Soliqua

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOLIQUA® (SOLIQUA®)

Composition:

Active substances: insulin glargine, lixisenatide;

1 ml of injection solution contains 100 units of insulin glargine and 33 mcg of lixisenatide;

1 pre-filled pen contains 3 ml of injection solution, equivalent to 300 units of insulin glargine and 100 mcg of lixisenatide;

1 dose increment corresponds to 1 unit of insulin glargine and 0.33 mcg of lixisenatide;

Excipients: glycerol (85%); methionine; metacresol; zinc chloride; concentrated hydrochloric acid; sodium hydroxide; water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless or almost colorless solution.

Pharmacotherapeutic group. Medicinal products used in diabetes mellitus. Insulins and their long-acting analogues for injection.

ATC code A10AE54.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Soliqua® is a combination of two active substances with complementary mechanisms of action to improve glycemic control: insulin glargine (a basal insulin analog whose primary function is to control fasting plasma glucose levels) and lixisenatide (a glucagon-like peptide-1 [GLP-1] receptor agonist whose primary function is to control postprandial glucose levels).

Insulin glargine. The principal action of insulin, including insulin glargine, is the regulation of glucose metabolism. Insulin and its analogs lower blood glucose levels by stimulating glucose uptake in peripheral tissues, particularly skeletal muscle and adipose tissue, and by suppressing glucose production in the liver. Insulin also inhibits lipolysis and proteolysis, and stimulates protein synthesis.

Lixisenatide. Lixisenatide is a glucagon-like peptide-1 receptor (GLP-1R) agonist. GLP-1 receptors are the target of endogenous GLP-1, an incretin hormone that enhances glucose-dependent insulin secretion from pancreatic β-cells and suppresses glucagon secretion from α-cells.

Lixisenatide stimulates insulin secretion in response to elevated blood glucose levels, but does not affect insulin secretion during normoglycemia, thereby limiting the risk of hypoglycemia. Glucagon secretion is simultaneously suppressed. In the event of hypoglycemia, the glucagon-mediated rescue mechanism remains intact. Prandial administration of lixisenatide also slows gastric emptying, thereby reducing the rate of glucose absorption and entry into the systemic circulation from food.

Pharmacodynamic effects

The combination of insulin glargine and lixisenatide does not affect the pharmacodynamics of insulin glargine. The effect of the combination of insulin glargine and lixisenatide on the pharmacodynamics of lixisenatide has not been studied in phase 1 trials.

Given the relatively stable "concentration-time" profile of insulin glargine over 24 hours without pronounced peaks when administered alone, the "glucose utilization rate-time" profile was similar when the combination of insulin glargine and lixisenatide was administered.

The duration of action of insulins, including Soliqua®, may vary between individuals and even within the same individual.

Insulin glargine. Clinical studies using insulin glargine (100 units/mL) have shown that its glucose-lowering effect on a molar basis (i.e., at equivalent doses) is approximately equal to that of human insulin when administered intravenously.

Lixisenatide. In a 28-day placebo-controlled study in patients with type 2 diabetes, administration of lixisenatide at doses of 5–20 mcg resulted in statistically significant reductions in postprandial glucose levels after breakfast, lunch, and dinner.

Gastric emptying. After ingestion of a standardized test meal in the aforementioned study, it was confirmed that lixisenatide delays gastric emptying, thereby reducing the rate of postprandial glucose absorption. The effect of delayed gastric emptying was maintained throughout the study period.

Clinical efficacy and safety. The safety and efficacy of Soliqua® in glycemic control were evaluated in three randomized clinical trials involving patients with type 2 diabetes:

• Addition to metformin (in patients not previously treated with insulin).
• Transition from basal insulin.
• Transition from a GLP-1 receptor agonist.

In each of the active-controlled trials, treatment with Soliqua® resulted in clinically and statistically significant improvements in glycated hemoglobin (HbA1c) levels.

Achieving lower HbA1c levels and greater HbA1c reductions did not increase the frequency of hypoglycemia with combination therapy compared to monotherapy with insulin glargine (see section "Adverse Reactions").

In the clinical trial adding the drug to metformin, treatment was initiated at a dose corresponding to 10 dose units (10 units of insulin glargine and 5 mcg of lixisenatide). In the clinical trial transitioning from basal insulin, the initial dose was either 20 dose units (20 units of insulin glargine and 10 mcg of lixisenatide) or 30 dose units (30 units of insulin glargine and 10 mcg of lixisenatide) (see section "Dosage and Administration"), depending on the prior insulin dose. In both trials, dose titration was performed once weekly based on self-monitored fasting plasma glucose levels.

Addition to metformin (in patients not previously treated with insulin)

Clinical trial in patients with type 2 diabetes inadequately controlled on oral antidiabetic therapy. A total of 1170 patients with type 2 diabetes were randomized in a 30-week, open-label, active-controlled trial to evaluate the efficacy and safety of Soliqua® compared to its individual components—insulin glargine (100 units/mL) and lixisenatide (20 mcg).

Patients with type 2 diabetes receiving metformin as monotherapy or in combination with another oral antidiabetic agent (such as a sulfonylurea, glinide, sodium-glucose cotransporter-2 [SGLT-2] inhibitor, or dipeptidyl peptidase-4 [DPP-4] inhibitor), and who had inadequate glycemic control on such therapy (HbA1c levels ranging from 7.5% to 10.0% in patients previously on metformin monotherapy, and from 7.0% to 9.0% in those previously on metformin plus another oral antidiabetic agent), were included in a 4-week run-in period. During this run-in phase, metformin therapy was optimized, and other oral antidiabetic agents were discontinued. At the end of the run-in period, patients with persistent inadequate glycemic control (HbA1c levels between 7% and 10%) were randomized to receive the study drug, insulin glargine, or lixisenatide. Of the 1479 patients enrolled in the run-in phase, 1170 were randomized. The main reasons for exclusion from the randomized phase were fasting plasma glucose levels >13.9 mmol/L and HbA1c <7% or >10% at the end of the run-in period.

Characteristics of the randomized population with type 2 diabetes were as follows: mean age was 58.4 years, with the majority (57.1%) aged between 50 and 64 years; 50.6% were male; mean baseline body mass index (BMI) was 31.7 kg/m², with 63.4% of patients having a BMI >30 kg/m²; mean duration of diabetes was approximately 9 years. Metformin was required as background therapy, and 58% of patients were also receiving another oral antidiabetic agent at screening, with sulfonylurea being used in 54% of these patients.

At week 30, treatment with the study drug resulted in statistically significant improvement in HbA1c levels (p-value <0.0001) compared to treatment with individual components. Pre-specified subgroup analyses of this primary endpoint showed consistent results across baseline HbA1c levels (<8% or ≥8%) and baseline oral antidiabetic therapy (metformin monotherapy or combination with another oral antidiabetic agent). Information on other study endpoints is presented in Table 1 and Figure 1.

