Trulicity, 1.5 mg/0.5 ml 0.5 ml syringes in syringe pens 4 pcs

Hypoglycemic agent is an analogue of glucagon-like peptide-1 (GFP-1).

ATX code: A10BJ05

Pharmacological properties

.Mechanism of action

Dulaglutide is a long-acting GFP-1 receptor agonist. Its molecule consists of two identical chains linked by disulfide bonds, each containing a modified human GFP-1 analog covalently linked to a heavy chain (Fc) fragment of modified human immunoglobulin G4 (IgG4) via a small polypeptide chain. The dulaglutide portion, which is analogous to GFP-1, is approximately 90% homologous to native human GFP-1. The half-life (t_1/2) of native human GFP-1 is 1.5-2 min due to cleavage by dipeptidyl peptidase-4 (DPP-4) and renal clearance. Unlike native GFP-1, dulaglutide is resistant to cleavage by DPP-4 and has a large size, which slows absorption and reduces renal clearance. These structural features provide a soluble form and a half-life of 4.7 days, making it suitable for subcutaneous (p/k) administration once a week. In addition, the dulaglutide molecule was designed to prevent the Fcγ receptor-mediated immune response and reduce the immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GFP-1. At elevated glucose concentrations, dulaglutide increases intracellular cyclic adenosine monophosphate (cAMP) in pancreatic beta cells, resulting in increased insulin secretion. Dulaglutide suppresses excessive glucagon secretion in patients with type 2 diabetes mellitus (DM2), which leads to a decrease in glucose release by the liver. In addition, dulaglutide slows the rate of gastric emptying.

Pharmacodynamics

. In patients with DM2, starting with the first administration, dulaglutide improves glycemic control by steadily reducing blood glucose concentrations on an empty stomach, before meals and after meals, which is maintained for a week until the next dose is administered.

A pharmacodynamic study of dulaglutide showed that in patients with DM2 there was a recovery of first-phase insulin secretion to values greater than those of healthy volunteers receiving placebo, and improvement of second-phase insulin secretion in response to intravenous bolus infusion of dextrose (glucose) solution. The same study also showed that a single dose of 1.5 mg of dulaglutide increased maximum pancreatic β-cell insulin secretion and improved β-cell function in DM2 patients compared to placebo.

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

Clinical efficacy and safety

Glycemic control

. The efficacy and safety of dulaglutide has been studied in clinical trials where dulaglutide has been used in monotherapy, in combination therapy with metformin, combination therapy with metformin and a sulfonylurea derivative, and combination therapy with a sulfonylurea derivative, combination therapy with a type 2 sodium-dependent glucose transporter inhibitor (SGLT2i) with or without metformin, combination therapy with metformin and pioglitazone, combination therapy with titrated basal insulin with or without metformin, combination therapy with prandial insulin with or without metformin.

In all studies, dulaglutide provided clinically meaningful improvement in glycemic control as assessed by glycated hemoglobin (HbA1c).

Baseline blood glucose concentration

The use of dulaglutide resulted in a significant decrease in fasting blood glucose concentration compared to baseline. The main effect on fasting blood glucose concentration was observed after 2 weeks. The improvement in fasting blood glucose concentration was maintained over the longest study period of 104 weeks.

Blood glucose concentration after meals (postprandial glycemia)

. Use of dulaglutide resulted in a significant reduction in mean postprandial glycemia compared with baseline (change in glycemia from baseline to the primary time point was -1.95 mmol/L to
-4.23 mmol/L).

Pancreatic beta cell function

. Results of clinical studies have shown improvement in pancreatic beta-cell function with dulaglutide, as determined by a homeostatic evaluation model (HOMA2-%B index). The effect on beta-cell function persisted for the longest study period of 104 weeks.

Body weight

. When dulaglutide was administered at a dose of 1.5 mg once weekly, there was a sustained decrease in body weight over the course of the studies (change from baseline was -0.35 kg to -2.90 kg at the final time point). The change in body weight with dulaglutide at a dose of 0.75 mg once weekly ranged from 0.86 kg to -2.63 kg. The decrease in body weight was observed in patients who received dulaglutide regardless of the occurrence of nausea, although numerically the decrease was greater in the group of patients who had nausea.

