Trulicity solution for subcutaneous. enter 1.5 mg/0.5 ml syringe pen 0.5 ml №4

The solution for SC injection is clear, colorless.

Excipients:

sodium citrate dihydrate 1.37 mg, anhydrous citric acid 0.07 mg, mannitol 23.2 mg, polysorbate 80 (vegetable) 0.10 mg, water d / and q.s. up to 0.5 ml.
0.5 ml - syringes (1) - syringe pens (4) - packs cardboard.

Clinico-pharmacological group:

Parenteral hypoglycemic drug

Pharmaco-therapeutic group:

Hypoglycemic agent - glucagon-like receptor polypeptide agonist

Indications

Drug trilicity^Tm indicated in adult patients with type 2 diabetes to improve glycemic control in the form of:
- monotherapy
If diet and exercise do not provide the necessary glycemic control in patients who do not show the use of Metformin due to intolerance or the presence of contraindications.
- combination therapy
In combination with other hypoglycemic drugs, including insulin, if these drugs along with diet and exercise do not provide the necessary glycemic control.

Dosing regimen

Drug trilicity^Tm should be injected s / c in the abdomen, thigh or shoulder area. The drug should not be administered in / in or in / m.
The drug can be administered at any time of the day, regardless of the reception write.
Monotherapy
The recommended dose is 0.75 mg once a week.
Combination therapy
The recommended dose is 1.5 mg once a week.
In patients aged 75 years and older, the recommended initial dose of the drug is 0.75 mg once a week.
With the addition of dulaglutide to 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 or prandial insulin, it may be necessary to reduce the dose of the sulfonylurea or prandial insulin to reduce the risk of hypoglycemia.
Additionally, glycemia control is not required for dose adjustment of dulaglutide. Additional glycemic control may be required to adjust the dose of sulfonylurea or prandial insulin derivatives.
Skip dose
If the dose of the drug is Trulicity^Tm was missed, it should be entered as soon as possible, if before the introduction of the next scheduled dose is not less than 3 days (72 hours). If less than 3 days (72 hours) remains before the next scheduled dose, you should skip the drug and enter the next dose in accordance with the schedule. In each case, patients can resume the usual mode of administration of the drug 1 time per week.
The day of drug administration, if necessary, can be changed, provided that the last dose was administered at least 3 days (72 hours) ago.
Elderly patients (over 65)
Dose adjustment depending on age is not required.However, the experience of treating patients aged> 75 years is very limited, in these patients the recommended initial dose of the drug is 0.75 mg 1 time per week.
Patients with impaired renal function
In patients with impaired renal function, mild or moderate severity of dose adjustment is not required. There is very limited experience with the use of dulaglutid in patients with severe impaired renal function (estimated glomerular filtration rate (GFR) <30 ml / min / 1.73m²) or end-stage renal failure, therefore, the use of dulaglutide in this population is not recommended.
Patients with impaired liver function
In patients with impaired liver function dose adjustment is not required.
Children
The safety and efficacy of dulaglutid in children under 18 years of age has not been established. No data available.

Side effect

Security Profile Overview
In the course of clinical studies II and III, 4006 patients received dulaglutid as monotherapy or in combination with other hypoglycemic drugs. The most frequent adverse reactions in clinical studies have been gastrointestinal reactions, including nausea, vomiting, and diarrhea. In general, these reactions were mild or moderate and temporary in nature.
The following adverse reactions were identified during the evaluation of the results of clinical studies of phase II and III: 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: infrequently:> 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 adverse reactions when using dulaglutide

* documented symptomatic hypoglycemia and blood glucose concentration <3.9 mmol / l.
¹ - only for dulaglutid in a dose of 1.5 mg. The frequency of adverse reactions for dulaglutid at a dose of 0.75 mg corresponds to a lower category.

