Ryzodeg® flextouch®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RYZODEG® FLEXTOUCH® (RYZODEG® FLEXTOUCH®)

Composition:

Active substances: insulin degludec, insulin aspart;

1 ml of solution contains 100 IU of insulin degludeq/insulin aspart*, containing 70% insulin degludec (equivalent to 2.56 mg) and 30% insulin aspart (equivalent to 1.05 mg).

1 pre-filled pen contains 3 ml of solution, equivalent to 300 IU of insulin degludec/insulin aspart;

Excipients: glycerol; metacresol; phenol; sodium chloride; zinc acetate, dihydrate; hydrochloric acid (for pH adjustment); sodium hydroxide (for pH adjustment); water for injections.

* Produced using recombinant DNA technology in Saccharomyces cerevisiae.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, almost particle-free liquid without cloudiness.

Pharmacotherapeutic group. Gastrointestinal tract and metabolism. Drugs used in diabetes. Insulins and analogues for injection, combinations of short-acting insulins with intermediate- and long-acting insulins. ATC code A10AD06.

Pharmacological properties.

Mechanism of action

Insulin degludec and insulin aspart specifically bind to the human insulin receptor and produce the same pharmacological effect as human insulin.

The glucose-lowering effect of insulin results from promoting glucose uptake by tissues following insulin binding to receptors on muscle and fat cells, as well as simultaneous inhibition of glucose release from the liver.

Pharmacodynamics.

The pharmacodynamic effect of Ryduged® FlexTouch® is clearly defined by two components, and the resulting profile of action reflects the effects of individual components – fast-acting insulin aspart and basal insulin degludec.

The basal component of the drug (insulin degludec) forms a soluble multihexamer after subcutaneous injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the bloodstream, providing a smooth and sustained reduction in blood glucose levels. This property is preserved in the combined preparation containing both insulin degludec and insulin aspart and does not interfere with the absorption of monomers of fast-acting insulin aspart.

The onset of action of Ryduged® FlexTouch® occurs rapidly, shortly after injection, meeting the insulin demand during meals, while the basal component provides a smooth and stable action profile and ensures continuous coverage of basal insulin requirements. The duration of action of a single dose lasts more than 24 hours.

The overall maximum glucose-lowering effect of the drug increases linearly with increasing dose. Steady-state blood concentration is achieved after 2–3 days of administration.

No differences in the pharmacodynamic effect of Ryduged® FlexTouch® were observed between younger and elderly patients.

Clinical efficacy and safety

Seven multinational, randomized, controlled, open-label, treat-to-target clinical trials lasting from 26 to 52 weeks were conducted involving a total of 1761 patients with diabetes (1 trial involving 362 patients with type 1 diabetes and 6 trials involving 1399 patients with type 2 diabetes) to evaluate the use of Ryduged® FlexTouch®. In two trials involving patients with type 2 diabetes, once-daily administration of Ryduged® FlexTouch® was compared with once-daily insulin glargine (100 IU/mL). The use of Ryduged® FlexTouch® twice daily was compared with twice-daily administration of biphasic insulin aspart 30 in two trials involving patients with type 2 diabetes, and with once-daily insulin degludec in combination with insulin aspart administered two to four times daily in one trial involving patients with type 2 diabetes. In one trial involving patients with type 2 diabetes, once-daily administration of Ryduged® FlexTouch® was compared with once-daily insulin glargine in combination with insulin aspart. After 26 weeks of treatment with Ryduged® FlexTouch®, the dose could be split into two daily injections. In all trials involving patients with type 2 diabetes, concomitant use of oral glucose-lowering agents was permitted.

In patients with type 1 diabetes, once-daily administration of Ryduged® FlexTouch® in combination with insulin aspart was compared with once- or twice-daily insulin detemir in combination with insulin aspart.

Non-inferior efficacy in HbA1c change from baseline to end of study compared to all comparator drugs was confirmed in 6 out of 7 trials in patients treated to target, whereas non-inferior efficacy was not confirmed in one trial in patients with type 2 diabetes (comparing insulin degludec/insulin aspart twice daily with once-daily insulin degludec in combination with insulin aspart 2–4 times daily).

There are no data on clinically relevant insulin antibody formation during long-term treatment with Ryduged® FlexTouch®.

