Soliqua SoloStar, 100 units+33 mcg/ml 3 ml cartridges in SoloStar syringe pens 3 pcs

Soliqua SoloStar® is a combination drug, which consists of two hypoglycemic agents with complementary mechanisms of action: insulin glargine, an analogue of long-acting insulin, and lixisenatide, an agonist of glucagon-like peptide-1 (GFP-1) receptors.

The action of the drug is aimed at reducing the concentration of glucose in blood on an empty stomach and after a meal (postprandial blood glucose concentration), which improves glycemic control in patients with type 2 diabetes (T2DM), but minimizes the increase in body weight and the risk of hypoglycemia.

Insulin glargine

The primary function of insulin, including insulin glargine, is to regulate glucose metabolism. Insulin and its analogues reduce blood glucose concentrations by increasing glucose consumption by peripheral tissues (especially skeletal muscle and fat tissue) and suppressing glucose formation in the liver. Insulin suppresses lipolysis and proteolysis and increases protein synthesis.

Lixisenatide

Lixisenatide is a GFP-1 receptor agonist. The GFP-1 receptor is a target for native GFP-1, an endogenous hormone of internal secretion that potentiates glucose-dependent insulin secretion by beta cells and suppresses glucagon secretion by pancreatic alpha cells.

The action of lixisenatide, similar to that of endogenous GFP-1, is through specific interaction with GFP-1 receptors, including GFP-1 receptors located in pancreatic alpha and beta cells. After ingestion, lixisenatide activates the following physiological responses:
– increased insulin secretion by pancreatic beta cells;
– delayed gastric emptying;
– suppression of glucagon secretion by pancreatic alpha cells.

Lixisenatide stimulates insulin secretion in response to increased blood glucose concentrations. At the same time it suppresses the secretion of glucagon. In addition, lixisenatide slows gastric emptying, thereby reducing the rate of absorption of glucose from food and its entry into the systemic bloodstream. It was shown that lixisenatide in isolated human pancreatic islets preserves the function of beta cells and prevents their death (apoptosis).

Pharmacodynamic properties

The drug Soliqua SoloStar®

The combination of insulin glargine and lixisenatide has no effect on the pharmacological action of insulin glargine. The effect of the combination of insulin glargine and lixisenatide on the pharmacological effect of lixisenatide has not been studied in phase I clinical trials.

Similar to the relatively constant concentration/time profile with no pronounced peaks over 24 h when administered with insulin glargine alone, the glucose utilization rate/time profile was similar, with no pronounced peaks, when administered with the combination of insulin glargine + lixisenatide.
The duration of action of insulins, including Soliqua SoloStar®, may vary from patient to patient, as well as in the same patient.

Insulin glargine

In clinical trials of insulin glargine (100 U/ml), the hypoglycemic effect of intravenously administered insulin glargine was approximately the same as that of human insulin (when both drugs are given intravenously at the same dose).

Lixisenatide

In a 28-day placebo-controlled study in patients with DM2 to evaluate the effect of lixisenatide at doses of 5-20 mcg 1 or 2 times daily on blood glucose concentration after a standard breakfast meal, lixisenatide at doses of 10 mcg and 20 mcg 1 or 2 times daily improved glycemic control by reducing both postprandial (after meals) blood glucose concentration and fasting blood glucose concentration.

Lixisenatide, administered in this study in the morning at a dose of 20 mcg once daily, maintained a statistically significant reduction in postprandial blood glucose concentration after breakfast, lunch, and dinner.

Effect on postprandial blood glucose concentration

In a 4-week study in combination with metformin and in an 8-week study in combination with insulin glargine with/without metformin, lixisenatide at a dose of 20 mcg once daily, administered before breakfast in patients with DM2, showed a decrease in postprandial blood glucose concentration (glucose concentration/time curve 0:30-4:30 h) after the breakfast trial. The number of patients with a 2-hour postprandial glucose concentration below 140 mg/dL (7.77 mmol/L) was 69.3% after 28 days of treatment and 76.1% after 56 days of treatment.

Effect on insulin secretion

In patients with DM2, lixisenatide monotherapy, compared with placebo, restores glucose-dependent first phase insulin secretion, increasing it 2.8-fold (90% confidence interval, 2.5-3.1) and increasing second phase insulin secretion 1.6-fold (90% confidence interval 1.4-1.7) (measured by area under the concentration-time curve [AUC]).

Effect on gastric emptying

After a standardized isotope-labeled test meal, lixisenatide slowed gastric emptying, thereby reducing the rate of postprandial glucose absorption. In patients with DM2 on monotherapy with lixisenatide the effect of slowing gastric emptying persisted after 28 days of treatment.

