Trulisity - instructions for use, dose, side effects, contraindications

Active substanceDulaglutideDulaglutide

Similar drugsTo uncover

Trulisiti ™

solution PC

Eli Lilly East SA Switzerland

Dosage form: & nbspRAzvor for subcutaneous administration.

Composition:

In 0.5 ml of the preparation contains:

For a dosage of 0.75 mg:

Active substance: dulaglutide 0.75 mg;

Excipients: citric acid anhydrous 0.07 mg; mannitol 23.2 mg; polysorbate 80 (vegetable) 0.10 mg; sodium citrate dihydrate 1.37 mg; water for injections q.s. up to 0.5 ml.

For a dosage of 1.5 mg:

Active substance: dulaglutide 1.5 mg;

Excipients: citric acid anhydrous 0.07 mg; mannitol 23.2 mg; polysorbate 80 (vegetable) 0.10 mg; sodium citrate dihydrate 1.37 mg; water for injections q.s. up to 0.5 ml.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:hypoglycemic agent - a glucagon-like receptor polypeptide agonist

ATX: & nbsp

A.10.B.X Other hypoglycemic drugs

Pharmacodynamics:

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. Its molecule consists of two identical chains connected by disulfide bonds, each of which contains an analog of modified human GLP-1. covalently bound to a fragment of the heavy chain (Fc) of a modified human immunoglobulin G4 (IgG4) using a small polypeptide chain.Part of dulaglutide, which is an analog of GLP-1, is approximately 90% homologous to native human GLP-1. The half-life (t_1/2) of native human GLP-1 due to cleavage of dipeptidyl peptidase-4 (DPP-4) and renal clearance is 1.5-2 minutes. In contrast to the native GLP-1 dulaglutide is resistant to splitting of DPP-4 and has a large size, which slows down absorption and reduces renal clearance. Such structural features provide a soluble form and a half-life of 4.7 days, which makes the drug suitable for subcutaneous administration once a week. In addition, the dulaglutide molecule was created to reduce the immune response mediated Fcγreceptor, and reduce immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. With an increased concentration of glucose dulaglutide increases the content of intracellular cyclic adenosine monophosphate (cAMP) in beta cells of the pancreas, which leads to an increase in the secretion of insulin. Dulaglutide suppresses the excessive secretion of glucagon in patients with type 2 diabetes mellitus,which leads to a decrease in the release of glucose by the liver. Besides, dulaglutide slows the rate of emptying the stomach.

Pharmacodynamics

In patients with type 2 diabetes, starting with the first injection, dulaglutide improves glycemic control by a steady decrease in fasting blood glucose, before meals and after meals, which is maintained for a week before the next dose.

A pharmacodynamic study of dulaglutide showed that in patients with type 2 diabetes mellitus, the first phase of insulin secretion was restored to a value observed in healthy subjects receiving a placebo and an improvement in the second phase of insulin secretion in response to intravenous bolus glucose administration. The same study also showed that a single dose of dulaglutide 1.5 mg increased the maximum secretion of insulin with pancreatic β cells and improved β-cell function in patients with type 2 diabetes compared with placebo.

The pharmacokinetic profile and the corresponding pharmacodynamic profile of dulaglutide allow the drug to be administered once a week.

Clinical efficacy and safety

Control of glycemia

The safety and efficacy of dulaglutide was evaluated in 6 randomized controlled phase III trials in which 5171 patients with type 2 diabetes mellitus participated. Of these, 958 were over the age of 65, of which 93 were over the age of 75 years. These studies included 3136 patients who received dulaglutide, of which 1719 were received dulaglutide in a dose of 1.5 mg once a week, and 1417 received dulaglutide in a dose of 0.75 mg once a week. In all studies dulaglutide provided a clinically significant improvement in glycemic control, which was assessed by glycated hemoglobin (HbAlc).

Monotherapy

The use of dulaglutide in monotherapy was studied in a clinical trial with active control of 52 weeks in comparison with metformin. The effectiveness of dulaglutide when used at doses of 1.5 mg or 0.75 mg once a week exceeded the efficacy of metformin at a dose of 1500-2000 mg / day in terms of reduction HbAlc and significantly more patients reached the target HbAlc <7.0% and ≤ 6.5% with dulaglutide at doses of 1.5 mg or 0.75 mg once a week than with metformin after 26 weeks.

Frequencydocumented cases of symptomatic hypoglycemia with dulaglutide in doses of 1.5 mg or 0.75 mg once a week, and when metformin was 0.62; 0.15 and 0.09 episodes / patient / year, respectively. Cases of severe hypoglycemia were not observed with dulaglutide.

Therapy in combination with metformin

The safety and efficacy of dulaglutide was evaluated in a placebo-controlled and actively-controlled clinical trial (sitagliptin 100 mg / day) for 104 weeks, in which all drugs were used in combination with metformin. The use of dulaglutide in doses of 1.5 mg or 0.75 mg once a week after 52 weeks resulted in a greater decrease HbAlc compared with the use of sitagliptin, while a significantly greater number of patients with dulaglutide reached the target HbAlc <7.0% and ≤ 6.5%. These effects were maintained until the end of the study (104 weeks).

The incidence of documented symptomatic hypoglycemia with dulaglutide in doses of 1.5 mg or 0.75 mg once a week and with the use of sitagliptin was 0.19; 0.18 and 0.17 episodes / patient / year, respectively. Cases of severe hypoglycemia were not observed with dulaglutide.

