The pharmacological action
The mechanism of action
Dulaglutid glucagon-like peptide is an agonist of receptors l (GLP-1) is long-acting. Its molecule consists of two identical chains connected by disulfide bonds, each of which comprises an analog of the modified human GLP-1 covalently linked to a heavy chain fragment (Fc) of a modified human immunoglobulin G4 (IgG4) with a small polypeptide chain. Part dulaglutida which is an analogue of GLP-1, approximately 90% homologous with native human GLP-1. The half-life (t1 / 2) of native human GLP-1 due to cleavage by dipeptidyl peptidase-4 (DPP-4) and the renal clearance is 1.5-2 minutes. In contrast to the native GLP-1 dulaglutid resistant to cleavage by DPP-4 and has a high resolution, which slows the absorption and reduces renal clearance. These structural features provide a soluble form of the half-life and duration of 4.7 days, so that the drug is suitable for subcutaneous administration of 1 times a week. In addition, dulaglutida molecule has been created in order to reduce the immune response mediated by the Fc-receptor and reduce the immunogenic potential.
Hypoglycemic effect dulaglutida caused by several mechanisms of action of GLP-1. At higher concentrations of glucose dulaglutid increases intracellular cyclic adenosine monophosphate (cAMP) in the beta cells of the pancreas, which leads to increased insulin secretion. Dulaglutid suppresses excessive glucagon secretion in patients with type 2 diabetes, resulting in reduced hepatic glucose release. In addition, dulaglutid slows the rate of gastric emptying.
Patients with type 2 diabetes, starting with the first administration, dulaglutid improves glycemic control by steady reduction in fasting blood glucose concentrations before meal and after a meal, which is maintained for a week before the next dose.
Pharmacodynamic dulaglutida study showed that patients with type 2 diabetes was observed restoring first phase insulin secretion to the values observed in healthy subjects receiving placebo and improved second-phase insulin secretion in response to intravenous bolus administration of glucose.
In the same study it was also shown that a single administration at a dose of 1.5 dulaglutida mg maximal insulin secretion increased β-cells of the pancreas and improves the function of β-cells in patients with type 2 diabetes compared to placebo.
The pharmacokinetic profile and the corresponding pharmacodynamic profile dulaglutida allows preparation administered 1 time per week.
Clinical efficacy and safety
Safety and efficacy dulaglutida evaluated during 6 randomized controlled trials phase III, which involved 5171 patients with type 2 diabetes. Of these, 958 were under the age of 65 years, of which 93 were over the age of 75 years. These studies included 3136 patients who received dulaglutid, of which 1719 received dulaglutid at a dose of 1.5 mg 1 time per week, and in 1417 received dulaglutid at a dose of 0.75 mg 1 time per week. In all studies dulaglutid provides a clinically significant improvement in glycemic control, as measured by glycated hemoglobin (HbAlc).
Application dulaglutida monotherapy was studied in a clinical trial with an active control of the 52 weeks, compared with metformin. Efficacy dulaglutida when used in doses of 1.5 mg or 0.75 mg 1 time per week superior efficacy of metformin a dose of 1500-2000 mg / day in reducing HbAlc, and significantly more patients reached the target HbAlc < 7.0% and < 6.5% with dulaglutida in doses of 1.5 mg or 0.75 mg 1 time per week than in the metformin after 26 weeks.
Frequency documented cases of symptomatic hypoglycemia dulaglutida when applied at doses of 1.5 mg or 0.75 mg 1 time per week and when metformin was 0.62; 0.15 and 0.09 episodes / patient / year, respectively. Cases of severe hypoglycemia when used dulaglutida not observed.
therapy in combination with metformin
Safety and efficacy dulaglutida evaluated in a placebo-controlled and active-controlled clinical study (sitagliptin 100 mg / d) Time duration 104, wherein all drugs used in combination with metformin. Application dulaglutida at doses of 1.5 mg or 0.75 mg 1 time per week over 52 weeks resulted in a greater reduction in HbAlc compared with sitagliptin, with significantly more patients in the application dulaglutida reached target HbAlc < 7.0% and < 6.5%. These effects persisted until the end of the study (104 weeks),.