Effect on glucagon secretion

Lixisenatide at a dose of 20 mcg once daily in monotherapy demonstrated a decrease in postprandial glucagon concentration compared with the outcome after a test meal in DM2 patients. In a placebo-controlled hypoglycemic clamp study conducted in healthy volunteers evaluating a single administration of lixisenatide at a dose of 20 mcg on glucagon secretion, the response of glucagon secretion in response to decreased blood glucose concentrations during hypoglycemic states persisted despite the presence of effective plasma concentrations of lixisenatide.

Effect on cardiac electrophysiology (QTc interval)

The effect of lixisenatide on cardiac repolarization was studied in a QTc interval study (at a dose 1.5 times the recommended maintenance dose), which showed no effect of lixisenatide on ventricular repolarization.

Effect on heart rate (HR)

In placebo-controlled phase III clinical trials, no increase in mean heart rate was shown.

Clinical efficacy

The efficacy and safety of Soliqua SoloStar® were studied in two randomized, controlled, active-controlled clinical trials in patients with DM2.

The efficacy and safety of Soliqua SoloStar® (n=468) compared with insulin glargine (n=466) and lixisenatide (n=233) in patients with DM2 who had not previously received insulin therapy and who lacked glycemic control with oral hypoglycemic agents was evaluated in one randomized, open-label, 30-week, active-controlled study.

When Soliqua SoloStar® was added to treatment, 74% (n=345) of patients achieved glycated hemoglobin Alc (HbAlc) values <7% by week 30, compared to 59% (n=277) of patients when insulin glargine alone was added and 33% (n=77) of patients when lixisenatide alone was added.

The decrease in mean HbAlc values by week 30 in patients treated with Soliqua SoloStar® was -1.6%, while it was -1.3% and -0.9% in patients in the insulin glargine and lixisenatide treatment groups, respectively.

Average fasting plasma glucose concentrations in patients treated with Soliqua SoloStar® decreased by 3.46 mmol/L by the end of the study, and by 3.27 mmol/L and 1.5 mmol/L when insulin glargine or lixisenatide were added, respectively.

The reduction in mean postprandial blood glucose concentrations (2 hours after meals) in patients by week 30 when Soliqua SoloStar® was added to treatment was -5.68 mmol/L, compared to -3.31 mmol/L when insulin glargine alone was added and -4.58 mmol/L when lixisenatide alone was added.

By the end of the 30-week period, the mean change in body weight was -0.3 kg in patients receiving Soliqua SoloStar and +1.1 kg in patients receiving insulin glargine. When lixisenatide was added, the change in body weight was -2.3 kg.

A second randomized, 30-week, controlled, open-label, multicenter, active-controlled clinical trial evaluated the efficacy and safety of Soliqua SoloStar® compared with insulin glargine. The study included 736 patients with DM2 with insufficient glycemic control on therapy with oral hypoglycemic drugs in combination with basal insulin.

With Soliqua SoloStar®, 54.9% of patients (n=201) achieved HbA1c <7% by week 30, compared with 29.6% of patients (n=108) in the insulin glargine treatment group alone. The mean HbAlC reduction by week 30 was -1.1% in patients treated with Soliqua SoloStar® and -0.6% in patients in the insulin glargine treatment group. Fasting plasma glucose concentration in patients treated with the drug

SoloSolar® by the end of the study decreased by 0.35 mmol/l, and by 0.47 mmol/l in patients treated with insulin glargine.

The mean value of the decrease in postprandial blood glucose concentration (2 hours after a meal) in patients by week 30 when treated with Soliqua SoloStar® was -4.72 mmol/l, compared to -1.39 mmol/l in the insulin glargine group.

By the end of the 30-week period, the mean change in body weight was -0.7 kg in patients treated with Soliqua SoloStar® and +0.7 kg in patients treated with insulin glargine.

Thus, treatment with Soliqua SoloStar® caused clinically and statistically significant improvement of HbAlc index. Moreover, achievement of lower HbAlc values and greater HbAlc reduction with Soliqua SoloStar® did not increase the incidence of hypoglycemia compared to insulin glargin monotherapy.

Studies of the effects of lixisenatide and insulin glargine on the cardiovascular system (CVS)
The effect on the development of complications of CVS therapy with insulin glargine was established in the ORIGIN clinical trial, and lixisenatide – in the ELIXA clinical trial. There have been no studies of the effects of fixed combination therapy of insulin glargine and lixisenatide on the CCC.

Insulin glargine

The ORIGIN (Outcome Reduction with Initial Glargine Intervention) clinical trial was an open-label, randomized trial conducted in 12537 patients treated with Lantus® (insulin glargine 100 units/ml) versus standard hypoglycemic therapy with respect to the time to development of the first major cardiovascular complication (MVC).