Description of individual unwanted reactions
Hypoglycemia
When using dulaglutid in doses of 0.75 mg or 1.5 mg 1 time per week as monotherapy or in combination with metformin or metformin and pioglitazone, the frequency of documented symptomatic hypoglycemia ranged from 5.9% to 10.9% or 0.14 to 0.62 events / patient / year, severe cases hypoglycemia was not observed.
When using dulaglutide in doses of 0.75 mg or 1.5 mg 1 time per week in combination with sulfonylurea (plus metformin) derivatives, the frequency of documented symptomatic hypoglycemia was 39.0% and 40.3% or 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 using dulaglutide in doses of 0.75 mg or 1.5 mg 1 time per week in combination with prandial insulin, the frequency 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 gastrointestinal reactions
Cumulative reporting of gastrointestinal events over a period of up to 104 weeks with the use of dulaglutide in 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 observed during the first 2 weeks of therapy and quickly decreased over the next 4 weeks, after which the frequency remained relatively constant.
In clinical and pharmacological studies that were conducted with the participation of patients with type 2 diabetes and lasted up to 6 weeks, most of the phenomena on the part of the gastrointestinal tract were observed during the first 2-3 days after the first dose, their frequency decreased with the use of the following doses.
Acute pancreatitis
The incidence of acute pancreatitis in clinical studies of Phase II and Phase was 0.07% with dulaglutide compared with 0.14% with placebo and 0.19% with comparison drugs, with or without additional baseline hypoglycemic therapy.
Pancreatic Enzymes
The use of dulaglutide is associated with an average increase in the activity of pancreatic enzymes (lipase and / or pancreatic amylase) by 11-21% compared with 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 using dulaglutid in doses of 0.75 mg or 1.5 mg 1 time per week, there was a slight average increase in heart rate by 2–4 beats per minute (beats / min) and sinus tachycardia rates by 1.3% and 1.4%, respectively, which was accompanied by an increase compared to with baseline at> 15 beats / min.
Atrioventricular block I degree / increase in the interval of PR
When using dulaglutid in doses of 0.75 mg or 1.5 mg 1 time per week, there was a slight average increase in the PR interval by 2-3 ms, compared to the baseline, and the frequency of atrioventricular block I degree by 1.5% and 2.4%, respectively.
Immunogenicity
In clinical studies, the use of dulaglutid was accompanied by the detection of antibodies to dulaglutide with a frequency of 1.6%, which indicates thatthat structural changes in GLP-1 and modified IgG4 regions in the dulaglutide molecule, along with high homology to native GLP-1 and native IgG4, minimize the risk of an immune response during therapy with dulaglutid. Patients who developed antibodies to dulaglutide usually had a low antibody titer; nevertheless, despite the small number of patients in whom antibodies to dulaglutide were formed, the evaluation of the results of phase III clinical trials did not reveal a clear effect of antibodies to dulaglutid on the change in HbAlc.
Hypersensitivity
In clinical studies of phase II and phase III, systemic hypersensitivity phenomena (severe urticaria, extensive eruptions, swelling of the face, and lip swelling) were observed in 0.5% of patients who received dulaglutide. No patients with systemic hypersensitivity produced antibodies to dulaglutide.
Reactions at the injection site
Reactions at the injection site were observed in 1.9% of patients receiving dulaglutide. Potentially immune-mediated adverse events at the injection site (eg, rash, erythema) were observed in 0.7% of patients and were usually mild.
Early termination of participation in clinical trials due to adverse events
During the 26-week study, the frequency of early termination due to adverse events was 2.6% (0.75 mg 1 time per week) and 6.1% (1.5 mg 1 time per week) when using dulaglutide compared to 3.7% when using placebo.Throughout the study (up to 104 weeks), the frequency of early termination of participation due to adverse events when using dulaglutid was 5.1% (0.75 mg once a week) and 8.4% (1.5 mg once a week). The most frequent adverse reactions that led to early termination of participation in groups of the use of dulaglutid in doses of 0.75 mg or 1.5 mg 1 time per week were nausea (1.0% and 1.9%), diarrhea (0.5% and 6%) and vomiting (0.4% and 0.6%), mainly such reactions were observed during the first 4-6 weeks of therapy.

