Actrapid® nm flexpen®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACTRAPID® NM FLEXPEN® (ACTRAPID® NM FLEXPEN®)

Composition:

Active substance: human insulin (rDNA);

1 ml of injection solution contains 100 IU of biosynthetic human insulin (recombinant DNA, produced using Saccharomyces cerevisiae);

1 IU (international unit) equals 0.035 mg of anhydrous human insulin;

1 multidose disposable pen contains 3 ml of injection solution, equivalent to 300 IU;

Excipients: zinc chloride, glycerol, metacresol, sodium hydroxide (for pH adjustment), hydrochloric acid diluted (for pH adjustment), water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless, clear liquid free of foreign particles; very slight traces of fine precipitate may appear during storage.

Pharmacotherapeutic group. Antidiabetic agents. Insulins and analogues for injection, short-acting. ATC code A10AB01.

Pharmacological properties.

Pharmacodynamics.

The blood glucose-lowering effect of insulin is due to its promotion of glucose uptake by tissues following insulin binding to receptors on muscle and fat cells, as well as simultaneous suppression of glucose release from the liver.

Results from a single-center intensive care study on the treatment of hyperglycemia (blood glucose levels above 10 mmol/L) in 204 diabetic patients and 1,344 non-diabetic patients who underwent major surgery showed that normoglycemia (blood glucose level of 4.4–6.1 mmol/L), induced by intravenous administration of the drug, reduced mortality by 42% (from 8% to 4.6%).

Actrapid® NM FlexPen® is a short-acting insulin preparation.

The onset of action occurs within 30 minutes, the maximum effect is reached within 1.5–3.5 hours, and the duration of action is approximately 7–8 hours.

Pharmacokinetics.

The half-life of insulin in blood is only several minutes; therefore, the pharmacological profile of insulin is determined exclusively by the characteristics of its absorption. This process depends on several factors (e.g., insulin dose, method and site of injection, thickness of subcutaneous tissue, type of diabetes), resulting in considerable variability in insulin effect both within the same patient and among different patients.

Absorption. Peak plasma concentration occurs within 1.5–2.5 hours after subcutaneous injection.

Distribution. No significant binding of insulin to plasma proteins has been observed, except for circulating anti-insulin antibodies (if present).

Metabolism. Human insulin is degraded by insulin proteases or insulin-degrading enzymes, and possibly by protein disulfide isomerase. Several sites of hydrolysis of the human insulin molecule have been identified. None of the metabolites formed after hydrolysis possess biological activity.

Elimination. The terminal half-life of insulin is determined by the rate of its absorption from the subcutaneous tissue. Therefore, the terminal half-life (t½) reflects the rate of absorption rather than elimination per se of insulin from plasma (the t½ of insulin in circulation is only several minutes). According to available study data, t½ ranges from 2 to 5 hours.

Children

The pharmacokinetic profile of the drug was studied in a small number of children (n = 18, aged 6–17 years) with diabetes. Limited data indicate that the pharmacokinetic profile of insulin in children is practically the same as in adults. However, Cmax (maximum concentration) varied with age, indicating the importance of individual dose adjustment.

Preclinical safety data

Preclinical studies (repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity) revealed no safety concerns associated with administration of the drug.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus.

Contraindications.

Hypersensitivity to human insulin or to any of the excipients of the product.

Interaction with other medicinal products and other forms of interaction.

It is known that several medicinal products affect glucose metabolism.

Substances that may decrease the patient's insulin requirements:

oral hypoglycemic agents (OHA), monoamine oxidase inhibitors (MAOIs), β-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulfonamides.

Substances that may increase the patient's 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 diminish the hypoglycemic effect of insulin.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered product must be clearly recorded.

Patients should consult their physician before travelling across time zones, as this may require adjustment of insulin injection and meal schedules.

Hyperglycemia

Inadequate dosing or discontinuation of treatment (especially in type 1 diabetes) may lead to hyperglycemia and diabetic ketoacidosis. Typically, the first symptoms of hyperglycemia develop gradually over several hours or days. These include thirst, frequent urination, nausea, vomiting, drowsiness, skin redness and dryness, dry mouth, loss of appetite, and acetone breath odor.