Results based on patient survey

Dulaglutide significantly improved overall satisfaction with therapy.

Arterial pressure (BP)

The effect of dulaglutide on BP was evaluated in a study involving patients with DM2 using ambulatory BP monitoring. Dulaglutide therapy was accompanied by a decrease in systolic BP (-2.8 mmHg difference compared to placebo) after 16 weeks. No difference in diastolic BP was observed. Similar results for systolic and diastolic BP were shown at the study endpoint of 26 weeks.

Cardiovascular Impact Assessment

. Results of a meta-analysis of phase II and III studies showed that dulaglutide did not increase the risk of cardiovascular events compared with therapy with comparison drugs.

In a long-term cardiovascular outcome study, Trulicity^® significantly reduced the risk of serious cardiovascular complications compared with placebo. The incidence of serious cardiovascular complications (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was lower in patients treated with dulaglutide, both those with cardiovascular disease and those with risk factors but no diagnosed cardiovascular disease, than in patients in the placebo group. The relative risk of serious cardiovascular complications was consistently lower than 1.00 for all three serious cardiovascular complications.

The use of Trulicity^® in addition to standard therapy compared to placebo showed a significant and sustained decrease in HbA1c after 60 months compared to baseline. The drug Trulicity^® demonstrated stable efficacy in major population subgroups and disease subgroups, including prior cardiovascular disease stage, baseline HbA1c, gender, duration of diabetes, age and glomerular filtration rate (GFR).

Special patient groups

Patients with renal impairment

. In a 52-week study, dulaglutide at doses of 1.5 mg and 0.75 mg was compared with insulin glargine as an adjunct to prandial insulin lispro to evaluate the effect on glycemic control and safety in patients with mild to severe renal impairment (15 mL/min/1.73 m² ≤ SCF < 60 mL/min/1.73 m²).

After 26 weeks of therapy, dulaglutide at doses of 1.5 mg and 0.75 mg was not inferior to insulin glargine in reducing HbA1c, with the effect persisting for 52 weeks. The proportion of patients achieving target HbA1c < 8.0% at weeks 26 and 52 was similar with dulaglutide at both doses and with insulin glargine.

The safety profile of dulaglutide in patients with severe renal impairment was similar to that seen in other studies of dulaglutide.

.Pharmacokinetics

absorption <./p>

After p/u administration to patients with type 2 DM2, the maximum concentration (C_max) of dulaglutide in plasma is observed after 48 h. Following multiple p/c administration of dulaglutide at a dose of 1.5 mg to DM2 patients, the mean C_max and area under the concentration-time curve (AUC) were approximately 114 ng/mL and 14,000 ng/h/mL, respectively. Equilibrium plasma concentrations were observed after 2-4 weeks of dulaglutide administration at a dose of 1.5 mg once weekly. Concentrations after a single dose of dulaglutide (1.5 mg) administered p/c to the abdomen, thigh, or shoulder were comparable. The mean absolute bioavailability of dulaglutide after a single per oral dose of 1.5 mg or 0.75 mg was 47% and 65%, respectively.

Distribution

After p/k administration of dulaglutide at doses of 0.75 mg or 1.5 mg to patients with DM2 at equilibrium, the mean volume of distribution was approximately 19.2 L and 17.4 L, respectively.

Metabolism

Dulaglutide is thought to be broken down into its component amino acids through the major protein catabolic pathways.

Elevation

The average clearance of dulaglutide in humans in equilibrium after administration at

doses of 0.75 mg or 1.5 mg was 0.111 L/h and 0.107 L/h, respectively, with half-lives of

4.5 and 4.7 days, respectively.

Pharmacokinetics of dulaglutide in special patient groups

In elderly patients .

Patient age had no clinically significant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide.

Gender and race

Gender and race had no clinically significant effect on the pharmacokinetics of dulaglutide.

body weight or body mass index

. Pharmacokinetic analysis showed a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutide exposure; however, there was no clinically significant effect of body weight or BMI on glycemic control.