Contraindications

- hypersensitivity to the active or any of the excipients that make up the drug;
- diabetes mellitus type 1;
- diabetic ketoacidosis;
- Severe renal dysfunction;
- chronic heart failure ;
- pregnancy;
- breastfeeding period;
- Severe diseases of the gastrointestinal tract, including severe paresis of the stomach;
- acute pancreatitis;
- children's age up to 18 years.
With care: in patients taking oral medications that require rapid absorption in the gastrointestinal tract; in patients aged 75 and over.

Use during pregnancy and lactation

Pregnancy
Data on the use of dulaglutid in pregnant women are missing or their volume is limited. Animal studies have shown the presence of reproductive toxicity, so the use of dulaglutide is contraindicated during pregnancy.
Breast-feeding
Information about the penetration of dulaglutid in breast milk is missing. Risk to newborns / infants cannot be excluded. The use of dulaglutide during breastfeeding is contraindicated.

Application for violations of the liver
In patients with impaired liver function dose adjustment is not required.

Application for violations of kidney function
In patients with impaired renal function, mild or moderate severity of dose adjustment is not required. There is very limited experience with the use of dulaglutid in patients with severe impaired renal function (estimated glomerular filtration rate (GFR) <30 ml / min / 1.73m²) or end-stage renal failure, therefore, the use of dulaglutide in this population is not recommended.

Use in children

The safety and efficacy of dulaglutid in children under 18 years of age has not been established. No data available.

Use in elderly patients

Dose adjustment depending on age is not required. However, the experience of treating patients aged> 75 years is very limited, in these patients the recommended initial dose of the drug is 0.75 mg 1 time per week.

special instructions

Dulaglutide is not recommended for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Disorders of the gastrointestinal tract
The use of GLP-1 receptor agonists may be associated with adverse reactions from the gastrointestinal tract.This should be considered when using dulaglutid in patients with impaired renal function, since dyspeptic symptoms (nausea, vomiting and / or diarrhea) can cause dehydration, which can lead to deterioration of renal function. The use of dulaglutid in patients with severe gastrointestinal diseases, including severe stomach 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, there have been cases of acute pancreatitis associated with therapy with dulaglutide.
Patients should be informed about the characteristic symptoms of acute pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, dulaglutide therapy should be discontinued. When confirming the diagnosis of pancreatitis, dulaglutide should be canceled without resuming therapy. In the absence of other signs and characteristic symptoms of acute pancreatitis, an increase in the activity of pancreatic enzymes is not in itself a prognostic factor for acute pancreatitis.
Hypoglycemia
In patients receiving dulaglutide simultaneously with sulfonylurea derivatives or insulin, the risk of hypoglycemia may be increased. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylurea or insulin derivatives.
Unknown patient groups
The experience of using dulaglutide in patients with chronic heart failure is limited.
Sodium content
The drug contains less than 1 mmol of sodium (23 mg) per dose of 1.5 mg, those. practically does not contain sodium.
Fertility
Data on the effect of dulaglutid on fertility in humans are not available. In rats, no direct effect on mating or fertility was observed after administration of dulaglutide.
Influence on ability to drive vehicles and mechanisms
Dulaglutid has a minimal effect or does not affect 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 when driving vehicles and mechanisms.

Overdose

Symptoms of a dulaglutide overdose in clinical studies included gastrointestinal disorders and hypoglycemia.
Treatment. In case of overdose, it is necessary to start symptomatic therapy in accordance with the clinical signs and symptoms.

