Trulicity^® (Solution) Instructions for Use

Marketing Authorization Holder

Swix Healthcare LLC (Russia)

Manufactured By

Eli Lilly and Company (USA)

Packaging and Quality Control Release

ELI LILLY and Company (USA)

Or

ELI LILLY ITALIA, S.P.A. (Italy)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

Contact Information

ELI LILLY EAST S.A. (Switzerland)

ATC Code

A10BJ05 (Dulaglutide)

Active Substance

Dulaglutide (Rec.INN registered by WHO)

Dosage Forms

	Trulicity®	Solution for subcutaneous injection 0.75 mg/0.5 ml: 4 pen-injectors
		Solution for subcutaneous injection 1.5 mg/0.5 ml: 4 pen-injectors

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection clear, colorless.

Excipients: sodium citrate dihydrate, anhydrous citric acid, mannitol, polysorbate 80 (vegetable origin), water for injection.

0.5 ml – syringes (1) – pen-injectors (4) – carton packs.

Solution for subcutaneous injection clear, colorless.

Excipients: sodium citrate dihydrate, anhydrous citric acid, mannitol, polysorbate 80 (vegetable origin), water for injection.

0.5 ml – syringes (1) – pen-injectors (4) – carton packs.

Clinical-Pharmacological Group

Parenteral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – glucagon-like peptide-1 (GLP-1) analog

Pharmacological Action

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. Its molecule consists of two identical chains linked by disulfide bonds, each containing an analog of modified human GLP-1, covalently linked to the heavy chain (Fc) fragment of modified human immunoglobulin G4 (IgG4) via a small polypeptide linker. The part of dulaglutide that 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 by dipeptidyl peptidase-4 (DPP-4) and renal clearance is 1.5-2 min. Unlike native GLP-1, Dulaglutide is resistant to DPP-4 cleavage and has a large size, which slows absorption and reduces renal clearance. These structural features provide a soluble form and a T_1/2 of 4.7 days, making the drug suitable for subcutaneous administration once a week. Furthermore, the dulaglutide molecule was designed to reduce Fc receptor-mediated immune response and reduce immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. At elevated glucose concentrations, Dulaglutide increases intracellular cyclic adenosine monophosphate (cAMP) in pancreatic β-cells, leading to increased insulin secretion. Dulaglutide suppresses excess glucagon secretion in patients with type 2 diabetes, leading to reduced hepatic glucose release. In addition, Dulaglutide slows gastric emptying.

Pharmacodynamics

In patients with type 2 diabetes, starting from the first administration, Dulaglutide improves glycemic control through sustained reduction in fasting, preprandial, and postprandial blood glucose concentrations, which is maintained for a week until the next dose.

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

The pharmacokinetic profile and corresponding pharmacodynamic profile of dulaglutide allow for once-weekly administration of the drug.

Clinical efficacy and safety

Glycemic control

The safety and efficacy of dulaglutide were evaluated in 6 randomized controlled Phase III trials involving 5171 patients with type 2 diabetes. Of these, 958 were over 65 years of age, of whom 93 were over 75 years of age. These studies included 3136 patients who received Dulaglutide, of whom 1719 received Dulaglutide 1.5 mg once weekly, and 1417 received Dulaglutide 0.75 mg once weekly. In all studies, Dulaglutide provided a clinically significant improvement in glycemic control as assessed by glycated hemoglobin (HbA1c).

Monotherapy

The use of dulaglutide in monotherapy was studied in a 52-week active-controlled clinical trial compared with metformin. The efficacy of dulaglutide at doses of 1.5 mg or 0.75 mg once weekly was superior to metformin at a dose of 1500-2000 mg/day in reducing HbA1c, and a significantly greater number of patients achieved the target HbA1c <7.0% and <6.5% with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly than with metformin at 26 weeks.

The rate of documented symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly and with metformin was 0.62; 0.15 and 0.09 episodes/patient/year, respectively. No cases of severe hypoglycemia were observed with dulaglutide.