The safety and efficacy of dulaglutide was also evaluated in an actively controlled study compared with 1.8 mg / day of liraglutide (initial dose 0.6 mg / day, after 1 week, the dose was raised to 1.2 mg / day, and then 2 week - up to 1.8 mg / day) with a duration of 26 weeks; both drugs were used in combination with metformin. The use of dulaglutide in a dose of 1.5 mg once a week led to a comparable decrease HbAlc and the number of patients achieving the target HbAlc <7.0% and ≤ 6.5%, compared with therapy with liraglutide.

The frequency of documented symptomatic hypoglycemia with dulaglutide 1.5 mg once a week was 0.12 episodes / patient / year, and with liraglutide 0.29 episodes / patient / year. Cases of severe hypoglycemia were not observed.

Therapy in combination with metformin and sulfonylurea derivatives

In a study with active control of 78 weeks dulaglutide compared with insulin glargine, both drugs were used in combination with metformin and sulfonylurea derivatives. After 52 weeks, the use of dulaglutide in a dose of 1.5 mg once a week led to a significantly greater decrease HbAlc compared with the use of insulin glargine, which persisted after 78 weeks; while a decrease HbAlc when dulaglutide was used at a dose of 0.75 mg once a week was comparable with a decrease HbAlc when using insulin glargine. In the group of dulaglutide 1.5 mg use, significantly more patients reached the target HbAlc <7.0% or ≤6.5% at 52 and 78 weeks compared with the group of insulin glargine.

The incidence of documented cases of symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once a week and with insulin glargine was 1.67; 1.67 and 3.02 episodes / patient / year, respectively. When dulaglutide was used at a dose of 1.5 mg once a week and with the use of insulin glargine, the same number of cases of severe hypoglycemia was observed (in 2 cases).

Therapy in combination with metformin and pioglitazone

In placebo-controlled studies and studies with active control (the dose of exenatide was 5 μg 2 times a day for the first 4 weeks and 10 μg twice a day), when both drugs were used in combination with metformin and pioglitazone, with dulaglutide in doses of 1.5 mg or 0.75 mg once a week showed a significantly more significant decrease HbAlc compared with placebo and exenatide, which was accompanied by a significantly larger number of patients achieving the target HbAlc <7.0% or ≤ 6.5%.

The incidence of documented cases of symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once a week and with exenatide 2 times a day was 0.19; 0.14 and 0.75 episodes / patient / year, respectively. When dulaglutide was used, no cases of severe hypoglycemia were observed, with the use of exenatide there were 2 cases of severe hypoglycemia.

Therapy in combination with insulin, with metformin or without metformin

In a clinical study, patients who received insulin 1 or 2 times a day prior to the study discontinued the previous regimen and were randomized to dulaglutide once a week or insulin glargine once a day; Both regimens were performed in combination with prandial insulin lispro. administered 3 times a day in combination with metformin or without metformin. After 26 weeks, the efficacy of dulaglutide when administered at doses of 1.5 mg or 0.75 mg once a week was superior to insulin glargine in reducing HbAlc, the same effect persisted until the 52nd week of the study. Average change HbAlc for groups of dulaglutide 1.5 mg or 0.75 mg once a week and insulin glargine once a day was -1.64% [p <0.025], -1.59% [p <0.025 ] and -1.41%, respectively, after 26 weeks; -1.48% [p <0.025], -1.42% [p <0.025] and -1.23%, respectively, after 52 weeks. More patients with dulaglutide reached the target HbAlc <7.0% or ≤6.5% at 26 weeks and <7.0% at 52 weeks than with insulin glargine.

The incidence of documented cases of symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once a week and with insulin glargine was 31.06; 35.66 and 40.95 episodes / patient / year, respectively. 10 patients reported severe hypoglycemia with dulaglutide 1.5 mg once a week, 7 patients with dulaglutide 0.75 mg once a week, and 15 patients with insulin glargine.

Concentration of blood glucose on an empty stomach

The use of dulaglutide resulted in a significantly greater decrease in fasting blood glucose compared with baseline. The main effect in terms of fasting blood glucose was observed after 2 weeks.Improvement in the concentration of blood glucose on an empty stomach persisted for the longest period of the study - 104 weeks.

Concentration of blood glucose after meals (postprandial glycemia)

The use of dulaglutide resulted in a significant decrease in mean post-prandial glycemia compared with baseline (the change in glycemia from baseline to the primary time point was -1.95 mmol / L to -4.23 mmol / L).

Function of beta cells of the pancreas

The results of clinical studies showed an improvement in the function of beta cells of the pancreas with dulaglutide, as determined using a homeostatic assessment model (HOMA2-% B). The effect on beta cell function persisted for the longest period of the study - 104 weeks.

Body mass

When dulaglutide was used at a dose of 1.5 mg once a week, there was a steady decrease in body weight during the study (the change in the mean value from the initial value to the final time point was -0.35 kg to 2.90 kg). The change in body weight with dulaglutide 0.75 mg once a week varied from 0.86 kg to -2.63 kg.A decrease in body weight was observed in patients who received dulaglutide, regardless of the appearance of nausea, although the decrease was numerically larger in the group of patients who experienced nausea.

results, based on patient interviews

Dulaglutide significantly improved the overall satisfaction rate of therapy compared with exenatide therapy 2 times a day. In addition, the incidence of hyperglycemia and hypoglycemia with dulaglutide was significantly lower than with exenatide twice daily.

Blood pressure (BP)

The effect of dulaglutide on blood pressure was evaluated in a study involving 755 patients with type 2 diabetes using ambulatory blood pressure monitoring. Dulaglutide therapy was accompanied by a decrease in systolic blood pressure (a difference of -2.8 mmHg compared with placebo) at 16 weeks. Differences in diastolic blood pressure were not observed. Similar results for systolic and diastolic blood pressure were shown at the end point of the study - 26 weeks.