In type 1 diabetes, untreated hyperglycemia may lead to diabetic ketoacidosis, which is potentially life-threatening.

Hypoglycemia

Skipping meals or unexpected physical exertion may lead to hypoglycemia.

Hypoglycemia may occur if the insulin dose is too high relative to insulin requirements. The product should not be administered during episodes of hypoglycemia or when hypoglycemia is suspected. After blood glucose levels have stabilized, the patient's insulin dose should be re-evaluated (see sections "Adverse reactions" and "Overdose").

Patients who have achieved significantly improved glycemic control through intensive insulin therapy may experience changes in the usual warning symptoms of hypoglycemia, and should be warned accordingly. Typical warning symptoms may diminish in patients with long-standing diabetes.

Concomitant illnesses, particularly infections and fever, usually increase insulin requirements. Concomitant kidney, liver, or adrenal, pituitary, or thyroid gland disorders may necessitate insulin dose adjustments.

When a patient is switched to another type of insulin, the symptoms of hypoglycemia may change or become less pronounced compared to those experienced with the previous insulin.

Switching from other insulins

Switching a patient to another type or brand of insulin should be done under strict medical supervision. Changes in insulin concentration, type (manufacturer), species (animal insulin, human insulin, or human insulin analog), and/or production method (recombinant DNA technology or animal insulin) may require insulin dose adjustments. Patients switching to Actrapid® NM FlexPen® from another insulin may require an increased number of daily injections or changes in dosage compared to their previous insulin regimen. Dose adjustments may be necessary both at the initiation of the new product and during the first weeks or months of treatment.

Injection site reactions

With any insulin therapy, injection site reactions may occur, including pain, redness, urticaria, inflammation, bruising, swelling, and itching. Regularly rotating injection sites within a given area may reduce or prevent these reactions. Reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Actrapid® NM FlexPen®.

Actrapid® NM FlexPen® must not be used in insulin infusion pumps for continuous subcutaneous insulin infusion due to the risk of precipitation in the pump tubing.

Disorders of the skin and subcutaneous tissue

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 abrupt changes from injecting into affected areas to unaffected sites. It is recommended to monitor blood glucose levels after switching injection sites from affected to unaffected areas and to adjust antidiabetic medication doses accordingly.

Combination of Actrapid® NM FlexPen® with pioglitazone

Cases of congestive heart failure have been reported when pioglitazone is used in combination with insulin, particularly in patients with risk factors for congestive heart failure. This should be considered when prescribing combination therapy with pioglitazone and insulin. Patients receiving this combination should be monitored for signs and symptoms of heart failure, weight gain, and edema. If cardiac function worsens, treatment with pioglitazone should be discontinued.

Prevention of accidental administration errors

Patients should be instructed to always check the label on the insulin packaging before each injection to avoid accidentally confusing Actrapid® NM FlexPen® with other insulin products.

Actrapid® NM FlexPen® contains less than 1 mmol of sodium (23 mg) and can therefore be considered essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy

Since insulin does not cross the placental barrier, there are no restrictions on insulin treatment for diabetes during pregnancy.

Both hypoglycemia and hyperglycemia, which may occur with inadequate diabetes management, increase the risk of congenital malformations or fetal death. Therefore, intensified monitoring of blood glucose levels and close supervision of diabetic pregnant women are recommended throughout pregnancy and whenever pregnancy is suspected.

Insulin requirements usually decrease during the first trimester of pregnancy and increase significantly during the second and third trimesters. After delivery, insulin requirements typically return rapidly to pre-pregnancy levels.

Breastfeeding period

There are no restrictions on the use of Actrapid® NM FlexPen® during breastfeeding, as treatment of the mother does not pose any risk to the infant. However, dose adjustments may be necessary.

Fertility

Reproductive toxicity studies in animals using human insulin have not shown any adverse effects on fertility.

Ability to influence reaction speed when driving or operating machinery.

