Tirzetta^® (Solution) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

Or

Medsintez Plant, LLC (Russia)

Contact Information

PROMOMED RUS LLC (Russia)

ATC Code

A10BX16 (Tirzepatide)

Active Substance

Tirzepatide (Rec.INN registered by WHO)

Dosage Forms

	Tirzetta®	Solution for subcutaneous injection 2.5 mg: pre-filled pens 0.5 ml
		Solution for subcutaneous injection 5 mg: pre-filled pens 0.5 ml
		Solution for subcutaneous injection 7.5 mg: pre-filled pens 0.5 ml
		Solution for subcutaneous injection 10 mg: pre-filled pens 0.5 ml
		Solution for subcutaneous injection 12.5 mg: pre-filled pens 0.5 ml
		Solution for subcutaneous injection 15 mg: pre-filled pens 0.5 ml

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

Solution for subcutaneous injection clear, from colorless to slightly yellowish.

Excipients: sodium chloride, disodium hydrogen phosphate heptahydrate, 1M sodium hydroxide solution or 1M hydrochloric acid solution, water for injections.

0.5 ml – single-dose disposable plastic pre-filled pens (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – cardboard packs***^×.
0.5 ml – single-dose disposable plastic pre-filled pens (1) – blister packs (1) – cardboard packs*^×.
0.5 ml – single-dose disposable plastic pre-filled pens (2) – blister packs (1) – cardboard packs**^×.
0.5 ml – single-dose disposable plastic pre-filled pens (4) – blister packs (1) – cardboard packs***^×.
0.5 ml – single-dose disposable autoinjectors (1) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (2) – cardboard packs^×.
0.5 ml – single-dose disposable autoinjectors (4) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (1) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (2) – blister packs (1) – cardboard packs^×.
0.5 ml – single-dose disposable colorless glass syringes (4) – blister packs (1) – cardboard packs^×.

^▼ The pre-filled syringe can be installed in a single-dose disposable autoinjector.
The cartridge is installed in a single-dose disposable plastic pre-filled pen.

* May additionally be equipped with 2 sterile disposable needles up to 8 mm in length.
** May additionally be equipped with 3 sterile disposable needles up to 8 mm in length.
*** May additionally be equipped with 5 sterile disposable needles up to 8 mm in length.
^× Cardboard packs with or without first-opening control.

Clinical-Pharmacological Group

Drug for the treatment of obesity and type 2 diabetes mellitus – an agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; other hypoglycemic drugs, other than insulins

Pharmacological Action

Mechanism of action

Tirzepatide is a long-acting agonist of GIP and GLP-1 receptors. Both receptors are present on α- and β-endocrine cells of the pancreas, heart, vascular system, immune cells (leukocytes), in the intestine and kidneys. GIP receptors are also present on adipocytes.

In addition, GIP and GLP-1 receptors are expressed in areas of the brain involved in appetite regulation.

Tirzepatide has high selectivity for human GIP and GLP-1 receptors. Tirzepatide has high affinity for both GIP and GLP-1 receptors. The activity of tirzepatide at the GIP receptor is similar to that of the native GIP hormone. The activity of tirzepatide at the GLP-1 receptor is lower compared to the native GLP-1 hormone.

Glycemic control

Tirzepatide improves glycemic control by reducing blood glucose concentrations both fasting and postprandial in patients with T2DM through several mechanisms.

Appetite regulation and energy metabolism

Tirzepatide reduces body weight and body fat mass. Mechanisms associated with the reduction in body weight and fat mass include reduced food intake through appetite regulation. According to clinical studies, Tirzepatide reduces energy intake and appetite by enhancing feelings of satiety and fullness, as well as blunting the feeling of hunger.

Pharmacodynamic effects

Insulin secretion

Tirzepatide increases the sensitivity of pancreatic β-cells to glucose. It provides glucose-dependent enhancement of first and second phase insulin secretion. In a hyperglycemic clamp study in patients with T2DM, Tirzepatide was compared with placebo and the selective GLP-1 receptor agonist semaglutide at a dose of 1 mg regarding insulin secretion. Tirzepatide at a dose of 15 mg increased the first and second phase insulin secretion rates by 466% and 302% from baseline, respectively. No changes in first and second phase insulin secretion rates were observed with placebo.

Insulin sensitivity

Tirzepatide increases insulin sensitivity.

Tirzepatide at a dose of 15 mg increased whole-body insulin sensitivity by 63%, as measured by the M-value, an indicator of tissue glucose uptake using the hyperinsulinemic-euglycemic clamp method. The M-value did not change with placebo.

Tirzepatide reduces body weight in patients with obesity and overweight, as well as in patients with T2DM (regardless of body weight), which may contribute to increased insulin sensitivity. Reduced food intake with tirzepatide contributes to weight loss. Weight loss is primarily due to a reduction in fat mass.

Glucagon concentration

Tirzepatide reduced fasting and postprandial glucagon concentrations in a glucose-dependent manner. Tirzepatide at a dose of 15 mg reduced fasting glucagon concentration by 28% and postprandial glucagon AUC by 43% compared to no change in the placebo group.

Gastric emptying

Tirzepatide delays gastric emptying, which may slow glucose absorption after a meal and have a positive effect on postprandial glycemia. The delay in gastric emptying caused by tirzepatide decreases over time.

Clinical efficacy and safety

T2DM

The safety and efficacy of tirzepatide were evaluated in five global randomized controlled Phase III trials (SURPASS 1-5), the primary objective of which was glycemic control. The studies involved 6263 patients with T2DM receiving therapy (4199 patients received treatment with tirzepatide). Secondary objectives included body weight control, percentage of patients achieving weight loss targets, fasting serum glucose level, and percentage of patients achieving the target glycated hemoglobin (HbA_1c) level. All five Phase III trials evaluated Tirzepatide at doses of 5, 10, and 15 mg. All patients receiving Tirzepatide started treatment with a dose of 2.5 mg for 4 weeks. The tirzepatide dose was then increased by 2.5 mg every 4 weeks until the assigned dose was reached.