Table 1

Results from the clinical trial adding the drug to metformin at week 30 (treated patient population)

Parameter	Soliqua®	Insulin glargine	Lixisenatide
Number of patients treated	468	466	233
HbA1c level (%)
Baseline (mean value, after run-in phase)	8.1	8.1	8.1
End of study (mean value)	6.5	6.8	7.3
Change from baseline, determined by least squares method (mean value)	-1.6	-1.3	-0.9
Difference vs. insulin glargine [95% confidence interval] (p-value)		-0.3 [-0.4; -0.2] (< 0.0001)
Difference vs. lixisenatide [95% confidence interval] (p-value)			-0.8 [-0.9; -0.7] (< 0.0001)
Number of patients (%) achieving HbA1c < 7% at week 30*	345 (74%)	277 (59%)	77 (33%)
Fasting plasma glucose level (mmol/L)
Baseline (mean value)	9.88	9.75	9.79
End of study (mean value)	6.32	6.53	8.27
Change from baseline, determined by least squares method (mean value)	-3.46	-3.27	-1.50
Change vs. insulin glargine, determined by least squares method (mean value) [95% confidence interval] (p-value)		-0.19 [-0.420 to 0.038] (0.1017)
Change vs. lixisenatide, determined by least squares method (mean value) [95% confidence interval] (p-value)			-1.96 [-2.246 to -1.682] (< 0.0001)
2-hour postprandial glucose level (mmol/L)**
Baseline (mean value)	15.19	14.61	14.72
End of study (mean value)	9.15	11.35	9.99
Change from baseline, determined by least squares method	-5.68	-3.31	-4.58
Change vs. insulin glargine, determined by least squares method (mean value) [95% confidence interval]		-2.38 [-2.79 to -1.96]
Change vs. lixisenatide, determined by least squares method (mean value) [95% confidence interval]			-1.10 [-1.63 to -0.57]
Mean body weight (kg)
Baseline (mean value)	89.4	89.8	90.8
Change from baseline, determined by least squares method (mean value)	-0.3	1.1	-2.3
Comparison with insulin glargine [95% confidence interval] (p-value)		-1.4 [-1.9 to -0.9] (< 0.0001)
Comparison with lixisenatide [95% confidence interval]*			2.01 [1.4 to 2.6]
Number of patients (%) achieving HbA1c < 7.0% without weight gain at week 30	202 (43.2%)	117 (25.1%)	65 (27.9%)
Proportional difference vs. insulin glargine [95% confidence interval] (p-value)		18.1 [12.2 to 24.0] (< 0.0001)
Proportional difference vs. lixisenatide [95% confidence interval]*			15.2 [8.1 to 22.4]
Daily dose of insulin glargine
Insulin dose at week 30, determined by least squares method (mean value)	39.8	40.5	Not applicable

* Not included in the predefined study procedure of gradual lowering of levels.

** Postprandial glucose level 2 hours after meal minus glucose level before meal.

Fig. 1. Mean HbA1c (%) levels at visits during 30 weeks of treatment – treatment population

Patients in the investigational drug group showed a statistically significant greater reduction in mean plasma glucose profile assessed by self-monitoring at 7 time points from baseline to week 30 (-3.35 mmol/L) compared to patients in the insulin glargine group (-2.66 mmol/L; difference 0.69 mmol/L) and compared to patients in the lixisenatide group (-1.95 mmol/L; difference 1.40 mmol/L) (p < 0.0001 for both comparisons). At all time points at week 30, mean plasma glucose levels were lower in the investigational drug group compared to both the insulin glargine group and the lixisenatide group, except for pre-breakfast glucose levels, which were similar in the investigational drug group and the insulin glargine group.

Transition from basal insulin

Clinical study in patients with type 2 diabetes not adequately controlled on basal insulin therapy

Overall, 736 patients with type 2 diabetes participated in a randomized, 30-week, active-controlled, open-label, two-treatment-arm, parallel-group, multicenter study evaluating the efficacy and safety of Soliqua® compared to insulin glargine (100 units/mL).

Screened patients with type 2 diabetes had been receiving basal insulin for at least 6 months at a stable daily dose of 15 to 40 IU as monotherapy or in combination with one or two oral antidiabetic agents (metformin, sulfonylurea, glinide, alpha-glucosidase inhibitor, or DPP-4 inhibitor), with HbA1c levels between 7.5% and 10% (mean HbA1c at screening was 8.5%), and fasting plasma glucose levels ≤ 10.0 mmol/L or ≤ 11.1 mmol/L depending on prior antidiabetic treatment.

After screening, patients determined eligible for the study (n = 1018) entered a 6-week run-in phase during which they continued to receive insulin glargine or were switched to insulin glargine if they were previously on another basal insulin; insulin dose was titrated/stabilized while continuing metformin therapy (if previously used). Treatment with any other oral antidiabetic agents was discontinued.

After completion of the run-in period, patients with HbA1c levels between 7% and 10%, fasting plasma glucose levels ≤ 7.77 mmol/L, and a daily dose of insulin glargine between 20 and 50 units were randomized to receive either Soliqua® (n = 367) or insulin glargine (n = 369).

Characteristics of the randomized population with type 2 diabetes were as follows: mean age was 60.0 years, with the majority of patients (56.3%) aged between 50 and 64 years; 53.3% of patients were female; mean body mass index (BMI) at baseline was 31.1 kg/m², with 57.3% of patients having BMI ≥ 30 kg/m²; mean duration of diabetes was approximately 12 years, and mean duration of prior basal insulin therapy was approximately 3 years. At screening, 64.4% of patients were receiving insulin glargine as basal insulin, and 95.0% were receiving at least one oral antidiabetic agent.

At week 30 of treatment, the investigational drug demonstrated statistically significant improvement in HbA1c levels (p-value < 0.0001) compared to insulin glargine. Information on other study endpoints is presented in Table 2 and Figure 2.

Table 2

Results from the clinical study in patients with type 2 diabetes not adequately controlled on basal insulin therapy at week 30 (treatment population)

Parameter	Soliqua® Product	Insulin Glargine
Number of patients receiving treatment	366	365
HbA1c level (%)
Baseline (mean value after the run-in phase)	8.1	8.1
End of treatment (mean value)	6.9	7.5
Change from baseline, determined by least squares method (mean value)	-1.1	-0.6
Difference vs. insulin glargine [95% confidence interval] (p-value)	-0.5 [-0.6; -0.4] (< 0.0001)
Number of patients [n (%)] achieving HbA1c < 7% at week 30*	201 (54.9%)	108 (29.6%)
Fasting plasma glucose level (mmol/L)
Baseline (mean value)	7.33	7.32
End of study (mean value)	6.78	6.69
Change from baseline, determined by least squares method (mean value)	-0.35	-0.46
Difference vs. insulin glargine [95% confidence interval]	0.11 (-0.21 to 0.43)
2-hour postprandial glucose level (mmol/L)**
Baseline (mean value)	14.85	14.97
End of study (mean value)	9.91	13.41
Change from baseline, determined by least squares method (mean value)	-4.72	-1.39
Change vs. insulin glargine, determined by least squares method (mean value) [95% confidence interval]	-3.33 [-3.89 to -2.77]
Mean body weight (kg)
Baseline (mean value)	87.8	87.1
Change from baseline, determined by least squares method (mean value)	-0.7	0.7
Comparison with insulin glargine [95% confidence interval] (p-value)		-1.4 [-1.8 to -0.9] (< 0.0001)
Number of patients (%) achieving HbA1c < 7.0% without weight gain at week 30	125 (34.2%)	49 (13.4%)
Proportional difference vs. insulin glargine [95% confidence interval] (p-value)	20.8 [15.0 to 26.7] (< 0.0001)
Daily dose of insulin glargine
Baseline (mean value)	35.0	35.2
End point (mean value)	46.7	46.7
Change in insulin dose at week 30, determined by least squares method (mean value)	10.6	10.9

* Not included in the predefined study procedure of gradual dose escalation.