Patients with type 2 diabetes

In two trials evaluating the combination of insulin and oral glucose-lowering agents in patients with type 2 diabetes, including insulin-naïve patients and those requiring intensification of insulin therapy, once-daily Ryduged® FlexTouch® demonstrated similar glycemic control (HbA1c) compared to insulin glargine (administered according to instructions). Because Ryduged® FlexTouch® contains the fast-acting insulin component (insulin aspart) administered at mealtime, postprandial glycemic control was improved compared to administration of basal insulin alone. Treatment with Ryduged® FlexTouch® was associated with a lower frequency of nocturnal hypoglycemic episodes (defined as episodes occurring between midnight and 6 a.m., confirmed by plasma glucose < 3.1 mmol/L or requiring assistance from a third party) compared to insulin glargine. In patients with type 2 diabetes, twice-daily administration of Ryduged® FlexTouch® demonstrated similar glycemic control (HbA1c) compared to twice-daily biphasic insulin aspart 30. Treatment with Ryduged® FlexTouch® resulted in improved fasting plasma glucose control compared to biphasic insulin aspart 30. Ryduged® FlexTouch® reduces the incidence of both overall and nocturnal hypoglycemia.

Twice-daily administration of Ryduged® FlexTouch® was compared with once-daily insulin degludec in combination with insulin aspart (2–4 injections per day) in patients with type 2 diabetes previously treated with basal insulin who required intensification with prandial insulin. The clinical trial protocol allowed for a standardized treatment regimen with some permitted individual adjustments. Both treatment regimens improved glycemic control: the estimated mean reduction in the primary endpoint – change in HbA1c from baseline to week 26 – was -1.23% with Ryduged® FlexTouch® versus -1.42% with insulin degludec in combination with insulin aspart. This difference did not meet the predefined non-inferiority margin of 0.4% [0.18 (-0.04; 0.41)]. There were no statistically significant differences between the two treatment groups.

In one trial involving patients with type 2 diabetes previously treated with basal insulin and requiring intensification with prandial insulin, once-daily Ryduged® FlexTouch® was compared with once-daily insulin glargine in combination with once-daily insulin aspart over 26 weeks. After 26 weeks of treatment with Ryduged® FlexTouch®, the dose could be split into two daily injections in the Ryduged® FlexTouch® group, and additional doses of insulin aspart could be administered with other meals (up to three times daily) in the insulin glargine group. The clinical trial protocol allowed for a standardized treatment regimen with some permitted individual adjustments. Once-daily Ryduged® FlexTouch® demonstrated similar glycemic control (HbA1c) compared to once-daily insulin glargine in combination with once-daily insulin aspart over 26 weeks (estimated mean reduction: -1.01% vs. -1.09%). Once- or twice-daily administration of Ryduged® FlexTouch® demonstrated similar glycemic control (HbA1c) compared to once-daily insulin glargine in combination with insulin aspart 1–3 times daily over 38 weeks (estimated mean reduction: -1.17% vs. -1.26%). Treatment with Ryduged® FlexTouch® was associated with a lower frequency of nocturnal hypoglycemic episodes compared to insulin glargine once daily in combination with insulin aspart over 26 weeks (0.42 vs. 0.76 estimated events per patient-year of exposure) and over 38 weeks (0.51 vs. 0.83 estimated events per patient-year of exposure).

Patients with type 1 diabetes

In patients with type 1 diabetes, once-daily administration of Ryduged® FlexTouch® in combination with insulin aspart (to cover insulin needs at non-main meals) demonstrated similar glycemic control (HbA1c and fasting plasma glucose) with a lower frequency of nocturnal hypoglycemic episodes compared to the basal-bolus regimen with insulin detemir in combination with insulin aspart (to cover insulin needs at all meals).

There are no data on clinically relevant insulin antibody formation during long-term treatment with Ryduged® FlexTouch®.

Cardiovascular safety

The DEVOTE trial – a randomized, double-blind, event-driven clinical trial of insulin degludec, the long-acting component of Ryduged® FlexTouch®. This clinical trial, with a median duration of 2 years, compared the cardiovascular safety of insulin degludec and insulin glargine (100 IU/mL) in 7637 patients with type 2 diabetes and high cardiovascular risk.

The primary analysis assessed the time from randomization to the first occurrence of one of three major adverse cardiovascular events (MACE): death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The trial was designed as a non-inferiority study with a pre-specified risk boundary of 1.3 for the hazard ratio (HR) of MACE with insulin degludec compared to insulin glargine. Cardiovascular safety of insulin degludec compared to insulin glargine was confirmed (HR 0.91 [0.78; 1.06]) (see Table 1).

