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 in combination with metformin as an adjunct to diet therapy and increased physical activity in order to improve glycemic control when metformin monotherapy or a combination of metformin with another oral hypoglycemic drug, or basal insulin monotherapy are not effective.

Active ingredient

Insulin glargine, Lixisenatide

Composition

In 1 ml of a solution for subcutaneous injection of 100 IU/ml of insulin glargine and 33 µg/ml of lixisenatide contains:

active ingredients:

insulin glargine – 3.6378 mg (100 IU),

lixisenatide – 33 µg;

excipients:

glycerol (85%);

methionine (L-methionine);

metacresol (m-cresol);

Zinc chloride;

Hydrochloric acid;

Sodium hydroxide;

Water for injection.

How to take, the dosage

For ease of personalized dosing, Soliqua SoloStar® is available in two syringe pens that provide a choice of different doses. The difference between the two syringe pens is the dose range of the active ingredients in the syringe pens (see below).

• Soliqua SoloStar® 100 IU/ml and 50 µg/ml: 10-40 syringe pen
  – 1 unit of product in this Soliqua SoloStar® syringe pen contains 1 IU of insulin glargine and 0.5 µg of lixisenatide.
  – This syringe pen gives you the opportunity to receive a daily dose of 10 to 40 units of Solikva SoloStar® (10 to 40 IU of insulin glargine combined with lixisenatide at a dose of 5 mcg to 20 mcg).
• Soliqua SoloStar® 100 IU/ml and 33 µg/ml: 30-60 syringe pen
  – 1 unit of drug in this Soliqua SoloStar® syringe pen contains 1 IU of insulin glargine and 0.33 µg of lixisenatide.
  – This syringe pen allows for a daily dose of 30 to 60 units of Solikva SoloStar® (30 to 60 units of insulin glargine combined with lixisenatide at a dose of 10 mcg to 20 mcg).

In order to avoid administering the drug by mistake from a different syringe pen (with a different dosage), make sure that the prescription lists the appropriate Soliqua SoloStar® syringe pen for the prescription: the Soliqua SoloStar® Syringe Pen (10-40) or the Soliqua SoloStar® Syringe Pen (30-60).

The maximum daily dose of Soliqua SoloStar® is 60 units (60 units of insulin glargine and 20 µg of lixisenatide).

Soliqua SoloStar® is given subcutaneously once daily for 1 hour before any meal. Preferably, a prandial (pre-meal) injection of Soliqua SoloStar® should be given daily before the same meal, chosen as the most appropriate for the patient. If a dose of Soliqua SoloStar® was missed, it should be administered within 1 hour before the next meal.

The dose of Soliqua SoloStar® should be adjusted individually based on clinical response and titrated based on the patient’s insulin needs. The dose of lixisenatide increases or decreases with the dose of insulin glargine and also depends on which of the above syringes is used.

Dose adjustments or changes in the time of administration of Soliqua SoloStar® should only be made under medical supervision with appropriate monitoring of blood glucose concentration (see Special Instructions section).

The initial dose of Soliqua SoloStar®

The starting dose of Soliqua SoloStar® is selected based on previous treatment with hypoglycemic drugs and should not exceed the starting dose of lixisenatide 10 mcg.

The starting dose of Soliqua SoloStar®

* If another basal insulin was used:

– For basal insulin administered twice daily or insulin glargine 300 units/ml administered once daily, the initial daily dose of Soliqua SoloStar® must be reduced by 20%.

– For any other basal insulin, the same recommendations as for insulin glargine (100 IU/ml) should apply.

Dose titration of Soliqua SoloStar®

Soliqua SoloStar® should be dosed according to the patient’s individual insulin needs. In order to improve glycemic control, it is recommended to adjust the dose of the drug on the basis of determining the plasma glucose concentration on an empty stomach.

When switching to therapy with Soliqua SoloStar® and in subsequent weeks, close monitoring of blood glucose concentrations is recommended.