** Postprandial glucose level 2 hours after meal minus glucose level before meal.

Fig. 2. Mean HbA1c (%) levels at visits during 30 weeks of treatment – treated patient population

Transition from a GLP-1 receptor agonist

Clinical study in patients with type 2 diabetes inadequately controlled on a GLP-1 receptor agonist

The efficacy and safety of Soliqua® compared to continued treatment with a GLP-1 receptor agonist were evaluated in a 26-week randomized, open-label study. The study included 514 patients with type 2 diabetes who were inadequately controlled (HbA1c level between 7% and 9%, inclusive) while receiving treatment with liraglutide or exenatide for at least 4 months, or dulaglutide, albiglutide, or extended-release exenatide for at least 6 months (all agents administered at the maximum tolerated dose), in combination with metformin as monotherapy or in combination with pioglitazone, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or both. Eligible patients were randomized either to switch to the investigational medicinal product or to continue their previous GLP-1 receptor agonist, in addition to their prior oral antidiabetic therapy.

At screening, 59.7% of subjects were receiving a GLP-1 receptor agonist once or twice daily, and 40.3% were receiving a GLP-1 receptor agonist once weekly. During screening, 6.6% of subjects received pioglitazone, and 10.1% received an SGLT-2 inhibitor in combination with metformin. Baseline characteristics of the study population were as follows: mean age was 59.6 years, 52.5% of subjects were male, mean duration of diabetes was 11 years, mean duration of prior GLP-1 receptor agonist treatment was 1.9 years, mean BMI was approximately 32.9 kg/m², mean eGFR was 87.3 mL/min/1.73 m², and 90.7% of patients had eGFR ≥ 60 mL/min.

At week 26 of treatment, the investigational medicinal product demonstrated statistically significant improvement in HbA1c levels (p < 0.0001). A predefined subgroup analysis by type of GLP-1 receptor agonist (daily or weekly) used at screening showed that the change in HbA1c at week 26 was similar across subgroups and consistent with the primary analysis of the overall population. The mean daily dose of the investigational product at week 26 was 43.5 dose units. Information on other study endpoints is presented in Table 3 and Figure 3.

Table 3

Results from the clinical study in patients with type 2 diabetes inadequately controlled on GLP-1 receptor agonists at week 26 (treated patient population)

Parameter	Solviqua®	GLP-1 receptor agonist*
Number of patients who received treatment	252	253
HbA1c level (%)
Baseline (mean value after run-in phase)	7.8	7.8
End of treatment (mean value)	6.7	7.4
Change from baseline, determined by least squares method (mean value)	-1.0	-0.4
Difference vs. GLP-1 receptor agonist [95 % CI] (p-value)	-0.6 [-0.8; -0.5] (< 0.0001)
Number of patients [n (%)], in whom HbA1c levels < 7 % were achieved at week 26	156 (61.9 %)	65 (25.7 %)
Proportional difference vs. GLP-1 receptor agonist (95 % CI)	36.1 % (28.1 % to 44.0 %)
p-value	< 0.0001
Fasting plasma glucose level (mmol/L)
Baseline (mean value)	9.06	9.45
End of study (mean value)	6.86	8.66
Change from baseline, determined by least squares method (mean value)	-2.28	-0.60
Difference vs. GLP-1 receptor agonist [95 % CI] (p-value)	-1.67 [-2.00 to -1.34] (< 0.0001)
Postprandial glucose level 2 hours after meal (mmol/L)**
Baseline (mean value)	13.60	13.78
End of study (mean value)	9.68	12.59
Change from baseline, determined by least squares method (mean value)	-4.0	-1.11
Change vs. GLP-1 receptor agonist, determined by least squares method (mean value) [95 % CI] (p-value)	-2.9 [-3.42 to -2.28] (< 0.0001)
Body weight (kg)
Baseline (mean value)	93.01	95.49
Change from baseline, determined by least squares method (mean value)	1.89	-1.14
Comparison with GLP-1 receptor agonist [95 % CI] (p-value)	-3.03 [2.417 to 3.643] (< 0.0001)

* Liraglutide, exenatide twice daily or with prolonged release, dulaglutide, or albiglutide.

** Postprandial glucose level 2 hours after meal minus glucose level before meal.

Figure 3. Mean HbA1c (%) levels at visits during 26 weeks of treatment – treated patient population

Concomitant use of Soliqua® with sodium-glucose cotransporter-2 (SGLT2) inhibitors

Concomitant use of Soliqua® with SGLT2 inhibitors is supported by subgroup analyses from three phase 3 randomized clinical trials (119 patients receiving fixed-ratio combination of insulin glargine/lixisenatide who also received SGLT2 inhibitors).

One study conducted in Europe and North America included data from 26 patients (10.1%) who concurrently received the fixed-ratio combination of insulin glargine and lixisenatide, metformin, and SGLT2 inhibitors. Two additional phase 3 studies from a dedicated Japanese clinical development program, involving patients who did not achieve adequate glycemic control with oral antidiabetic agents, provided data from 59 patients (22.7%) and 34 patients (21.1%), respectively, who concurrently received SGLT2 inhibitors and the fixed-ratio combination of insulin glargine and lixisenatide.

Data from these three studies indicate that initiating Soliqua® in patients with inadequate control on SGLT2 inhibitors demonstrates greater improvement in HbA1c levels compared to comparator agents (insulin glargine, lixisenatide, liraglutide, exenatide twice daily or with prolonged release, dulaglutide, or albiglutide). In patients receiving SGLT2 inhibitors, there was no increased risk of hypoglycemia and no significant differences in overall safety profile compared to those not receiving SGLT2 inhibitors.

Studies on cardiovascular outcomes

The safety of insulin glargine and lixisenatide regarding cardiovascular events was evaluated in the ORIGIN and ELIXA clinical trials, respectively. No separate study on the cardiovascular effects of Soliqua® has been conducted.

Insulin glargine. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial was an open-label, randomized study involving 12,537 patients, comparing insulin glargine 100 units/mL with standard care in terms of first occurrence of a major cardiovascular event. A major cardiovascular event included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The median follow-up duration in the ORIGIN trial was 6.2 years. The rate of major cardiovascular events was similar in the group receiving insulin glargine 100 units/mL and the standard care group (hazard ratio [95% CI] for major cardiovascular events: 1.02 [0.94; 1.11]).

Lixisenatide. The ELIXA trial was a randomized, double-blind, placebo-controlled, multinational study assessing cardiovascular complications during treatment with lixisenatide in patients with type 2 diabetes (n = 6068) following a recent acute coronary syndrome. The primary composite endpoint was time to first occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Median follow-up duration was 25.8 months in the lixisenatide group and 25.7 months in the placebo group.

The rate of the primary endpoint was similar in the lixisenatide group (13.4%) and the placebo group (13.2%): the hazard ratio for lixisenatide versus placebo was 1.017, with an associated two-sided 95% confidence interval (CI) of 0.886 to 1.168.

Pharmacokinetics

Absorption. The insulin glargine/lixisenatide ratio does not significantly affect the pharmacokinetics of insulin glargine and lixisenatide in Soliqua®.

After subcutaneous administration of the insulin glargine/lixisenatide combination in patients with type 1 diabetes, insulin glargine did not show a pronounced peak. Exposure to insulin glargine after administration of the insulin glargine/lixisenatide combination was 86–88% of the exposure observed after separate simultaneous injections of insulin glargine and lixisenatide. This difference is not considered clinically significant.