As the primary objective, across all studies, treatment with tirzepatide demonstrated sustained, statistically significant, and clinically significant reduction in HbA_1c from baseline and compared to placebo or active control treatment (semaglutide, insulin degludec, and insulin glargine) for up to 1 year. In one study, these effects persisted for up to 2 years. A statistically significant and clinically significant reduction in body weight from baseline was also demonstrated. The results of the Phase III trials are presented below based on data from treatment without rescue therapy in the modified intent-to-treat population (mITT), consisting of all randomized patients who received at least 1 dose of the study drug, excluding patients who discontinued study treatment due to erroneous inclusion in the study.

SURPASS-1 – Monotherapy

In a double-blind, placebo-controlled study over 40 weeks, 478 patients with inadequate glycemic control with diet and exercise were randomized to receive tirzepatide 5 mg, 10 mg, or 15 mg once weekly or placebo. The mean age of patients was 54 years, 52% were male. At baseline, the mean duration of diabetes in patients was 5 years, and the mean BMI was 32 kg/m².

Table 1. SURPASS-1: Results at Week 40

*p <0.05, **p <0.001 for superiority, adjusted for multiplicity.

^†p <0.05, ^††p <0.001 compared to placebo, not adjusted for multiplicity.

^#p <0.05, ^##p <0.001 compared to baseline, not adjusted for multiplicity.

Figure 5. Mean HbA_1c (%) and mean body weight (kg) from baseline to week 40

Body weight control

The efficacy and safety of tirzepatide for weight control in combination with reduced calorie intake and increased physical activity were evaluated in three international, randomized, double-blind, placebo-controlled Phase 3 trials (SURMOUNT-1, SURMOUNT-3, SURMOUNT-4) in patients with obesity (BMI≥30 kg/m²) or overweight (BMI≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity (e.g., dyslipidemia, treated or untreated, hypertension, obstructive sleep apnea, or cardiovascular disease), and with prediabetes or normoglycemia, but without T2D. The trials included 3900 adult patients, of whom 2518 were randomized to receive Tirzepatide.

Tirzepatide therapy demonstrated clinically significant and sustained weight reduction compared to placebo. Furthermore, in the SURMOUNT-1 trial, a higher percentage of patients achieved weight loss of ≥5%, ≥10%, ≥15%, and ≥20% with tirzepatide compared to placebo.

The efficacy and safety of tirzepatide for weight control in patients with T2D were evaluated in a randomized, double-blind, placebo-controlled Phase 3 trial (SURMOUNT-2) and in a subgroup of patients with BMI≥27 kg/m² from five randomized Phase III trials (SURPASS-1 – 5). These trials included 6330 patients with BMI≥27 kg/m² (4249 were randomized to tirzepatide treatment). In the SURMOUNT-2 trial, tirzepatide treatment demonstrated clinically significant and sustained weight reduction compared to the placebo group. The proportion of patients achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss with tirzepatide treatment was significantly greater compared to the placebo group. Analysis of subgroups of patients with obesity or overweight in the SURPASS trials (comprising 86% of the total SURPASS 1 – 5 population) showed sustained weight reduction, as well as a higher percentage of patients achieving weight loss targets compared to active comparator/placebo.

All SURMOUNT trials used the same tirzepatide dose escalation regimen as in the SURPASS trials (starting at 2.5 mg for 4 weeks, then increasing the dose in 2.5 mg increments every 4 weeks until the assigned dose was reached).

SURMOUNT-1

In this double-blind, placebo-controlled 72-week trial, 2539 adult patients with obesity (BMI≥30 kg/m²) or overweight (BMI≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity were randomized to receive tirzepatide 5 mg, 10 mg, or 15 mg once weekly or placebo. All patients were advised on a reduced-calorie diet and increased physical activity throughout the trial. At baseline, the mean age of patients was 45 years, 67.5% were female, and 40.6% had prediabetes. The mean baseline BMI was 38 kg/m².

Table 6. SURMOUNT-1: Results at week 72

^††p<0.001 compared to baseline.

**p<0.001 compared to placebo, adjusted for multiplicity.

^##p<0.001 compared to placebo, not adjusted for multiplicity.

Figure 6. Mean change in body weight (%) from baseline to week 72

In the SURMOUNT-1 trial, tirzepatide doses of 5 mg, 10 mg, and 15 mg led to significant improvements compared to placebo in systolic BP (-8.1 mmHg vs. -1.3 mmHg), triglycerides (-27.6% vs. -6.3%), non-HDL cholesterol (-11.3% vs. -1.8%), HDL cholesterol (7.9% vs. 0.3%), and fasting insulin concentration (-46.9% vs. -9.7%).

Among patients with prediabetes at baseline (N=1032) in SURMOUNT-1, 95.3% of patients receiving Tirzepatide achieved normoglycemia at week 72 compared to 61.9% of patients in the placebo group.

SURMOUNT-2

In this 72-week double-blind, placebo-controlled trial, 938 adult patients with obesity (BMI≥30 kg/m²) or overweight (BMI from 27 kg/m² to <30 kg/m²) and T2D were randomized to receive tirzepatide 10 mg or 15 mg once weekly or placebo. Patients with an HbA_1c level of 7-10% at study entry were receiving either diet and exercise alone or one or more oral antihyperglycemic medications. All patients were advised on reduced calorie intake and increased physical activity throughout the trial. The mean age of patients was 54 years, 51% were female. The mean baseline BMI was 36.1 kg/m².

Table 7. SURMOUNT-2: Results at week 72

^†p<0.05 compared to baseline.

^††p<0.001 compared to baseline.

**p<0.001 compared to placebo, adjusted for multiplicity.

^##p<0.001 compared to placebo, not adjusted for multiplicity.

Figure 7. Mean change in body weight (%) from baseline to week 72

In the SURMOUNT-2 trial, patients receiving Tirzepatide 10 mg and 15 mg showed significant improvements in systolic BP (-7.2 mmHg vs. -1.0 mmHg), triglycerides (-28.6% vs. -5.8%), non-HDL (-6.6% vs. 2.3%), and HDL (8.2% vs. 1.1%) compared to placebo.