In patients with renal impairment

. The pharmacokinetics of dulaglutide were evaluated in a clinical-pharmacological study and were generally similar in healthy participants and in patients with mild to severe renal impairment (creatinine clearance < 30 mL/min), including terminal renal failure (while undergoing hemodialysis). Additionally, in a 52-week clinical trial involving patients with DM2 and moderate to severe renal impairment (15 mL/min/1.73 m² ≤ SCF < 60 mL/min/1.73 m²) the pharmacokinetics profile of dulaglutide at 0.75 mg and 1.5 mg once weekly was similar to that seen in other studies of dulaglutide. This study did not include patients with end-stage renal failure.

In patients with hepatic impairment

. The pharmacokinetics of dulaglutide were evaluated in a clinical and pharmacological study in which patients with hepatic impairment showed statistically significant decreases in mean C_max and AUC of 30% and 33%, respectively, compared with healthy volunteers. The time to reach C_max (t_max) of dulaglutide increased when liver function worsened. Exposure to dulaglutide was independent of the degree of liver failure. These changes were not considered clinically significant.

In children and adolescents under 18 years of age

There have been no studies of the pharmacokinetics of dulaglutide in children and adolescents under 18 years of age.

Indications

Type 2 diabetes

The drug Trulicity^® is indicated for adult patients with type 2 diabetes with insufficient glycemic control on diet and exercise as:

• monotherapy

in patients who are not indicated for metformin because of intolerance or contraindications;

• combination therapy

in combination with other diabetes medications.

The drug Trulicity^® is indicated to reduce the risk of serious cardiovascular complications (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke)

• in adult patients with type 2 diabetes and diagnosed cardiovascular disease as an adjunct to standard therapy for cardiovascular disease.

.

Active ingredient

Dulaglutide

Composition

The 0.5 ml of the drug contains:

For a dosage of 1.5 mg:

Active ingredient: dulaglutide 1.5 mg;

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

How to take, the dosage

Trulicity® should be injected subcutaneously into the abdomen, thigh, or upper arm.

The drug should not be given intravenously or intramuscularly.

The drug can be taken at any time of day regardless of the time of eating.

Monotherapy

The recommended dose is 0.75 mg once weekly.

Combination therapy

The recommended dose is 1.5 mg once weekly.

If dulaglutide is added to current therapy with metformin and/or pioglitazone, metformin and/or pioglitazone may be continued at the same dose. When dulaglutide is added to current therapy with metformin and/or SGLT2i, metformin and SGLT2i may be continued at the same dose. When dulaglutide is added to current therapy with a sulfonylurea derivative or insulin, a reduction in the dose of the sulfonylurea derivative or insulin may be required to reduce the risk of hypoglycemia.

No additional glycemic self-monitoring is required during therapy with dulaglutide. In case of combination with sulfonylurea derivatives or insulin, especially in cases of initiation of therapy with Trulicity^®, self-monitoring is required, as adjustment of the dose of insulin or sulfonylurea derivative may be required. A stepwise decrease in insulin dose is recommended.

Missed Dose

If a dose of Trulicity^® has been missed, it should be given as soon as possible if it is at least 3 days (72 h) before the next scheduled dose. If the next scheduled dose is less than 3 days
(72 h) away, the drug should be skipped and the next dose administered as scheduled. In each case, patients can resume the normal regimen of administration once a week.

The day of administration may be changed if necessary, provided the last dose was administered at least three days (72 hours) ago.

The use of the drug in special clinical groups of patients

.em>In elderly patients

Dose adjustment based on age is not required.

In patients with renal impairment

. In patients with mild, moderate, or severe renal impairment (15 ml/min/1.73 m² ≤ SCF < 90 ml/min/1.73 m²) no dose adjustment is required.

There is very limited experience with dulaglutide in patients with terminal renal failure (< 15 mL/min/1.73 m²), so dulaglutide is contraindicated in this population.

In patients with hepatic impairment

Dose adjustment is not necessary in patients with hepatic impairment.