CCSI was defined as the composite end point: cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The incidence of CSA in the Lantus® treatment groups and the standard hypoglycemic therapy groups was comparable [hazard ratio (95% confidence interval) 1.02 (0.94, 1.11)].

In the ORIGIN clinical trial, the mean incidence of cancer (all types) [hazard ratio (95% confidence interval) 0.99 (0.88, 1.11)] or cancer death [hazard ratio (95% confidence interval) 0.94 (0.77, 1.15)] was comparable between treatment groups.

Lixisenatide

The ELIXA clinical trial was a randomized, double-blind, placebo-controlled, multinational study evaluating CCC complications during lixisenatide treatment in patients with DM2 (n=6068) after a recent acute coronary syndrome.

The primary efficacy endpoint was the time to the first occurrence of any of the following events positively evaluated by the Cardiovascular Events Assessment Committee: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina pectoris.

Secondary cardiovascular end points included a combination of the primary end point with either hospitalization for heart failure or coronary artery revascularization. Also a preplanned secondary endpoint was a change in urinary albumin/creatinine ratio by week 108.

The incidence of events from the primary endpoint was comparable in the lixisenatide group and the placebo group: the hazard ratio for lixisenatide versus placebo was 1.017, with a two-sided 95% confidence interval of 0.886, 1.168. Similar percentages between treatment groups were observed for secondary endpoints and for all individual components of composite endpoints.

The percentages of patients hospitalized for heart failure were 4.0% and 4.2% in the lixisenatide and placebo groups, respectively [hazard ratio (95% confidence interval) 0.96 (0.75, 1.23)].

There was a smaller increase in urinary albumin/creatinine ratio by week 108, compared with the outcome: -10.04±3.53%; 95% confidence interval was -16.95%, -3.13% in the lixisenatide group compared with the placebo group.

Indications

In adult patients with type 2 diabetes mellitus in combination with metformin as an addition to diet therapy and increased physical activity to improve glycemic control when metformin monotherapy or a combination of metformin with another oral hypoglycemic drug, or basal insulin monotherapy is ineffective.

Pharmacological effect

Pharmacological action
Soliqua SoloStar® is a combination drug that contains two hypoglycemic agents with complementary mechanisms of action: insulin glargine, a long-acting insulin analogue, and lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist.

The action of the drug is aimed at reducing fasting and postprandial blood glucose concentrations (postprandial blood glucose concentrations), which improves glycemic control in patients with type 2 diabetes mellitus (T2DM), while minimizing weight gain and the risk of hypoglycemia.

Insulin glargine

The main function of insulin, including insulin glargine, is to regulate glucose metabolism. Insulin and its analogues reduce blood glucose concentrations by increasing glucose uptake by peripheral tissues (especially skeletal muscle and adipose tissue) and inhibiting glucose production in the liver. Insulin suppresses lipolysis and proteolysis and also increases protein synthesis.

Lixisenatide

Lixisenatide is a GLP-1 receptor agonist. The GLP-1 receptor is the target of native GLP-1, an endogenous endocrine hormone that potentiates glucose-dependent insulin secretion by beta cells and suppresses glucagon secretion by alpha cells of the pancreas.

The action of lixisenatide, similar to the action of endogenous GLP-1, occurs through specific interaction with GLP-1 receptors, including GLP-1 receptors located in the alpha and beta cells of the pancreas. After food intake, lixisenatide activates the following physiological reactions:
– increased secretion of insulin by beta cells of the pancreas;
– slower gastric emptying;
– suppression of glucagon secretion by alpha cells of the pancreas.

Lixisenatide stimulates insulin secretion in response to increased blood glucose concentrations. At the same time, glucagon secretion is suppressed. In addition, lixisenatide slows gastric emptying, thereby reducing the rate of absorption of glucose from food and its entry into the systemic circulation. Lixisenatide in isolated human pancreatic islets has been shown to preserve beta cell function and prevent cell death (apoptosis).

Pharmacodynamic properties

Soliqua SoloStar®

The combination of insulin glargine and lixisenatide does not affect the pharmacological action of insulin glargine. The effect of the combination of insulin glargine and lixisenatide on the pharmacological action of lixisenatide has not been studied in phase I clinical studies.

Similar to the relatively constant concentration/time profile without pronounced peaks over 24 hours when administering insulin glargine alone, when administering the insulin glargine + lixisenatide combination, the glucose utilization rate/time profile was similar, without pronounced peaks.
The duration of action of insulins, including Soliqua SoloStar®, may vary between patients and within the same patient.

Insulin glargine

In clinical studies of insulin glargine (100 U/ml), the hypoglycemic effect of intravenously administered insulin glargine was approximately the same as that of human insulin (when both drugs were administered intravenously at the same doses).