SURMOUNT-3

In this 84-week trial, 806 adult patients with obesity (BMI>30 kg/m²) or overweight (BMI from >27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity participated in a 12-week lead-in period prior to the trial, which included a low-calorie diet (1200-1500 kcal/day), increased physical activity, and frequent counseling on eating behavior. After the 12-week lead-in period, 579 patients who achieved more than 5.0% weight loss were randomized to receive tirzepatide at the maximum tolerated dose (MTD) of 10 mg or 15 mg once weekly or placebo for 72 weeks (double-blind period). Patients followed a reduced-calorie diet and increased physical activity throughout the trial. The mean age of patients at randomization was 46 years, 63% were female. The mean BMI at randomization was 35.9 kg/m².

Table 8. SURMOUNT-3: Results at week 72

¹ Randomization (Week 0)

^††p<0.001 compared to baseline¹.

**p<0.001 compared to placebo, adjusted for multiplicity.

^##p<0.001 compared to placebo, not adjusted for multiplicity.

Figure 8. Mean change in body weight (%) from week 12 to week 72

SURMOUNT-4

In this 88-week trial, 783 adult patients with obesity (BMI>30 kg/m²) or overweight (BMI from >27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity were enrolled in a 36-week lead-in period including tirzepatide therapy. At the start of the lead-in period, the mean patient body weight was 107.0 kg, and the mean BMI was 38.3 kg/m². At the end of the lead-in period, 670 patients who reached the MTD of tirzepatide 10 mg or 15 mg were randomized to continue tirzepatide once weekly or switch to placebo for 52 weeks (double-blind phase). Throughout the trial, patients received advice on reduced calorie intake and increased physical activity. At randomization (week 36), the mean age of patients was 49 years, 71% were female. The mean body weight at randomization was 85.2 kg, and the mean BMI was 30.5 kg/m².

Patients who continued tirzepatide treatment for an additional 52 weeks (up to 88 weeks total) maintained and continued weight loss after the initial weight loss achieved during the 36-week lead-in phase. Weight loss was greater and clinically significant compared to the placebo group, which showed significant regain of body weight lost during the lead-in phase (see Table 9 and Figure 9). Nevertheless, the observed mean body weight of patients receiving placebo at week 88 was lower than at the start of the lead-in phase (see Fig. 9).

Table 9. SURMOUNT-4: Results at week 88

^††p<0.001 compared to baseline.

**p<0.001 compared to placebo, adjusted for multiplicity.

^##p<0.001 compared to placebo, not adjusted for multiplicity.

Figure 9. Mean change in body weight (%) from baseline (week 0) to week 88

Risk of weight regain to a level >95% of baseline weight (week 0) at week 88 of the study

Time-to-event analysis showed that continued treatment with tirzepatide during the double-blind period reduced the risk of returning to a body weight greater than 95% of that observed at week 0 for those who had already lost at least 5% from week 0 by approximately 99% compared to placebo (hazard ratio 0.013 [95% CI, 0.004-0.046]; p<0.001).

Effect on body composition

Changes in body composition were assessed in an additional SURMOUNT-1 study using dual-energy X-ray absorptiometry (DXA). The DXA study results showed that tirzepatide use was associated with a greater reduction in fat mass compared to lean body mass, leading to an improvement in body composition compared to placebo at 72 weeks. Furthermore, the reduction in total fat mass was accompanied by a decrease in visceral fat. These results suggest that the reduction in total body weight is primarily associated with a decrease in adipose tissue, including visceral fat.

Improvement in physical functioning

In patients with obesity or overweight without diabetes treated with Tirzepatide, small improvements in health-related quality of life, including physical functioning, were demonstrated. Improvements in patients taking Tirzepatide were more significant than in those receiving placebo. Health-related quality of life was assessed using the overall 36-Item Short Form Health Survey, version 2 (SF-36v2).

Cardiovascular system examination

Cardiovascular (CV) risk was assessed via a meta-analysis of patients who had at least one major adverse cardiovascular event (MACE). The 4-component MACE (MACE-4) composite endpoint included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.

According to the results of the primary meta-analysis of phase II and III registration studies in patients with type 2 diabetes, a total of 116 patients (Tirzepatide: 60 [n=4410]; all comparators: 56 [n=2169]) experienced at least one adjudicated MACE-4 event: results showed that Tirzepatide was not associated with an increased risk of cardiovascular events compared to several comparators (HR: 0.81; CI: 0.52 to 1.26).

An additional analysis was conducted specifically for the SURPASS-4 study, which included patients with established cardiovascular disease. All 109 patients (Tirzepatide: 47 [n=995]; insulin glargine: 62 [n=1000]) experienced at least one adjudicated MACE-4 event: results showed that Tirzepatide was not associated with an increased risk of cardiovascular events compared to insulin glargine (HR: 0.74; CI: 0.51 to 1.08).

In three placebo-controlled phase III weight management studies (SURMOUNT 1-3), a total of 27 patients experienced at least one adjudicated MACE (TZP: 17 (n=2,806); placebo: 10 (n=1,250)); the event rate was similar for placebo and tirzepatide.

Blood pressure

In placebo-controlled phase III studies in patients with T2D, tirzepatide led to a reduction in systolic and diastolic BP by an average of 6-9 mmHg and 3-4 mmHg, respectively. Patients receiving placebo showed an average reduction in systolic and diastolic BP of 2 mmHg for each measure.

In three placebo-controlled phase III weight management studies (SURMOUNT 1-3), treatment with tirzepatide led to an average reduction in systolic and diastolic BP of 7 mmHg and 4 mmHg, respectively. Patients receiving placebo had an average reduction in systolic and diastolic BP of <1 mmHg.

Fasting serum glucose level

In the SURPASS-1-5 studies, tirzepatide led to a significant reduction in fasting blood glucose from baseline (changes from baseline to the primary endpoint ranged from -2.4 mmol/L to -3.8 mmol/L). A significant reduction in fasting blood glucose from baseline was observed as early as 2 weeks. Further improvement in fasting blood glucose was observed up to 42 weeks, then maintained for the longest study period of 104 weeks.

Postprandial glucose level

In the SURPASS 1-5 studies, tirzepatide led to a significant reduction in the mean glucose level 2 hours after a meal (mean of three main meals per day) from baseline (changes from baseline to the primary endpoint ranged from -3.35 mmol/L to -4.85 mmol/L).