Risk for the cardiovascular system

According to the results of the meta-analysis of Phase II and III studies, 51 patients (dulaglutide: 26 (N= 3885); all comparisons: 25 (N= 2125)), at least one phenomenon was observed from the cardiovascular system (death caused by cardiovascular disorders, non-lethal myocardial infarction, non-lethal stroke, or hospitalization due to unstable angina). The results showed that when dulaglutide was used, the risk of cardiovascular disorders did not increase as compared with comparison therapy therapy (risk ratio: 0.57; confidence interval: (0.30; 1.10)).

Pre-clinical safety

Preclinical studies of dulaglutide did not reveal a particular risk to a person according to standard studies of pharmacological safety and toxicity of multiple doses.

During a 6-month carcinogenicity study, no oncogenic response was observed in transgenic mice. In a 2-year study of carcinogenicity in rats with a concentration of dulaglutide, ≥7 times the therapeutic dose of dulaglutide in humans, 1.5 mg once a week, dulaglutide caused a significant dose-dependent increase in the frequency of C-cell tumors of the thyroid gland (adenomas and carcinomas).The significance of such results for a person at the moment is not known.

In fertility studies at doses that were associated with a decrease in food intake and weight gain in the mother, a decrease in the number of yellow bodies and an increase in the duration of the estrous cycle were observed; However, there were no effects on fertility and conception rates or on embryonic development. In studies of reproductive toxicity in rats and rabbits, the formation of the skeleton and fetal growth decreased with exposure to dulaglutide, which was 11-44 times greater than the clinical one, but congenital anomalies were not observed. The introduction of dulaglutide to rats during the period of pregnancy and lactation caused a memory deficit in female offspring at an exposure that was 16 times higher than the proposed clinical exposition.

Pharmacokinetics:

Suction

After subcutaneous administration to patients with type 2 diabetes mellitus, the maximum concentration (C_mOh) dulaglutide in plasma is observed after 48 hours. After repeated subcutaneous administration of dulaglutide in a dose of 1.5 mg in patients with type 2 diabetes mellitus, the average C_mOh and the area under the "concentration-time" curve (AUC) were approximately 114 ng / ml and 14,000 ng / ml, respectively. The equilibrium concentration in plasma was observed after 2-4 weeks of administration of dulaglutide at a dose of 1.5 mg once a week. Concentrations after subcutaneous administration of a single dose of dulaglutide (1.5 mg) into the abdominal, hip or shoulder regions were comparable. The mean absolute bioavailability of dulaglutide after a single subcutaneous injection at a dose of 1.5 mg or 0.75 mg was 47% and 65%, respectively.

Distribution

After subcutaneous administration of dulaglutide at doses of 0.75 mg or 1.5 mg in patients with type 2 diabetes mellitus in an equilibrium state, the mean volume of distribution was approximately 19.2 1 and 17.4 1, respectively.

Metabolism

It is believed that dulaglutide is split into constituent amino acids through the main pathways of protein catabolism.

Excretion

The average clearance of dulaglutide in humans in the equilibrium state after administration at doses of 0.75 mg or 1.5 mg was 0.073 l / h and 0.107 l / h, respectively, with a period half-lives of 4.5 and 4.7 days, respectively.

Special patient groups

Patients of advanced age (over 65 years)

The patient's age had no clinically significant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide.

Sex and race

Sex and race did not have a clinically significant effect on the pharmacokinetics of dulaglutide.

Body weight or body mass index

Pharmacokinetic analysis showed a statistically significant feedback between body weight or body mass index (BMI) and dulaglutide therapy, but there was no clinically significant effect of body weight or BMI on glycemic control.

Patients with impaired renal function

The pharmacokinetics of dulaglutide were evaluated during clinical pharmacological the study was generally similar in healthy participants and in patients with impaired renal function from mild to severe (creatinine clearance <30 mL / min), including the terminal stage of renal failure (in hemodialysis). In clinical studies, the safety profile of dulaglutide in patients with impaired renal function of the middle degree was similar to the safety profile in the general population of patients with type 2 diabetes mellitus. These studies did not include patients with severe renal dysfunction or with terminal renal failure.

Patients with impaired hepatic function

The pharmacokinetics of dulaglutide were evaluated during clinical pharmacological a study in which a statistically significant decrease in the mean C_mOh and AUC by 30% and 33%, respectively, compared with healthy patients. With worsening liver function, the time to achieve C_max (t_max) dulaglutide. The pharmacokinetic indices of dulaglutide did not depend on the degree of impaired hepatic function. Such changes were not considered clinically significant.

Children

Studies of the pharmacokinetics of dulaglutide in children have not been conducted.

Indications:

Trulisiti^™ is shown in adult patients with type 2 diabetes mellitus in order to improve glycemic control in the form of:

- Monotherapy

In the event that diet and exercise do not provide the necessary glycemic control in patients who are not shown the use of metformin due to intolerance or contraindications.

- Combined therapy

In combination with other hypoglycemic drugs, including insulin, if these drugs, along with diet and exercise, do not provide the necessary glycemic control.

Contraindications:

- Hypersensitivity to the active or any of the excipients that make up the drug;

- Type 1 diabetes mellitus;

- diabetic ketoacidosis;

- severe renal dysfunction;

- Chronic heart failure;

- Pregnancy;

- the period of breastfeeding;

- Severe diseases of the gastrointestinal tract, incl. severe paresis of the stomach;

acute pancreatitis;

- Children under 18 years.

Carefully:

Patients taking oral medications that require rapid absorption in the gastrointestinal tract; in patients aged 75 years and older.