Results of subgroup analyses (e.g., by sex, duration of diabetes, cardiovascular risk, and prior insulin therapy regimen) were consistent with the primary analysis results.

Table 1. Results of the analysis of the composite 3-component MACE endpoint and individual cardiovascular endpoints in the DEVOTE trial

N – number of patients with the first event confirmed by EAC that occurred during the study.

% – percentage of patients with the first event confirmed by EAC out of the total number of randomized patients.

EAC – Expert Adjudication Committee.

C-V – cardiovascular.

MI – myocardial infarction.

CI – 95 % confidence interval.

At baseline, HbA1c levels were 8.4 % in both treatment groups, and after 2 years, HbA1c was 7.5 % in both the insulin degludec group and the insulin glargine group.

Children

The efficacy and safety of Rydulgade® FlexTouch® were evaluated in a randomized 16-week clinical trial (n = 362) involving children and adolescents with type 1 diabetes. The study included 40 children aged 2 to 5 years, 61 children aged 6 to 11 years, and 80 adolescents aged 12 to 17 years. Rydulgade® FlexTouch® administered once daily with the main meal, plus insulin aspart with other meals, showed similar reduction in glycated hemoglobin at week 16 and no differences in fasting plasma glucose levels or self-monitoring of blood glucose levels compared to insulin detemir administered once or twice daily plus insulin aspart with meals. At week 16, the mean total daily dose of insulin Rydulgade® FlexTouch® and detemir was 0.88 versus 1.01 IU/kg, respectively. Rates (events per patient-year of exposure) of confirmed hypoglycemia (defined by ISPAD-2009: 46.23 vs 49.55) and confirmed nocturnal hypoglycemia (5.77 vs 5.40) were comparable between the Rydulgade® FlexTouch® and insulin detemir groups, while the rate of severe hypoglycemia (0.26 vs 0.07) was higher in the Rydulgade® FlexTouch® group, although the difference was not statistically significant. Several episodes of severe hypoglycemia were recorded in each group; the rate of severe hypoglycemia in the Rydulgade® FlexTouch® group was higher in patients aged 2–5 years compared to those aged 6–11 years or 12–17 years (0.42 vs 0.21 and 0.21, respectively). Assessment of efficacy and safety in adolescents with type 2 diabetes was based on data from a study involving adolescents and adults with type 1 diabetes and adult patients with type 2 diabetes. This assessment supports the use of Rydulgade® FlexTouch® in adolescent patients with type 2 diabetes.

Pharmacokinetics.

Absorption

After subcutaneous injection, soluble and stable multihexamers of insulin degludec are formed, creating an insulin depot in the subcutaneous tissue, which does not hinder the rapid release of insulin aspart monomers into the bloodstream. Insulin degludec monomers gradually dissociate from the multihexamers, providing slow and continuous delivery of insulin degludec into the bloodstream. Steady-state concentration of the basal component (insulin degludec) in serum is achieved after 2–3 days of daily administration of Rydulgade® FlexTouch®.

The rapid absorption characteristic of well-studied insulin aspart is preserved in Rydulgade® FlexTouch®. The pharmacokinetic profile of insulin aspart appears within 14 minutes after injection, with peak plasma concentration reached at 72 minutes.

Distribution

The binding affinity of insulin degludec to human plasma albumin is > 99 %. Insulin aspart has low plasma protein binding (< 10 %), similar to that observed with regular human insulin.

Metabolism

Degradation of insulin degludec and insulin aspart is similar to that of human insulin; none of the metabolites formed have biological activity.

Elimination

After subcutaneous administration of Rydulgade® FlexTouch®, the elimination half-life is determined by the rate of absorption from the subcutaneous tissue. The half-life of the basal component (insulin degludec) at steady state is 25 hours, independent of dose.

Linearity

Total exposure to Rydulgade® FlexTouch® increases proportionally with increasing doses of the basal component (insulin degludec) and prandial component (insulin aspart) in both type 1 and type 2 diabetes.

Gender

No differences in pharmacokinetic properties of the drug were observed based on patient gender.

Age, race, renal and hepatic impairment

No clinically significant differences in pharmacokinetics of Rydulgade® FlexTouch® were observed between elderly and younger adult patients, among patients of different races, or between healthy volunteers and patients with renal or hepatic impairment.

Children

The pharmacokinetics of Rydulgade® FlexTouch® in type 1 diabetes were studied in children (6–11 years) and adolescents (12–18 years) and compared to adults after a single dose. Steady-state pharmacokinetics of insulin degludec in Rydulgade® FlexTouch® were evaluated using population pharmacokinetic analysis in children under 1 year of age.