Lixisenatide

In a 28-day placebo-controlled study in patients with T2DM assessing the effect of lixisenatide 5–20 mcg once or twice daily on blood glucose concentrations following a standard breakfast, lixisenatide 10 mcg and 20 mcg once or twice daily improved glycemic control by reducing both postprandial (postprandial) blood glucose concentrations and blood glucose concentrations. on an empty stomach.

Lixisenatide, administered in the morning at a dose of 20 mcg once daily in this study, maintained statistically significant reductions in postprandial blood glucose concentrations after breakfast, lunch, and dinner.

Effect on postprandial blood glucose concentration

In a 4-week study in combination with metformin and in an 8-week study in combination with insulin glargine with or without metformin, lixisenatide 20 mcg once daily administered before breakfast in patients with T2DM showed a decrease in postprandial blood glucose concentrations (glucose concentration/time curve 0:30-4:30 hours) after the breakfast trial. The number of patients with 2-hour postprandial glucose concentrations below 140 mg/dL (7.77 mmol/L) was 69.3% after 28 days of treatment and 76.1% after 56 days of treatment.

Effect on insulin secretion

In patients with T2DM, lixisenatide monotherapy, compared with placebo, restores the first phase of glucose-dependent insulin secretion, increasing it by 2.8 times (90% confidence interval, 2.5-3.1) and increases the second phase of insulin secretion by 1.6 times (90% confidence interval, 1.4-1.7) (measured by the area under the concentration-time curve [AUC]).

Effect on gastric emptying

Following a standardized test ingestion of an isotope-labeled meal, lixisenatide slowed gastric emptying, thereby reducing the rate of postprandial glucose absorption. In patients with T2DM treated with lixisenatide monotherapy, the effect of slowing gastric emptying was maintained after 28 days of treatment.

Effect on glucagon secretion

Lixisenatide 20 mcg once daily as monotherapy demonstrated a decrease in postprandial glucagon concentrations compared with postprandial test meal outcome in patients with T2DM. In a placebo-controlled hypoglycemic clamp study conducted in healthy volunteers, evaluating a single dose of lixisenatide 20 mcg per glucagon secretion, the glucagon secretion response to decreased blood glucose concentrations during hypoglycemic conditions was maintained despite the presence of effective plasma concentrations of lixisenatide.

Effect on cardiac electrophysiology (QTc interval)

The effect of lixisenatide on cardiac repolarization was studied in a QTc study (at a dose of 1.5 times the recommended maintenance dose), which showed no effect of lixisenatide on ventricular repolarization.

Effect on the number of heart contractions (HR)

Placebo-controlled phase III clinical trials showed no increase in mean heart rate.

Clinical effectiveness

The effectiveness and safety of Soliqua SoloStar® were studied in two randomized, controlled clinical trials with active control in patients with T2DM.

One randomized, open-label, 30-week, active-controlled study conducted in insulin-naive T2DM patients with poor glycemic control on oral hypoglycemic agents assessed the efficacy and safety of Soliqua SoloStar® (n=468) compared with insulin glargine (n=466) and lixisenatide (n=233).

When Soliqua SoloStar® was added to treatment, 74% (n=345) of patients achieved glycated hemoglobin Alc (HbAlc) values ​​<7% by week 30, compared to 59% (n=277) of patients with the addition of insulin glargine alone and 33% (n=77) of patients with the addition of lixisenatide alone.The decrease in mean HbAlc values ​​by week 30 in patients treated with Soliqua SoloStar® was -1.6%, and in patients treated with insulin glargine and lixisenatide it was -1.3% and -0.9%, respectively.The average fasting plasma glucose concentrations in patients receiving Soliqua SoloStar® decreased by 3.46 mmol/L at the end of the study, and when adding insulin glargine or lixisenatide, by 3.27 mmol/L and 1.5 mmol/L, respectively.The decrease in mean postprandial blood glucose concentrations (2 hours after a meal) in patients by week 30 when Soliqua SoloStar® was added to treatment was -5.68 mmol/L, compared to -3.31 mmol/L when only insulin glargine was added and -4.58 mmol/L when only lixisenatide was added.At the end of the 30-week period, the average change in body weight in patients receiving Soliqua SoloStar was -0.3 kg, and insulin glargine +1.1 kg. With the addition of lixisenatide, the change in body weight was -2.3 kg.The second randomized, 30-week, controlled, open-label, multicenter, active-controlled clinical trial assessed the efficacy and safety of Soliqua SoloStar® compared with insulin glargine. The study included 736 patients with T2DM with insufficient glycemic control when treated with oral hypoglycemic drugs in combination with basal insulin.When using Soliqua SoloStar®, 54.9% of patients (n=201) achieved HbA1c <7% by week 30, compared with 29.6% of patients (n=108) in the insulin glargine-only group. The average reduction in HbAlC by week 30 in patients treated with Soliqua SoloStar® was -1.1%, and in patients treated with insulin glargine the reduction in HbAlC was -0.6%. Fasting plasma glucose concentration in patients treated with the drugSoliqua SoloStar® decreased by 0.35 mmol/l by the end of the study, and by 0.47 mmol/l when using insulin glargine.The average decrease in postprandial blood glucose concentration (2 hours after a meal) in patients by week 30 when treated with Soliqua SoloStar® was -4.72 mmol/l, compared to -1.39 mmol/l in the insulin glargine group.At the end of the 30-week period, the average change in body weight in patients receiving Soliqua SoloStar® was -0.7 kg, and in patients receiving insulin glargine – +0.7 kg.Thus, treatment with Soliqua SoloStar® caused a clinically and statistically significant improvement in HbAlc. Moreover, achieving lower HbAlc values ​​and a greater reduction in HbAlc when using Soliqua SoloStar® did not increase the incidence of hypoglycemia compared to insulin glargine monotherapy.Studies on the effects of lixisenatide and insulin glargine on the cardiovascular system (CVS)
The effect of treatment with insulin glargine on the development of cardiovascular complications was established in the ORIGIN clinical trial, and with lixisenatide in the ELIXA clinical trial. There have been no studies of the effect of therapy with a fixed combination of insulin glargine and lixisenatide on CVS.