In children and adolescents under 18 years

The safety and effectiveness of dulaglutide in children and adolescents under 18 years has not been established. No data are available.

Interaction

Dulaglutide causes delayed gastric emptying, therefore, has the ability to affect the absorption of oral drugs when used simultaneously. Dulaglutide should be used with caution in patients taking oral medications that require rapid absorption in the GI tract. Delayed gastric emptying may slightly increase the exposure of delayed-release drugs by increasing the time of drug release.

Paracetamol

After the first administration of dulaglutide at doses of 1 and 3 mg, the C_max paracetamol decreased by 36% and 50%, respectively, and median t_max was reached later (after 3 and 4 h, respectively). No statistically significant difference in AUC _(0-12) (area under the concentration-time curve from 0 to 12 h), C_max or t_max values of paracetamol was observed after concurrent use with dulaglutide at a dose up to 3 mg at equilibrium. No paracetamol dose adjustment is required when used with dulaglutide.

Atorvastatin

The concomitant use of dulaglutide with atorvastatin caused a decrease in C_max and

AUC_(0-∞) of atorvastatin and its major metabolite o-hydroxyatorvastatin to 70% and 21%, respectively. Mean t_1/2 atorvastatin and o-hydroxyatorvastatin increased by 17% and 41%, respectively, after dulaglutide administration. Such changes are not considered clinically significant. No dose adjustment of atorvastatin is required when coadministered with dulaglutide.

Digoxin

After concomitant use of digoxin at equilibrium with two consecutive doses of dulaglutide, total exposure (AUCτ) and t_max of digoxin did not change; C_max decreased by a maximum of 22%. This change is considered to have no clinical implications. No dose adjustment of digoxin is required when used with dulaglutide.

Hypotensive drugs

The concomitant use of multiple doses of dulaglutide with lisinopril at equilibrium did not cause clinically significant changes in AUC or C_max of lisinopril. A statistically significant delay in t_max lisinopril by approximately 1 h was observed on days 3 and 24 of the study. When a single dose of dulaglutide was used concomitantly with metoprolol, the AUC or C_max of metoprolol increased by 19% and 32%, respectively. Although t_max metoprolol was reached 1 h later, this change was not statistically significant. These changes were not considered to be clinically significant; thus, no dose adjustment of lisinopril or metoprolol when used with dulaglutide is required.

Warfarin

After concomitant use with dulaglutide, the S- and R-warfarin concentrations and C_max of R-warfarin did not change, and C_max of S-warfarin decreased by 22%. The area under the concentration-time curve for the international normalized ratio (AUC_MNO) increased by 2%, which probably has no clinical significance; there was no effect on the maximum international normalized ratio (INR_max). The international normalized ratio response time (tMNO_max) was prolonged by 6 h, which is consistent with a t_max delay of approximately 4 and 6 h for S- and R-warfarin, respectively. Such changes are not considered clinically significant. No dose adjustment of warfarin is required when used with dulaglutide.

Oral contraceptives

The concomitant use of dulaglutide with oral contraceptives (norelgestimat 0.18 mg/ethinylestradiol 0.025 mg) had no effect on total exposure to norelgestromine and ethinylestradiol. For norelgestromine and ethinylestradiol, there was a statistically significant decrease in C_max of 26% and
13% and a delay in t_max of 2 and 0.30 h, respectively. Such observations are not considered clinically significant. No oral contraceptive dose adjustment is required when used with dulaglutide.

Metformin

After concomitant use of multiple doses of dulaglutide and normal-release metformin at equilibrium, AUCτ increased by up to 15% and C_max decreased to 12%; t_max was unchanged. These changes are consistent with the delayed gastric emptying that dulaglutide causes and are within the variability of metformin pharmacokinetics, so are not considered clinically significant. No dose adjustment of normal-release metformin is required for concomitant use with dulaglutide.

Sitagliptin

The concentration of sitagliptin was not altered by concomitant use with a single dose of dulaglutide. After concomitant use with two consecutive doses of dulaglutide, the AUC_(0-τ) and C_max of sitagliptin decreased by approximately 7.4% and 23.1%, respectively. The t_max of sitagliptin increased by approximately 0.5 h after concomitant use with dulaglutide compared with sitagliptin monotherapy.