Combination therapy with metformin

The safety and efficacy of dulaglutide were evaluated in a 104-week placebo-controlled and active-controlled clinical trial (sitagliptin 100 mg/day), where all drugs were used in combination with metformin. The use of dulaglutide at doses of 1.5 mg or 0.75 mg once weekly at 52 weeks resulted in a greater reduction in HbA1c compared to sitagliptin, with a significantly greater number of patients achieving the target HbA1c <7.0% and <6.5% with dulaglutide. These effects persisted until the end of the study (104 weeks).

The rate of documented symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly and with sitagliptin was 0.19; 0.18 and 0.17 episodes/patient/year, respectively. No cases of severe hypoglycemia were observed with dulaglutide.

The safety and efficacy of dulaglutide were also evaluated in an active-controlled trial compared with liraglutide 1.8 mg/day (starting dose 0.6 mg/day; after 1 week the dose was increased to 1.2 mg/day, and then at week 2 to 1.8 mg/day) lasting 26 weeks; both drugs were used in combination with metformin. The use of dulaglutide 1.5 mg once weekly resulted in a comparable reduction in HbA1c and number of patients achieving the target HbA1c <7.0% and <6.5% compared to liraglutide therapy.

The rate of documented symptomatic hypoglycemia with dulaglutide 1.5 mg once weekly was 0.12 episodes/patient/year, and with liraglutide was 0.29 episodes/patient/year. No cases of severe hypoglycemia were observed.

Combination therapy with metformin and sulfonylureas

In a 78-week active-controlled study, Dulaglutide was compared with insulin glargine, both drugs were used in combination with metformin and sulfonylureas. At 52 weeks, the use of dulaglutide 1.5 mg once weekly resulted in a significantly greater reduction in HbA1c compared to insulin glargine, which persisted at 78 weeks; whereas the reduction in HbA1c with dulaglutide 0.75 mg once weekly was comparable to the reduction with insulin glargine. In the dulaglutide 1.5 mg group, a significantly greater number of patients achieved the target HbA1c <7.0% or <6.5% at 52 and 78 weeks compared to the insulin glargine group.

The rate of documented symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly and with insulin glargine was 1.67; 1.67 and 3.02 episodes/patient/year, respectively. The same number of severe hypoglycemia cases (2 cases each) were observed with dulaglutide 1.5 mg once weekly and with insulin glargine.

Combination therapy with metformin and pioglitazone

In placebo-controlled and active-controlled studies (the dose of exenatide was 5 mcg twice daily for the first 4 weeks and 10 mcg twice daily thereafter), with both drugs used in combination with metformin and pioglitazone, administration of dulaglutide at doses of 1.5 mg or 0.75 mg once weekly demonstrated a significantly greater reduction in HbA1c compared to placebo and exenatide, accompanied by a significantly greater number of patients achieving the target HbA1c <7.0% or <6.5%.

The rate of documented symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly and with exenatide twice daily was 0.19; 0.14 and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycemia were observed with dulaglutide, while 2 cases of severe hypoglycemia were noted with exenatide.

Combination therapy with insulin, with or without metformin

In a clinical trial, patients who were receiving insulin once or twice daily prior to the study discontinued their previous therapy and were randomized to receive dulaglutide once weekly or insulin glargine once daily; both regimens were administered in combination with prandial insulin lispro administered three times daily, with or without metformin. At 26 weeks, the efficacy of dulaglutide at doses of 1.5 mg or 0.75 mg once weekly was superior to insulin glargine in reducing HbA1c, and the same effect persisted until week 52 of the study. The mean change in HbA1c for the dulaglutide 1.5 mg or 0.75 mg once weekly groups and the insulin glargine once daily group was: -1.64% [p<0.025], -1.59% [p<0.025] and -1.41%, respectively, at 26 weeks; -1.48% [p<0.025], -1.42% [p<0.025] and -1.23%, respectively, at 52 weeks. A greater number of patients achieved the target HbA1c <7.0% or <6.5% at 26 weeks and <7.0% at 52 weeks with dulaglutide than with insulin glargine.