Frequency documented symptomatic hypoglycemia dulaglutida when applied at doses of 1.5 mg or 0.75 mg once every 1 week and when applied sitagliptin was 0.19; 0.18 and 0.17 episodes / patient / year, respectively. Cases of severe hypoglycemia when used dulaglutida not observed.
Safety and efficacy dulaglutida also assessed during the active-controlled study in comparison with liraglutide at a dose of 1.8 mg / day (initial dose 0.6 mg / day, after 1 week dose was increased to 1.2 mg / day, followed by 2 week – to 1.8 mg / day) lasting 26 weeks; both drugs are used in combination with metformin. Application dulaglutida at a dose of 1.5 mg 1 per week resulted in a comparable decrease in HbAlc, and the number of patients achieving target HbAlc < 7.0% and < 6.5%, compared with liraglutide therapy.
Frequency of documented symptomatic hypoglycaemia when used dulaglutida at a dose of 1.5 mg 1 time per week was 0.12 episodes / patient / year, and the application of liraglutide – 0.29 episodes / patient / year. The incidence of severe hypoglycemia was observed.
therapy in combination with metformin and a sulfonylurea
In a study of active control of the duration of 78 weeks dulaglutid compared with insulin glargine, both drugs were used in combination with metformin and a sulfonylurea. After 52 weeks use dulaglutida at a dose of 1.5 mg 1 per week resulted in a significantly greater decrease in HbAlc compared to insulin glargine, and which persisted through 78 weeks; whereas lowering HbAlc dulaglutida when applied in a dose of 0.75 mg once a week was comparable with the reduction in HbAlc with insulin glargine. Under application dulaglutida at a dose of 1.5 mg significantly more patients reached the target HbAlc < 7.0% and < 6.5% after 52 and after 78 weeks compared to group application glargine insulin.
Frequency documented cases of symptomatic hypoglycemia dulaglutida when applied at doses of 1.5 mg or 0.75 mg 1 time per week and when applied insulin glargine was 1.67; 1.67 and 3.02 episodes / patient / year, respectively. When applied in a dose of 1.5 dulaglutida mg 1 time per week and when applied insulin glargine observed same number of severe hypoglycemia (2 cases).
therapy in combination with metformin and pioglitazone
In a placebo-controlled studies and studies with active control (exenatide dose was 5 mg 2 times a day during the first 4 weeks, and 10 mg 2 times a day, etc.), the application of both drugs in combination with metformin and pioglitazone when administered dulaglutida doses 1.5 mg or 0.75 mg once a week 1 demonstrated significantly greater reduction in HbAlc relative to placebo and exenatide, which was accompanied by a significantly large number of patients achieving target HbAlc < 7.0% and < 6.5%
Frequency documented cases of symptomatic hypoglycemia dulaglutida when applied at doses of 1.5 mg or 0.75 mg once a week 1 and exenatide 2 times a day, was 0.19; 0.14 and 0.75 episodes / patient / year, respectively. When applying dulaglutida no cases of severe hypoglycemia when exenatide was observed 2 cases of severe hypoglycemia.