After subcutaneous administration of the insulin glargine/lixisenatide combination in patients with type 1 diabetes, the median tmax of lixisenatide ranged from 2.5 to 3.0 hours. AUC was comparable, while a slight reduction in Cmax of lixisenatide by 22–34% was observed compared to Cmax after separate simultaneous injections of insulin glargine and lixisenatide; however, this reduction is unlikely to be clinically significant.

Clinically significant differences in the absorption rate of lixisenatide following subcutaneous administration in the abdominal area, deltoid muscle, or thigh have not been observed when used as monotherapy.

Distribution. Lixisenatide has a low (55%) plasma protein binding rate in humans. The predicted volume of distribution of lixisenatide after subcutaneous administration of the insulin glargine/lixisenatide combination (unbound volume of distribution, Vz/F) is approximately 100 L. The predicted volume of distribution of insulin glargine after subcutaneous administration of the insulin glargine/lixisenatide combination (steady-state volume of distribution, Vss/F) is approximately 1700 L.

Biotransformation and elimination. Metabolism studies in patients with diabetes receiving insulin glargine as monotherapy indicate that insulin glargine is rapidly metabolized at the carboxy-terminal end of the B-chain, forming two active metabolites – M1 (21A-glycine-insulin) and M2 (21A-glycine-des-30B-threonine-insulin). In plasma, the main circulating compound is metabolite M1. Pharmacokinetic and pharmacodynamic data suggest that the effect of subcutaneous insulin glargine injection primarily depends on M1 exposure.

Like all peptides, lixisenatide is eliminated via glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation into smaller peptides and amino acids, which are reincorporated into protein metabolism.

After single subcutaneous administration of the insulin glargine/lixisenatide combination, the mean apparent clearance (CL/F) of insulin glargine was 120 L/h. After multiple subcutaneous doses of lixisenatide in patients with type 2 diabetes, the mean terminal half-life was approximately 3 hours, and the mean apparent clearance (CL/F) was approximately 35 L/h.

Special patient populations

Patients with renal impairment. In patients with mild (creatinine clearance, calculated by Cockcroft-Gault formula, 60–90 mL/min), moderate (creatinine clearance 30–60 mL/min), and severe (creatinine clearance 15–30 mL/min) renal impairment, AUC of lixisenatide increased by 46%, 51%, and 87%, respectively.

The use of insulin glargine in patients with renal impairment has not been studied. However, insulin requirements may be reduced in patients with renal impairment due to decreased insulin metabolism.

Patients with hepatic impairment. Since lixisenatide is primarily eliminated by the kidneys, no pharmacokinetic studies have been conducted in patients with acute or chronic liver insufficiency. Hepatic impairment is not expected to affect the pharmacokinetics of lixisenatide.

The use of insulin glargine in patients with diabetes and hepatic impairment has not been studied. Insulin requirements may be reduced in patients with hepatic impairment due to decreased gluconeogenic capacity and reduced insulin metabolism.

Age, race, gender, and patient body weight

Insulin glargine. The effects of age, race, and gender on the pharmacokinetics of insulin glargine have not been studied. Subgroup analyses by age, race, and gender in controlled clinical trials in adult patients receiving insulin glargine (100 units/mL) showed no differences in safety and efficacy.

Lixisenatide. Patient age does not have a clinically significant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic study involving elderly subjects without diabetes, administration of lixisenatide 20 mcg resulted in a mean increase in AUC of lixisenatide by 29% (11 study participants aged 65–74 years and 7 participants aged ≥75 years) compared to 18 subjects aged 18–45 years, likely related to decreased renal function in elderly individuals.

Patient ethnicity does not have a clinically significant effect on the pharmacokinetics of lixisenatide, as demonstrated by pharmacokinetic studies in Caucasian, Japanese, and Chinese populations.

Patient gender does not have a clinically significant effect on the pharmacokinetics of lixisenatide.

Patient body weight does not have a clinically significant effect on AUC of lixisenatide.

Immunogenicity. In the presence of anti-lixisenatide antibodies, exposure to lixisenatide and variability in its exposure are significantly increased, regardless of dose level.

Children

Studies on the use of Soliqua® in children have not been conducted.

Preclinical safety data

No animal studies with the combination of insulin glargine and lixisenatide evaluating repeated-dose toxicity, carcinogenicity, genotoxicity, or reproductive toxicity have been conducted.

Insulin glargine. Preclinical data obtained from standard pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies indicate no specific risks to humans with the use of insulin glargine.

Lixisenatide. In 2-year carcinogenicity studies with subcutaneous administration in rats and mice, non-lethal C-cell tumors of the thyroid gland were observed, considered to be mediated by a non-genotoxic mechanism involving GLP-1 receptors, to which rodents are particularly sensitive. C-cell hyperplasia and adenoma were observed in rats at all tested doses, and a no-observed-adverse-effect level could not be established. In mice, these effects occurred at exposures approximately 9.3 times higher than in humans at therapeutic doses. No C-cell carcinomas were observed in mice, while in rats they occurred at exposures approximately 900 times higher than in humans at therapeutic doses.

In a 2-year carcinogenicity study with subcutaneous administration in mice, 3 cases of endometrial adenocarcinoma were observed, with a statistically significant increase in incidence in the medium-dose group, which resulted in exposures 97 times higher than in humans at therapeutic doses. No drug-related effects were noted.

Animal studies do not indicate any direct harmful effect of the drug on fertility in male and female rats. In dogs receiving lixisenatide, reversible changes in testes and epididymides were observed. No effect on spermatogenesis associated with drug use was observed in healthy men.

In studies of drug effects on embryofetal development in rats at all tested doses of lixisenatide (exposures 5 times higher than in humans) and in rabbits at high doses (exposures 32 times higher than in humans), developmental abnormalities, fetal growth retardation, delayed ossification, and skeletal side effects were observed. In both animal models, minor toxic effects on the maternal organism were noted, manifested by reduced food intake and body weight loss. Slowed growth was observed in male rat pups exposed to high doses of lixisenatide during late gestation and lactation, along with a slight increase in mortality rate.

Clinical Characteristics

Indications

The medicinal product Soliqua® is indicated for the treatment of adult patients with inadequately controlled type 2 diabetes mellitus to improve glycemic control as an adjunct to diet and exercise, in combination with metformin with or without sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Information on the effects on glycemic control and the studied patient populations can be found in the sections "Pharmacodynamics" and "Special Warnings and Precautions for Use".

Contraindications

Hypersensitivity to the active substances or to any of the excipients of the product.

Interaction with other medicinal products and other forms of interaction

No drug interaction studies with Soliqua® have been conducted. The information below is based on studies performed with the individual components of the product.

Pharmacodynamic interactions. A number of substances affect glucose metabolism and, therefore, their use may necessitate dose adjustments of Soliqua®.

Substances that may enhance the glucose-lowering effect and increase the risk of hypoglycemia include antidiabetic agents, angiotensin-converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors (MAOIs), pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics.

Substances that may reduce the glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, estrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic agents (e.g., epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, atypical antipsychotics (e.g., clozapine and olanzapine), and protease inhibitors.

Beta-blockers, clonidine, lithium salts, or alcohol may either potentiate or weaken the glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

In addition, under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the symptoms of adrenergic counter-regulation may be reduced or absent.

Pharmacokinetic interactions. Lixisenatide is a peptide and is not metabolized by cytochrome P450 enzymes. In vitro studies have shown that lixisenatide does not affect the activity of human cytochrome P450 isoenzymes or transporters.