Sitagliptin can cause inhibition of DPP-4 activity by up to 80% within 24 hours. When dulaglutide and sitagliptin were used concomitantly, the exposure and C_max of dulaglutide increased by approximately 38% and 27%, respectively, and the median t_max increased to approximately 24 h. Thus, dulaglutide has a high degree of protection against DPP-4 inactivation. Increased exposure may increase the effect of dulaglutide on blood glucose concentration.

Special Instructions

Dulaglutide is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Dulaglutide is not a substitute for insulin. Cases of diabetic ketoacidosis have been reported in insulin-dependent patients after rapid withdrawal or reduction of the insulin dose.

dehydration

Patients treated with Trulicity^®, especially at the beginning of therapy, have reported dehydration, sometimes leading to acute renal failure or impaired renal function. Many adverse renal events have been observed in patients with a history of nausea, vomiting, diarrhea or dehydration. Patients treated with Trulicity® should be advised of the potential risk of dehydration, especially with respect to adverse gastrointestinal reactions, and precautions should be taken to avoid hypovolemia.

The use of dulaglutide in patients with severe GI disease, including severe gastric paresis, has not been studied, so the drug is contraindicated in this patient cohort.

acute pancreatitis

The use of GFP-1 receptor agonists is associated with the risk of acute pancreatitis. Cases of acute pancreatitis associated with dulaglutide therapy have been reported in clinical trials.

Patients should be informed of the characteristic symptoms of acute pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, dulaglutide therapy should be discontinued. If the diagnosis of pancreatitis is confirmed, dulaglutide should be withdrawn without resuming therapy. In the absence of other signs and characteristic symptoms of acute pancreatitis, increased pancreatic enzyme activity alone is not a prognostic factor for acute pancreatitis.

If a patient has a history of pancreatitis, therapy with other hypoglycemic agents should be considered.

Hypoglycemia

Patients receiving dulaglutide concomitantly with a sulfonylurea derivative or insulin may be at increased risk of hypoglycemia. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylurea derivative or insulin.

CSN

The experience with dulaglutide in patients with CSN is limited.

Dulaglutide should be used with caution in patients with CHF class I or II (according to NYHA classification).

acute renal failure

In post-registration experience with GFP-1 receptor agonists, including dulaglutide, cases of acute renal failure and worsening chronic renal failure have been reported that required hemodialysis. Some of these events have been reported in patients without diagnosed kidney disease. Most of the reported events were in patients experiencing nausea, vomiting, diarrhea, or dehydration. Since these reactions may impair renal function, caution should be exercised when prescribing therapy and increasing the dose of the drug in patients with renal impairment. Renal function should be monitored in patients with renal impairment who report severe GI HF.

Macrovascular Complications

There are no clinical trial data supporting a reduced risk of macrovascular complications in patients with DM2 with Trulicity^®.

Risk of medullary thyroid cancer

Patients should be informed about the potential risk of medullary thyroid cancer when using dulaglutide and the clinical symptoms of a thyroid tumor (increased tissue volume or nodules in the neck area, shortness of breath, persistent hoarseness).

Sodium content

The drug contains less than 1 mmol of sodium (23 mg) per 1.5 mg dose, i.e., virtually no sodium.

Fertility

Data on the effect of dulaglutide on fertility in humans are not available. No direct effect on mating or fertility has been observed in rats after dulaglutide use.

Influence on driving and operating ability

Dulaglutide has minimal or no effect on driving and operating ability. Caution is recommended when using dulaglutide in combination with a sulfonylurea derivative or insulin to avoid hypoglycemia during driving and operating machinery.

Synopsis

Transparent colorless solution.