A patient's reaction and ability to concentrate may be impaired during episodes of hypoglycemia. This may represent a risk factor in situations where such abilities are particularly important (e.g., driving a car or operating machinery).

Patients should be advised to take preventive measures against hypoglycemia before driving. This is especially important for patients with diminished or absent hypoglycemia warning symptoms or those who experience frequent hypoglycemic episodes. In such circumstances, the appropriateness of driving should be carefully considered.

Method of Administration and Dosage

Dosing

The potency of human insulin is expressed in International Units (IU).

The dosage of insulin is individual and must be determined by a physician according to the patient's needs. The drug may be used alone or in combination with short- or long-acting insulin before a main or additional meal.

The individual daily insulin requirement usually ranges from 0.3 to 1.0 IU/kg/day. Dose adjustments may be necessary for patients during increased physical activity, changes in diet, or during concomitant illnesses.

Special Populations

Elderly Patients (≥ 65 years)

The drug Actrapid® NM FlexPen® can be used in elderly patients.

In elderly patients, enhanced glucose monitoring is recommended, and the insulin dose should be individually adjusted.

Renal and Hepatic Impairment

Renal and hepatic impairment may reduce insulin requirements. In patients with renal or hepatic impairment, intensified glucose monitoring and individual dose adjustment of insulin are required.

Children

Actrapid® NM FlexPen® can be used in children.

Switching from Other Insulin Preparations

When switching from other insulin preparations, dose adjustments of Actrapid® NM FlexPen® and the background insulin may be necessary.

Careful blood glucose monitoring is recommended during the transition to Actrapid® NM FlexPen® and throughout the first several weeks of treatment. (See section "Special Warnings and Precautions for Use").

Administration

Actrapid® NM FlexPen® is a short-acting insulin preparation contained in a pen device. It can be used in combination with intermediate- or long-acting insulin.

Subcutaneous Administration

Actrapid® NM FlexPen® is administered subcutaneously by injection into the abdominal wall, thigh, buttocks, or deltoid region of the shoulder. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated, even within the same body area (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Injecting into a lifted skin fold significantly reduces the risk of accidental intramuscular injection.

After injection, the needle should remain under the skin for at least 6 seconds to ensure complete delivery of the dose. Absorption of insulin is faster following subcutaneous injection into the abdominal area compared to other injection sites. Duration of action may vary depending on dose, injection site, blood flow, body temperature, and the patient's level of physical activity.

The injection should be administered 30 minutes before a main or additional meal containing carbohydrates.

The drug must not be used in insulin infusion pumps for continuous subcutaneous insulin infusion due to the risk of precipitation in the pump catheter.

Intramuscular injections may be performed under medical supervision.

Intravenous Administration

Intravenous administration of Actrapid® NM FlexPen® must be performed only by a healthcare professional. Intravenous administration of Actrapid® NM FlexPen® from the pen or cartridge is permitted only when vials are unavailable. In this case, the preparation should be drawn into an insulin syringe, ensuring that all air is expelled from the syringe, and then administered into an infusion system. This procedure must be performed only by a healthcare professional.

Infusion systems containing Actrapid® NM 100 IU/mL, with human insulin concentrations ranging from 0.05 IU/mL to 1.0 IU/mL in infusion solutions of 0.9% sodium chloride, 5% or 10% dextrose, and 40 mmol/L potassium chloride, using polypropylene infusion containers, are stable at room temperature for up to 24 hours. Some insulin may be adsorbed onto the inner surface of the infusion container initially. Blood glucose concentration must be monitored during insulin infusion.

The pre-filled insulin pen FlexPen® is intended for use with NovoFine® or NovoTwist® disposable needles up to 8 mm in length. The FlexPen® allows administration of doses from 1 to 60 units in 1-unit increments. Actrapid® NM FlexPen® must be administered only subcutaneously. If administration via insulin syringe or intravenous route is required, the drug in vial form should be used.

Strict adherence to the instructions for use of these medical devices is essential.

Handling and Disposal Precautions

Do not use the medicinal product if you notice that the solution is not clear and colorless.