No pharmacokinetic interactions are known for insulin glargine.

Effect of gastric emptying on orally administered medicinal products. Delayed gastric emptying caused by lixisenatide may reduce the rate of absorption of orally administered drugs. Close monitoring is recommended for patients receiving medicinal products with a narrow therapeutic index or those requiring careful clinical monitoring, especially at the initiation of lixisenatide therapy. These medicinal products should be taken in a standardized sequence relative to lixisenatide administration. If such medicinal products must be taken with food, patients should be advised to take them with a meal during which lixisenatide is not administered, if possible.

For oral medicinal products whose efficacy is particularly dependent on threshold concentrations (e.g., antibiotics), patients should be advised to take these products at least 1 hour before or 4 hours after lixisenatide injection.

Enteric-coated formulations containing substances sensitive to gastric degradation should be taken 1 hour before or 4 hours after lixisenatide injection.

Paracetamol. Paracetamol was used as a model drug to evaluate the effect of lixisenatide on gastric emptying. After a single 1000 mg dose of paracetamol, the AUC and elimination half-life (t1/2) of paracetamol remained unchanged regardless of the timing of administration (before or after lixisenatide injection). When paracetamol was administered 1 hour or 4 hours after injection of 10 mcg lixisenatide, the Cmax of paracetamol decreased by 29% and 31%, respectively, and the median tmax increased by 2.0 and 1.75 hours, respectively. With the maintenance dose of 20 mcg lixisenatide, a further increase in tmax and reduction in Cmax of paracetamol is expected.

When paracetamol was taken 1 hour before lixisenatide injection, Cmax and tmax of paracetamol were unchanged.

Based on these results, no dose adjustment of paracetamol is required; however, the prolonged tmax observed when paracetamol was administered 1–4 hours after lixisenatide injection should be considered when a rapid onset of action is required for efficacy.

Oral contraceptives. After a single dose of an oral contraceptive (0.03 mg ethinylestradiol / 0.15 mg levonorgestrel) taken 1 hour before or 11 hours after injection of 10 mcg lixisenatide, the Cmax, AUC, t1/2, and tmax of ethinylestradiol and levonorgestrel were unchanged.

When the oral contraceptive was taken 1 hour or 4 hours after lixisenatide injection, AUC and t1/2 of ethinylestradiol and levonorgestrel were unchanged, although Cmax of ethinylestradiol decreased by 52% and 39%, respectively, Cmax of levonorgestrel decreased by 46% and 20%, respectively, and median tmax increased by 1–3 hours. This reduction in Cmax has limited clinical significance, and no dose adjustment of oral contraceptives is required.

Atorvastatin. When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, exposure to atorvastatin was unchanged, while Cmax decreased by 31% and tmax increased by 3.25 hours.

This increase in tmax was not observed when atorvastatin was taken in the evening and lixisenatide was administered in the morning; however, AUC and Cmax of atorvastatin increased by 27% and 66%, respectively.

These changes are not considered clinically significant; therefore, no dose adjustment of atorvastatin is required when co-administered with lixisenatide.

Warfarin and other coumarin derivatives. When warfarin 25 mg was administered concomitantly with multiple doses of lixisenatide 20 mcg, no effect on AUC or INR (International Normalized Ratio) was observed, while Cmax decreased by 19% and tmax increased by 7 hours.

Based on these data, no dose adjustment of warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR is recommended at the start and end of lixisenatide therapy in patients taking warfarin or other coumarin derivatives.

Digoxin. When lixisenatide 20 mcg and digoxin 0.25 mg were co-administered at steady state, AUC of digoxin was unchanged. However, tmax of digoxin increased by 1.5 hours and Cmax decreased by 26%.

Based on these data, no dose adjustment of digoxin is required when co-administered with lixisenatide.

Ramipril. When lixisenatide 20 mcg and ramipril 5 mg were co-administered for 6 days, AUC of ramipril increased by 21%, while Cmax decreased by 63%. However, AUC and Cmax of the active metabolite (ramiprilat) were unchanged. The tmax of both ramipril and ramiprilat increased by approximately 2.5 hours.

Based on these data, no dose adjustment of ramipril is required when co-administered with lixisenatide.

Special precautions for use

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded in the patient's medical records.

Type 1 diabetes

This medicinal product should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Injection site rotation

Patients should be advised to regularly rotate injection sites to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and impaired glycaemic control following insulin injections into areas affected by these reactions. Changing the injection site to a new anatomical area has been reported to lead to hypoglycaemia. Blood glucose monitoring is recommended after changing the injection site, and dose adjustment of antidiabetic medications may be considered.

Hypoglycaemia

Hypoglycaemia was the most frequently reported adverse reaction during treatment with this medicinal product (see section "Undesirable effects"). Hypoglycaemia may occur if the dose of Soliqua® is higher than required.

Factors that increase the risk of hypoglycaemia require particularly careful monitoring and may necessitate dose adjustments. These factors include:

• change in injection site,
• increased insulin sensitivity (e.g. due to resolution of stress factors),
• unusual, excessive, or prolonged physical activity,
• concomitant illness (e.g. associated with vomiting or diarrhoea),
• inadequate nutrition,
• missed meals,
• alcohol consumption,
• certain uncompensated endocrine disorders (e.g. hypothyroidism, hypopituitarism, or adrenal insufficiency),
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction"),
• when lixisenatide and/or insulin is used in combination with sulphonylurea agents, the risk of hypoglycaemia may be increased; therefore, this medicinal product should not be used in combination with sulphonylureas.

The dosage of Soliqua® should be individually adjusted based on clinical response, and titration should be performed according to the patient's insulin requirements (see section "Method of administration and dosage").

Acute pancreatitis

Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of acute pancreatitis. A small number of cases of acute pancreatitis have been reported during treatment with lixisenatide, although a causal relationship with the drug has not been established. Patients should be informed about the characteristic symptoms of acute pancreatitis, such as persistent, severe abdominal pain. If pancreatitis is suspected, the medicinal product should be discontinued; if acute pancreatitis is confirmed, lixisenatide should not be restarted. Caution should be exercised when prescribing the product to patients with a history of pancreatitis.

Severe gastrointestinal disease

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions (see section "Undesirable effects"). The use of this medicinal product has not been studied in patients with severe gastrointestinal diseases, including severe gastroparesis; therefore, use of Soliqua® in such patients is not recommended.

Severe renal impairment

There is no therapeutic experience with the use of this medicinal product in patients with severe renal impairment (creatinine clearance <30 mL/min) or in those with end-stage renal disease. Use of this medicinal product is not recommended in patients with severe renal impairment or end-stage renal disease (see sections "Pharmacological properties. Pharmacokinetics" and "Method of administration and dosage").

Concomitant use with other medicinal products

The delayed gastric emptying caused by lixisenatide may reduce the rate of absorption of orally administered medicinal products. Soliqua® should be used with caution in patients receiving medicinal products that require rapid gastrointestinal absorption, that need close clinical monitoring, or that have a narrow therapeutic index. Specific recommendations regarding the use of such medicinal products are provided in the section "Interaction with other medicinal products and other forms of interaction".

Aspiration in combination with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonists under general anaesthesia or deep sedation. Therefore, before undergoing procedures involving general anaesthesia or deep sedation, the increased risk of residual gastric content due to delayed gastric emptying should be considered (see section "Undesirable effects").