Insulin glargine

The ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial was an open-label, randomized trial of 12,537 patients studying Lantus® (insulin glargine 100 U/mL) versus standard hypoglycemic therapy in terms of time to first major cardiovascular event (MACE).

CSMR was defined as a composite endpoint: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. The incidence of CSSO in the Lantus® treatment groups and the standard hypoglycemic therapy groups was comparable [risk ratio (95% confidence interval) 1.02 (0.94, 1.11)].

In the ORIGIN clinical trial, the mean incidence of cancer (all types) [hazard ratio (95% confidence interval) 0.99 (0.88, 1.11)] or cancer death [hazard ratio (95% confidence interval) 0.94 (0.77, 1.15)] was comparable between treatment groups.

Lixisenatide

The ELIXA clinical trial was a randomized, double-blind, placebo-controlled, multinational study evaluating cardiovascular complications during treatment with lixisenatide in patients with T2DM (n=6068) following recent acute coronary syndrome.

The primary efficacy endpoint was the time to the first occurrence of any of the following events considered positive by the Cardiovascular Event Review Committee: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.

Secondary cardiovascular endpoints included the combination of the primary endpoint with either hospitalization for heart failure or coronary revascularization. A preplanned secondary endpoint was change in urinary albumin/creatinine ratio at 108 weeks.

The incidence of events from the primary endpoint was comparable in the lixisenatide group and in the placebo group: the hazard ratio for lixisenatide versus placebo was 1.017, with a two-sided 95% confidence interval of 0.886, 1.168. Similar percentages between treatment groups were observed for secondary endpoints and for all individual components of the composite endpoints.

The percentages of patients hospitalized for heart failure were 4.0% and 4.2% in the lixisenatide and placebo groups, respectively [hazard ratio (95% confidence interval) 0.96 (0.75, 1.23)].

The lixisenatide group, compared with the placebo group, had a smaller increase in urinary albumin/creatinine ratio at week 108, compared with outcome: -10.04±3.53%; The 95% confidence interval was -16.95%, -3.13%.

Special instructions

Soliqua SoloStar® is contraindicated in patients with type 1 diabetes mellitus or for the treatment of ketoacidosis.
Conversion from a GLP-1 receptor agonist to Soliqua SoloStar® has not been studied.

The simultaneous use of Soliqua SoloStar® with dipeptidyl peptidase IV inhibitors, sulfonylureas, glinides, pioglitazone and sodium-dependent glucose transporter inhibitors has not been studied.

Risk of pancreatitis

The use of GLP-1 receptor agonists has been associated with a risk of acute pancreatitis. Rare cases of acute pancreatitis have been reported with the use of lixisenatide, although a cause-and-effect relationship has not been established. Patients should be informed about the characteristic symptoms of pancreatitis: long-term (persistent) severe abdominal pain. If pancreatitis is suspected, use of Soliqua SoloStar® should be discontinued. If the diagnosis of acute pancreatitis is confirmed, treatment with Soliqua SoloStar® should not be resumed. Soliqua SoloStar® should be used with caution in patients with a history of pancreatitis.