• If patient treatment begins with the Soliqua SoloStar® syringe pen (10-40), the dose can be titrated up to 40 units of the drug using this syringe pen.
• At total daily doses of >40 units of drug/day, switch to the Solikva SoloStar® syringe pen (30-60).
• If a patient begins treatment with the Soliqua SoloStar® (30-60) syringe pen, the dose can be titrated up to 60 units using this pen.
• At total daily doses of >60 drug units/day, Soliqua SoloStar® should not be used.

Injection method

Soliqua SoloStar® is injected into the subcutaneous fatty tissue of the anterior abdominal wall, shoulders, or hips.

In order to reduce the risk of lipodystrophy, the injection site should be changed with each new injection within one of the recommended injection sites.

The rate of absorption and thus the onset and duration of action may be affected by physical activity and other changing factors such as stress, intercurrent illness, or changes in concurrent medications or diet.

Soliqua SoloStar® should not be given intravenously or intramuscularly.

The syringe pen may be used for up to 4 weeks after the first administration of the drug, stored below 25°C in a light-proof place (do not freeze or refrigerate).

For more information about injecting with the Soliqua SoloStar® 10-40 syringe pen, see “Instructions for Use of the Soliqua SoloStar® 10-40 Syringe Pen (for doses of 10-40 units per day)” below.

For more information on injecting with the Soliqua SoloStar® 30-60 Syringe Pen, see “Instructions for Use Soliqua SoloStar® 30-60 Syringe Pen (for doses of 30-60 units per day)” below.

Use in special clinical patient groups

Children and adolescents under 18 years of age

The safety and effectiveness of Soliqua SoloStar® in children and adolescents under 18 years of age has not been established.

Patients aged ≥65 years

Soliqua SoloStar® can be used in patients aged ≥65 years. The dose should be adjusted individually based on monitoring of blood glucose concentrations. The experience of using the drug in patients aged ≥75 years is limited.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of Soliqua SoloStar® has not been studied.

Lixisenatide dose adjustment is not required in patients with hepatic impairment. In patients with hepatic impairment, insulin requirements may decrease due to decreased gluconeogenesis capacity and slower insulin metabolism. In patients with hepatic insufficiency, frequent monitoring of blood glucose concentration and dose adjustment of Soliqua SoloStar® may be required.

Patients with renal impairment

There is no therapeutic experience with lixisenatide in patients with severe renal impairment (CKD less than 30 ml/min) and terminal renal failure, so the use of lixisenatide in these patient groups is contraindicated. In patients with mild to moderate renal failure, insulin requirement may decrease due to slowed insulin metabolism. In patients with renal insufficiency, frequent monitoring of blood glucose concentration and dose adjustment of Soliqua SoloStar® may be required.

Interaction

Studies on the interaction of the drug Soliqua SoloStar® with other medicinal products have not been conducted.

Insulin glargine

A number of drugs affect glucose metabolism, so their concomitant use with insulin may require adjustment of insulin dose and especially close monitoring, including monitoring of blood glucose concentrations.

• Drugs that may increase the hypoglycemic effect of insulin and tend to develop hypoglycemia: Oral hypoglycemic drugs, angiotensin-converting enzyme (ACE) inhibitors, salicylates, disopyramide; fibrates; fluoxetine, monoamine oxidase (MAO) inhibitors; pentoxifylline; propoxyphene; antimicrobials from the sulfonamide group.
• Drugs that may 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, progestagens (e.g., oral contraceptives), protease inhibitors, and atypical neuroleptics (e.g., olanzapine and clozapine).
• Beta-adrenoblockers, clonidine, lithium salts, and ethanol may either enhance or impair the hypoglycemic effects of insulin.
• Pentamidine may cause hypoglycemia, which may be followed in some cases by hyperglycemia.

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

Lixisenatide

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

Delayed gastric emptying during use of lixisenatide may reduce the absorption rate of oral medications. Caution should be exercised when concomitant ingestion of drugs with a narrow therapeutic range or requiring close clinical monitoring. If such drugs should be taken with meals, patients should be advised to take them with the meal when lixisenatide is not administered. Oral medications whose efficacy is particularly dependent on threshold concentrations, such as antibiotics, should be taken at least 1 h before or 4 h after the Soliqua SoloStar® injection.