Dehydration

Patients receiving this medicinal product should be informed about the potential risk of dehydration associated with gastrointestinal adverse reactions, and measures should be taken to prevent hypovolaemia in such patients.

Antibody formation

Use of this medicinal product may lead to the formation of antibodies against insulin glargine and/or lixisenatide. In rare cases, the presence of such antibodies may necessitate dose adjustments to prevent hyper- or hypoglycaemia.

Prevention of medication errors

Patients should be instructed to always check the labelling of the pen injector before each injection to avoid accidental confusion between the two different strengths of Soliqua® and confusion with other injectable antidiabetic medicinal products.

To avoid dosing errors and potential overdose, neither patients nor healthcare professionals should ever use a syringe to withdraw the medicinal product from the cartridge of a pre-filled pen injector.

Antidiabetic medicinal products not studied in combination with Soliqua®

The use of Soliqua® has not been studied in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas, glinides, or pioglitazone.

Travel

To avoid dosing errors and potential overdoses when crossing time zones, patients should consult their physician before travelling.

Excipients

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

This medicinal product contains metacresol, which may cause allergic reactions.

Use during pregnancy or breastfeeding

Soliqua® is not recommended for use in women of reproductive potential who are not using contraception.

Pregnancy. There are no clinical data from controlled clinical trials on the use of Soliqua®, insulin glargine, or lixisenatide during pregnancy. A large amount of data from use of insulin glargine in pregnant women (over 1000 pregnancy cases) does not indicate malformative or fetal/neonatal toxicity of insulin glargine. Animal studies have not revealed signs of reproductive toxicity of insulin glargine.

There are no or only limited data on the use of lixisenatide in pregnant women. Animal studies indicate reproductive toxicity of lixisenatide (see section "Pharmacological properties. Preclinical safety data").

The medicinal product is not recommended for use during pregnancy or in women of reproductive potential who are not using contraception.

Breastfeeding. It is unknown whether insulin glargine or lixisenatide is excreted in human breast milk. A risk to newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment with this medicinal product.

Fertility. Animal studies have not revealed any direct harmful effect of lixisenatide or insulin glargine on fertility.

Effect on ability to drive and use machines

Soliqua® has no effect or a negligible effect on the ability to drive and use machines. However, a patient's ability to concentrate and their reaction speed may be impaired as a result of hypoglycaemia or hyperglycaemia, or, for example, due to visual disturbances. This may be dangerous in situations where these abilities are of particular importance (e.g. when driving a vehicle or operating machinery).

Patients should be advised to take necessary precautions to avoid hypoglycaemia while driving or operating machinery. This is especially important for patients who have weak or absent early warning symptoms of hypoglycaemia, as well as for those who experience frequent episodes of hypoglycaemia. Careful consideration should be given to whether it is safe to drive or operate machinery under such conditions.

Method of Administration and Dosage

The medicinal product Soliqua® is available in two types of prefilled pen injectors with different dosing options, namely Soliqua® pen (10–40) and Soliqua® pen (30–60). The difference between the pen injectors relates to their dosage ranges.

• Soliqua® 100 units/mL + 50 mcg/mL in a prefilled pen: the dosage range is from 10 to 40 units of insulin glargine in combination with 5–20 mcg of lixisenatide (Soliqua® pen (10–40)).
• Soliqua® 100 units/mL + 33 mcg/mL in a prefilled pen: the dosage range is from 30 to 60 units of insulin glargine in combination with 10–20 mcg of lixisenatide (Soliqua® pen (30–60)).

To avoid medication errors, the prescribing physician must ensure that the prescription clearly specifies the correct dosage and the dosing range of the pen injector (see section "Instructions for Use").

Dosage

Dosage must be individually adjusted according to the patient's individual response, and titration should be performed according to the patient's insulin requirements. The lixisenatide dosage increases or decreases in parallel with the insulin glargine dosage and also depends on which pen injector is used.

Initial dose. Treatment with basal insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, or oral antidiabetic medicinal products (except metformin and sodium-glucose cotransporter-2 [SGLT2] inhibitors) should be discontinued prior to initiating Soliqua®.

The initial dose of the medicinal product is determined based on prior antidiabetic therapy. The recommended initial dose of lixisenatide should not exceed 10 mcg (see Table 4).

Table 4

		Previous therapy
		Patients previously not treated with insulin (oral antidiabetic drugs or GLP-1 receptor agonist)	Insulin glargine (100 units/mL)** ≥ 20 to < 30 units	Insulin glargine (100 units/mL)** ≥ 30 to ≤ 60 units
Starting dose and pen type	Soliqua® Pen (10–40)	10 dose increments (10 units/5 mcg)	20 dose increments (20 units/10 mcg)*
	Soliqua® Pen (30–60)			30 dose increments (30 units/10 mcg)*

* Insulin glargine units (100 units/mL) / micrograms of lixisenatide.

Patients using less than 20 units of insulin glargine may be considered as insulin-naïve.

** If another basal insulin has been used:

• When using a basal insulin twice daily or insulin glargine (300 units/mL), the previous total daily dose should be reduced by 20% when selecting the initial dose of Soliqua®.
• When using any other basal insulin, the same rule as for insulin glargine (100 units/mL) should be applied.

The maximum daily dose is 60 units of insulin glargine and 20 micrograms of lixisenatide, corresponding to 60 dose increments.

Soliqua® should be injected once daily within one hour before a meal. It is advisable that the prandial injection is administered before the same meal each day, after the patient has selected the most convenient mealtime for themselves.

Dose titration. The medicinal product should be administered according to the individual patient's insulin requirements. Glycemic control should be optimized by adjusting the dose based on fasting plasma glucose levels (see section "Pharmacological properties", subsection "Pharmacodynamics"). Careful monitoring of glucose levels is recommended during the transition to this product and during the first weeks thereafter.

• If a patient starts using the Soliqua® (10–40) pen, dosing may be titrated up to 40 dose increments.
• For dosing > 40 dose increments per day, titration should continue using the Soliqua® (30–60) pen.
• If a patient starts using the Soliqua® (30–60) pen, dosing may be titrated up to 60 dose increments.
• For total daily dosing > 60 dose increments, the medicinal product should not be used.

Patients who adjust the amount or timing of administration must do so only under medical supervision with appropriate glucose monitoring (see section "Special precautions for use").

Missed dose. If a dose of the medicinal product is missed, it should be administered within one hour before the next meal.

Special patient populations

Elderly patients (≥ 65 years of age)

The medicinal product can be used in elderly patients. Dosing should be individually adjusted based on glucose monitoring results. In elderly patients, progressive deterioration of renal function may lead to a continuous decrease in insulin requirements. Dose adjustment of lixisenatide based on patient age is not required. Therapeutic experience in patients aged ≥ 75 years is limited.

Patients with renal impairment

The medicinal product is not recommended in patients with severe renal impairment or end-stage renal disease, as therapeutic experience with lixisenatide in these cases is insufficient.

For patients with mild or moderate renal impairment, dose adjustment of lixisenatide is not required.

In patients with renal impairment, insulin requirements may be reduced due to decreased insulin metabolism.

Patients with mild or moderate renal impairment using Soliqua® may require frequent glucose monitoring and appropriate dose adjustments.

Patients with hepatic impairment

For patients with hepatic impairment, dose adjustment of lixisenatide is not required (see section "Pharmacological properties", subsection "Pharmacokinetics"). In patients with hepatic impairment, insulin requirements may be reduced due to decreased gluconeogenesis and reduced insulin metabolism. Patients with hepatic impairment may require frequent glucose monitoring and appropriate dose adjustments.