Pregnancy and lactation:

Pregnancy

Data on the use of dulaglutide in pregnant women are absent or their volume is limited. Studies on animals have shown the presence of reproductive toxicity, therefore the use of dulaglutide is contraindicated during pregnancy.

Breast-feeding

Data on the penetration of dulaglutide into breast milk are absent. It is impossible to exclude the risk for newborns / infants. The use of dulaglutide during breastfeeding is contraindicated.

Dosing and Administration:

Trulisiti^™ should be administered subcutaneously in the abdomen, thigh or shoulder area.The drug can not be administered intravenously or intramuscularly.

The drug can be administered at any time of the day, regardless of food intake.

Monotherapy

The recommended dose is 0.75 mg once a week.

Combination Therapy

The recommended dose is 1.5 mg once a week.

Patients aged 75 years and older the recommended initial dose of the drug is 0.75 mg once a week.

When dulaglutide is added to the current therapy with metformin and / or pioglitazone, metformin and / or pioglitazone can be continued at the same dose.

When dulaglutide is added to current therapy with sulfonylurea derivatives or prandial insulin, a dose reduction of the sulfonylurea derivative or prandial insulin may be required to reduce the risk of developing hypoglycemia.

In addition, glycemic control is not required to correct the dose of dulaglutide. Additional glycemic control may be required to correct the dose of sulfonylurea derivatives or prandial insulin.

Dose skip

If the dose of Trulisity^™ was missed, it should be administered as soon as possible, if at least 3 days (72 hours) remained before the next scheduled dose was administered.If before the next scheduled dose is left less than 3 days (72 hours), it is necessary to skip the injection and enter the next dose in accordance with the schedule. In each case, patients can resume the usual mode of administering the drug once a week.

The day of administration of the drug, if necessary, can be changed, provided that the last dose has been introduced at least 3 days (72 hours) ago.

Patients of advanced age (over 65 years)

Dose adjustment according to age is not required. However, the experience of treating patients aged ≥75 years is very limited, in such patients the recommended initial dose of the drug is 0.75 mg once a week.

Patients with impaired renal function

In patients with impaired renal function of mild or moderate severity, dose adjustment is not required. There is very limited experience with dulaglutide in patients with severe renal dysfunction (estimated glomerular filtration rate (GFR) <30 mL / min / 1.73 m²) or terminal stage of renal insufficiency, so the use of dulaglutide in this population is not recommended.

Patients with impaired hepatic function

In patients with impaired liver function, dose adjustment is not required.

Children

The safety and efficacy of dulaglutide in children under the age of 18 years is not established. No data available.

Side effects:

Security Profile Overview

In the course of Phase II and Phase III clinical trials, 4006 patients received dulaglutide in the form of monotherapy or in combination with other hypoglycemic drugs. The most frequent adverse reactions in clinical trials have been gastrointestinal reactions, including nausea, vomiting and diarrhea. In general, these reactions were mild or moderate and temporary in nature.

The following undesirable reactions were identified during the evaluation of the results of Phase II and Phase III clinical trials; they are listed in the table in accordance with the damage to organs and organ systems in order of decreasing frequency (very often: ≥1 / 10; often: ≥1 / 100 - <1/10; infrequent: ≥1 / 1000 - <1/100; rarely : ≥1 / 10000 - <1/1000, very rarely: <1/10000). Within each category, unwanted reactions are presented in order of decreasing frequency.

Table: Frequency of undesired reactions with dulaglutide

Organs and organ systems	Often	Often	Infrequently	Rarely
Disorders of metabolism and nutrition	Hypoglycemia * (when used in conjunction with prandial insulin, metformin^†or metformin and glimepiride)	Hypoglycemia * (when used as a monotherapy or in combination with metformin plus pioglitazone)
Violations from hand gastro-intestinal tract	Nausea, diarrhea, vomiting^†, abdominal pain^†	Loss of appetite, indigestion, constipation, flatulence, bloating, gastroesophageal reflux disease, eructation		Acute pancreatitis
Are common disorders and disorders at the site of administration		Weakness	Reactions in the place of reference
Laboratory and instrumental data		Sinus tachycardia, atrioventricular block (AVB) of the first degree

* Documented symptomatic hypoglycemia and blood glucose concentration ≤3.9 mmol / l.

^†Only for dulaglutide in a dose of 1.5 mg. The frequency of adverse reactions for dulaglutide at a dose of 0.75 mg corresponds to a lower category.

Description of individual adverse reactions

Hypoglycaemia

In applying dulaglutida at doses of 0.75 mg or 1.5 mg 1 time per week as a single agent or in combination with metformin or metformin and pioglitazone frequency documented symptomatic hypoglycemia ranged from 5.9% to 10.9% or from 0.14 up to 0.62 events / patient / year,there were no cases of severe hypoglycemia.

When dulaglutide is used in doses of 0.75 mg or 1.5 mg once a week in combination with sulfonylurea derivatives (plus metformin), the incidence of documented symptomatic hypoglycaemia was 39.0% and 40.3% or 1.67 and 1.67 events / patient / year, respectively. The incidence of severe hypoglycemia was 0% and 0.7%, or 0.00 and 0.01 events / patient / year, respectively.

When dulaglutide was used in doses of 0.75 mg or 1.5 mg once a week in combination with prandial insulin, the incidence of hypoglycemia was 85.3% and 80.0% or 35.66 and 31.06 events / patient / year, respectively. The incidence of severe hypoglycemia was 2.4% and 3.4% or 0.05 and 0.06 events / patient / year, respectively.