Triglycerides

In the SURPASS 1-5 studies, Tirzepatide at doses of 5 mg, 10 mg, and 15 mg led to a reduction in serum triglyceride levels of 15-19%, 18-27%, and 21-25%, respectively.

In a 40-week study compared to semaglutide 1 mg, Tirzepatide at doses of 5 mg, 10 mg, and 15 mg led to a reduction in serum triglycerides of 19%, 24%, and 25%, respectively, compared to a 12% reduction with semaglutide 1 mg.

In a 72-week placebo-controlled phase III study in patients with obesity or overweight without T2D, treatment with tirzepatide at doses of 5 mg, 10 mg, and 15 mg led to a reduction in serum triglyceride levels of 24%, 27%, and 31%, respectively, compared to a 6% reduction with placebo.

Proportion of patients achieving HbA_1c<5.7% without clinically significant hypoglycemia

In 4 studies without combination of tirzepatide with basal insulin (SURPASS-1-4), from 93.6% to 100% of patients achieved normoglycemia HbA_1c<5.7% (≤39 mmol/mol) at the primary endpoint visit with tirzepatide treatment without clinically significant hypoglycemia. In the SURPASS-5 study, 85.9% of patients taking Tirzepatide who achieved HbA_1c<5.7% (<39 mmol/mol) had no clinically significant hypoglycemia.

Age, sex, race

Age, sex, race, ethnicity, region, as well as baseline BMI, HbA_1c, duration of diabetes, and level of renal impairment did not affect the efficacy of tirzepatide in the treatment of T2D.

Age, sex, race, ethnicity, region, baseline BMI, and the presence or absence of prediabetes did not affect the efficacy of tirzepatide regarding weight control.

Non-clinical safety data

Non-clinical data based on safety pharmacology, chronic toxicity, and genotoxicity studies revealed no risk to humans.

A 2-year carcinogenicity study was conducted in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.12, 0.36, and 1.02 times the maximum recommended human dose (MRHD) based on AUC), administered subcutaneously twice a week. Tirzepatide caused an increase in the number of thyroid C-cell tumors (adenomas and carcinomas) at all doses compared to control. The significance of these findings for humans is unknown.

In a 6-month carcinogenicity study in rasH2 transgenic mice, Tirzepatide at doses of 1, 3, and 10 mg/kg administered subcutaneously twice a week did not cause an increase in the incidence of thyroid C-cell hyperplasia or neoplasia at all doses tested.

Animal studies with tirzepatide did not reveal any direct adverse effects on fertility.

In reproductive toxicity studies, Tirzepatide was shown to cause fetal growth retardation and fetal developmental abnormalities at exposures below the maximum recommended human dose based on AUC. In offspring, there was an increased incidence of malformations of external, internal organs and skeleton, as well as changes in the development of internal organs and skeleton. In rats and rabbits, fetal growth reduction was observed. All adverse effects on reproduction were observed at toxic doses, multiples of therapeutic doses.

Pharmacokinetics

Tirzepatide consists of 39 amino acids and has an attached C20 fatty diacid component that provides albumin binding and prolongs T_1/2.

Absorption

The C_max of tirzepatide is achieved 8-72 hours after dose administration. Steady-state exposure is achieved after 4 weeks of once-weekly administration. Tirzepatide exposure increases proportionally with dose.

Similar exposure is achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm.

The absolute bioavailability of tirzepatide after subcutaneous administration was 80%.

Distribution

The mean apparent V_d of tirzepatide at steady state after subcutaneous administration in patients with T2D is approximately 10.3 L, and in patients with obesity is 9.7 L.

Tirzepatide is highly bound to plasma albumin (99%).

Metabolism

Tirzepatide is metabolized by proteolysis of the peptide backbone, β-oxidation of the C20 fatty diacid component, and amide hydrolysis.

Elimination

The observed mean population clearance of tirzepatide is about 0.06 L/h, and the T_1/2 is about 5 days, allowing for once-weekly administration.

Tirzepatide is eliminated by metabolism. Metabolites of tirzepatide are excreted mainly in urine and feces. Tirzepatide is not detected unchanged in urine or feces.

Pharmacokinetics in special patient groups

Age, sex, race, ethnicity, body weight. Age, sex, race, ethnicity, or body weight do not have a clinically significant impact on the PK of tirzepatide. According to population pharmacokinetic analysis, tirzepatide exposure increases with decreasing body weight; however, the effect of body weight on the PK of tirzepatide is not considered clinically significant.

Renal impairment. Renal impairment does not affect the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with varying degrees of renal impairment (mild, moderate, severe, ESRD) compared to patients with normal renal function; no clinically significant differences were observed. This was also demonstrated in patients with both T2D and renal impairment based on clinical study data.

Hepatic impairment. Hepatic impairment does not affect the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with varying degrees of hepatic impairment (mild, moderate, severe) compared to patients with normal hepatic function; no clinically significant differences were observed.

Children. Tirzepatide has not been studied in pediatric patients.

Indications

Adults aged 18 years and older for the treatment of

Type 2 diabetes mellitus (T2D)

The drug Tirzetta^® is indicated for the treatment of adults with poorly controlled T2D as an adjunct to diet and exercise:

• As monotherapy, when metformin is unsuitable due to intolerance or contraindications;
• In addition to other medicinal products for the treatment of T2D.

Weight control

The drug Tirzetta^® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight reduction and weight management in adults over 18 years of age with an initial body mass index (BMI)

• ≥30 kg/m² (obesity);

Or

• ≥27 kg/m² to <30 kg/m² (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, prediabetes or T2D).

ICD codes

Dosage Regimen

The initial dose of tirzepatide is 2.5 mg once weekly. After 4 weeks, the dose should be increased to 5 mg once weekly. If needed, dose increases can be made in 2.5 mg increments at intervals of at least 4 weeks on the current dose.

Table 1. Dose escalation schedule

The recommended maintenance doses are 5 mg, 10 mg, and 15 mg.

The maximum dose is 15 mg once weekly.