therapy in combination with insulin, with or without metformin, metformin
In a clinical study, patients who received insulin 1 or 2 times a day before the study was terminated prior regimen and were randomized into groups dulaglutida applying 1 time per week or insulin glargine once daily 1; both modes of therapy were conducted in conjunction with the prandial insulin lispro, administered 3 times a day in combination with metformin or without metformin. After 26 weeks dulaglutida efficiency when used in doses of 1.5 mg or 0.75 mg 1 time per week superior effectiveness of insulin glargine in reducing HbAlc, the same effect was maintained and 52 week study. The mean change in HbAlc for groups of applications dulaglutida at a dose of 1.5 mg or 0.75 mg 1 time per week and the group of insulin glargine 1 time per day was as follows: -1.64% [p < 0.025], -1.59% [p < 0.025] and -1.41% with
After n / k administration to patients with type 2 diabetes, the maximum concentration (Cmax) in plasma dulaglutida observed after 48 hours. After repeated subcutaneous administration dulaglutida 1.5 mg in patients with type 2 diabetes, mean Cmax and area under the curve, “concentration- time »(AUC) was approximately 114 ng / ml and 14,000 NMS / ml respectively. The equilibrium concentration in plasma was observed after 2-4 weeks dulaglutida administration at a dose of 1.5 mg 1 time per week. Concentration after n / k dulaglutida a single dose (1.5 mg) in the region of the abdomen, thigh or shoulder were comparable. Mean absolute bioavailability dulaglutida after a single s / c injection at a dose of 1.5 mg or 0.75 mg was 47% and 65% respectively.
After n / k dulaglutida administration at doses of 0.75 mg or 1.5 mg in patients with type 2 diabetes at steady state mean Vd was approximately 19.2 L and 17.4 L, respectively.
It is believed that dulaglutid broken down into its constituent amino acids through the main path of protein catabolism.
Average clearance dulaglutida humans at steady state after administration in doses of 0.75 mg or 1.5 mg was 0.073 L / h and 0.107 L / hr respectively, from T1 / 2 4.5 and 4.7 days, respectively.
Special patient groups
Elderly patients (over 65 years)
Age of the patient did not have a clinically significant effect on the pharmacokinetic and pharmacodynamic properties dulaglutida.
Gender and race
Gender and race do not have a clinically meaningful effect on the pharmacokinetics dulaglutida.
The body weight or body mass index
The pharmacokinetic analysis showed a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutilom therapy, but no clinically significant effect of body weight or BMI on glycemic control were observed.
Patients with impaired renal function
Pharmacokinetics dulaglutida assessed during clinical pharmacological studies, in general, it was similar in healthy participants, and in patients with renal dysfunction ranging from mild to severe (creatinine clearance < 30 ml / min), including end-stage renal failure (during hemodialysis ). In clinical studies dulaglutida safety profile in patients with impaired renal function average degree was similar to the safety profile of the general population of patients with type 2 diabetes. These studies did not include patients with severe renal impairment, or with end-stage renal failure.
Patients with hepatic impairment
Dulaglutida pharmacokinetics were assessed during clinical pharmacological studies in which patients with impaired liver function, a statistically significant decrease in the mean values Cmax and AUC by 30% and 33%, respectively, compared to healthy patients. With deteriorating liver function while achieving increased Cmax (tmax) dulaglutida. Pharmacokinetic parameters dulaglutida not depend on the degree of liver dysfunction. Such changes were not considered clinically significant.
Dulaglutida pharmacokinetic studies have not been conducted in children.
Eli Lilly and Company / Eli Lilly Italy SpA, USA
Hypoglycemic drugs. Glucagon receptor agonist.
The drug Trulisiti ™ is shown in adult patients with type 2 diabetes mellitus to improve glycemic control in the form of:
If diet and exercise do not provide the desired glycemic control in patients who have not shown the use of metformin due to intolerance or contraindications.
In combination with other hypoglycemic drugs, including insulin, if these preparations together with diet and exercise do not provide the desired glycemic control.
– hypersensitivity to active or any of the excipients included in the formulation;
– type 1 diabetes;
– diabetic ketoacidosis;
– severe renal dysfunction;
– Chronic heart failure;
– the period of breast-feeding;
– serious diseases of the gastrointestinal tract, including severe gastroparesis;
– acute pancreatitis;
-. Children under 18 years
Precautions: in patients receiving oral medications that require rapid absorption in the gastrointestinal tract; in patients aged 75 years and older.
