Soliqua solution for injection 100 U/ml + 50 mcg/ml 3 ml cartridge mounted in a syringe pen without needle No. 3

Instructions for Soliqua solution for injection 100 U/ml + 50 mcg/ml 3 ml cartridge mounted in a syringe pen without needle No. 3

Composition

active ingredient: insulin glargine, lixisenatide;

1 ml of solution for injection contains 100 units of insulin glargine and 50 micrograms of lixisenatide;

1 syringe pen contains 3 ml of solution for injection, equivalent to 300 U of insulin glargine and 150 mcg of lixisenatide;

1 dosage division corresponds to 1 U of insulin glargine and 0.5 μg of lixisenatide;

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

Dosage form

Solution for injection.

Main physicochemical properties: colorless or almost colorless solution.

Pharmacotherapeutic group

Medicines used for diabetes, insulins and their long-acting analogues for injection.

ATX 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, namely insulin glargine (a basal insulin analogue whose main function is to control fasting plasma glucose levels) and lixisenatide (a GLP-1 receptor agonist whose main function is to control postprandial glucose levels).

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

Lixisenatide. Lixisenatide is an agonist of glucagon-like peptide-1 (GLP-1) receptors. GLP-1 receptors are the target of natural GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion by β-cells and inhibits glucagon secretion by α-cells of the pancreas.

Lixisenatide stimulates insulin secretion when blood glucose levels rise, without affecting insulin secretion in normoglycemia, which limits the risk of hypoglycemia. In parallel, glucagon secretion is suppressed. In the event of hypoglycemia, the rescue mechanism of glucagon secretion is maintained. Postprandial administration of lixisenatide also slows gastric emptying, thus reducing the rate of absorption and entry into the bloodstream of glucose contained in 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 studies.

Given the relatively constant concentration/time profile of insulin glargine over 24 hours with no pronounced peaks when used alone, the glucose disposal rate/time profile was similar when insulin glargine and lixisenatide were used in combination.

The duration of action of insulins, including Soliqua, can vary from person to person and even within the same person.

Insulin glargine: Clinical studies with insulin glargine (100 units/ml) have shown that the glucose-lowering effect on a molar basis (i.e. at the same doses) of insulin glargine administered intravenously is approximately the same as that of human insulin.

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

Gastric emptying: Following ingestion of a standard labelled test meal in the above study, lixisenatide was shown to delay gastric emptying, thereby reducing the rate of postprandial glucose absorption. The effect of delaying gastric emptying was maintained until the end of the study.

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

Addition to metformin (in patients not receiving insulin).

Switching from basal insulin.

Switching from a GLP-1 receptor agonist.

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

In the add-on to metformin clinical study, treatment was initiated with a dose of 10 dose steps (10 units insulin glargine and 5 micrograms lixisenatide). In the switch from basal insulin clinical study, the starting dose was 20 dose steps (20 units insulin glargine and 10 micrograms lixisenatide) or 30 dose steps (30 units insulin glargine and 10 micrograms lixisenatide) (see section 4.2), depending on the previous insulin dose. In both studies, dose titration was performed once a week based on self-reported fasting plasma glucose levels.

Add-on to metformin (in patients not receiving insulin)

Clinical study in patients with type 2 diabetes inadequately controlled on oral antidiabetic therapy. A total of 1,170 patients with type 2 diabetes were randomized in an open-label, 30-week, active-controlled study to evaluate the efficacy and safety of Soliqua compared to the individual components insulin glargine (100 units/mL) and lixisenatide (20 mcg).

Patients with type 2 diabetes mellitus who were receiving metformin as monotherapy or in combination with another oral antidiabetic agent, which could be a sulfonylurea, glinide, sodium-dependent glucose cotransporter-2 (SGCT-2) inhibitor or dipeptidyl peptidase-4 (DPP-4) inhibitor, and who were not adequately controlled on this treatment (HbA1c levels ranged from 7.5% to 10.0% in patients previously treated with metformin as monotherapy and from 7.0% to 9.0% in patients previously treated with metformin in combination with another oral antidiabetic agent), were included in a 4-week run-in period. During this run-in phase, metformin treatment was optimized and other oral antidiabetic agents were discontinued. At the end of the run-in period, patients who continued to have inadequate control (HbA1c levels ranging from 7% to 10%) were randomized to receive Soliqua, insulin glargine, or lixisenatide. Of the 1,479 patients who were enrolled in the run-in phase, 1,170 were randomized. The main reasons for excluding patients from the randomization phase were fasting plasma glucose levels > 13.9 mmol/L and HbA1c levels < 7% or > 10% at the end of the run-in phase.