When adding tirzepatide to ongoing metformin and/or a sodium-glucose cotransporter-2 inhibitor (SGLT2i), the current dose of metformin and/or SGLT2i does not need to be adjusted.

When adding tirzepatide to existing therapy with sulfonylureas and/or insulin, a reduction in the dose of sulfonylurea or insulin may be considered to reduce the risk of hypoglycemia. Self-monitoring of blood glucose is necessary for adjusting the dose of sulfonylurea and insulin. A stepwise approach to insulin reduction is recommended (see sections “Special Instructions” and “Adverse Reactions”).

Missed dose

If a dose is missed, the drug should be administered as soon as possible within 4 days of the scheduled dose administration. If more than 4 days have passed, the missed dose should be skipped and the next dose administered on the scheduled day. In either case, patients may resume their usual once-weekly dosing schedule. If necessary, the day of weekly administration can be changed provided that the time between two doses is at least 3 days.

Special patient groups

Elderly patients

No dose adjustment of Tirzetta^® is required in elderly patients (see sections “Pharmacodynamics” and “Pharmacokinetics”). Limited data are available on the use of tirzepatide in patients aged ≥85 years.

Age, sex, race, body weight

No dose adjustment based on age, sex, race, or body weight is required (see sections “Pharmacodynamics” and “Pharmacokinetics”).

Patients with renal impairment

No dose adjustment is required in patients with renal impairment, including end-stage renal disease (ESRD). Experience with tirzepatide in patients with severe renal impairment and ESRD is limited. Caution should be exercised when treating these patients with tirzepatide.

Patients with hepatic impairment

No dose adjustment is required in patients with hepatic impairment. Experience with tirzepatide in patients with severe hepatic impairment is limited. Caution should be exercised when treating these patients with tirzepatide (see section “Pharmacokinetics”).

Children

The safety and efficacy of Tirzetta^® in children under 18 years of age have not been established at this time. No data are available.

Method of administration

The drug is administered subcutaneously in the abdomen, thigh, or upper arm. The drug can be administered at any time of day, regardless of meals. The injection site should be rotated with each administration. If a patient is also administering insulin, they should administer the Tirzetta^® injection in a different injection area.

Patients and caregivers should be trained in subcutaneous injection technique before administering Tirzetta^®.

Before administering Tirzetta^®, patients must carefully read the accompanying Instructions for Use leaflet (see below).

Instructions for using the Tirzetta^® single-dose pre-filled pen

Tirzetta^® must not be frozen

The single-dose pre-filled pen (hereinafter referred to as the pen) is for single use only.

The instructions for using the pen for subcutaneous injection must be followed carefully.

The patient should be informed that a new pen must be used for each injection.

Figure 1

1. Preparation for use

A. Pull the pen cap to remove it. Do not remove the label from the pen.

B. Remove the protective seal from a new needle (Figure 2).

Figure 2

Screw the needle directly onto the cartridge holder (Figure 3).

Figure 3

Remove the outer, then the inner needle cap (Figure 4). Do not discard the caps; they will be needed for pen disposal.

Figure 4

C. It is important to prepare the pen before use to remove any air that may be inside the cartridge and needle.

Slowly turn the dose selector to set the symbol “-…” in the dose selector window, following the 0 mark (Figure 5).

Figure 5

Hold the pen with the needle pointing upwards. Press the injection button and continue to press it until a drop of medication appears or the zero mark in the dose selector window aligns with the pointer on the pen body. If medication does not appear at the needle tip after this, repeat the steps in section 1.C until medication appears at the needle tip (Figure 6).

Figure 6

The pen is now ready for use.

If the dose selector does not return to the zero mark and medication does not appear at the needle tip, the pen needle being used may be blocked. In this case, remove the old needle and replace it with a new one. Then repeat the steps in section 1.C.

2. Performing the injection

A. Ensure that the pointer on the body of the pre-filled pen is pointing to the zero mark in the dose selector window. By turning the dose selector, set the numerical value corresponding to the pen dose. Each pen corresponds to one of the doses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg. Do not set the dose by counting the number of clicks heard when turning the dose selector. Do not rely on clicks until the prescribed dose for the patient appears in the window.

For example, Figure 7 shows the numerical value “2.5”, which corresponds to a pen-injector with a dose of 2.5 mg.

B. The drug should be administered subcutaneously into the abdomen, thigh, or upper arm. The injection site should be rotated with each administration. Wipe the skin with an alcohol swab. Insert the needle into the chosen site and press the trigger button, continuing to press it until the zero mark in the dose selector window aligns with the pointer on the pen body. Count to 10 and remove the needle from the skin (Figure 7).

Figure 7

3. Disposal

Carefully place the inner and outer needle caps back on the needle and dispose of the pen-injector (Figure 8).

Figure 8

All remaining medicinal product and waste materials should be disposed of in accordance with the requirements established by national legislation.

Instructions for Use of Tirzetta^® as a single-dose prefilled syringe with autoinjector

1. Preparation for Use

Do not shake the autoinjector. Immediately before injection, remove the cap from the autoinjector by pulling it straight off with a little force using one hand (Figure 1). Do not twist the cap.

Figure 1

2. Injection

With one hand, pinch the skin fold, cleaned with an alcohol swab, and hold it throughout the injection procedure (Figure 2).

Figure 2

With the other hand, hold the autoinjector by the body. Press the autoinjector firmly against the skin at a 90-degree angle and keep it pressed firmly throughout the injection procedure (Figure 3).

Pressing the autoinjector against the surface of the skin fold will initiate the injection. Monitor the injection by observing the plunger movement in the viewing window.

Figure 3

When the full dose has been administered, the plunger will be fully depressed and an audible click will be heard (Figure 4).

Figure 4

After the injection is complete, remove the autoinjector; the needle will be automatically covered by the protective sleeve (Figure 5).

Figure 5

3. Disposal

Replace the protective cap and dispose of the injector. Reuse of the injector is not possible, as it will be locked.

All remaining medicinal product and waste materials should be disposed of in accordance with the requirements established by national legislation.