In the course of clinical studies phases II and III patients received 4006 dulaglutid as monotherapy or in combination with other hypoglycemic drugs. The most common adverse reactions in clinical studies were reactions from the gastrointestinal tract, including nausea, vomiting and diarrhea. In general, these reactions were mild or moderate and transient but nature. The following adverse reactions were detected in the evaluation of clinical trials Phase II and III: they are in accordance with a lesion of organs and organ systems in order of decreasing frequency (very often: > 1/10: often: > 1/100 – < 1/10: infrequently: > 1/1000 – < 1/100: seldom: > 1/10000 – < 1/1000; rarely: < 1/10000). Within each category adverse reactions are presented in order of decreasing frequency.
Description of individual adverse reactions
In applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week as a monoterapni or in combination with metformin or metformin and pioglitazone frequency documented symptomatic hypoglycemia ranged from 5.9% to 10.9% or from 0.14 to 0.62 events / patient / year incidence of severe hypoglycemia were reported. In applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week in combination with derivatives sulfonilmocheviiy (plus metformin) documented the frequency of symptomatic hypoglycemia was 39.0% and 40.3%, or 1.67 and 1.67 events / patient / year, respectively. The frequency of severe hypoglycemic events was 0% and 0.7%, or 0.00 and 0.01 events / patient / year, respectively. In applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week in combination with prandial insulin hypoglycemia rate was 85.3% and 80.0% or 35.66 and 31.06 events / patient / year, respectively. Frequency phenomena severe hypoglycemia was 2.4% and 3.4% or 0.05 and 0.06 events / patient / year, respectively.
Adverse reactions from the gastrointestinal tract
The aggregate reporting events from the gastrointestinal tract for a period of up to 104 weeks in applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week, respectively, included nausea (12.9% and 21.2%), diarrhea (10.7% and 13.7%) and vomiting ( 6.9% and 11.5%). Usually they had mild or moderate severity, their maximum frequency observed during the first 2 weeks of treatment, and declined rapidly for the next 4 weeks, after which the rate remained relatively constant. At clinical-pharmacological studies conducted in patients with type 2 diabetes and continued until 6 weeks, most phenomena of the gastrointestinal tract were noted during the first 2-3 days after the first dose, their frequency was reduced when using the following doses.
The frequency of acute pancreatitis in clinical trials Phase II and III amounted to 0.07% with dulaglutida compared to 0.14% for placebo and 0.19% with the comparison preparations, if additional base hypoglycemic therapy or without it. Pancreatic enzymes Application dulaglutida related to the average increase in the activity of pancreatic enzymes (lipase and / or pancreatic amylase) in 11-21% compared with baseline. In the absence of other signs and symptoms of acute pancreatitis, increased activity of enzymes of the pancreas is not a prognostic factor for the development of acute pancreatitis.
The increase in heart rate
In applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week there was a slight increase in the mean heart rate by 2-4 bpm (beats / min) and the frequency of sinus tachycardia at 1.3% and 1.4% respectively, which was accompanied by an increase in comparison from baseline in > 15 beats / min. Degree AV block I / increase PR interval dulaglutida When used in doses of 0.75 mg or 1.5 mg 1 time per week there was a slight increase in the mean PR interval of 2-3 ms, compared to baseline, frequency and degree atrioventricular block I to 1.5% and 2.4%, respectively.
In clinical trials, application dulaglutida accompanied by the identification appearing during antibody therapy to dulaglutidu a frequency of 1.6%, indicating that the structural changes in the GLP-1 and modified portions IgG4 in dulaglutida molecule along with high homology to native GLP-1 and native IgG4 minimize the risk of an immune response during therapy dulaglutidom. Patients who developed antibodies to dulaglutidu usually have low antibody titers; Nevertheless, despite the small number of patients who have antibodies to dulaglutidu formed, evaluation phase III clinical trials revealed no apparent effect on antibody dulaglutidu change in the HbAlc.
In clinical studies, phase II and III hypersensitivity phenomena system (severe urticaria, extensive rash, swelling of face, mouth edema) were observed in 0.5% of patients who received dulaglutid. None of the patients with systemic hypersensitivity did not develop antibodies to dulaglutidu.