Total exposure and peak concentration of insulin aspart were higher in children than in adults, and were similar in adolescents and adults.

Steady-state pharmacokinetic properties of insulin degludec in children (1–11 years) and adolescents (12–18 years) were comparable to those in adults with type 1 diabetes. However, total exposure to insulin degludec after a single dose was higher in children and adolescents than in adults with type 1 diabetes.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus in adults, adolescents, and children aged 2 years and older.

Contraindications.

Hypersensitivity to insulin degludec, insulin aspart, or to any of the excipients contained in the medicinal product.

Interaction with other medicinal products and other forms of interaction.

It is known that certain medicinal products affect glucose metabolism.

Medicinal products that may reduce insulin requirements

Oral hypoglycemic agents (OHA), GLP-1 receptor agonists, monoamine oxidase inhibitors (MAO inhibitors), β-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulphonamides.

Medicinal products that may increase insulin requirements

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, and danazol.

β-blockers may mask the symptoms of hypoglycemia.

Octreotide/lanreotide may either decrease or increase insulin requirements.

Alcohol may potentiate or reduce the hypoglycemic effect of insulin.

Special precautions for use.

Hypoglycemia

Skipping meals or engaging in intense physical activity may lead to hypoglycemia.

Hypoglycemia may occur if the insulin dose is too high relative to insulin requirements.

Particular caution is required when using in children: insulin doses must match meal intake and physical activity to minimize the risk of hypoglycemia. Rydulgade® FlexTouch® may lead to a higher frequency of severe hypoglycemia compared to basal-bolus insulin regimens in children, especially those aged 2 to 5 years (see section "Pharmacodynamics"). The appropriateness of using Rydulgade® FlexTouch® in this age group should be determined individually.

Patients in whom intensive insulin therapy has substantially improved blood glucose control may experience changes in the usual warning symptoms of hypoglycemia, and they should be informed about this in advance. Typical warning symptoms may disappear in patients with long-standing diabetes.

Concomitant illnesses, particularly infections and fever, generally increase the patient's insulin requirements. Renal or hepatic diseases, or disorders of the adrenal glands, pituitary, or thyroid gland, may necessitate insulin dose adjustments.

As with other basal insulin preparations or insulin formulations containing a basal component, the prolonged action of Rydulgade® FlexTouch® may delay recovery from hypoglycemia.

Hyperglycemia

Rapid-acting insulin is recommended in cases of severe hyperglycemia.

Inadequate dosing or discontinuation of insulin therapy in patients requiring insulin may lead to hyperglycemia and diabetic ketoacidosis. Additionally, concomitant illnesses, especially infections, may cause hyperglycemia and thus increase insulin requirements.

Typically, the first symptoms of hyperglycemia develop gradually over several hours or days. These include increased thirst, frequent urination, nausea, vomiting, drowsiness, skin redness and dryness, dry mouth, loss of appetite, and acetone odor on the breath. In type 1 diabetes, untreated hyperglycemia leads to diabetic ketoacidosis, which is life-threatening.

Skin and subcutaneous tissue disorders

Patients should be instructed to rotate injection sites regularly to reduce the risk of lipodystrophy and cutaneous amyloidosis. Injecting into areas with such reactions may result in delayed insulin absorption and impaired glycemic control. Cases of hypoglycemia have been reported following sudden changes from affected to unaffected injection sites. It is recommended to monitor blood glucose levels after switching injection sites from affected to unaffected areas and adjust antidiabetic medication doses accordingly.

Switching from another insulin type

Changing a patient from another type or brand of insulin, or from insulin produced by another manufacturer, should be done under strict medical supervision and may require insulin dose adjustments.

Combination of pioglitazone with insulin products

Cases of congestive heart failure have been reported when pioglitazone was used in combination with insulin, particularly in patients with risk factors for congestive heart failure. This should be considered when prescribing treatment combining pioglitazone with Rydulgade® FlexTouch®. Patients receiving this combination should be monitored by a physician for early signs of congestive heart failure, weight gain, or edema. If cardiac function worsens, pioglitazone treatment should be discontinued.

Visual disturbances

Intensification of insulin therapy with rapid improvement in glycemic control may temporarily worsen diabetic retinopathy, whereas long-term improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

Prevention of accidental errors

Patients should be informed of the necessity to check the label on the insulin vial before each injection to avoid accidentally confusing Rydulgade® FlexTouch® with other insulin products.