Instructions for Use of Tirzetta^® as a single-dose prefilled syringe

1. Preparation for Use

Figure 1

Remove the protective cap by first twisting it and then pulling it straight off the protective cover. Do not touch the needle after removing the cap and do not allow the needle to come into contact with any surfaces (Figure 1).

If air bubbles are present in the syringe, do not remove them before injection, as this may lead to loss of part of the drug. Hold the syringe in the other hand with the graduated scale facing up (Figure 2).

Figure 2

2. Injection

The drug should be administered subcutaneously into the abdomen, thigh, or upper arm. The injection site can be rotated. The skin fold, cleaned with an alcohol swab, should be held between the thumb and forefinger until the injection is complete (Figure 3).

Figure 3

The injection should be administered at a 45 or 90-degree angle to the skin surface, depending on skin thickness and the amount of subcutaneous fat (Figure 4). For a pronounced subcutaneous fat layer, the injection should be given at a 90-degree angle.

Figure 4

Inject the entire contents of the syringe by pressing the plunger. Inject the entire solution with a slow, constant pressure on the syringe plunger over 2-5 seconds (Figure 5).

Figure 5

When the syringe is empty, withdraw the needle from the skin at the same angle (Figure 6). Gently press the injection site with a dry sterile pad or cotton ball, but do not rub the area.

Figure 6

3. Disposal

All remaining medicinal product and waste materials should be disposed of in accordance with the requirements established by national legislation.

Adverse Reactions

Summary of the safety profile

In 10 completed Phase III trials, 7925 patients received Tirzepatide alone or in combination with other glucose-lowering drugs. The most commonly reported adverse reactions were gastrointestinal disorders. These adverse reactions were generally mild or moderate in severity. The incidence of nausea, diarrhea, and vomiting was higher during dose escalation and decreased over time (see sections “Dosage and Administration” and “Special Instructions”).

Tabulated summary of adverse reactions

The following adverse reactions are possible with the use of tirzepatide. Adverse reaction frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

^#Data from post-marketing studies.

* Definition of hypoglycemia is described in the subsection “Description of selected adverse reactions”.

^a Fatigue includes terms such as fatigue, asthenia, malaise, and lethargy.

¹ Adverse reaction observed only in patients with T2D.

² Adverse reaction observed mainly in patients with overweight or obesity, with or without T2D.

³ In weight control trials, frequency is very common; in T2D trials, frequency is common.

⁴ In weight control trials, frequency is common; in T2D trials, frequency is uncommon.

Description of selected adverse reactions

Hypersensitivity reactions

In a pool of placebo-controlled T2D trials, hypersensitivity reactions to Tirzepatide were reported, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2% of patients receiving Tirzepatide compared to 1.7% of patients receiving placebo. Cases of anaphylactic reaction and angioedema with tirzepatide use were reported rarely.

In a pool of placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, hypersensitivity reactions to Tirzepatide were reported, sometimes severe (e.g., rash and dermatitis); hypersensitivity reactions were reported in 5.0% of patients taking Tirzepatide compared to 2.3% of patients taking placebo.

Hypoglycemia in patients with T2D

T2D trials

Clinically significant hypoglycemia (blood glucose <3.0 mmol/L (<54 mg/dL)) or severe hypoglycemia (requiring assistance from another person) was observed in 10-14% (0.14-0.16 events/patient-year) of patients when tirzepatide was added to sulfonylureas and in 14-19% (0.43-0.64 events/patient-year) of patients when tirzepatide was added to basal insulin.

The incidence of clinically significant hypoglycemia with tirzepatide as monotherapy or in combination with other oral antidiabetic drugs was up to 0.04 events/patient-year (see subsection “Tabulated summary of adverse reactions” and sections “Pharmacodynamics”, “Dosage and Administration”, and “Special Instructions”).

In Phase III clinical trials, 12 episodes of severe hypoglycemia were reported in 10 (0.2%) patients. Of these 10 patients, 5 (0.1%) patients were receiving therapy with insulin glargine or a sulfonylurea, with each patient having 1 episode.

Weight control trials

In Phase III placebo-controlled weight control trials in T2D, hypoglycemia (blood glucose <3.0 mmol/L (<54 mg/dL)) was reported in 4.2% of patients receiving Tirzepatide and 1.3% of patients receiving placebo. In this trial, the incidence of hypoglycemia was higher in patients receiving Tirzepatide in combination with insulin secretagogues (e.g., sulfonylureas) (10.3%) compared to patients receiving Tirzepatide without sulfonylureas (2.1%).

No cases of severe hypoglycemia were reported.

Gastrointestinal adverse reactions

In a pool of Phase III placebo-controlled T2D trials, gastrointestinal disorders increased with tirzepatide dose: 5 mg (37.1%), 10 mg (39.6%), and 15 mg (43.6%) compared to placebo (20.4%). Nausea was observed in 12.2%, 15.4%, and 18.3% compared to 4.3%, and diarrhea in 11.8%, 13.3%, and 16.2% compared to 8.9% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively, compared to placebo. Gastrointestinal adverse reactions were predominantly mild (74%) or moderate (23.3%) in severity. The frequency of nausea, vomiting, and diarrhea was higher during the dose escalation period and decreased over time.

More patients in the tirzepatide 5 mg (3.0%), 10 mg (5.4%), and 15 mg (6.6%) groups permanently discontinued the drug due to gastrointestinal events compared to the placebo group (0.4%).

In Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, gastrointestinal disorders increased with tirzepatide dose: 5 mg (51.3%), 10 mg (55.2%), and 15 mg (55.6%) compared to placebo (28.5%). Nausea was observed in 22.1%, 28.8%, and 27.9% compared to 8.3%, and diarrhea in 16.9%, 19.3%, and 21.7% compared to 8.0% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively, compared to placebo. Gastrointestinal adverse reactions were predominantly mild (63%) or moderate (32.6%) in severity. The frequency of nausea, vomiting, and diarrhea was higher during the dose escalation period and decreased over time.

More patients in the tirzepatide 5 mg (2.0%), 10 mg (4.5%), and 15 mg (4.3%) groups permanently discontinued the drug due to gastrointestinal events compared to the placebo group (0.5%).