Hypoglycemia

Hypoglycemia is the most frequently reported adverse effect during treatment with Soliqua SoloStar®. Hypoglycemia may occur if the dose of Soliqua SoloStar® is higher than the requirement. Factors that increase susceptibility to hypoglycemia require careful monitoring and may require adjustment of the dosage regimen.

These factors include:
– changing the injection area;
– increased sensitivity to insulin (for example, due to the cessation of stress factors);
– unusual, heavier or longer physical activity;
– concomitant diseases (for example, vomiting, diarrhea);
– insufficient food intake;
– skipping meals;
– drinking alcohol (ethanol);
– some uncompensated endocrine disorders (such as hypothyroidism and hormone deficiency of the anterior pituitary gland or adrenal cortex);
– concomitant therapy with certain drugs (see section “Interaction with other drugs”).

The dose of Soliqua SoloStar® should be selected individually according to the clinical effect and titrated based on the patient’s need for insulin.

The prolonged action of subcutaneously administered insulin glargine can slow down the patient’s recovery from hypoglycemia.

When lixisenatide and/or insulin are used simultaneously with sulfonylureas, the risk of hypoglycemia is increased, and therefore Soliqua SoloStar® should not be used in combination with sulfonylureas.

Use in patients with severe gastroparesis

The use of GLP-1 receptor agonists may be associated with gastrointestinal HP. Soliqua SoloStar® has not been studied in patients with severe gastrointestinal diseases, including severe gastroparesis, and therefore the use of Soliqua SoloStar® in these patients is contraindicated.

Kidney failure

There is no therapeutic experience with the drug in patients with severe renal failure (creatinine clearance less than 30 ml/min) or end-stage renal failure. The use of the drug is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min) or end-stage renal failure.

Concomitant use of drugs

Slowing gastric emptying by lixisenatide may decrease the rate of absorption of drugs taken by mouth.
Soliqua SoloStar® should be used with caution in patients taking medications that require rapid absorption from the gastrointestinal tract, require close clinical monitoring, or have a narrow therapeutic index.

Dehydration

Patients receiving treatment with Soliqua SoloStar® should be advised of the potential risk of dehydration due to the development of gastrointestinal HP and to take precautions to avoid fluid loss.

Antibody formation
The use of Soliqua SoloStar® may cause the formation of antibodies to insulin glargine and/or lixisenatide. In rare cases, the presence of such antibodies may require a change in the dose of Soliqua SoloStar® in order to correct the tendency to develop hyper- or hypoglycemia.

Fertility
Animal studies with insulin glargine and lixisenatide have shown no direct adverse effects on fertility.

Excipients

Soliqua SoloStar® contains metacresol, which can cause allergic reactions.

Preventing drug administration errors

Patients should be instructed to always check the pen label before each administration of the drug to avoid accidental confusion between two Soliqua SoloStar® pens that have different concentrations of active ingredients, or confusion with other pens containing other injectable antidiabetic drugs.

To avoid dosing errors and overdose, patients and healthcare professionals should never use a syringe to remove medication from the Soliqua SoloStar® pre-filled pen cartridge.

Impact on the ability to drive vehicles and machinery

The patient’s ability to concentrate and reactivity may be impaired as a result of hypoglycemia or hyperglycemia, or as a result of visual impairment. This may pose a risk in situations where these abilities are of particular importance (for example, when driving or operating machinery).

Patients should be advised to take precautions to avoid the development of hypoglycemia while driving. This is especially important in those patients who have reduced or absent recognition of symptoms that predict the development of hypoglycemia, or in patients with frequent episodes of hypoglycemia. In such cases, the question of the appropriateness of driving vehicles or machinery should be considered.

Active ingredient

Insulin glargine, Lixisenatide

Composition

1 ml of solution for subcutaneous administration of 100 units/ml insulin glargine and 33 µg/ml lixisenatide contains:

active ingredients:

insulin glargine – 3.6378 mg (100 units),

lixisenatide – 33 mcg;

excipients:

glycerol (85%);

methionine (L-methionine);

metacresol (m-cresol);

zinc chloride;

hydrochloric acid;

sodium hydroxide;

water for injection.

Pregnancy

Pregnancy

There are no data from controlled clinical studies on the use of Soliqua SoloStar®, insulin glargine or lixisenatide during pregnancy.

Reproductive toxicity of lixisenatide has been demonstrated in animal studies; lack of embryotoxicity and teratogenicity of insulin glargine.

The potential risk to humans is unknown. Soliqua SoloStar® is contraindicated during pregnancy (due to the content of lixisenatide).

If pregnancy is planned or occurs, treatment with Soliqua SoloStar® should be discontinued.

Breastfeeding period

There is no data on the excretion of insulin glargine or lixisenatide into human breast milk. The use of Soliqua SoloStar® during breastfeeding is contraindicated.