Patients should visually confirm the number of units displayed on the pen device dose counter. Blind patients or those with poor vision should seek assistance from another person with good eyesight who knows how to use the insulin delivery device.

To avoid dosing errors and potential overdose, patients and healthcare providers must never use a syringe to withdraw medication from the cartridge of a pre-filled pen device.

In case of needle blockage, patients should follow the recommendations described in the pen device user instructions (see "Care and handling of the pen device").

Production of insulin antibodies

Insulin administration may lead to the production of insulin antibodies. In rare cases, the presence of such antibodies may require insulin dose adjustments to correct a tendency toward hyperglycemia or hypoglycemia.

This medicinal product contains less than 1 mmol sodium (23 mg); therefore, the product can be considered essentially sodium-free.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly documented on the packaging.

Use during pregnancy or breastfeeding.

Pregnancy

There is no clinical experience with the use of Rydulgade® FlexTouch® in pregnant women.

Animal reproductive studies have shown no differences between insulin degludec and human insulin regarding embryotoxicity or teratogenicity.

Generally, intensified blood glucose monitoring and close surveillance of pregnant women with diabetes are recommended during pregnancy and when planning pregnancy. Insulin requirements usually decrease during the first trimester and increase during the second and third trimesters. After delivery, insulin requirements typically return rapidly to pre-pregnancy levels.

Breastfeeding

There is no clinical experience with the use of Rydulgade® FlexTouch® during breastfeeding. In animals, insulin degludec was excreted into breast milk at lower concentrations than in plasma.

It is unknown whether insulin degludec or insulin aspart passes into human breast milk. Metabolic adverse effects in breastfed newborns/infants are not expected.

Fertility

Reproductive studies in animals following administration of insulin degludec showed no adverse effects on fertility.

Ability to affect reaction speed when driving or operating machinery.

This medicinal product has no effect or a negligible effect on the ability to drive or operate machinery.

However, hypoglycemia may impair a patient's reaction and ability to concentrate. This could represent a risk factor, for example, when driving a car or operating machinery.

Patients should take preventive measures against hypoglycemia before driving. This is especially important for patients with impaired or absent hypoglycemia warning symptoms or those experiencing frequent episodes of hypoglycemia. Under such circumstances, the appropriateness of driving should be carefully considered.

Method of Administration and Dosage.

Dosage

The medicinal product Ryduged® FlexTouch® is a soluble insulin preparation consisting of ultra-long-acting basal insulin – degludec and fast-acting prandial insulin – aspart.

The potency of insulin analogues, including the medicinal product Ryduged® FlexTouch®, is expressed in units of activity. One (1) unit of insulin corresponds to 1 IU of human insulin, 1 unit of insulin glargine activity, 1 unit of insulin detemir activity, or 1 unit of activity of biphasic insulin aspart.

The dosage of the medicinal product Ryduged® FlexTouch® should be individualized according to the patient's needs. Individual dose titration is recommended based on plasma glucose measurements in the fasting state.

Dose adjustments may be necessary during increased physical activity, changes in usual dietary patterns, or during concomitant illness.

For patients with type 2 diabetes, the medicinal product can be administered once or twice daily with main meals, either alone or in combination with oral antidiabetic agents, or in combination with bolus insulin (see section "Pharmacodynamics"). When Ryduged® FlexTouch® is used once daily, if higher insulin doses are required (e.g., to avoid hypoglycemia), switching to twice-daily administration is recommended. The dose should be divided according to the patient’s needs and administered with main meals.

For patients with type 1 diabetes, the medicinal product is administered once daily with a main meal, in combination with short-/fast-acting insulin at additional meals.

Flexibility in Timing of Administration

Ryduged® FlexTouch® allows flexible timing of insulin administration, provided it is given with a main meal.

If a dose is missed, the patient may take the missed dose with the next main meal on the same day and then resume the usual dosing schedule. Patients should not administer an additional dose to compensate for a missed dose.

Initiation of Treatment

Patients with type 2 diabetes

The recommended initial total daily dose is 10 units with a meal, followed by individual dose adjustments.

Patients with type 1 diabetes

The recommended initial dose of Ryduged® FlexTouch® is 60–70% of the patient’s total daily insulin requirement.

The product should be administered once daily in combination with short-/fast-acting insulin at additional meals, followed by individual dose adjustments.

Switching from Other Insulin Preparations

Close monitoring of blood glucose levels is recommended during the transition to Ryduged® FlexTouch® and during the first weeks of treatment. Dose adjustments and timing of short-/fast-acting insulin or other antidiabetic agents may be required.