Gastro-resistant medications should be taken at least 1 h before or 4 h after the Soliqua SoloStar® injection.

With Paracetamol
No adjustment of the dose of paracetamol is required when used concomitantly with Soliqua SoloStar®, but if rapid onset of paracetamol is required, it should be taken 1-4 hours after Soliqua SoloStar® injection due to possible increased tmax of paracetamol in blood plasma.

With oral contraceptive drugs
Patients who use oral contraceptive drugs should be advised to take at least 1 hour before or 11 hours after Soliqua SoloStar® injection.

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

With warfarin
Warfarin dosage adjustment is not required when combined with Soliqua SoloStar®, but frequent monitoring of the international normalized ratio (INR) at the beginning and after the end of therapy with Soliqua SoloStar® is recommended.

With digoxin
No dose adjustment of digoxin is required when combined with Soliqua SoloStar®.

With ramipril
No dose adjustment is required for ramipril when combined with Soliqua SoloStar®.

Special Instructions

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

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

Risk of pancreatitis

Use of GFP-1 receptor agonists has been associated with the risk of acute pancreatitis. Rare cases of acute pancreatitis have been reported with lixisenatide use, although no causal relationship between the two has been established. Patients should be informed about the characteristic symptoms of pancreatitis: prolonged (persistent) severe abdominal pain. If pancreatitis is suspected, the use of Soliqua SoloStar® should be discontinued. If the diagnosis of acute pancreatitis is confirmed, 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 common adverse effect during treatment with Soliqua SoloStar®. Hypoglycemia may occur if the dose of Soliqua SoloStar® is higher than the need. Factors that increase the predisposition to hypoglycemia require close monitoring and may require adjustment of the dosing regimen.

These factors include:
– change in injection site;
– increased insulin sensitivity (e.g., due to cessation of stressors);
– unusual, heavier or longer physical activity;
– comorbidities (e.g., vomiting, diarrhea);
– inadequate food intake;
– skipping meals;
– consumption of alcohol (ethanol);
– some uncompensated endocrine disorders (such as hypothyroidism and insufficiency of anterior pituitary or adrenal cortex hormones);
– concomitant therapy with certain medications (see “Interaction with other medicines” section).

The dose of the preparation Soliqua SoloStar® should be chosen individually by the clinical effect and titrated based on the patient’s need for insulin.

Long-lasting effect of insulin glargine injected subcutaneously may slow down the patient’s recovery from hypoglycemia.

Simultaneous use of lixisenatide and/or insulin with sulfonylurea derivatives increases the risk of hypoglycemia, in this regard, the drug Soliqua SoloStar® should not be used in combination with sulfonylurea drugs.

Use in patients with severe gastroparesis

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

Renal failure

There is no therapeutic experience of the drug administration in patients with severe renal failure (CKR less than 30 ml/min) or with the terminal stage of renal failure. The drug is contraindicated in patients with renal failure of a severe degree (CKD less than 30 ml/min) or terminal renal failure.

Concomitant use of medicinal products

Slowing emptying of the stomach by lixisenatide may decrease the rate of absorption of oral medications.
Soliqua SoloStar® should be used with caution in patients taking drugs that require rapid absorption from the gastrointestinal tract, need careful clinical monitoring or have a narrow therapeutic range.

Dehydration

Patients treated with Soliqua SoloStar® should be informed about the potential risk of dehydration due to the development of gastrointestinal HP and about precautionary measures to avoid fluid loss.

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

Fertility
Studies conducted on animals with insulin glargine and lixisenatide have shown no direct adverse effects on fertility.

Excipients

Solikva SoloStar® contains methacresol, which may cause allergic reactions.

Prevention of drug administration errors

Patients should be instructed to always check the label on the syringe pen before each administration to avoid accidentally mixing up two Soliqua SoloStar® syringe pens with different concentrations of active ingredients or mixing up other syringe pens with other injectable antidiabetic medications.

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

Effect on driving and operating ability

Patients’ ability to concentrate and respond may be impaired by the development of hypoglycemia or hyperglycemia, or by visual impairment. This may pose a risk in situations where these abilities are particularly important (e.g., driving or operating machinery).