The rate of documented symptomatic hypoglycemia with dulaglutide at doses of 1.5 mg or 0.75 mg once weekly 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 weekly, 7 patients with dulaglutide 0.75 mg once weekly, and 15 patients with insulin glargine.

Fasting blood glucose concentration

The use of dulaglutide led to a significantly greater reduction in fasting blood glucose concentration from baseline. The main effect on fasting blood glucose concentration was observed at 2 weeks. Improvement in fasting blood glucose concentration persisted throughout the longest study period of 104 weeks.

Postprandial blood glucose concentration (postprandial glycemia)

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

Pancreatic β-cell function

Clinical trial results showed improvement in pancreatic β-cell function with dulaglutide, as determined by the homeostasis model assessment (HOMA2-%B). The effect on β-cell function persisted for the longest study period of 104 weeks.

Body weight

With dulaglutide 1.5 mg once weekly, sustained body weight reduction was observed throughout the study (the mean change from baseline to the final time point ranged from -0.35 kg to -2.90 kg). The change in body weight with dulaglutide 0.75 mg once weekly ranged from 0.86 kg to -2.63 kg. Body weight reduction was observed in patients receiving Dulaglutide, regardless of the occurrence of nausea, although numerically the reduction was greater in the group of patients who experienced nausea.

Patient-reported outcomes

Dulaglutide significantly improved the overall treatment satisfaction score compared to exenatide twice daily therapy. Furthermore, the reported frequency of hyperglycemia and hypoglycemia with dulaglutide was significantly lower than with exenatide twice daily.

Blood pressure (BP)

The effect of dulaglutide on BP was evaluated in a study involving 755 patients with type 2 diabetes using ambulatory BP monitoring. Therapy with dulaglutide was accompanied by a reduction in systolic BP (difference -2.8 mmHg compared to placebo) at 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 risk

Based on a meta-analysis of Phase II and III trials, 51 patients (Dulaglutide: 26 (N=3885); all comparator drugs: 25 (N=2125)) experienced at least one cardiovascular event (death due to cardiovascular causes; nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina). The results showed that the use of dulaglutide did not increase the risk of cardiovascular events compared to comparator therapy (hazard ratio: 0.57; confidence interval: (0.30: 1.10)).

Preclinical safety

Preclinical studies of dulaglutide did not reveal any special risk to humans based on standard pharmacological safety and repeat-dose toxicity studies.

In a 6-month carcinogenicity study in transgenic mice, no oncogenic response was observed. In a 2-year carcinogenicity study in rats at dulaglutide concentrations ≥7 times the human therapeutic dose of dulaglutide 1.5 mg once weekly, Dulaglutide caused a significant dose-dependent increase in the incidence of C-cell thyroid tumors (adenomas and carcinomas). The significance of these findings for humans is currently unknown.

In fertility studies at doses associated with reduced food intake and maternal weight gain, a decrease in the number of corpora lutea and an increase in the duration of the estrous cycle were observed; however, no effect on fertility and conception rates or on embryonic development was observed. In reproductive toxicity studies in rats and rabbits, effects on skeletal formation and reduced fetal growth were observed at dulaglutide exposures 11-44 times the clinical exposure, but no congenital anomalies were observed. Administration of dulaglutide to rats during pregnancy and lactation caused memory deficits in female offspring at exposures 16 times the proposed clinical exposure.