Gallbladder adverse reactions

In a pool of Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, the overall incidence of cholecystitis and acute cholecystitis was 0.5% and 0% for Tirzepatide and placebo, respectively.

In a pool of Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, acute gallbladder disease was reported by 1.6% of patients taking Tirzepatide and 1.0% of patients taking placebo. These acute gallbladder events were directly proportional to weight loss.

Immunogenicity

In Phase III clinical trials in T2D, 5025 patients treated with Tirzepatide were evaluated for anti-drug antibodies (ADA). Of these, 51.1% developed treatment-emergent ADA during the treatment period. In 38.3% of the tested patients, treatment-emergent ADA were persistent (ADA were present for 16 weeks or more). Neutralizing antibodies to tirzepatide activity at the GIP and GLP-1 receptors were present in 1.9% and 2.1%, respectively, and neutralizing antibodies to native GIP and GLP-1 were present in 0.9% and 0.4%, respectively. No data on changes in pharmacokinetic (PK) parameters or effects on tirzepatide efficacy associated with ADA development were obtained.

In Phase III clinical trials in 6206 patients with BMI≥27 kg/m² with or without T2D treated with Tirzepatide, the presence of ADA was assessed. Of these, 56.1% developed treatment-emergent ADA during the treatment period. In 43.1% of the tested patients, treatment-emergent ADA were persistent (ADA were present for 16 weeks or more). Neutralizing antibodies to tirzepatide activity at the GIP and GLP-1 receptors were present in 2.2% and 2.4%, respectively, and neutralizing antibodies to native GIP and GLP-1 were present in 0.8% and 0.3%, respectively.

Heart rate (HR)

In Phase III placebo-controlled T2D trials, treatment with tirzepatide resulted in a maximum mean increase in HR of 3-5 bpm. The maximum mean increase in HR in patients taking placebo was 1 bpm.

The percentage of patients with a change from baseline HR >20 bpm at 2 or more consecutive visits was 2.1%, 3.8%, and 2.9% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively, compared to 2.1% for placebo.

A small mean increase in PR interval was observed with tirzepatide compared to placebo (mean increase from 1.4 ms to 3.2 ms and mean decrease of 1.4 ms, respectively). No differences in the incidence of arrhythmia and cardiac conduction disorders were observed between treatment with tirzepatide 5 mg, 10 mg, 15 mg, and placebo (3.8%, 2.1%, 3.7%, and 3%, respectively).

In Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, treatment with tirzepatide resulted in a maximum mean increase in HR of 3-5 bpm. The maximum mean increase in HR in patients taking placebo was 1 bpm.

The percentage of patients with a change from baseline HR >20 bpm at 2 or more consecutive visits was 1.0%, 2.4%, and 3.3% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively, compared to 0.7% for placebo.

A small mean increase in PR interval was observed with tirzepatide and placebo (mean increase from 0.3 to 1.3 ms and 0.6 ms, respectively). No differences in the incidence of arrhythmia and cardiac conduction disorders were observed between treatment with tirzepatide 5 mg, 10 mg, 15 mg, and placebo (3.9%, 3.1%, 3.6%, and 3.3%, respectively).

Injection site reactions

In Phase III placebo-controlled T2D trials, the incidence of injection site reactions was higher with tirzepatide (3.2%) compared to placebo (0.4%).

In Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, the incidence of injection site reactions was higher with tirzepatide (7.2%) compared to placebo (1.8%).

In Phase III trials, the most common signs and symptoms of injection site reactions were erythema and pruritus. The maximum severity of injection site reactions in patients was mild (91%) or moderate (9%). Injection site reactions were not considered serious.

Pancreatic enzymes

In Phase III placebo-controlled T2D trials, treatment with tirzepatide resulted in a mean increase in pancreatic amylase of 33 to 38% and lipase of 31 to 42% from baseline. Patients receiving placebo showed a 4% increase in amylase from baseline, with no change in lipase levels.

In Phase III placebo-controlled trials in patients with BMI≥27 kg/m² with or without T2D, treatment with tirzepatide resulted in a mean increase in pancreatic amylase of 20 to 24% and lipase of 29 to 35% from baseline. Patients taking placebo showed a 3.8% increase in amylase and a 5.3% increase in lipase from baseline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important to ensure continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions via the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to tirzepatide or to any of the excipients;
• Personal or family history of medullary thyroid carcinoma (MTC);
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2);
• Type 1 diabetes mellitus (T1D);
• Diabetic ketoacidosis.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of tirzepatide in pregnant women are absent or limited. Animal studies have shown reproductive toxicity of the drug. Tirzepatide is not recommended for use in pregnant women and in women of reproductive potential who are not using contraception.

Breast-feeding

Information on the excretion of tirzepatide in human milk is not available. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from/discontinue tirzepatide therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of tirzepatide on fertility in humans is unknown. Animal studies with tirzepatide have not revealed any direct harmful effects on fertility.

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment. Experience with tirzepatide in patients with severe hepatic insufficiency is limited. Caution should be exercised when treating these patients with tirzepatide.

Use in Renal Impairment

No dose adjustment is required in patients with renal impairment, including end-stage renal disease (ESRD). Experience with tirzepatide in patients with severe renal impairment and ESRD is limited. Caution should be exercised when treating these patients with tirzepatide.

Pediatric Use

The safety and efficacy of Tirzetta^® in children under 18 years of age have not been established. Data are not available.

Geriatric Use

No dose adjustment is required in elderly patients. Limited data are available on the use of tirzepatide in patients aged ≥85 years.

Special Precautions

Risk of Thyroid C-Cell Tumors

In rats of both sexes, Tirzepatide caused a dose-dependent and treatment duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a two-year study at clinically relevant plasma exposures. It is unknown whether Tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been definitively established.

Tirzepatide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). The physician should counsel patients regarding the potential risk of MTC with the use of tirzepatide and inform them about the symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin levels or thyroid ultrasound is of uncertain value for the early detection of MTC in patients treated with Tirzepatide. Such monitoring may increase the risk of unnecessary procedures due to the low specificity of the serum calcitonin test and the high background incidence of thyroid disease. Significantly elevated serum calcitonin levels may indicate MTC, and in patients with MTC, calcitonin levels are typically >50 ng/L. If serum calcitonin measurement reveals an elevation, the patient should be further evaluated. Patients with thyroid nodules detected on physical examination or neck imaging should also undergo further evaluation.