The characteristics of the randomised type 2 diabetes population were as follows: mean age was 58.4 years, with the majority of patients (57.1%) aged 50 to 64 years; 50.6% of patients 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 mandatory background therapy, and 58% of patients were also receiving another oral antidiabetic agent at screening, of which 54% were sulfonylureas.

At week 30, Soliqua treatment demonstrated statistically significant improvements in HbA1c levels (p-value < 0.0001) compared to the individual components. In a pre-specified analysis of this primary endpoint, the observed differences were consistent with baseline HbA1c levels (< 8% or ≥ 8%) or baseline oral antidiabetic treatment (metformin monotherapy or in combination with another oral antidiabetic).

Information on other study endpoints is provided below in Table 1 and Figure 1.

Table 1

Clinical study results with the addition of the drug to metformin at week 30 (patient population who received treatment)

* Not included in the predefined tapering study procedure.

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

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

Patients in the Soliqua group had a statistically significant greater reduction in mean self-reported plasma glucose profiles 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 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 Soliqua group compared to both the insulin glargine and lixisenatide groups, with the exception of pre-breakfast glucose levels, which were similar between the Soliqua and insulin glargine groups.

Switching from basal insulin

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

A total of 736 patients with type 2 diabetes participated in a randomized, 30-week, active-controlled, open-label, 2-treatment, parallel-group, multicenter study of the efficacy and safety of Soliqua compared with insulin glargine (100 U/mL).

Screened patients with type 2 diabetes received 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 drugs (metformin, sulfonylurea, glinide, ACE-2 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 previous antidiabetic treatment.

After screening, patients who were deemed 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 receiving another basal insulin; insulin dose titration/stabilization was performed while metformin therapy (if previously taken) was continued. Treatment with any other oral antidiabetic agents was discontinued.

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

At week 30, Soliqua treatment showed a statistically significant improvement in HbA1c levels (p-value < 0.0001) compared to insulin glargine.

Information on other study endpoints is provided below in Table 2 and Figure 2.

Table 2

Results of a clinical study in patients with type 2 diabetes mellitus who were not adequately controlled on basal insulin treatment at week 30 (patient population who received treatment)

* Not included in the predefined tapering study procedure.

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

Mean HbA1c levels (%) at visits during 30 weeks of treatment

Switching from a GLP-1 receptor agonist

Clinical study in patients with type 2 diabetes who were not adequately controlled on GLP-1 receptor agonist treatment

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. At screening, 6.6% of subjects were receiving pioglitazone, and 10.1% were receiving a sodium-glucose cotransporter type 2 inhibitor in combination with metformin. The study population characteristics 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 an eGFR ≥ 60 mL/min.

At week 26, treatment with Soliqua resulted in statistically significant improvements in HbA1c levels (p < 0.0001). A pre-specified analysis of the GLP-1 receptor agonist subtype (once/twice daily or weekly) used at screening showed that the change in HbA1c at week 26 was similar for each subgroup and consistent with the primary analysis for the overall population. The mean daily dose of Soliqua at week 26 was 43.5 dosing units.

Information on other study endpoints is provided below in Table 3 and Figure 3.

Table 3

Results of a clinical study in patients with type 2 diabetes mellitus who were not adequately controlled on GLP-1 receptor agonist treatment at week 26 (patient population who received treatment)

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

Fig. 3. Mean HbA1c levels (%) at visits during 26 weeks of treatment

Concomitant use of Soliqua with sodium-glucose cotransporter type 2 inhibitors (NSCG-2 inhibitors)

The concomitant use of Soliqua with NGK-2 inhibitors is supported by subgroup analyses from three randomised phase 3 clinical studies (119 patients treated with a fixed-ratio combination of insulin glargine/lixisenatide who were also treated with NGK-2 inhibitors).