Pharmacokinetics

Absorption

After subcutaneous administration to patients with type 2 diabetes, the maximum plasma concentration (C_max) of dulaglutide is observed at 48 hours. After multiple subcutaneous administrations of dulaglutide 1.5 mg to patients with type 2 diabetes, the mean C_max and area under the concentration-time curve (AUC) were approximately 114 ng/ml and 14,000 ng×h/ml, respectively. Steady-state plasma concentration (C_ss) was observed after 2-4 weeks of administration of dulaglutide 1.5 mg once weekly. Concentrations after a single subcutaneous dose of dulaglutide (1.5 mg) in the abdomen, thigh, or upper arm were comparable. The mean absolute bioavailability of dulaglutide after a single subcutaneous administration 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 to patients with type 2 diabetes at steady state, the mean V_d was approximately 19.2 L and 17.4 L, respectively.

Metabolism

Dulaglutide is considered to be degraded to its constituent amino acids via general protein catabolism pathways.

Elimination

The mean clearance of dulaglutide in humans at steady state after administration of 0.75 mg or 1.5 mg doses was 0.073 L/h and 0.107 L/h, respectively, with a T_1/2 of 4.5 and 4.7 days, respectively.

Special patient groups

Elderly patients (over 65 years)

The patient’s age did not have a clinically significant effect on the pharmacokinetic and pharmacodynamic properties of dulaglutide.

Gender and race

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

Body weight or body mass index (BMI)

Pharmacokinetic analysis showed a statistically significant inverse relationship between body weight or BMI and dulaglutide therapy, but no clinically significant effect of body weight or BMI on glycemic control was noted.

Patients with renal impairment

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar in healthy participants and in patients with mild to severe renal impairment (CrCl <30 ml/min), including end-stage renal disease (on hemodialysis). In clinical trials, the safety profile of dulaglutide in patients with moderate renal impairment was similar to the safety profile in the overall population of patients with type 2 diabetes. This study did not include patients with severe renal impairment or end-stage renal disease.

Patients with hepatic impairment

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study, which showed a statistically significant decrease in mean C_max and AUC by 30% and 33%, respectively, in patients with hepatic impairment compared to healthy patients. With worsening hepatic function, the time to reach C_max (T_max) of dulaglutide increased. The pharmacokinetic parameters of dulaglutide were independent of the degree of hepatic impairment. These changes were not considered clinically significant.

Children

Pharmacokinetic studies of dulaglutide in children have not been conducted.

Indications

The drug Trulicity^® is indicated in adult patients with type 2 diabetes mellitus to improve glycemic control

• As monotherapy when diet and exercise do not provide adequate glycemic control in patients for whom metformin is not suitable due to intolerance or contraindications;
• As part of combination therapy in combination with other hypoglycemic drugs, including insulin, if these drugs together with diet and exercise do not provide adequate glycemic control.

ICD codes

Dosage Regimen

Trulicity^® should be administered subcutaneously into the abdomen, thigh, or upper arm. The drug must not be administered intravenously or intramuscularly.

The drug can be administered at any time of day, regardless of meals.

Monotherapy

The recommended dose is 0.75 mg once weekly.

Combination therapy

The recommended dose is 1.5 mg once weekly.

In patients aged 75 years and older, the recommended starting dose of the drug is 0.75 mg once weekly.

When adding dulaglutide to ongoing metformin and/or pioglitazone therapy, metformin and/or pioglitazone can be continued at the same dose. When adding dulaglutide to ongoing sulfonylurea or prandial insulin therapy, a reduction in the dose of the sulfonylurea or prandial insulin may be required to reduce the risk of hypoglycemia.

Additional glycemic control to adjust the dulaglutide dose is not required. Additional glycemic control may be required to adjust the dose of sulfonylureas or prandial insulin.

Missed dose

If a dose of Trulicity^® is missed, it should be administered as soon as possible if there are at least 3 days (72 hours) remaining until the next scheduled dose. If there are less than 3 days (72 hours) remaining until the next scheduled dose, the missed dose should be skipped and the next dose administered according to the schedule. In each case, patients can resume their regular once-weekly dosing regimen.

