses of dulaglutide in comparison to exenatide
multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo, assessed for HbA1c only p < 0.05, p < 0.001 dulaglutide treatment group compared to placebo p < 0.05, p < 0.001 dulaglutide treatment group compared to exenatide Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and exenatide twice daily were 0.19, 0.14, and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily. Combination therapy with prandial insulin with or without metformin In this study, patients on 1 or 2 insulin injections per day prior to study entry, discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily, both in combination with prandial insulin lispro three times daily, with or without metformin. At 26 weeks, both Trulicity 1.5 mg and 0.75mg were superior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks. A greater percentage of patients achieved HbA1c targets of < 7.0 % or ≤ 6.5 % at 26 weeks and < 7.0 % at 52 weeks than with insulin glargine. Table 7: Results of a 52 week active controlled study with two doses of dulaglutide in comparison to insulin glargine
p < 0.05, p < 0.001 dulaglutide treatment group compared to insulin glargine Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of < 5.6 mmol/L The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and insulin glargine were 31.06, 35.66, and 40.95 episodes/patient/year, respectively. Ten patients reported severe hypoglycaemia with Trulicity 1.5 mg, seven with Trulicity 0.75 mg, and fifteen with insulin glargine. Fasting blood glucose Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose. The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks. The improvement in fasting glucose was sustained through the longest study duration of 104 weeks. Postprandial glucose Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline (changes from baseline to primary time point -1.95 mmol/L to -4.23 mmol/L). Beta-cell function Clinical studies with dulaglutide have indicated enhanced beta-cell function as measured by homeostasis model assessment (HOMA2-%B). The durability of effect on beta-cell function was maintained through the longest study duration of 104 weeks. Body weight Trulicity 1.5 mg was associated with sustained weight reduction over the duration of studies (from baseline to final time point -0.35 kg to -2.90 kg). Changes in body weight with Trulicity 0.75 mg ranged from 0.86 kg to -2.63 kg. Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea, though the reduction was numerically larger in the group with nausea. Patient reported outcomes Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily. Blood pressure The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes. Treatment with dulglutide provided reductions in systolic blood pressure (SBP) (-2.8 mmHg difference compared to placebo) at 16 weeks. There was no difference in diastolic blood pressure (DBP). Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study. Cardiovascular Evaluation In a meta-analysis of phase II and III studies, a total of 51 patients (dulaglutide: 26 [N = 3,885]; all comparators: 25 [N = 2,125]) experienced at least one cardiovascular (CV) event (death due to CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina). The results showed that there was no increase in CV risk with dulaglutide compared with control therapies (HR: 0.57; CI: [0.30, 1.10]). Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with dulaglutide in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following subcutaneous administration to patients with type 2 diabetes, dulaglutide reaches peak plasma concentrations in 48 hours. The mean peak (Cmax) and total (AUC) exposures were approximately 114 ng/ml and 14,000 ngh/ml, respectively, after multiple subcutaneous 1.5 mg doses of dulaglutide in patients with type 2 diabetes. Steady-state plasma concentrations were achieved between 2 to 4 weeks of once-weekly administration of dulaglutide (1.5 mg). Exposures after subcutaneous administration of single dulaglutide (1.5 mg) doses in the abdomen, thigh, or upper arm were comparable. The mean absolute bioavailability of dulaglutide following single-dose subcutaneous administration of single 1.5 mg and 0.75 mg doses was 47 % and 65%, respectively. Distribution The mean volume of distribution after subcutaneous administration of dulaglutide 0.75 mg and 1.5 mg at steady state in patients with type 2 diabetes mellitus were approximately 19.2 L and 17.4 L. Biotransformation Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. Elimination The mean apparent clearance of dulaglutide 0.75 mg and 1.5 mg at steady state was 0.073 L/h and 0.107 L/h with an elimination half-life of 4.5 and 4.7 days, respectively. Special populations Elderly patients (> 65 years old) Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide. Gender and race Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide. Body weight or body mass index Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutide exposure, although there was no clinically relevant impact of weight or BMI on glycaemic control. Patients with renal impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment (CrCl < 30 ml/min), including end stage renal disease (requiring dialysis). In clinical studies, the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DM population. These studies did not include patients with severe renal impairment or end stage renal disease. Patients with hepatic impairment The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study, where subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30 % to 33 % for mean Cmax and AUC, respectively, compared to healthy controls. There was a general increase in tmax of dulaglutide with increased hepatic impairment. However, no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment. These effects were not considered to be clinically relevant. Paediatric population Studies characterising the pharmacokinetics of dulaglutide in paediatric patients have not been performed. 5.3 Preclinical safety data Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat-dose toxicity. In a 6-month carcinogenicity study in transgenic mice, there was no tumorigenic response. In a 2-year carcinogenicity study in rats, at ≥ 7 times the human clinical exposure following 1.5 mg dulaglutide per week, dulaglutide caused statistically significant, dose-related increases in the incidence of thyroid C-cell tumours (adenomas and carcinomas combined). The clinical relevance of these findings is currently unknown. During the fertility studies, a reduction in the number of corpora lutea and prolonged oestrous cycle were observed at dose levels that were associated with decreased food intake and body weight gain in maternal animals; however, no effects on indices of fertility and conception or embryonic development were observed. In reproductive toxicology studies, skeletal effects and a reduction in foetal growth were observed in the rat and rabbit at exposures of dulaglutide 11- to 44-fold higher than those proposed clinically, but no foetal malformations were observed. Treatment of rats throughout pregnancy and lactation produced memory deficits in female offspring at exposures that were 16-fold higher than those proposed clinically. 6. Pharmaceutical particulars 6.1 List of excipients Sodium citrate Citric acid, anhydrous Mannitol Polysorbate 80 Water for injections 6.2 Incompatibilities In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2 °C – 8 °C). Do not freeze. Store in original package in order to protect from light. In use: Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 °C. 6.5 Nature and contents of container Pre-filled pen Glass syringe (type I) encased in a disposable pen. Each pre-filled pen contains 0.5 ml of solution. Packs of 2 and 4 pre-filled pens and multipack of 12 (3 packs of 4) pre-filled pens. Pre-filled syringe Glass syringe (type I). Each pre-filled syringe contains 0.5 ml of solution. Packs of 4 pre-filled syringes and multipack of 12 (3 packs of 4) pre-filled syringes. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Pre-filled pen Instructions for use The pre-filled pen is for single-use only. The instructions for using the pen, included with the package leaflet, must be followed carefully. Trulicity should not be used if particles appear or if the solution is cloudy and/or coloured. Trulicity that has been frozen must not be used. Pre-filled syringe Instructions for use The pre-filled syringe is for single-use only. The instructions for using the syringe, included with the package leaflet, must be followed carefully. Trulicity should not be used if particles appear or if the solution is cloudy and/or coloured. Trulicity that has been frozen must not be used. 7. Marketing authorisation holder Eli Lilly Nederland B.V., Grootslag 1-5, NL-3991 RA Houten, The Netherlands. 8. Marketing authorisation number(s) Pre-filled pen EU/1/14/956/001 0.75mg, pack of 2 pre-filled pens EU/1/14/956/002 0.75mg, pack of 4 pre-filled pens EU/1/14/956/003 0.75 mg, pack of 3 x 4 pre-filled pens EU/1/14/956/006 1.5mg, pack of 2 pre-filled pens EU/1/14/956/007 1.5mg, pack of 4 pre-filled pens EU/1/14/956/008 1.5mg, pack of 3 x 4 pre-filled pens Pre-filled syringe EU/1/14/956/004 0.75 mg, pack of 4 pre-filled syringes EU/1/14/956/005 0.75 mg, pack of 3 x 4 pre-filled syringes EU/1/14/956/009 1.5 mg, pack of 4 pre-filled syringes EU/1/14/956/010 1.5 mg, pack of 3 x 4 pre-filled syringes 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 21 November 2014 10. Date of revision of the text Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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Trulicity(dulaglutide Solution for injection)简介:
英文药名:Trulicity(dulaglutide Solution for injection)
中文药名:度拉糖肽注射剂
生产厂家:礼来制药药品介绍每周一次即用型糖尿病注射药物Trulicity(中文药名:度拉糖肽)获欧盟上市批准Trulici ... 责任编辑:admin |
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