Undesirable reactions from the gastrointestinal tract

Comprehensive reporting of gastrointestinal events for up to 104 weeks with dulaglutide at doses of 0.75 mg or 1.5 mg once a 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 was noted during the first 2 weeks of therapy and rapidly decreased over the next 4 weeks, after which the frequency remained relatively constant.

In clinico-pharmacological studies, which were conducted with the participation of patients with type 2 diabetes and lasted up to 6 weeks, most of the phenomena from the gastrointestinal tract were noted within the first 2-3 days after the first dose, their frequency decreased with application following doses.

Acute pancreatitis

The incidence of acute pancreatitis in Phase II and Phase III clinical trials was 0.07% with dulaglutide compared with 0.14% with placebo and 0.19% with reference medications, with or without additional basic hypoglycemic therapy.

Enzymes of the pancreas

The use of dulaglutide is associated with an average increase in activity of pancreatic enzymes (lipase and / or pancreatic amylase) by 11-21% compared to baseline values. In the absence of other signs and symptoms of acute pancreatitis, an increase in the activity of pancreatic enzymes is not a prognostic factor for the development of acute pancreatitis.

Increased heart rate

When dulaglutide was used in doses of 0.75 mg or 1.5 mg once a week, there was a slight mean increase in the heart rate by 2-4 beats per minute (bpm) and a sinus tachycardia rate of 1.3% and 1.4 %, respectively,which was accompanied by an increase in comparison with the initial index by> 15 bpm.

Atrioventricular block of degree I / interval increase PR

When dulaglutide was used in doses of 0.75 mg or 1.5 mg once a week, there was observed small mean increase in interval PR on 2-3 ms, in comparison with the initial index, and the frequency of atrioventricular blockade of the 1st degree by 1.5% and 2.4% respectively.

Immunogenicity

In clinical trials, the use of dulaglutide was accompanied by the detection of antibodies to dulaglutide that appeared during therapy with a frequency of 1.6%, indicating that structural changes in GLP-1 and modified sites IgG4 in the molecule of dulaglutide along with high homology to native GLP-1 and native IgG4 minimize the risk of developing an immune response in dulaglutide therapy. Patients who developed antibodies to dulaglutide usually had a low antibody titer; nevertheless, despite the small number of patients who developed antibodies to dulaglutide, the evaluation of the results of Phase III clinical trials did not reveal an obvious effect of antibodies to dulaglutide on the change in the index HbAlc.

Hypersensitivity

In clinical studies of phase II and III, systemic hypersensitivity phenomena (severe urticaria, extensive rash, facial edema, edema of the lips) were observed in 0.5% of patients who received dulaglutide. None of the patients with systemic hypersensitivity developed antibodies to dulaglutide.

Reactions at the site of administration

Reactions at the site of administration were observed in 1.9% of patients who received dulaglutide. Potentially immuno-mediated adverse events at the injection site (eg, rash, erythema) were noted in 0.7% of patients and usually were mild.

Early termination of participation in clinical trials due to adverse events

In studies of 26 weeks, the rate of early termination for reasons of adverse events was 2.6% (0.75 mg once a week) and 6.1% (1.5 mg once a week) with dulaglutide compared with 3.7% with placebo. Throughout the study (up to 104 weeks), the frequency of premature termination due to adverse events with dulaglutide was 5.1% (0.75 mg once a week) and 8.4% (1.5 mg once a week) . The most frequent undesirable reactions,which led to early termination of participation in the groups of application of dulaglutide in doses of 0.75 mg or 1.5 mg once a week, were nausea (1.0% and 1.9%), diarrhea (0.5% and 0.6 %) and vomiting (0.4% and 0.6%), mainly such reactions were noted during the first 4-6 weeks of therapy.

Overdose:

Overdose Symptoms dulaglutide in clinical studies included disorders of the gastrointestinal tract and hypoglycemia.

Treatment

In case of an overdose, symptomatic therapy should be started in accordance with clinical signs and symptoms.

Interaction:

Dulaglutide causes a delay in the rate of gastric emptying, therefore, it has the ability to influence the absorption of oral preparations while simultaneously applying. Dulaglutide should be used with caution in patients taking oral medications that require rapid absorption in the gastrointestinal tract. The delay in the rate of gastric emptying may slightly increase the exposure of sustained-release preparations by increasing the release time of the preparation.

Paracetamol

After the administration of the first dose of dulaglutide in doses of 1 or 3 mg C_mOh paracetamol decreased by 36% and 50%, respectively, and the median t_max was achieved later (after 3 and 4 hours, respectively). After simultaneous application with dulaglutide in a dose of up to 3 mg in the equilibrium state, there was no statistically significant difference in the values AUC ₍o-12) (area under the concentration-time curve from 0 to 12 h), FROM_max or t_max paracetamol. When used with dulaglutide, dose adjustment of paracetamol is not required.

Atorvastatin

The simultaneous use of dulaglutide with atorvastatin caused a decrease in C_max and AUC_(0-∞) atorvastatin and its main metabolite o-hydroxy-altvastatin up to 70% and 21%, respectively. Average t_1/2atorvastatin and ohydroxyorthurovastatin after dulaglutide administration increased by 17% and 41%, respectively. Such changes are not considered clinically significant. When combined with dulaglutide, dose adjustment of atorvastatin is not required.

Digoxin

After simultaneous use of digoxin in the equilibrium state with two consecutive doses of dulaglutide, the total exposure (AUC_τ) and t_max digoxin did not change; FROM_mOh decreased by 22% as much as possible. It is believed that such a change has no clinical consequences. When used with dulaglutide, dose adjustment of digoxin is not required.