Patients with type 2 diabetes

For patients switching from basal or previously mixed insulin regimens administered once or twice daily, the dose of Ryduged® FlexTouch® (when administered once daily) may be converted on a unit-to-unit basis from the previous insulin dose at the same total daily insulin dose previously received.

For patients switching from basal or previously mixed insulin regimens administered once or twice daily, the dose of Ryduged® FlexTouch® (when administered twice daily) may also be converted on a unit-to-unit basis from the previous insulin dose at the same total daily insulin dose previously received.

For patients switching from basal-bolus insulin therapy to Ryduged® FlexTouch®, the dose should be recalculated according to individual needs. Generally, therapy is initiated with the same number of units of basal insulin previously used.

Patients with type 1 diabetes

The recommended initial dose is 60–70% of the total daily insulin requirement, administered in combination with short-/fast-acting insulin at additional meals, followed by individual dose adjustments.

Special Populations

Elderly patients (≥ 65 years)

Ryduged® FlexTouch® can be used in elderly patients. More careful monitoring of blood glucose levels and individual dose adjustments are recommended (see section "Pharmacokinetics").

Impaired liver or kidney function

Ryduged® FlexTouch® can be used in patients with impaired liver or kidney function. More careful monitoring of blood glucose levels and individual dose adjustments are recommended (see section "Pharmacokinetics").

Administration of the Medicinal Product

Ryduged® FlexTouch® must be administered subcutaneously by injection into the abdominal wall, thigh, or upper arm. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated within the same region (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

The medicinal product must not be administered:

• intravenously, as this may lead to severe hypoglycemia;
• intramuscularly, as this may alter the rate of absorption;
• via an insulin infusion pump.

Ryduged® FlexTouch® must not be drawn into a syringe from the prefilled cartridge of the injection pen (see section "Special Warnings and Precautions for Use").

Patients should be instructed to always use a new injection needle. Reuse of insulin pen needles increases the risk of needle blockage, which may lead to under- or overdosing of insulin. In case of needle blockage, patients should follow the recommendations described in the pen user manual (see section "Care and Handling of the Pen").

Precautions for Handling and Disposal

This medicinal product in a prefilled pen is intended for use by a single patient only. The pen must not be refilled.

Ryduged® FlexTouch® must not be used if the solution is not clear and colorless.

Ryduged® FlexTouch® that has been frozen must not be used.

A new needle must be attached before each use. Needles must not be reused. Patients should remove the needle after each use.

In case of needle blockage, patients should follow the recommendations described in the pen user manual.

All waste must be disposed of in accordance with local requirements.

Ryduged® FlexTouch® is supplied in a prefilled pen (FlexTouch®), designed for use with NovoFine® or NovoTwist® injection needles up to 8 mm in length. The prefilled pen allows administration of insulin doses from 1 to 80 units in 1-unit increments.

For more detailed information, refer to the Patient Information Leaflet for Ryduged® FlexTouch®.

Instructions for Use of Ryduged® FlexTouch® for Patients

Before using the FlexTouch® pen, carefully read these instructions. If you do not follow these instructions exactly, you may receive too little or too much insulin, which could lead to significantly high or low blood sugar levels.

Do not use the pen without prior training from your doctor or nurse.

First, check the label to ensure the pen contains Ryduged® FlexTouch®, 100 IU/mL, then review the illustrations below to become familiar with the different parts of the pen and needle.

Blind patients or patients with poor vision who cannot visually verify the number of units set on the pen’s dose counter should not use the pen without assistance from another person. Seek help from someone with good vision who knows how to use an insulin delivery device.

The prefilled pen contains 300 IU of insulin. The FlexTouch® pen, 100 IU/mL, allows administration of doses from 1 to 80 units per injection in 1-unit increments.

Ryduged® FlexTouch® is intended for use with disposable injection needles NovoTwist® or NovoFine® up to 8 mm in length. Needles are not included in the package.

Important Information.

Please read this instruction carefully, as it is essential for the correct use of the pen.

1. Preparing the Pen for Injection

For each injection, always use a new needle to reduce the risk of infection, prevent insulin leakage, needle blockage, or incorrect insulin dosing.

Never use a bent or damaged needle.

1. Check insulin flow

A small air bubble may remain at the needle tip, but it will not be injected during the injection.

If no drop of insulin appears, repeat the steps (from Fig. A to Fig. C) up to 6 times. If still no drop of insulin appears, replace the needle and repeat the steps from Fig. A to Fig. C once again.