Data from these 3 studies show that initiating Soliqua in patients inadequately controlled on NGST-2 inhibitors demonstrates greater improvements in HbA1c levels compared to comparators. Patients treated with NGST-2 inhibitors had no increased risk of hypoglycemia and no significant differences in the overall safety profile compared to those not treated with NGST-2 inhibitors.

Research on the impact on cardiovascular events

The safety of insulin glargine and lixisenatide with respect to cardiovascular events was studied in the ORIGIN and ELIXA clinical trials, respectively. No separate study of the effect of Soliqua on cardiovascular events was conducted.

Insulin glargine. The Insulin Glargine Cardiovascular Outcome Reduction Study (ORIGIN) was an open-label, randomized study that enrolled 12,537 patients and compared Lantus treatment with standard of care at the time of the first occurrence of a serious cardiovascular event. Serious cardiovascular events included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The median duration of follow-up in the study was 6.2 years. The incidence of serious cardiovascular adverse events in the ORIGIN study was similar in the Lantus and standard care groups (hazard ratio [95% CI] for serious cardiovascular adverse events: 1.02 [0.94, 1.11]).

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

The incidence of the primary endpoint was similar in the lixisenatide group (13.4%) and the placebo group (13.2%): the hazard ratio for lixisenatide compared to placebo was 1.017 with an associated 2-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.

Following subcutaneous administration of insulin glargine/lixisenatide in patients with type 1 diabetes, insulin glargine did not show a pronounced peak. Insulin glargine exposure after administration of insulin glargine/lixisenatide was 86-88% of the exposure observed with separate co-injections of insulin glargine and lixisenatide. This difference is not considered clinically relevant.

Following 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 there was a small decrease in lixisenatide Cmax of 22-34% compared to the Cmax observed with separate co-injections of insulin glargine and lixisenatide; however, this decrease is unlikely to be clinically relevant.

There are no clinically relevant differences in the absorption rate of lixisenatide when administered as monotherapy via subcutaneous injection into the abdomen, deltoid muscle or thigh.

Distribution: Lixisenatide is poorly bound to human plasma proteins (55%). The estimated 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 estimated 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. Results of a metabolism study in diabetic patients treated with insulin glargine as monotherapy indicate that insulin glargine is rapidly metabolised at the carboxyl terminus of the B-chain to form two active metabolites, M1 (21A-glycine-insulin) and M2 (21A-glycine-des-30B-threonine-insulin). In plasma, metabolite M1 is the major circulating compound. Pharmacokinetic and pharmacodynamic data indicate that the effect of subcutaneous injection of insulin glargine is mainly due to the exposure to metabolite M1.

Like all peptides, lixisenatide is eliminated by glomerular filtration followed by tubular reabsorption and further metabolic degradation to smaller peptides and amino acids, which are re-incorporated into protein metabolism. After multiple administration 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.

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

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

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

Insulin glargine has not been studied in patients with diabetes mellitus and hepatic impairment. In patients with hepatic impairment, insulin requirements may be reduced due to reduced gluconeogenesis and reduced insulin metabolism.

Patient age, race, gender, and body weight

Insulin glargine: The effects of age, race, and gender on the pharmacokinetics of insulin glargine have not been studied. Subgroup analyses of age, race, and gender in controlled clinical trials in adult patients treated with insulin glargine (100 U/mL) did not reveal any differences in the safety and efficacy of insulin glargine.

Lixisenatide: Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic study in elderly non-diabetic subjects, administration of 20 mcg lixisenatide resulted in a mean increase in lixisenatide AUC of 29% (11 subjects aged 65 to 74 years and 7 subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, which is likely related to decreased renal function in the elderly.

The patient's ethnicity does not have a clinically relevant effect on the pharmacokinetics of lixisenatide, as demonstrated by pharmacokinetic studies conducted in subjects of European, Japanese and Chinese ethnicity.

Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide.

Patient body weight has no clinically relevant effect on the AUC of lixisenatide.

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

Preclinical safety data

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

Insulin glargine: Non-clinical data reveal no special hazard for humans with insulin glargine based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Lixisenatide. In 2-year subcutaneous carcinogenicity studies in rats and mice, non-lethal thyroid C-cell tumours were observed, which were considered to be due to a non-genotoxic mechanism mediated by GLP-1 receptors, to which rodents are particularly sensitive. C-cell hyperplasia and adenoma were observed in rats at all doses tested, and the highest dose,