Contraindications

Hypersensitivity to lixisenatide, insulin glargine or any of the excipients included in the drug.
Pregnancy.
Breastfeeding period.
Diabetes mellitus type 1.
Diabetic ketoacidosis.
Severe diseases of the gastrointestinal tract (GIT), including gastroparesis.
Severe renal failure (creatinine clearance less than 30 ml/min).
Age up to 18 years (due to the lack of data on the effectiveness and safety of use in this age group).
With caution
History of pancreatitis (due to the content of lixisenatide in the drug.
In patients concomitantly taking drugs that require rapid absorption from the gastrointestinal tract, have a narrow therapeutic index, or require careful clinical monitoring.

Side Effects

The following adverse reactions (HP) are presented by organ system (according to the Medical Dictionary for Regulatory Activities (MedDRA) classification), using the CIOMS (Council of International Organizations of Medical Sciences) HP incidence classification: very common (≥10%); often (≥1%; <10%); uncommon (≥0.1%; rare (≥0.01%; very rare (<0.01%), frequency unknown (it is not possible to determine the incidence of HP from the available data).

Security Profile Summary

The most frequently observed HP during use of Soliqua SoloStar® was the development of hypoglycemia and HP from the gastrointestinal tract.

List of HP

Infectious and parasitic diseases: Uncommon: nasopharyngitis, upper respiratory tract infections.

Immune system disorders: Uncommon: urticaria.

Metabolic and nutritional disorders: Very common: hypoglycemia.

Nervous system disorders: Common: dizziness. Uncommon: headache.

Gastrointestinal disorders: Common: nausea, diarrhea, vomiting. Uncommon: dyspepsia, abdominal pain.

General disorders and administration site disorders: Uncommon: feeling of fatigue, reactions at the injection site.

Description of individual HP

Hypoglycemia

Episodes of severe hypoglycemia, especially if they occur repeatedly, can lead to the development of neurological disorders. Cases of prolonged or severe hypoglycemia can be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia – a lack of glucose in the brain (feeling tired, inappropriate fatigue or weakness, decreased ability to concentrate, drowsiness, visual disturbances, headache, nausea, confusion or loss of consciousness, seizures) are preceded by signs of adrenergic counterregulation (activation of the sympathetic nervous system in response to hypoglycemia): hunger, irritability, nervous agitation or tremor, anxiety, pallor, “cold” sweat, tachycardia, palpitations. In general, the more significant and rapid the decrease in blood glucose concentration, the more pronounced adrenergic counterregulation and its manifestations are.

Documented hypoglycemic HP occurring with clinical symptoms, or severe hypoglycemic HP

Patients not treated with insulin
Transfer from basal insulin

Soliqua SoloStar®
Insulin glargine
Lixisenatide
Soliqua SoloStar®
Insulin glargine
Number of patients
469
467
233
365
365
Documented hypoglycemia occurring with clinical symptoms *
Patients with an episode of hypoglycemia, number of patients
120
110
15
146
155
(%)
(25.6%)
(23.6%)
(6.4%)
(40.0%)
(42.5%)
Episodes of hypoglycemia per patient-year, number
1.44
1.22
0.34
3.03
4.22
Severe hypoglycemia**
Episodes of hypoglycemia per patient-year, number
0
<0.01 0 0.02 <0.01
* Documented symptomatic hypoglycemia was an episode during which typical symptoms of hypoglycemia were associated with a measured plasma blood glucose concentration of ≤70 mg/dL (3.9 mmol/L).
** Severe symptomatic hypoglycemia was an episode that required the assistance of others to actively administer carbohydrates, glucagon, or other measures aimed at maintaining basic vital functions of the body.

Gastrointestinal disorders

Gastrointestinal HP (nausea, vomiting and diarrhea) were frequently observed HP during treatment. In patients treated with Soliqua SoloStar®, the incidence of treatment-related nausea, diarrhea and vomiting was 8.4%, 2.2% and 2.2%, respectively. HP from the gastrointestinal tract were mostly moderate and transient. In patients treated with lixisenatide, the incidence of treatment-related nausea, diarrhea, and vomiting was 22.3%, 3%, and 3.9%, respectively.

Lipodystrophy

Subcutaneous administration of injectable drugs containing insulin may lead to the development of lipoatrophy at the injection site (reduction of subcutaneous fat tissue) or lipohypertrophy (increase in tissue density).

Immune system disorders

An allergic reaction (urticaria), possibly associated with the use of Soliqua SoloStar®, has been reported in 0.3% of patients.

Cases of generalized allergic reactions, including anaphylactic reactions and angioedema, have been observed during post-marketing use of insulin glargine and lixisenatide.

Antibody formation

The use of Soliqua SoloStar® may cause the formation of antibodies to insulin glargine and/or lixisenatide (see section “Special Instructions”).