Patients should be advised to take precautions to avoid developing hypoglycemia while driving vehicles. This is particularly important in those patients who are impaired or lack recognition of symptoms that would predict the development of hypoglycemia, or in patients with frequent episodes of hypoglycemia. In such cases, the appropriateness of driving vehicles or mechanisms should be considered.

Contraindications

• Hypersensitivity to lixisenatide, insulin glargine or any of the excipients that make up the drug.
• Pregnancy.
• Breast-feeding period.
• Diabetes mellitus type 1.
• Diabetic ketoacidosis.
• Severe gastrointestinal (GI) disease, including gastroparesis.
• Severe renal insufficiency (CK less than 30 ml/min).
• Age before 18 years of age (due to lack of efficacy and safety data in this age group).

Caution

• Pancreatitis in anamnesis (due to lixisenatide content in the drug.
• Patients concomitantly taking drugs that require rapid gastrointestinal absorption, have a narrow therapeutic index, or require close clinical monitoring

.

Side effects

The adverse reactions (HP) listed below are presented by organ system (as classified by the Medical Dictionary for Regulatory Affairs (MedDRA)) and the CIOMS (Council for International Organizations of Medical Sciences) HP frequency classification was used: Very common (≥10%); common (≥1%; <10%); infrequent (≥0.1%; rare (≥0.01%; very rare (<0.01%), frequency unknown (it was not possible to determine the incidence of HP from available data).

A brief description of the safety profile

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

List of HP

Infectious and parasitic diseases: Infrequent: Nasopharyngitis, upper respiratory tract infections.

Immune system disorders: Infrequent: urticaria.

Metabolism and nutrition disorders: Very common: hypoglycemia.

Nervous system disorders: Often: dizziness. Infrequent: headache.

Gastrointestinal disorders: Often: nausea, diarrhea, vomiting. Infrequent: dyspepsia, abdominal pain.

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

Description of individual HP

Hypoglycemia

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

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

Documented hypoglycemic HP with clinical symptoms or severe hypoglycemic HP

*Documented, clinically symptomatic hypoglycemia was an episode during which typical symptoms of hypoglycemia were combined with an established plasma blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
** Severe clinically symptomatic hypoglycemia was an episode that required the assistance of others to actively administer carbohydrates, glucagon, or other measures to maintain basic body functions.

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. Gastrointestinal HP were, for the most part, moderately severe 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

The subcutaneous administration of injectable drugs containing insulin may lead to the development of lipoatrophy at the injection site (reduction of subcutaneous fatty tissue) or lipohypertrophy (increased tissue density).

Immune system disorders

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

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

Antibody formation

The use of the drug Soliqua SoloStar® may cause the formation of antibodies to insulin glargine and/or lixisenatide (see sect.

Injection site reactions

Some patients receiving insulin therapy, including Soliqua SoloStar®, have experienced erythema, local edema, and itching at the injection site. These phenomena usually diminished gradually and resolved without treatment.

Overdose

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

Hypoglycemia and gastrointestinal HP may occur if the required dose of Soliqua SoloStar® is exceeded.

Treatment:

Episodes of hypoglycemia of mild degree of severity can usually be stopped by taking 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, up to the development of coma, seizures or neurological disorders may be controlled by intramuscular/subcutaneous administration of glucagon or intravenous administration of concentrated dextrose (glucose) solution. Prolonged intake of carbohydrates and medical supervision may be required, since after visible clinical improvement there may be a relapse of hypoglycemia.

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

Pregnancy use

Pregnancy

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

Reproductive toxicity of lixisenatide has been demonstrated in animal studies; no embryotoxicity or teratogenicity of insulin glargine.

Potential risk to humans is unknown. Soliqua SoloStar® is contraindicated in pregnancy (due to the content of lixisenatide in the drug).

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

Breast-feeding period

There are no data on penetration of insulin glargine or lixisenatide into human breast milk. Use of the drug Soliqua SoloStar® during breastfeeding is contraindicated.