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

Dose adjustment is not required in elderly patients (over 65 years of age). However, experience with therapy in patients aged >75 years is very limited; in such patients, the recommended starting dose of the drug is 0.75 mg once weekly.

In patients with mild or moderate renal impairment, dose adjustment is not required. There is very limited experience with the use of dulaglutide in patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m²) or end-stage renal disease, therefore the use of dulaglutide in this population is not recommended.

In patients with hepatic impairment, dose adjustment is not required.

The safety and efficacy of dulaglutide in children and adolescents under 18 years of age have not been established. No data are available.

Instructions for Using the Pen

The Trulicity^® single-use pen (pen) is a disposable, prefilled, ready-to-use drug delivery device. Each pen contains one weekly dose of Trulicity^® (0.75 mg/0.5 ml or 1.5 mg/0.5 ml). Each pen is intended for the administration of only one dose.

Trulicity^® is administered once a week. The patient should mark a calendar to remember the next dose.

When the patient presses the green injection button, the pen automatically inserts the needle into the skin, delivers the drug, and retracts the needle after the injection is complete.

Before starting to use the pen, it is necessary to

• Remove the drug from the refrigerator;
• Check the label to ensure it is the correct drug and that its expiration date has not passed;
• Inspect the pen (it should not be used if the pen is damaged or if the drug is cloudy, discolored, or contains particles);
• Wash hands.

Choosing the Injection Site

The patient should be assisted in choosing the injection site that best suits them.

The drug can be injected into the abdomen or thigh. Another person can administer the injection into the upper arm.

The injection site should be changed (rotated) each week. The same area can be used, but different injection points must be selected.

Administering the Drug

1. Remove the cap.

Ensure the pen is locked.

Remove and discard the gray cap covering the base.

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

2. Position and unlock.

Firmly press the clear base against the skin surface at the injection site.

Unlock by turning the lock ring.

3. Press and hold.

Press and hold the green injection button: a loud click will be heard.

Continue to hold the clear base firmly against the skin until a second click is heard. This will happen when the needle begins to retract, approximately after 5-10 seconds.

Remove the pen from the skin.

The injection is complete when the gray part of the mechanism becomes visible.

Storage and Handling

The pen contains glass parts. Handle the device with care. If the patient drops it on a hard surface, the pen should not be used. A new pen should be used for the injection.

The pen should be stored in a refrigerator.

If refrigeration after purchase from the pharmacy is not possible, the pen can be stored at temperatures not exceeding 30°C (86°F) for no more than 14 days.

Do not freeze the pen. If the pen has been frozen, it should not be used.

The pen should be stored in the original cardboard carton to protect it from light, and kept out of the reach of children.

Pen Disposal

The pen must be disposed of in a sharps container or as recommended by the treating physician.

Do not recycle a full sharps container.

The patient should be informed about possible methods for disposing of medications they no longer use.

Other Information

If the patient has visual impairments, they should not use the Trulicity^® single-use pen without the assistance of a person specifically trained in its use.

Adverse Reactions

Summary of the safety profile

In Phase II and III clinical trials, 4006 patients received Dulaglutide as monotherapy or in combination with other hypoglycemic drugs. The most frequent adverse reactions in clinical trials were gastrointestinal reactions, including nausea, vomiting, and diarrhea. Overall, these reactions were mild or moderate and transient in nature.

The adverse reactions listed below were identified during the evaluation of Phase II and III clinical trial results: they are presented in the table according to the affected organ systems in order of decreasing frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each category, adverse reactions are listed in order of decreasing frequency.

Table Frequency of adverse reactions with dulaglutide use

* Documented symptomatic hypoglycemia and blood glucose concentration ≤3.9 mmol/L.
¹ For dulaglutide 1.5 mg only. The frequency of adverse reactions for dulaglutide 0.75 mg corresponds to a lower category.

Description of selected adverse reactions

Hypoglycemia

When using dulaglutide at doses of 0.75 mg or 1.5 mg once weekly 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 from 0.14 to 0.62 events/patient/year, with no cases of severe hypoglycemia reported.