If no drop of insulin still appears, discard this pen and use a new one.

Always check that a drop of insulin appears at the needle tip before injecting. This ensures that insulin is flowing. If no drop appears, do not inject insulin, even if the dose counter is turning. This may indicate a blocked or damaged needle.

Always check insulin flow through the needle before injection. If you do not check insulin flow, you may receive too low a dose of insulin or no dose at all. This could lead to significantly elevated blood sugar levels.

1. Setting the dose

The dose selector changes the number of units. Only the dose counter and dose indicator show how many units have been selected for injection.

You can dial up to 80 units for a single dose. If the pen contains fewer than 80 units, the dose counter will stop at the number of units remaining.

The dose selector clicks differently when turned toward increasing or decreasing the dose, or when more units are selected than remain in the pen. Do not count the clicks of the pen to select the insulin dose.

Always use the dose counter and dose indicator to verify the selected number of units before injecting the medication.

Do not count the pen clicks to select the dose. If you select and inject the wrong dose, your blood sugar level may become too high or too low.

Do not use the insulin scale, which only approximately shows how much insulin remains in the pen.

1. Injecting insulin

Sometimes a drop of insulin may be seen at the needle tip after an injection. This is acceptable and does not affect the dose.

Always watch the dose counter to control the number of units injected.

The dose counter displays the exact number of units.

Do not count the clicks of the pen to determine the number of units.

Keep holding the dose button pressed until the dose counter returns to the "0" mark after injection. If the dose counter stops before reaching "0", the full dose will not be delivered, which may result in a significant increase in blood sugar levels.

1. Removing the needle after injection

Always remove the needle after each injection. This will help reduce the risk of infection, insulin leakage, needle blockage, and inaccurate dosing. Insulin cannot be injected if the needle is blocked.

Dispose of the used pen without the needle according to your doctor's, nurse's, pharmacist's, or local authority's instructions.

To avoid accidental needlestick injury, never recap the inner needle cap once it has been removed.

After each injection, always remove the needle and store the pen without the needle attached. This will help reduce the risk of infection and prevent insulin leakage, needle blockage, and incorrect dosing.

1. Determining the amount of insulin in the pen.

Carefully calculate the dose when using two pens. If in doubt, it is better to administer the full dose from a new pen. If you make a mistake in calculating the dose when using two pens, you may administer too low or too high a dose of insulin, which could lead to a significant increase or decrease in blood glucose levels.

Other important information:

• Always keep your pen with you.
• Always carry a spare pen and new needles in case your pen is damaged or lost.
• Always keep the pen and needles out of reach of other people, especially children.
• Needles and the FlexTouch® pen are intended for individual use only. Never lend your pen or needles to other people. This may lead to cross-infection. Your medication may be harmful to their health.
• Persons assisting a patient should handle used needles with great care to reduce the risk of injury and infection.

Instructions for care and handling of the pen:

Handle your pen carefully. Inappropriate handling or misuse may result in inaccurate dosing, which could lead to a significant increase or decrease in blood glucose levels.

• Do not leave the pen in a car to prevent overheating or overcooling of the medication.
• Avoid contact of the pen with dust, dirt, or liquid.
• Do not wash, soak, or lubricate the pen with oil. If necessary, the FlexTouch® pen may be cleaned by wiping it with a damp cloth containing a mild detergent.
• Avoid dropping the pen. Do not strike the pen against a hard surface. After a pen has been dropped or if you suspect any problem, attach a new needle and check insulin flow before administering the medication.
• Do not attempt to refill the pen. If it is empty, it should be disposed of.
• Do not attempt to repair the pen or disassemble it into parts.

Children.

There is no clinical experience with the use of this medicinal product in children under 2 years of age.

This medicinal product can be used in adolescents and children aged 2 years and older (see section "Pharmacodynamics"). When switching from another insulin regimen to Tresiba® FlexTouch®, the patient's individual need for insulin dose reduction must be considered to minimize the risk of hypoglycemia (see section "Special precautions for use").

Tresiba® FlexTouch® must be used with particular caution in children aged 2 to 5 years, as clinical trial data indicate that children in this age group have an increased risk of developing severe hypoglycemia (see sections "Special precautions for use", "Side effects", and "Pharmacodynamics").

Overdose.

Although there is no specific definition of overdose for insulin, hypoglycemia of varying severity may occur following its administration if doses too high relative to the patient's needs are used.