Hypotensive drugs

Simultaneous use of multiple dulaglutide doses with lisinopril in the equilibrium state did not cause clinically significant changes AUC or with_mOhlisinopril. Statistically significant delay t_max lisinopril for approximately 1 h was observed on the 3rd and 24th days of the study. With the simultaneous use of a single dose of dulaglutide with metoprolol AUC or with_mOh metoprolol increased by 19% and 32%, respectively. Although t_max metoprolol was achieved one hour later, such a change was not statistically significant. These changes were not considered significant from a clinical point of view; Thus, dose adjustment of lisinopril or metoprolol when used with dulaglutide is not required.

Warfarin

After simultaneous application with dulaglutide concentration S- and R-warfarin, and also C_mOh R-warfarin did not change, and C_mOh S-warfarin was reduced to 22%. area under the concentration-time curve for the international normalized ratio (AUC_INR) increased by 2%, which probably has no clinical significance, the effect on the maximum value of the international normalized ratio (INR_max) was not observed.The response time for the international normalized ratio (tMHO_max) was extended by 6 h, which agrees with the delay t_max approximately 4 and 6 hours for S- and R-warfarin, respectively. Such changes are not considered clinically significant. Correction of the dose of warfarin when used with dulaglutide is not required.

Oral contraceptives

The simultaneous use of dulaglutide with oral contraceptives (norgestimate 0.18 mg / ethinyl estradiol 0.025 mg) had no effect on the total exposure of noregestromine and ethinylestradiol. For noregestromine and ethinyl estradiol, a statistically significant decrease in C_mOh by 26% and 13% and the delay t_max at 2 and 0.30 hr, respectively. Such observations are not considered clinically significant. Correction of the dose of oral contraceptives when used with dulaglutide is not required.

Metformin

After the simultaneous use of multiple dulaglutide and metformin with normal release in equilibrium AUC_τ increased to 15%, and C_mOh decreased to 12%, t_max did not change. Such changes correspond to the delay in emptying the stomach, which causes dulaglutide, and are within the variability of the pharmacokinetics of metformin and therefore are not considered clinically relevant.Correction of the dose of metformin of conventional release with simultaneous application with dulaglutide is not required.

Sitagliptin

With simultaneous application with a single dose of dulaglutide, the concentration of sitagliptin did not change. After simultaneous application with two consecutive doses of dulaglutide AUC_(0-_τ₎ and C_mOh Sitagliptin declined by approximately 7.4% and 23.1%, respectively. t_max Sitagliptin increased approximately 0.5 h after simultaneous use with dulaglutide compared to monotherapy with sitagliptin.

Sitagliptin can cause inhibition at 80% DPP-4 for 24 hours. With the simultaneous use of dulaglutide and sitagliptin, exposure and C_mOhdulaglutide increased by approximately 38% and 27%, respectively, and the median t_max increased to about 24 hours. Thus, dulaglutide has a high degree of protection against inactivation of DPP-4.

Special instructions:

Dulaglutide is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Disorders from the gastrointestinal tract

The use of GLP-1 receptor agonists can be associated with unwanted reactions from the gastrointestinal tract.This should be considered when using dulaglutide in patients with impaired renal function, since dyspeptic phenomena (nausea, vomiting and / or diarrhea) can cause dehydration, which can lead to impaired renal function. The use of dulaglutide in patients with severe diseases of the gastrointestinal tract, including severe gastric paresis, has not been studied, so the drug is not recommended for this group of patients.

Acute pancreatitis

The use of GLP-1 receptor agonists is associated with the risk of developing acute pancreatitis. In clinical studies, cases of acute pancreatitis associated with dulaglutide therapy have been reported.

Patients should be informed of the characteristic symptoms of acute pancreatitis, including persistent severe abdominal pain. If suspicion of pancreatitis, dulaglutide therapy should be discontinued. When confirming the diagnosis of pancreatitis dulaglutide should be canceled without resumption of therapy. In the absence of other signs and characteristic symptoms of acute pancreatitis, an increase in the activity of pancreatic enzymes in itself is not a prognostic factor for acute pancreatitis.

Hypoglycaemia

In patients receiving dulaglutide simultaneously with derivatives of sulfonylureas or insulin, the risk of hypoglycemia may be increased. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylureas or insulin derivatives.

Unexplored patient groups

The experience with dulaglutide in patients with chronic heart failure is limited.

The sodium content

The drug contains less than 1 mmol of sodium (23 mg) per dose of 1.5 mg, i.e. practically does not contain sodium.

Fertility

Data on the effect of dulaglutide on fertility in humans are absent. In rats, there was no direct effect on mating or fertility after the use of dulaglutide.

USER GUIDE TRULICITY ™

Dulaglutide

A solution for subcutaneous administration of 0.75 mg / 0.5 ml in a syringe-pen for a single application once a week

INFORMATION ABOUT THE SYRINGE-HANDLE FOR ONE-TIME APPLICATION OF TRULICITY ™

Please read this User's Manual and the Instruction for the medical use of the preparation carefully and completely before using the syringe pen for a single use of TRULICITY ™. Talk with your doctor about how to correctly administer TRULISITI ™.

- Syringe pen for a single use of the drug TRULISITI ™ (syringe-pen) is a disposable pre-filled device for drug administration, ready for use. Each syringe pen contains one weekly dose of TRULICITY ™ (0.75 mg / 0.5 mL). Each syringe-pen is intended for the introduction of only one dose.

- A drug TRULICITY ™ is administered once a week. You may want to make a note in your calendar so you do not forget about the next dose.

- When you press the green injection button, the syringe pen automatically inserts the needle in the skin, injects the drug and removes the needle after completion of the injection.