Children

The medicinal product is not intended for use in children.

Route of administration. The medicinal product should be administered by subcutaneous injection into the abdominal area, deltoid muscle, or thigh.

Injection sites should be rotated within one anatomical area (abdomen, deltoid muscle, or thigh) from one injection to the next to reduce the risk of lipodystrophy and/or cutaneous amyloidosis (see section "Special precautions for use" and "Adverse reactions").

Patients should be instructed about the necessity of always using a new needle. Reusing the needle of an insulin pen increases the risk of needle blockage, which may lead to underdosing or overdosing. In case of pen blockage, the patient should follow the instructions provided below in the subsection "Instructions for use of Soliqua® pen".

The medicinal product must not be withdrawn from the cartridge of the pre-filled pen into a syringe to avoid dosing errors and potential overdose (see section "Special precautions for use").

Special warnings for use

Before first use, the pen should be removed from the refrigerator and kept at a temperature not exceeding 25 °C for 1–2 hours.

Before use, inspect the pen cartridge. It may only be used if it contains a clear, colorless solution resembling water in consistency, without visible particles.

The medicinal product must not be mixed with any other insulin or diluted. Mixing or dilution may alter the time-action profile of the product; furthermore, mixing with other medicinal products may lead to precipitation.

Before each injection, a new needle must always be attached. Needles must not be reused. The patient must dispose of the needle after each injection.

Needles are not included in the packaging.

In case of needle blockage, patients must follow the recommendations described in STEP 3 of the Instructions for use of Soliqua® pen (see below).

Empty pens must never be reused and must be properly disposed of.

To prevent possible transmission of diseases, each pen must be used by only one patient.

Before each injection, the label must always be checked to avoid confusion between Soliqua® and other injectable antidiabetic medicinal products, including the two different types of Soliqua® pens (see section "Special precautions for use").

Before using the medicinal product, carefully read the section "Instructions for use of Soliqua® pen".

Important information on the use of Soliqua® pen

• The pen is intended for personal use only and must not be shared with other individuals.
• The pen must not be used if it is damaged or if there is any doubt about its proper functioning.
• Always perform a safety test (see STEP 3).
• Always keep a spare pen and spare needles in case the primary set is lost or damaged.
• Always check the pen label before use to ensure the correct pen is being used.

What you need to know for administering the injection

• Before using the pen, ask your doctor or nurse how to administer the injection.
• If you have any difficulties using the pen, for example due to vision problems, seek assistance.
• Before using the pen, reread these instructions. Failure to follow these instructions may result in receiving too high or too low a dose of the product.

Additional items needed for administering this product:

• a new sterile needle (see STEP 2);
• an alcohol swab;
• a puncture-resistant container for used needles and pens.

INSTRUCTIONS

for use of Soliqua® pen

* The plunger will not be visible until several doses have been administered.

STEP 1. Check your pen.

Remove the new pen from the refrigerator at least 1 hour before injection. Injecting cold medication is more painful. After first use, the pen should be stored at a temperature not exceeding 25 °C.

A. Check the product name and expiration date on the pen label.

• Make sure you have taken the correct product. This pen is olive-colored and has a brown injection button.
• Do not use this pen if your daily dose corresponds to less than 30 dose increments or more than 60 dose increments. Discuss with your doctor which pen best suits your needs.
• Do not use the pen after its expiration date.

B. Remove the cap from the pen.

C. Ensure the product is clear.

• Look at the transparent cartridge holder. Do not use the pen if the solution appears cloudy, discolored, or contains particles.

STEP 2. Attach a new needle.

• Do not reuse needles. Always use a new sterile needle for each injection. This helps prevent needle blockage, contamination, and infection.
• Always use only needles compatible for use with Soliqua®.

A. Take a new needle and peel off the protective film.

B. Hold the needle straight and screw it onto the pen until firmly attached. Do not overtighten the needle.

C. Remove the outer needle cap. Keep it – you will need it later.

D. Remove the inner needle cap and discard it.

If you attempt to reattach it, you may accidentally prick yourself with the needle.

Handling needles

Handle needles with care to prevent needlestick injuries and cross-contamination.

STEP 3. Perform the safety test.

Always perform the safety test before each injection to:

• check that your pen and needle are working properly;
• ensure you receive the correct dose of the product.

A. Select 2 dose increments by turning the dose selector until the dose indicator points to the "2" mark.

B. Press the injection button fully.

If the product solution comes out of the needle tip, your pen is working correctly. The dose selector will return to the "0" position.

If no solution comes out:

• You may need to repeat this step up to 3 times before seeing the solution.
• If no solution comes out after the third attempt, the needle may be blocked. If this occurs:
  • replace the needle (see STEP 6 and STEP 2);
  • then repeat the safety test (STEP 3).
• If no solution still comes out of the needle tip, do not use your pen. Use a new pen.
• Do not use a syringe to withdraw solution from your pen.

If you see air bubbles:

• You may see air bubbles in the product solution. This is normal and will not harm you.

STEP 4. Select the dose.

• Use this pen only for administering a single daily dose corresponding to 30 to 60 dose increments.
• Never select a dose or press the injection button without an attached needle. This may damage your pen.

A. Ensure the needle is attached to the pen and the dose indicator points to "0".

B. Turn the dose selector until the dose indicator points to your required dose.

• If you turn the selector past your required dose, you may turn it back in the opposite direction.
• If there are not enough units remaining in your pen for your dose, the dose selector will stop after selecting the number of units remaining in the pen.
• If you cannot select the full prescribed dose, use a new pen or administer the remaining dose increments from the current pen and the remainder from a new pen. In this case and only in this case, it is permitted to administer a partial dose corresponding to less than 30 dose increments. To complete your dose, always use another Soliqua® pen (30–60), not any other pen.

How to read the dose display window

• Even numbers are displayed next to the dose indicator, and odd numbers are shown as lines between even numbers.
• Do not use the pen if your single dose corresponds to less than 30 dose increments (these dose increments are marked with white numbers on a black background).

Number of product units in your pen

• Your pen contains a total of 300 dose increments. You can select your dose in 1-dose-increment steps.
• Do not use this pen if your single daily dose corresponds to less than 30 dose increments or more than 60 dose increments. Discuss with your doctor which pen best suits your needs.
• Each pen contains more than one daily dose.

STEP 5. Administer your required dose.

If you find it difficult to press the injection button, do not force it, as this may break your pen.

• Replace the needle (see STEP 6 "Remove the needle" and STEP 2 "Attach a new needle"), then perform the safety test (see STEP 3).
• If you still find it difficult to press the button, take a new pen.
• Do not use a syringe to withdraw solution from your pen.

A. Select the injection site according to the illustration below.

B. Insert the needle into your skin as shown by your doctor or nurse.

• Do not press the injection button yet.

C. Place the thumb of your hand on the injection button. Then press it fully and hold it in place.

• Do not press the button at an angle, as your thumb may block the rotation of the dose selector.

D. Keep the injection button pressed and after you see "0" in the dose display window, slowly count to 10.

This is necessary to ensure you receive the full dose of the product.

E. After holding the button and slowly counting to 10, release the injection button. Then withdraw the needle from the skin.

STEP 6. Remove the needle.

• Handle needles with care to prevent needlestick injuries and cross-contamination.
• Do not reattach the inner needle cap.