When using dulaglutide at doses of 0.75 mg or 1.5 mg once weekly in combination with sulfonylureas (plus metformin), the frequency of documented symptomatic hypoglycemia was 39.0% and 40.3% or 1.67 and 1.67 events/patient/year, respectively. The frequency of severe hypoglycemia events was 0% and 0.7% or 0.00 and 0.01 events/patient/year, respectively.

When using dulaglutide at doses of 0.75 mg or 1.5 mg once weekly 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 frequency of severe hypoglycemia events was 2.4% and 3.4% or 0.05 and 0.06 events/patient/year, respectively.

Gastrointestinal adverse reactions

Cumulative reporting of gastrointestinal events over a period of up to 104 weeks with dulaglutide at doses of 0.75 mg or 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 or moderate in severity, with peak frequency occurring within the first 2 weeks of therapy and rapidly decreasing over the next 4 weeks, after which the frequency remained relatively constant.

In clinical pharmacology studies conducted in patients with type 2 diabetes lasting up to 6 weeks, most gastrointestinal events occurred within the first 2-3 days after the first dose, and their frequency decreased with subsequent doses.

Acute pancreatitis

The frequency of acute pancreatitis in Phase II and III clinical trials was 0.07% with dulaglutide compared to 0.14% with placebo and 0.19% with comparator drugs, with or without additional background hypoglycemic therapy.

Pancreatic enzymes

The use of dulaglutide is associated with a mean increase in pancreatic enzyme activity (lipase and/or pancreatic amylase) of 11-21% compared to baseline. In the absence of other signs and symptoms of acute pancreatitis, an increase in pancreatic enzyme activity is not predictive of developing acute pancreatitis.

Increased heart rate (HR)

When using dulaglutide at doses of 0.75 mg or 1.5 mg once weekly, a small mean increase in HR of 2-4 beats per minute (bpm) and a frequency of sinus tachycardia of 1.3% and 1.4%, respectively, were observed, which was accompanied by an increase from baseline of ≥15 bpm.

First-degree AV block/PR interval prolongation

When using dulaglutide at doses of 0.75 mg or 1.5 mg once weekly, a small mean increase in the PR interval of 2-3 ms compared to baseline, and a frequency of first-degree AV block of 1.5% and 2.4%, respectively, were observed.

Immunogenicity

During clinical trials, treatment with dulaglutide was associated with the detection of treatment-emergent anti-dulaglutide antibodies at a frequency of 1.6%, indicating that structural changes in GLP-1 and the 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 dulaglutide therapy. Patients who developed antibodies to dulaglutide typically had low antibody titers; however, despite the small number of patients who formed antibodies to dulaglutide, evaluation of Phase III clinical trial results did not reveal a clear effect of anti-dulaglutide antibodies on the change in HbA1c.

Hypersensitivity

In Phase II and III clinical trials, systemic hypersensitivity events (severe urticaria, extensive rash, facial edema, lip edema) were observed in 0.5% of patients who received Dulaglutide. None of the patients with systemic hypersensitivity developed antibodies to dulaglutide.

Injection site reactions

Injection site reactions were observed in 1.9% of patients receiving Dulaglutide. Potentially immune-mediated adverse events at the injection site (e.g., rash, erythema) were reported in 0.7% of patients and were usually mild.

Premature discontinuation from clinical trials due to an adverse event

In trials lasting 26 weeks, the frequency of premature discontinuation due to adverse events was 2.6% (0.75 mg once weekly) and 6.1% (1.5 mg once weekly) with dulaglutide compared to 3.7% with placebo. Throughout the study (up to 104 weeks), the frequency of premature 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 adverse reactions leading to premature discontinuation in the dulaglutide 0.75 mg or 1.5 mg once weekly groups were nausea (1.0% and 1.9%), diarrhea (0.5% and 0.6%) and vomiting (0.4% and 0.6%), with such reactions mainly occurring within the first 4-6 weeks of therapy.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the drug;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Severe renal impairment;
• Chronic heart failure;
• Pregnancy;
• Breastfeeding period;
• Severe gastrointestinal diseases, including severe gastroparesis;
• Acute pancreatitis;
• Childhood and adolescence under 18 years of age.