The reactions at the injection site
Injection site reactions were observed in 1.9% of patients receiving dulaglutid. Potentially immune-mediated adverse effects at the injection site (e.g., rash, erythema) occurred in 0.7% of patients and was generally mild.
The early termination of participation in clinical trials due to an adverse event
During studies lasting 26 weeks, the frequency of premature discontinuation due to adverse events was 2.6% (0.75 mg 1 time per week) and 6.1% (1.5 mg 1 per week) when using dulaglutida compared to 3.7% with placebo. Throughout the study (up to 104 weeks), the frequency of early discontinuation due to adverse events in the application dulaglutida was 5.1% (0.75 mg 1 time per week) and 8.4% (1.5 mg 1 per week). The most common adverse events that led to early discontinuation Group use dulaglutida at doses of 0.75 mg or 1.5 mg 1 per week, were nausea (1.0% and 1.9%), diarrhea (0.5% and 6%) and vomiting (0.4% and 0.6%), mostly such reactions occurred within the first 4-6 weeks of therapy.
How to accept, acceptance rate and dosage
The drug should be administered Trulisiti ™ s / c in the abdomen, thigh or upper arm. The drug should not be administered in / in or / m. The drug can be administered at any time of the day regardless of the meal.
Recommended dosage is 0.75 mg 1 time per week.
The recommended dose is 1.5 mg of 1 times a week.
In patients aged 75 years and older the recommended initial dose is 0.75 mg 1 time per week.
When added to the current dulaglutida metformin and / or pioglitazone and metformin / pioglitazone or can be continued at the same dose. In addition to current therapy dulaglutida sulfonylureas or insulin may be required prandial lowering sulfonylurea dose or prandial insulin to reduce the risk of hypoglycemia.
In addition, blood glucose control for the dose adjustment is not required dulaglutida. Additional glycemic control may be required to correct dosage of the sulfonylurea compound or prandial insulin.
If Trulisiti ™ drug dose was missed, it should be introduced as soon as possible, if before administration of the next scheduled dose is left for at least 3 days (72 hours). If prior to the introduction of the next scheduled dose is less than 3 days (72 hours) is necessary to pass the preparation and administration of the next dose to enter, in accordance with the schedule. In each case, patients can resume normal injection one time per week. Day of administration can be changed if necessary, provided that the last dose was administered at least 3 days (72 hours) ago.
Elderly patients (over 65 years)
No dose adjustment based on age is not required. However, experience therapy patients aged > 75 years is very limited, in these patients the recommended initial dose is 0.75 mg 1 time per week.
Patients with impaired renal function
Patients with impaired renal function, mild or moderate dose adjustment is required. There is very limited experience dulaglutida in patients with severe renal impairment (estimated glomerular filtration rate (GFR) < 30 ml / min / 1.73m2) or end-stage renal failure, however dulaglutida use is not recommended in this population.
Patients with hepatic impairment
Patients with impaired hepatic function dose adjustment is not required.
Safety and effectiveness of dulaglutida in children under 18 years of age has not been established. Data not available.
In the dark place at a temperature of 2 to 8 ° C; Do not freeze.
Do not use the drug if it has been frozen.
Acquired drug in pharmacy may be stored at a temperature not higher than 30 ° C for 14 days.
Keep out of the reach of children.
Dulaglutid causes a delay in gastric emptying rate, therefore, has the ability to influence the absorption of oral preparations, while the application. Dulaglutid should be used with caution in patients receiving oral medications that require rapid absorption in the gastrointestinal tract. Delayed gastric emptying speed may slightly increase the exposure sustained-release preparations by increasing the time of release of the drug.
Dulaglutid not recommended for use in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Violations by the gastrointestinal tract
The content of sodium
Effects on ability to drive vehicles and mechanisms
Overdose symptoms dulaglutida in clinical trials include disorders of the gastrointestinal tract, and hypoglycemia.
Treatment. In the case of an overdose should start symptomatic therapy according to the clinical signs and symptoms.
Do not use beyond the expiration date printed on the package.