BEFORE ACCESSING USE:

"Get out of the fridge."

- Check the labeling to make sure that you have taken the correct preparation, and that its expiration date has not expired.

- Inspect the syringe pen. Do not use it if you notice that the syringe pen is damaged or the drug is cloudy, discolored, or contains particles.

- Prepare by washing your hands.

SELECT PLACE FOR INTRODUCTION

- Your health care provider can help you choose the place of administration that best suits you.

- You can inject the drug into the abdomen or thigh area.

- Another person can give you an injection in the shoulder area.

- Change (alternate) the injection site every week. You can use the same site, but be sure to choose different points for injection.

REMOVE THE CAP
LOCATE AND UNLOCK
CLICK AND HOLD (see Figure 3)

1. REMOVE THE CAP

! Make sure the syringe pen is locked.

- Remove and discard the gray cap that covers the base.

Do not put the cap back on, it may damage the needle. Do not touch the needle.

2. LOCATE AND UNLOCK

- Firmly press the transparent base against the surface of the skin at the injection site.

! Unlock, having turned a fixing ring.

3. CLICK AND HOLD

- Press and hold the green injection button; You will hear a loud click.

!! Continue to press the transparent base firmly against the skin until you hear a second click. This will happen when the needle begins to retract, approximately 5-10 seconds later.

- Remove the syringe pen from the skin.

- You will learn that the injection is completed when the gray part of the mechanism becomes visible.

IMPORTANT INFORMATION:

Storage and handling
Disposal of the syringe pen
Frequently asked Questions
Other information
Where can I find more information?

STORAGE AND HANDLING

- In the syringe-handle there are glass details. Handle the device with care. If you drop it on a hard surface, do not use it. Use a new syringe pen for injection.

- Store the syringe pen in the refrigerator.

- If after storage in the pharmacy you can not store it in the refrigerator, you can store the syringe pen at a temperature of no higher than 30 ° C for up to 14 days.

- Do not freeze the syringe pen. If the syringe pen has been frozen, DO NOT USE IT.

- Store the syringe pen in the original carton to protect it from light.

- Keep the syringe pen out of the reach of children.

- For complete information on proper storage conditions, read the instructions for the medical use of the drug.

DISPOSAL OF SYRINGE-HANDLE

- Dispose of the syringe pen in a container for sharp objects or as recommended by your health care provider.

- Do not recycle the filled container for sharp objects.

- Ask your doctor about possible ways to dispose of drugs that you no longer use.

FREQUENTLY ASKED QUESTIONS

What if I notice an air bubble in the syringe pen?

The presence of air bubbles is the norm. They will not cause you harm and will not affect your dose.

What should I do if I unlock the pen and press the green injection button without removing the cap from the base?

Do not remove the cap from the base and do not use the syringe pen. Discard the syringe as indicated in the User's Guide. Enter the drug with another syringe pen.

What if I see a drop of liquid on the tip of the needle when I remove the cap from the base?

A drop of liquid at the tip of the needle is not unusual and will not affect your dose.

Do I need to hold the injection button until the injection is complete?

This is not necessary, but it can help tightly and immovably press the syringe pen against the surface of the skin.

I heard (s) more than two clicks during the injection: two loud clicks and one quiet. Was the drug completely introduced?

Some patients may hear a silent click just before the second loud click. This is normal for a pen syringe. Continue to press the syringe pen against the surface of the skin until you hear the second loud click.

What to do if after the injection a drop of liquid or blood remains on the skin?

This is not unusual and will not affect your dose.

I'm not sure the syringe pen works correctly.

Check if you have entered the full dose. The dose is entered correctly if the gray part of the mechanism is visible. (See step 3.) Contact the Moscow Representative Office of Eli Lilly Vostok SA, Switzerland on + 7-495-258-50-01 or your PCP for further instructions. Until then, store the syringe pen so that you do not accidentally prick the needle.

OTHER INFORMATION

- If you have visual impairment, DO NOT use a syringe pen for a single use of TRULICITY ™ without the help of a specially trained person.

WHERE TO FIND ADDITIONAL INFORMATION

- If you have any questions or problems when using the syringe pen for a single use of the drug TRULISITI ™. please contact the Moscow Representative Office of Eli Lilly East SA, Switzerland on + 7-495-258-50-01 or with your doctor.

Name and address of the manufacturer:

"Eli Lilly and Company", USA "Eli Lilly and Company", USA

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA Representation at Of Russia:

Moscow Representation of JSC "Eli Lilly East SA", Switzerland 123317, Moscow, Presnenskaya nab., 10 tel. +7 (495) 258-50-01 fax +7 (495) 258-50-05

TRULICITY ™ is a trademark of Eli Lilly and Company.

The syringe pen for a single use of TRULISITI ™ corresponds to the current requirements for the accuracy of dosage and functioning according to ISO 11608-1: 2012 and 11608-5: 2012.

USER GUIDE TRULICITY ™

Dulaglutide

A solution for subcutaneous administration of 1.5 mg / 0.5 ml in a syringe-pen for a single application once a week

INFORMATION ABOUT THE SYRINGE-HANDLE FOR ONE-TIME APPLICATION OF TRULICITY ™

- The syringe pen for a single use of the drug TRULISITI ™ (syringe pen) is a disposable pre-filled device for drug administration, ready for use. Each syringe pen contains one weekly dose of TRULICITY ™ (1.5 mg / 0.5 mL). Each syringe-pen is intended for the introduction of only one dose.

- A drug TRULICITY ™ is administered once a week. You may want to make a note in your calendar so you do not forget about the next dose.