Reactions at the injection site

Some patients receiving insulin therapy, including Soliqua SoloStar®, experienced erythema, local swelling, and itching at the injection site. These phenomena usually gradually decreased and went away without treatment.

Interaction

Studies on the interaction of Soliqua SoloStar® with other drugs have not been conducted.

Insulin glargine

A number of drugs affect glucose metabolism, and as a result, when used concomitantly with insulin, insulin dosage adjustments and particularly careful monitoring, including monitoring of blood glucose concentrations, may be required.

Medicines that can increase the hypoglycemic effect of insulin and the tendency to develop hypoglycemia: oral hypoglycemic drugs, angiotensin-converting enzyme (ACE) inhibitors, salicylates, disopyramide; fibrates; fluoxetine, monoamine oxidase inhibitors (MAO); pentoxifylline; propoxyphene; antimicrobial agents from the sulfonamide group.
Medicines that can weaken the hypoglycemic effect of insulin: glucocorticosteroids and mineralocorticosteroids, danazol, diazoxide, diuretics, sympathomimetic drugs (such as epinephrine, salbutamol, terbutaline); glucagon, isoniazid, phenothiazine derivatives; somatropin; thyroid hormones; estrogens, progestogens (for example, as part of oral contraceptives), protease inhibitors and atypical antipsychotics (for example, olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts and ethanol can either enhance or weaken the hypoglycemic effect of insulin.
Pentamidine can cause hypoglycemia, after which hyperglycemia may develop in some cases.

In addition, under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine and reserpine, signs of adrenergic counterregulation (activation of the sympathetic nervous system in response to hypoglycemia) may be less pronounced or absent.

Lixisenatide

Lixisenatide is a peptide and is not metabolized by isoenzymes of the cytochrome P450 system. In in vitro studies, lixisenatide did not affect the activity of tested cytochrome P450 isoenzymes or transporters in humans.
The effect of delayed gastric emptying on the absorption of oral drugs

Delayed gastric emptying with lixisenatide may decrease the rate of absorption of oral medications. Caution should be exercised when concomitantly ingesting drugs with a narrow therapeutic index or requiring close clinical monitoring. If such drugs are to be taken with food, patients should be advised to take them with meals when lixisenatide is not administered. Oral medications whose effectiveness is particularly dependent on threshold concentrations, such as antibiotics, should be taken at least 1 hour before or 4 hours after an injection of Soliqua SoloStar®.

Gastro-resistant drugs should be taken at least 1 hour before or 4 hours after injection of Soliqua SoloStar®.

With paracetamol
No dose adjustment of paracetamol is required when used simultaneously with Soliqua SoloStar®, however, if a rapid onset of action of paracetamol is necessary, it should be taken 1-4 hours after injection of Soliqua SoloStar® due to a possible increase in tmax of paracetamol in the blood plasma.

With oral contraceptives
Patients using oral contraceptives should be advised to take at least 1 hour before or 11 hours after injection of Soliqua SoloStar®.

With atorvastatin
Patients taking atorvastatin should be advised to take it at least 1 hour before or 11 hours after injection of Soliqua SoloStar®.

With warfarin
No dose adjustment of warfarin is required when co-administered with Soliqua SoloStar®; however, frequent monitoring of the international normalized ratio (INR) is recommended at the beginning and after the end of therapy with Soliqua SoloStar®.

With digoxin
No dose adjustment of digoxin is required when used in combination with Soliqua SoloStar®.

With ramipril
No dose adjustment of ramipril is required when used in combination with Soliqua SoloStar®.

Overdose

Symptoms: There is limited clinical data regarding overdose of Soliqua SoloStar®.

It is possible to develop hypoglycemia and HP from the gastrointestinal tract if the required dose of Soliqua SoloStar® is exceeded.

Treatment:

Episodes of mild hypoglycemia can usually be controlled by taking easily digestible carbohydrates orally. It may be necessary to adjust the dose of the drug, diet or intensity of physical activity.

More severe episodes of hypoglycemia, including the development of coma, seizures or neurological disorders, can be treated with intramuscular/subcutaneous administration of glucagon or intravenous administration of a concentrated solution of dextrose (glucose). Long-term carbohydrate intake and medical supervision may be required, since after visible clinical improvement, hypoglycemia may recur.

Depending on the clinical manifestations and symptoms, therapy should be initiated to support vital signs, and the dose of Soliqua SoloStar® should be reduced to the dose prescribed for the patient.

Storage conditions

Store at a temperature between 2 °C and 8 °C, protected from light.

Do not freeze.

Keep out of the reach of children.

Shelf life

2 years.

Manufacturer

Sanofi-Vostok JSC, Russia