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

Use in Pregnancy and Lactation

Pregnancy

Data on the use of dulaglutide in pregnant women are absent or limited. Animal studies have shown reproductive toxicity, therefore the use of dulaglutide is contraindicated during pregnancy.

Breastfeeding

Information on the penetration of dulaglutide into breast milk is not available. A risk to newborns/infants cannot be excluded. The use of dulaglutide during breastfeeding is contraindicated.

Use in Hepatic Impairment

In patients with hepatic impairment, dose adjustment is not required.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment. In patients with mild or moderate renal impairment, dose adjustment is not required.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

The drug should be prescribed with caution to patients aged 75 years and older.

Special Precautions

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

Gastrointestinal disorders

The use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when using dulaglutide in patients with renal impairment, as dyspeptic symptoms (nausea, vomiting and/or diarrhea) can cause dehydration, which may lead to worsening of renal function. The use of dulaglutide in patients with severe gastrointestinal diseases, including severe gastroparesis, has not been studied, therefore the drug is not recommended for this group of patients.

Acute pancreatitis

The use of GLP-1 receptor agonists is associated with a risk of acute pancreatitis. Cases of acute pancreatitis associated with dulaglutide therapy have been observed in clinical trials.

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. If pancreatitis is confirmed, Dulaglutide should be discontinued and not restarted. In the absence of other signs and characteristic symptoms of acute pancreatitis, an increase in pancreatic enzyme activity alone is not predictive of acute pancreatitis.

Hypoglycemia

In patients receiving Dulaglutide concomitantly with sulfonylureas or insulin, the risk of hypoglycemia may be increased. The risk of hypoglycemia can be reduced by lowering the dose of sulfonylureas or insulin.

Unstudied patient groups

Experience with the use of dulaglutide in patients with chronic heart failure is limited.

Sodium content

The drug contains less than 1 mmol sodium (23 mg) per 1.5 mg dose, i.e., it is essentially sodium-free.

Fertility

Data on the effect of dulaglutide on human fertility are not available. No direct effects on mating or fertility were observed in rats after administration of dulaglutide.

Effect on ability to drive and use machines

Dulaglutide has minimal or no influence on the ability to drive and use machines. When dulaglutide is used in combination with sulfonylureas or insulin, caution is recommended to avoid hypoglycemia while driving and using machines.

Overdose

Symptoms of dulaglutide overdose in clinical studies included gastrointestinal disorders and hypoglycemia.

Treatment in case of overdose requires initiating symptomatic therapy according to clinical signs and symptoms.

Drug Interactions

Dulaglutide causes a delay in the rate of gastric emptying, and therefore has the potential to impact the absorption of concomitantly administered oral medications. Dulaglutide should be used with caution in patients taking oral medications that require rapid absorption from the gastrointestinal tract. The delay in gastric emptying may slightly increase the exposure of drugs with delayed release due to the increased time for drug release.

Paracetamol

After the first dose of dulaglutide at 1 or 3 mg, the C_max of paracetamol decreased by 36% and 50%, respectively, and the median T_max was reached later (at 3 and 4 hours, respectively). After coadministration with up to 3 mg dulaglutide at steady state, no statistically significant difference was observed in the AUC_(0-∞) (area under the concentration-time curve from 0 to 12 hours), C_max, or T_max of paracetamol. No dose adjustment of paracetamol is required when used with dulaglutide.