Contraindications

• hypersensitivity to dulaglutide or any of the excipients in the drug;
• diabetes mellitus type 1;
• diabetic ketoacidosis;
• terminal stage of renal failure (FFR < 15 ml/min/1.73 m²);
• pregnancy;
• breastfeeding period;
• serious gastrointestinal (GI) diseases, including.ч. severe gastric paresis;
• acute pancreatitis;
• patients with a personal or family history of medullary thyroid cancer
• Age
• under 18 years of age (due to lack of data on efficacy and safety of dulaglutide in this age group).

With caution

In patients taking oral medications that require rapid absorption in the GI tract; in patients with CHF class I and II (as classified by the New York Heart Association, NYHA).

Side effects

Safety profile review

The safety of dulaglutide has been studied in initial phase II and III clinical trials where patients received dulaglutide in monotherapy or in combination with other hypoglycemic drugs. The most common adverse reactions (ARs) in the clinical trials were GI reactions, including nausea, vomiting, and diarrhea. In general, these reactions were mild to moderate in severity and temporary in nature. The results of the long-term cardiovascular outcomes study were similar.

The NRs identified in the evaluation of the results of the phase II and III clinical trials, the long-term cardiovascular outcomes study, and the post-registration experience of use are categorized into system-organ classes, with the frequency of occurrence according to WHO recommendations: very common: ≥1/10; common: ≥1/100 to <1/10; infrequent: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000; incidence unknown (cannot be determined from available data).

Disorders of the immune system: infrequent – hypersensitivity, rare – anaphylactic reaction^#;

Disorders of metabolism and nutrition: very common – hypoglycemia* when used in combination with insulin, glimepiride, metformin^† or metformin and glimepiride; often – hypoglycemia* when used as monotherapy or in combination with metformin and pioglitazone; infrequent – dehydration;

Gastrointestinal disorders: very common – nausea, diarrhea, vomiting^†, abdominal pain^†; common – decreased appetite, dyspepsia, constipation, flatulence, bloating, gastroesophageal reflux disease, belching; infrequent – acute pancreatitis; with unknown frequency – non-mechanical intestinal obstruction;

Liver and biliary tract disorders: infrequent – cholelithiasis, cholecystitis;

Skin and subcutaneous tissue disorders: rarely – angioedema^#;

General disorders and disorders at the injection site: Frequent – weakness; infrequent – reactions at the injection site;

Laboratory and instrumental findings: frequent – sinus tachycardia, first-degree atrioventricular block.

^# Post-registration experience

* Documented symptomatic hypoglycemia with blood glucose concentrations ≤3.9 mmol/L.

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

Description of individual HP

Hypoglycemia

. When dulaglutide was used at doses of 0.75 mg and 1.5 mg once weekly as monotherapy or in combination with metformin or metformin and pioglitazone, the incidence of documented symptomatic hypoglycemia was 5.9% to 10.9%, or 0.14 to 0.62 events/patient/yr; no cases of severe hypoglycemia were noted.

The incidence of documented symptomatic hypoglycemia was 39.0% and 40.3%, or 1.67 and 1.67 events/patient/year, respectively, when dulaglutide was used at 0.75 mg and 1.5 mg once weekly in combination with sulfonylurea derivative and metformin. The frequency of severe hypoglycemia events was 0% and 0.7%, or 0.00 and 0.01 events/patient/year, respectively, for each dose. The incidence of documented symptomatic hypoglycemia with dulaglutide at 1.5 mg doses with a sulfonylurea derivative was 11.3% and 0.90 episodes/patient/year. No cases of severe hypoglycemia were reported.

The incidence of documented symptomatic hypoglycemia with dulaglutide at 1.5 mg doses with insulin glargine was 35.3% and 3.38 episodes/patient/year. The incidence of severe hypoglycemia was 0.7% and 0.01 episodes/patient/year.

The incidence of hypoglycemia was 85.3% and 80.0%, or 35.66 and 31.06 episodes/patient/year, respectively, when dulaglutide was used at 0.75 mg and 1.5 mg once weekly in combination with prandial insulin. The incidence of severe hypoglycemia was 2.4% and 3.4%, or 0.05 and 0.06 events/patient/year, respectively.