A. Take the outer needle cap by its widest part. Hold the needle straight and insert it into the outer needle cap. Then firmly press them together.

• The needle may pierce the cap if it is attached at an angle.

B. Hold the outer needle cap by its widest part and press it firmly at this point. With the other hand, turn the pen several times to remove the needle.

• If the needle does not detach the first time, try again.

C. Dispose of the used needle in a puncture-resistant container or according to your doctor's or local authority's recommendations.

D. Replace the pen cap back onto the pen.

• Do not put the pen back into the refrigerator.

Storage instructions

Before first use, store the pen in the refrigerator at +2 °C to +8 °C in a place protected from light. Do not freeze.

After first use, the pen should be stored for no more than 28 days at room temperature below 25 °C in a place protected from light.

Do not put your pen back into the refrigerator. Do not freeze.

After each injection, the pen cap should be replaced to protect from light. The pen must not be stored with a needle attached.

Handling

Handle the pen with care. If you suspect the pen is damaged, do not attempt to repair it; use a new one.

To protect the pen from dust and dirt: the outer surface of the pen may be cleaned by wiping with a damp cloth (moistened with water only). Do not immerse in liquid, rinse, or lubricate the pen, as this may damage it.

Disposal of the pen: remove the needle before disposal. Dispose of the pen as recommended by local regulatory authorities.

Children

The safety and efficacy of Soliqua® for the treatment of children (under 18 years of age) have not been established. Data are lacking.

Overdose

If a larger dose of Soliqua® is administered than required, adverse reactions such as hypoglycemia and gastrointestinal disorders may occur.

Mild episodes of hypoglycemia can generally be managed by oral carbohydrate intake. Dose adjustments of the medicinal product and changes in diet or physical activity may be required.

More severe episodes of hypoglycemia, accompanied by coma, seizures, or neurological impairment, require administration of glucagon or intravenous infusion of concentrated glucose solution. Since hypoglycemia may recur even after apparent clinical improvement, prolonged carbohydrate intake and patient observation may be necessary.

In case of gastrointestinal adverse reactions, supportive therapy should be initiated according to the clinical signs and symptoms observed in the patient.

Adverse reactions

The most commonly reported adverse reactions during treatment with Soliqua® were hypoglycaemia and gastrointestinal disorders (see section "Description of selected adverse reactions" below).

Adverse reactions associated with the use of the medicinal product observed during clinical studies are listed in Table 5 by "System Organ Class" 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; frequency not known: cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Table 5

System Organ Class	Frequency
	Very common	Common	Uncommon	Rare	Frequency not known
Infections and infestations			Nasopharyngitis Upper respiratory tract infection
Immune system disorders		Urticaria
Metabolism and nutrition disorders	Hypoglycaemia
Nervous system disorders		Dizziness	Headache Dysgeusia
Gastrointestinal disorders		Nausea Diarrhoea Vomiting	Dyspepsia Abdominal pain	Delayed gastric emptying
Hepatobiliary disorders			Cholelithiasis Cholecystitis
Skin and subcutaneous tissue disorders					Cutaneous amyloidosis Lipodystrophy
General disorders and administration site reactions		Injection site reactions	Increased fatigue

Description of individual adverse reactions

Hypoglycemia. Table 6 presents data on the frequency of documented symptomatic hypoglycemia (≤ 3.9 mmol/L) and severe hypoglycemia during treatment with Soliqua® and the comparator drug***.

Table 6

Adverse reactions in the form of documented symptomatic hypoglycemia or severe hypoglycemia

	Patients who have not previously received insulin			Transition from basal insulin		Transition from GLP-1 receptor agonist***
	Soliqua®	Insulin glargine	Lixisenatide	Soliqua®	Insulin glargine	Soliqua®	GLP-1 receptor agonist***
N	469	467	233	365	365	255	256
Documented symptomatic hypoglycemia*
Patients experiencing adverse reaction, n (%)	120 (25.6%)	110 (23.6%)	15 (6.4%)	146 (40.0%)	155 (42.5%)	71 (27.8%)	6 (2.3%)
Number of adverse reactions per patient-year, n	1.44	1.22	0.34	3.03	4.22	1.54	0.08
Severe hypoglycemia**
Number of adverse reactions per patient-year, n	0	< 0.01	0	0.02	< 0.01	< 0.01	0

* Documented symptomatic hypoglycemia was defined as an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L.

** Severe symptomatic hypoglycemia was defined as an event requiring assistance from another person to administer carbohydrates, glucagon, or other resuscitative measures.

*** Liraglutide, exenatide twice daily or with prolonged release, dulaglutide, or albiglutide.

Gastrointestinal disorders. Gastrointestinal disorders (nausea, vomiting, and diarrhea) were commonly reported adverse reactions during the treatment period. In patients receiving Soliqua® medication, the frequency of treatment-related nausea, diarrhea, and vomiting was 8.4%, 2.2%, and 2.2%, respectively. Gastrointestinal adverse reactions were predominantly mild in severity and had a transient nature.

Immune system disorders. Allergic reactions (urticaria), possibly related to the use of the medicinal product, were reported in 0.3% of patients. Cases of generalized allergic reactions, including anaphylactic reactions and angioedema, were reported during post-marketing use of insulin glargine and lixisenatide.

Immunogenicity. Administration of Soliqua® may lead to the formation of antibodies against insulin glargine and/or lixisenatide.

The frequency of antibody formation against insulin glargine was 21.0% and 26.2%. Approximately 93% of patients showed cross-reactivity of antibodies against insulin glargine with human insulin. The frequency of antibody formation against lixisenatide was approximately 43%. Neither the status of antibodies against insulin glargine nor the status of antibodies against lixisenatide had a clinically significant impact on the safety or efficacy of the drug.

Skin and subcutaneous tissue disorders. Lipodystrophy and cutaneous amyloidosis may occur at insulin injection sites and may lead to delayed insulin absorption. Regularly rotating injection sites within the same body area may help reduce or prevent these reactions (see section "Special instructions").

Injection site reactions. In some patients (1.7%) receiving therapy involving insulin administration, including Soliqua®, redness, local swelling, and itching at the injection site were observed.

Heart rate. Increased heart rate has been reported with GLP-1 receptor agonists; transient increases in heart rate were also observed in some studies with lixisenatide. Across all phase 3 studies, Soliqua® did not result in an increase in mean heart rate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Shelf life after first use of the pen – 28 days.

Store below 25 °C. Do not freeze. Do not cool. Do not store with attached needle. Store the pen in a place protected from direct heat and light. After each injection, the pen cap should be replaced to protect from light.

Storage conditions

Keep out of reach of children.

Pens not in use

Store in a refrigerator (at +2 °C to +8 °C).

Do not freeze and avoid contact with the freezer compartment or cold accumulators.

Store the pen in its outer cardboard packaging to protect from light.

Pens after first use

Storage conditions are specified in the section "Shelf life".

Incompatibilities

This medicinal product must not be mixed with any other medicinal product.

Packaging

No. 3 or No. 5: 3 mL in a cartridge contained in a disposable pen; 3 or 5 pens in a cardboard box. Needles are not included in the package.

Prescription status. By prescription only.

Manufacturer. Sanofi-Aventis Deutschland GmbH.

Manufacturer's address and location of its business operations

Brunner Strasse 50, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.

Marketing Authorization Holder: LLC "Sanofi-Aventis Ukraine".

Address of the Marketing Authorization Holder. 48-50A Zhylianska St., Kyiv, 01033, Ukraine.