Drug interaction

Dulaglutide causes a delay in the rate of gastric emptying, therefore, has the ability to affect the absorption of oral medications with simultaneous use. Dulaglutide should be used with caution in patients taking oral medications that require rapid absorption in the gastrointestinal tract. Delaying the rate of gastric emptying may slightly increase the exposure of sustained release drugs by increasing the release time.drug.
Paracetamol
After administration of the first dose of dulaglutide in doses of 1 or 3 mg C_maxparacetamol decreased by 36% and 50%, respectively, and the median T_maxwas achieved later (after 3 and 4 h, respectively). After simultaneous use with dulaglutid in a dose of up to 3 mg in an equilibrium state, no statistically significant difference in AUC values ​​was observed._(0-∞) (area under the concentration-time curve from 0 to 12 hours), C_maxor t_max paracetamol. When used with dulaglutidam dose adjustment of paracetamol is not required.
Atorvastatin
The simultaneous use of dulaglutid with atorvastatin caused a decrease in C_maxand AUC_(0-12) atorvastatin and its main metabolite, o-hydroxyatorvastatin, are up to 70% and 21%, respectively. MediumT_1/2 atorvastatin and o-hydroxyatorvastatin after administration of dulaglutide increased by 17% and 41%, respectively. Such changes are not considered clinically significant. When combined with dulaglutid dose adjustment of atorvastatin is not required.
Digoxin
After simultaneous use of digoxin in an equilibrium state with two consecutive doses of dulaglutide, the total exposure (AUC_t) and T_maxdigoxin did not change; C_max decreased by 22% as much as possible. It is believed that such a change has no clinical consequences. When used with dulaglutid dose adjustment of digoxin is not required.
Antihypertensive drugs
The simultaneous use of multiple doses of dulaglutide with lisinopril in an equilibrium state did not cause clinically significant changes in AUC or C_maxlisinopril.Statistically significant delay T_maxlisinopril for approximately 1 h was observed on days 3 and 24 of the study. With the simultaneous use of a single dose of dulaglutide with Metoprolol AUC or C_max metoprolol increased by 19% and 32%, respectively. Although C_max metoprolol was achieved 1 h 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 is not required when used with dulaglutide.
Warfarin
After simultaneous use with dulaglutid, the concentration of S- and R-warfarin, as well as C_maxR-warfarin did not change, and C_max S-warfarin was reduced to 22%, the area under the concentration-time curve for an 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. Response time by international normalized ratio (TMHO_max) was extended by 6 hours, which is consistent with the delay T_maxapproximately 4 and 6 hours for S- and R-warfarin, respectively. Such changes are not considered clinically significant. Dose adjustment of warfarin when used with dulaglutid is not required.
Oral contraceptives
The simultaneous use of dulaglutid with oral contraceptives (norgestimate 0.18 mg / ethinyl estradiol 0.025 mg) did not affect the total exposure of norelgestromin and eginiestradiol.For noregestromine and ethinyl estradiol, a statistically significant decrease in C was observed_max by 26% and 13% and delay T_maxat 2 and 0.30 h, respectively.
Such observations are not considered clinically significant. Dose adjustment of oral contraceptives when used with dulaglutide is not required.
Metformin
After simultaneous use of multiple doses of dulaglutide and metformin with normal release in an equilibrium state, AUC_t increased to 15%. a C_max decreased to 12% T_max did not change. Such changes correspond to the delayed gastric emptying, which is caused by dulaglutide, and are within the variability of the pharmacokinetics of metformin and are therefore not considered clinically significant. Dose adjustment of metformin normal release with simultaneous use with dulaglutidom is not required.
Sitagliptin
When used simultaneously with a single dose of Dulaglutide, the concentration of sitagliptin did not change. After simultaneous use with two consecutive doses of Dulaglutide AUC_0-t) and C_max Sitagliptin decreased by approximately 7.4% and 23.1%, respectively. T_maxSitagliptin increased by approximately 0.5 h after simultaneous use with dulaglutid compared with sitagliptin monotherapy.
Sitagliptin can cause inhibition by 80% of DPP-4 within 24 hours. With simultaneous use of dulaglutid and sitagliptin exposure and C_max dulaglutid increased by approximately 38% and 27%, respectively, and the median T_max increased to about 24 hoursThus, dulaglutid has a high degree of protection against inactivation of DPP-4.

Terms and conditions of storage

In the dark place at a temperature of from 2 to 8 ° C; do not freeze. Do not use the drug if it has been frozen. The drug purchased at a pharmacy may be stored at a temperature not exceeding 30 ° C for 14 days. Keep out of reach of children.