Gastrointestinal events

. Cumulative reports of GI phenomena for up to 104 weeks when dulaglutide was used at doses of 0.75 mg and 1.5 mg once weekly, respectively, included nausea (12.9% and 21.2%), diarrhea (10.7% and 13.7%), and vomiting (6.9% and 11.5%). They were usually mild to moderate in severity, their maximum frequency was noted during the first 2 weeks of therapy and decreased rapidly during the next 4 weeks, after which the frequency remained relatively constant.

In clinical and pharmacological studies involving patients with DM2 that lasted up to 6 weeks, most gastrointestinal events were noted within the first 2-3 days of the first dose, and their frequency decreased with subsequent doses.

Acute pancreatitis

. The incidence of acute pancreatitis in phase II and III clinical trials 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

. With dulaglutide, the average increase in pancreatic enzyme activity (lipase and/or pancreatic amylase) is 11-21% over baseline. In the absence of other signs and symptoms of acute pancreatitis, increased pancreatic enzyme activity is not a prognostic factor for the development of acute pancreatitis.

Up increase in heart rate

. When dulaglutide was used at doses of 0.75 mg and 1.5 mg once weekly, a small average increase in heart rate of 2-4 beats per minute (bpm) was observed, and the incidence of sinus tachycardia with an increase in heart rate of ≥15 bpm compared with baseline was 1.3% and 1.4%, respectively.

Atrioventricular block .Grade I/increased interval PR

. When dulaglutide was administered at doses of 0.75 mg and 1.5 mg once weekly, there was a slight average increase in the PR interval by 2-3 ms compared with baseline, with a 1.5 % and 2.4 % incidence of grade I atrioventricular block, respectively.

Immunogenicity

. In clinical studies, the use of dulaglutide was accompanied by the detection of antibodies to dulaglutide at a rate of 1.6%, indicating that structural changes in GFP-1 and modified IgG4 sites in the dulaglutide molecule, along with high homology to native GFP-1 and native IgG4, minimize the risk of developing an immune response with dulaglutide therapy. Patients who developed antibodies to dulaglutide generally had low antibody titers; however, despite the small number of patients who developed antibodies to dulaglutide, evaluation of the results of phase III clinical trials showed no clear effect of dulaglutide antibodies on changes in HbA1c. No patients with systemic hypersensitivity developed antibodies to dulaglutide.

Hypersensitivity

In phase II and III clinical trials, phenomena of systemic hypersensitivity (e.g., urticaria, edema) were observed in 0.5% of patients who received dulaglutide. In the post-registration experience with dulaglutide, anaphylactic reactions were rare.

Injection site reactions

Injection site reactions were observed in 1.9% of patients who used dulaglutide. Potentially immune-mediated injection site adverse events (e.g., rash, erythema) were observed in 0.7% of patients and were usually mild.

Early termination of participation in clinical trials due to an adverse event

. In the 26-week studies, the rate of early discontinuation due to adverse events was 2.6% (0.75 mg once weekly) and 6.1% (1.5 mg once weekly) with dulaglutide compared with 3.7% with placebo. Throughout the study (up to 104 weeks), the rate of early discontinuation due to adverse events with dulaglutide was 5.1% (0.75 mg once weekly) and 8.4% (1.5 mg once weekly). The most frequent HRs that led to early discontinuation in the 0.75 mg and 1.5 mg once-week dosage groups were nausea (1.0% and 1.9%), diarrhea (0.5% and 0.6%), and vomiting (0.4% and 0.6%), mostly during the first 4-6 weeks of therapy.

Overdose

Symptoms of dulaglutide overdose in clinical trials have included GI disturbances and hypoglycemia.

Treatment

In case of dulaglutide overdose, symptomatic therapy should be given according to clinical signs and symptoms.

Pregnancy use

Pregnancy

There are no or limited data on the use of dulaglutide in pregnant women. Animal studies have shown reproductive toxicity, so the use of dulaglutide is contraindicated during pregnancy.

Breastfeeding

There is no evidence of dulaglutide penetration into breast milk. Risks to newborns/breastfed infants cannot be excluded. The use of dulaglutide during breastfeeding is contraindicated.