Atorvastatin

Concomitant administration of dulaglutide with atorvastatin resulted in a reduction of C_max and AUC_(0-12) of atorvastatin and its primary metabolite, o-hydroxyatorvastatin, by up to 70% and 21%, respectively. The mean T_1/2 of atorvastatin and o-hydroxyatorvastatin after dulaglutide administration increased by 17% and 41%, respectively. These changes are not considered clinically significant. No dose adjustment of atorvastatin is required when co-administered with dulaglutide.

Digoxin

After coadministration of digoxin at steady state with two consecutive doses of dulaglutide, the total exposure (AUC_t) and T_max of digoxin were unchanged; C_max decreased by a maximum of 22%. This change is considered to have no clinical consequences. No dose adjustment of digoxin is required when used with dulaglutide.

Antihypertensive Drugs

Concomitant administration of multiple doses of dulaglutide with lisinopril at steady state did not cause clinically relevant changes in the AUC or C_max of lisinopril. A statistically significant delay in the T_max of lisinopril of approximately 1 hour was observed on study days 3 and 24. When a single dose of dulaglutide was co-administered with metoprolol, the AUC and C_max of metoprolol increased by 19% and 32%, respectively. Although the C_max of metoprolol was reached 1 hour later, this change was not statistically significant. These changes were not considered significant from a clinical perspective; therefore, no dose adjustment of lisinopril or metoprolol is required when used with dulaglutide.

Warfarin

After coadministration with dulaglutide, the concentrations of S- and R-warfarin, as well as the C_max of R-warfarin, were unchanged, while the C_max of S-warfarin decreased by up to 22%, the area under the concentration-time curve for the international normalized ratio (AUC_INR) increased by 2%, which is likely not clinically meaningful, and no effect on the maximum international normalized ratio (INR_max) was observed. The time to maximum international normalized ratio (T_INRmax) was prolonged by 6 hours, which is consistent with the delay in T_max of approximately 4 and 6 hours for S- and R-warfarin, respectively. These changes are not considered clinically significant. No dose adjustment of warfarin is required when used with dulaglutide.

Oral Contraceptives

Concomitant administration of dulaglutide with oral contraceptives (norgestimate 0.18 mg/ethinyl estradiol 0.025 mg) had no effect on the total exposure of norgestrelmin and ethinyl estradiol. For norelgestromin and ethinyl estradiol, a statistically significant decrease in C_max by 26% and 13% and a delay in T_max by 2 and 0.30 hours, respectively, were observed.

These observations are not considered clinically significant. No dose adjustment of oral contraceptives is required when used with dulaglutide.

Metformin

After coadministration of multiple doses of dulaglutide and immediate-release metformin at steady state, the AUC_t increased by up to 15%, and C_max decreased by up to 12%, while T_max was unchanged. These changes correspond to the delay in gastric emptying caused by Dulaglutide and are within the variability of metformin pharmacokinetics and therefore are not considered clinically significant. No dose adjustment of immediate-release metformin is required when co-administered with dulaglutide.

Sitagliptin

When co-administered with a single dose of dulaglutide, the concentration of sitagliptin was unchanged. After coadministration with two consecutive doses of dulaglutide, the AUC_0-t and C_max of sitagliptin decreased by approximately 7.4% and 23.1%, respectively. The T_max of sitagliptin increased by approximately 0.5 hours after coadministration with dulaglutide compared to sitagliptin monotherapy.

Sitagliptin can cause 80% inhibition of DPP-4 over 24 hours. When dulaglutide and sitagliptin were co-administered, the exposure and C_max of dulaglutide increased by approximately 38% and 27%, respectively, and the median T_max increased to approximately 24 hours. Thus, Dulaglutide has a high degree of protection from DPP-4 inactivation.

Storage Conditions

The drug should be stored in a place protected from light at a temperature between 2°C and 8°C (46.4°F); do not freeze. Do not use the drug if it has been frozen. The drug purchased at a pharmacy can be stored at a temperature not exceeding 30°C (86°F) for 14 days. Keep out of reach of children.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.