Acute Pancreatitis

The use of tirzepatide has not been studied in patients with a history of pancreatitis; therefore, Tirzepatide should be used with caution in these patients.

Acute pancreatitis has been reported in patients taking Tirzepatide.

Patients should be informed about the symptoms of acute pancreatitis. If pancreatitis is suspected, tirzepatide should be discontinued. If the diagnosis is confirmed, tirzepatide should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevation of pancreatic enzymes is not predictive of developing acute pancreatitis (see the “Adverse Reactions” section).

Hypoglycemia

Patients receiving Tirzepatide concomitantly with insulin secretagogues (e.g., sulfonylureas) or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia can be reduced by lowering the dose of the insulin secretagogue or insulin itself (see the “Dosage and Administration” and “Adverse Reactions” sections).

Effects on the Gastrointestinal (GI) Tract

Tirzepatide is associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea (see the “Adverse Reactions” section). These adverse reactions can lead to dehydration, which may cause worsening of renal function, including acute renal failure. Patients receiving Tirzepatide should be informed about the potential risk of dehydration due to GI adverse reactions and take precautions to avoid hypovolemia and electrolyte imbalances. This should be particularly considered in elderly individuals, who may be more susceptible to such complications.

Severe GI Disease

Tirzepatide has not been studied in patients with severe GI disease, including severe gastroparesis; it should be used with caution in such patients.

Acute Kidney Injury

Tirzepatide causes gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea. These events can lead to dehydration, which in severe cases may cause acute kidney injury.

Postmarketing reports of acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis, have been received for patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists. Some of these events occurred in patients without known pre-existing renal disease. Most of the reported cases occurred in patients who experienced nausea, vomiting, diarrhea, or dehydration. Renal function should be monitored at the start of treatment or upon dose increase of tirzepatide in patients with renal impairment reporting severe gastrointestinal adverse reactions.

Acute Gallbladder Disease

Acute gallbladder events, such as cholelithiasis or cholecystitis, have been reported in GLP-1 receptor agonist clinical trials and postmarketing studies. In placebo-controlled clinical trials of tirzepatide, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was reported. Acute gallbladder conditions were associated with weight loss. If cholelithiasis is suspected, gallbladder diagnostic tests and appropriate clinical follow-up are indicated.

Diabetic Retinopathy

Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute treatment, proliferative diabetic retinopathy, or diabetic macular edema; it should be used with caution in these patients with appropriate monitoring.

Aspiration with General Anesthesia or Deep Sedation

Cases of pulmonary aspiration have been reported in patients treated with GLP-1 receptor agonists undergoing general anesthesia or deep sedation.

When surgical procedures under general anesthesia or deep sedation are performed in patients receiving GLP-1 receptor agonists, there is a potential risk of pulmonary aspiration due to delayed gastric emptying (see the “Pharmacodynamics” section) and the presence of residual gastric contents.

Patients Over 85 Years of Age

There are only limited data on the use of tirzepatide in patients aged 85 years and older. Tirzepatide should be used with caution in patients aged 85 years and older, as higher sensitivity in some elderly patients cannot be ruled out.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially sodium-free.

Effect on Ability to Drive and Use Machines

Tirzepatide has no or negligible influence on the ability to drive and use machines. When used concomitantly with sulfonylureas or insulin, precautions are recommended to prevent hypoglycemia while driving and operating machinery.

Overdose

Symptoms in patients may include gastrointestinal adverse reactions, including nausea.

Treatment in case of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical manifestations and symptoms. There is no specific antidote for tirzepatide overdose. A prolonged period of observation and treatment may be required for these symptoms, considering the half-life of tirzepatide (approximately 5 days).

Drug Interactions

Tirzepatide delays gastric emptying and thus may affect the absorption rate of concomitantly administered oral medicinal products. This effect, leading to a reduction in C_max and a delay in median T_max, is most pronounced at the initiation of tirzepatide treatment.

Based on the results of a study with paracetamol, which was used as a model drug to assess the effect of tirzepatide on gastric emptying, no need for dose adjustment for most concomitantly administered oral medicinal products has been established. However, it is recommended to monitor patients taking oral medicinal products with a narrow therapeutic index (e.g., warfarin, digoxin), especially at the initiation of tirzepatide treatment and after dose increase. The risk of delayed effect should also be considered for oral medicinal products where a rapid onset of action is important.

Paracetamol

After a single dose of tirzepatide 5 mg, the C_max of paracetamol in plasma decreased by 50%, and T_max was delayed by 1 hour. The effect of tirzepatide on the oral absorption of paracetamol is dose- and time-dependent. With low doses (0.5 and 1.5 mg), only a minor change in paracetamol concentration was observed. After administration of four consecutive weekly doses of tirzepatide (5/5/8/10 mg), no effect on the C_max and T_max of paracetamol was observed. There was no effect on the overall exposure (AUC). No dose adjustment for paracetamol is required when co-administered with tirzepatide.

Oral Contraceptives

Administration of a combined oral contraceptive (0.035 mg ethinylestradiol + 0.25 mg norgestimate, a prodrug of norelgestromin) in the presence of a single dose of tirzepatide (5 mg) led to a reduction in the C_max and AUC of the oral contraceptive. The C_max of ethinylestradiol decreased by 59%, and AUC by 20%, with a delay in T_max of 4 hours. The C_max of norelgestromin decreased by 55%, and AUC by 23%, with a delay in T_max of 4.5 hours. The C_max of norgestimate decreased by 66%, and AUC by 20%, with a delay in T_max of 2.5 hours. This reduction in exposure after a single dose of tirzepatide is not considered clinically significant. No dose adjustment for oral contraceptives is required.

Incompatibilities

Due to a lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Storage Conditions

The medicinal product should be stored in the original package (carton) to protect from light at a temperature between 2°C and 8°C (46.4°F). Do not freeze.

Shelf Life

Shelf life is 2 years.

Dispensing Status

The medicinal product 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.