• Mild hypoglycemia can be treated by oral administration of glucose or sugar-containing products. Therefore, patients with diabetes are advised to always carry glucose-containing products with them.
• In cases of severe hypoglycemia, when the patient is unconscious, individuals who have received appropriate training should administer glucagon subcutaneously or intramuscularly (0.5–1.0 mg). A healthcare professional may administer glucose intravenously. Glucose should also be administered intravenously if the patient does not respond to glucagon within 10–15 minutes. After the patient regains consciousness, they should ingest carbohydrates to prevent recurrence of hypoglycemia.

Adverse Reactions

The most commonly reported adverse effect during treatment is hypoglycaemia (see "Description of selected adverse reactions").

Below is a list of adverse reactions based on clinical trial data. Adverse reactions are classified by frequency and by system organ class according to MedDRA. The reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated based on available data).

Immune system disorders:
Rare – hypersensitivity reactions, urticaria.

Metabolism and nutrition disorders:
Very common – hypoglycaemia.

Skin and subcutaneous tissue disorders:
Frequency not known – lipodystrophy, cutaneous amyloidosis†.

General disorders and administration site conditions:
Common – injection site reactions; uncommon – peripheral oedema.

† For adverse reactions known from post-marketing experience, see section "Description of selected adverse reactions".

Description of selected adverse reactions

Immune system disorders

Allergic reactions may occur during treatment with insulin products. Immediate-type allergic reactions to insulin or excipients may be life-threatening.

With the use of Ryduged® FlexTouch®, urticaria and hypersensitivity reactions manifesting as swelling of the tongue and lips, diarrhoea, nausea, fatigue, and pruritus are reported rarely.

Hypoglycaemia

Hypoglycaemia may occur when the insulin dose exceeds the patient's insulin requirements. Severe hypoglycaemia may lead to loss of consciousness and/or seizures, resulting in temporary or permanent impairment of brain function and even death. Hypoglycaemic symptoms usually appear suddenly. They include cold sweat, pale and cold skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, visual disturbances, headache, nausea, and palpitations.

Skin and subcutaneous tissue reactions

Lipodystrophy, including lipohypertrophy and lipoatrophy, and cutaneous amyloidosis may develop at injection sites and may delay insulin absorption from the injection site. Regular rotation of injection sites within a given body region may reduce or prevent the development of these reactions.

Injection site reactions

When administering Ryduged® FlexTouch®, skin reactions at injection sites may occur, including bruising, pain, bleeding, erythema, nodules, swelling, discoloration, pruritus, sensation of warmth, and induration at the injection site. These reactions are usually mild and transient and resolve with continued treatment.

Paediatric population

Ryduged® FlexTouch® has been administered to children and adolescents (up to 18 years of age) in pharmacokinetic studies (see section "Pharmacokinetics"). Safety and efficacy have been demonstrated in a study involving children aged 2 to 18 years. The frequency, type, and severity of adverse reactions in children are not different from those in the general diabetic patient population, except for a higher incidence of severe hypoglycaemia compared to basal-bolus therapy in children, particularly those aged 2 to 5 years (see sections "Dosage and administration", "Special warnings and precautions", and "Pharmacodynamics").

Special populations

Based on clinical trial data, the frequency, type, and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not differ from those in the general population.

Reporting of suspected adverse reactions and lack of drug efficacy

Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2.5 years.

After first opening or in a spare pen, the medicinal product may be stored for no more than 4 weeks at a temperature not exceeding 30°C. Storage in a refrigerator at 2–8°C is also acceptable. To protect from light, store the pen with the cap attached.

Storage conditions.

Store in a refrigerator at 2–8°C (not too close to the freezer compartment). Do not freeze. To protect from light, store the pen with the cap attached.

Incompatibilities.

Adding different substances to Ryduged® FlexTouch® may lead to degradation of insulin degludec and/or insulin aspart.

Ryduged® FlexTouch® must not be added to infusion solutions or mixed with any other medicinal product.

Packaging.

The multidose disposable pre-filled pen contains a 3 ml cartridge made of glass (type 1), sealed at one end with a plunger made of halobutyl rubber and at the other end with a laminated rubber stopper made of halobutyl/polysoprene rubber. The pen is made of polypropylene. Packs of 1 or 5 pens in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

A/T Novo Nordisk / Novo Nordisk A/S.

Novo Nordisk Production SAS

Manufacturers' addresses and locations of operations.

Novo Allé, Bagsværd, 2880, Denmark.

45, avenue d'Orléans, 28000 Chartres, France.