When you press the green injection button, the syringe pen automatically inserts the needle in the skin, injects the drug and removes the needle after completion of the injection.

BEFORE ACCESSING USE:

"Get out of the fridge."

- Check the labeling to make sure that you have taken the correct preparation, and that its expiration date has not expired.

- Inspect the syringe pen. Do not use it if you notice that the syringe pen is damaged or the drug is cloudy, discolored, or contains particles.

- Prepare by washing your hands.

SELECT PLACE FOR INTRODUCTION

- Your health care provider can help you choose the place of administration that best suits you.

- You can inject the drug into the abdomen or thigh area.

- Another person can give you an injection in the shoulder area.

- Change (alternate) the injection site every week. You can use the same site, but be sure to choose different points for injection.

REMOVE THE CAP
LOCATE AND UNLOCK
CLICK AND HOLD

1. REMOVE THE CAP

! Make sure the syringe pen is locked.

- Remove and discard the gray cap that covers the base.

Do not put the cap back on, it may damage the needle. Do not touch the needle.

2. LOCATE AND UNLOCK

- Firmly press the transparent base against the surface of the skin at the injection site.

Unlock, having turned a fixing ring.

3. CLICK AND HOLD

- Press and hold the green injection button; You will hear a loud click.

! Continue to press the transparent base firmly against the skin until you hear a second click. This will happen when the needle begins to retract, approximately 5-10 seconds later.

- Remove the syringe pen from the skin.

- You will learn that the injection is completed when the gray part of the mechanism becomes visible.

IMPORTANT INFORMATION

Storage and handling
Disposal of the syringe pen
Frequently asked Questions
Other information
Where can I find more information?

STORAGE AND HANDLING

- In the syringe-handle there are glass details. Handle the device with care. If you drop it on a hard surface, do not use it. Use a new syringe pen for injection.

- Store the syringe pen in the refrigerator.

- If after storage in the pharmacy you can not store it in the refrigerator, you can store the syringe pen at a temperature of no higher than 30 ° C for up to 14 days.

- Do not freeze the syringe pen. If the syringe pen has been frozen, DO NOT USE IT.

- Store the syringe pen in the original carton to protect it from light.

- Keep the syringe pen out of the reach of children.

- For complete information on proper storage conditions, read the instructions for the medical use of the drug.

DISPOSAL OF SYRINGE-HANDLE

- Dispose of the syringe pen in a container for sharp objects or as recommended by your health care provider.

- Do not recycle the filled container for sharp objects.

- Ask your doctor about possible ways to dispose of drugs that you no longer use.

FREQUENTLY ASKED QUESTIONS

What if I notice an air bubble in the syringe pen?

The presence of air bubbles is the norm. They will not cause you harm and will not affect your dose.

What should I do if I unlock the pen and press the green injection button without removing the cap from the base?

Do not remove the cap from the base and do not use the syringe pen. Discard the syringe as indicated in the User's Guide.Enter the drug with another syringe pen.

What if I see a drop of liquid on the tip of the needle when I remove the cap from the base?

A drop of liquid at the tip of the needle is not unusual and will not affect your dose.

Do I need to hold the injection button until the injection is complete?

This is not necessary, but it can help tightly and immovably press the syringe pen against the surface of the skin.

I heard (s) more than two clicks during the injection: two loud clicks and one quiet. Was the drug completely introduced?

Some patients may hear a silent click just before the second loud click. This is normal for a pen syringe. Continue to press the syringe handle against the surface of the skin until you hear the second loud click.

What to do if after the injection a drop of liquid or blood remains on the skin?

This is not unusual and will not affect your dose.

I'm not sure the syringe pen works correctly.

Check if you have entered the full dose. The dose is entered correctly if the gray part of the mechanism is visible. (See step 3.) Contact the Moscow Representative Office of Eli Lilly Vostok SA, Switzerland on + 7-495-258-50-01 or your PCP for further instructions.Until then, store the syringe pen so as to avoid accidental needle pricking.

OTHER INFORMATION

- If you have visual impairment, DO NOT use a syringe pen for a single use of TRULICITY ™ without the help of a specially trained person.

WHERE TO FIND ADDITIONAL INFORMATION

Name and address of the manufacturer:

"Eli Lilly and Company", USA "Eli Lilly and Company", USA

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA Representation at Of Russia:

Moscow Representation of JSC "Eli Lilly East SA", Switzerland 123317, Moscow, Presnenskaya nab., 10 tel. +7 (495) 258-50-01 fax +7 (495) 258-50-05

TRULICITY ™ is a trademark of Eli Lilly and Company.

The syringe pen for a single use of TRULISITI ™ corresponds to the current requirements for the accuracy of dosage and functioning according to ISO 11608-1: 2012 and 11608-5: 2012.

Effect on the ability to drive transp. cf. and fur:

Dulaglutide has minimal or no effect on the ability to drive vehicles and mechanisms. When using dulaglutide in combination with sulfonylurea derivatives or insulin, caution is recommended to avoid the development of hypoglycemia in the management of vehicles and mechanisms.

Form release / dosage:

A solution for subcutaneous administration, 0.75 mg / 0.5 ml or 1.5 mg / 0.5 ml.

Packaging:

0.5 ml of solution in a syringe. The syringe is sealed on one side, and on the other hand is equipped with an injection needle with a protective cap. A syringe is built in a syringe-pen.

By 4 syringes-pens together with the instruction on the use of the preparation, the manual on the use of the syringe-pen in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C. Do not freeze.

Do not use if it has been frozen.

The drug purchased at the pharmacy can be stored at a temperature of no higher than 30 ° C for 14 days.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003682

Date of registration:16.06.2016