Do not use Actrapid® NM FlexPen® after it has been frozen.

Patients should be advised to dispose of the needle after each injection.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Needles and pre-filled Actrapid® NM FlexPen® devices are intended for individual use only.

Refilling the cartridge is strictly prohibited.

Instructions for Use of Actrapid® NM FlexPen®

Before using the FlexPen®, carefully read these instructions. Failure to follow these instructions precisely may result in administration of too little or too much insulin, which could lead to a sudden increase or decrease in blood glucose levels.

FlexPen® is a pre-filled insulin pen with a dose selector allowing doses from 1 to 60 units of insulin in 1-unit increments. FlexPen® is used with NovoFine® or NovoTwist® needles up to 8 mm in length. As a precaution, always keep a spare insulin delivery device available in case the FlexPen® is damaged or lost.

Care of the FlexPen® pen-injector The FlexPen® pen-injector must be handled with care. If it has been dropped, damaged, or deformed, there is a risk of insulin leakage. This may lead to incorrect dosing, which can result in high or low blood sugar levels. The surface of the FlexPen® pen-injector can be cleaned by wiping it with cotton wool. Do not soak, wash, or lubricate it, as this may damage the pen-injector. Do not refill the pen-injector. If it is empty, it must be disposed of. Preparing the FlexPen® pen-injector for injection Check the name of the medicine and the label color to make sure that the correct type of insulin is in the pen-injector. This is especially important if you are using more than one type of insulin. Administering the wrong type of insulin may cause your blood sugar level to rise or fall sharply.
Fig. A. Remove the cap from the pen-injector.
Fig. B. Remove the protective membrane from a new disposable needle. Screw the needle tightly onto the FlexPen® pen-injector.
Fig. C. Remove the large outer needle cap. Do not throw it away.
Fig. D. Remove the inner needle cap and dispose of it. Never try to reattach the removed inner needle cap, as you may injure yourself with the needle.
Always use a new needle for each injection. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and inaccurate dosing. Be careful not to bend or damage the needle before use.
Checking insulin flow
Fig. E. Small amounts of air may accumulate in the cartridge when using the pen-injector. To prevent injecting air and to ensure the correct dose is delivered, do the following: Set the dose selector to 2 units.
Fig. F. Holding the FlexPen® vertically with the needle pointing upwards, gently tap the cartridge several times with your finger to collect air bubbles at the top of the cartridge.
Fig. G. Holding the FlexPen® vertically with the needle pointing upwards, press the injection button fully. The dose selector will return to zero. A drop of insulin should appear at the tip of the needle. If it does not, replace the needle and repeat this procedure no more than 6 times. If a drop of insulin still does not appear, this indicates that the pen-injector is defective and a new pen-injector should be used.
Before each injection, always confirm that a drop of insulin appears at the needle tip. This ensures that insulin is flowing through the needle. If no drop appears, you will not deliver insulin, even if the dose selector moves. This indicates that the needle is blocked or damaged. Always check insulin flow through the needle before injection. If you do not do this, you may receive too little insulin or none at all, which could lead to a significant increase in blood sugar levels.
Setting the dose
Fig. H. Ensure the dose selector is set to "0". Turn the dose selector to select the required number of units for injection. The dose can be adjusted higher or lower by rotating the dose selector in the appropriate direction until the required dose aligns with the dose indicator. While turning the selector, be careful not to press the injection button accidentally, as this may cause insulin to leak. You cannot set a dose exceeding the number of units remaining in the cartridge.
Always use the dose selector and dose indicator to verify how many units you have selected before injecting insulin. Do not count the clicks of the pen-injector to determine the insulin dose. If you select and inject an incorrect dose of insulin, your blood sugar level may rise or fall. Do not use the insulin remaining scale, as it only shows an approximate amount of insulin left in your pen-injector.
Administering insulin
Fig. I. Insert the needle under the skin. Follow the injection technique taught by your doctor or nurse. Administer the dose by fully pressing the injection button until "0" aligns with the dose indicator. Be careful to press only the injection button during the injection. Rotating the dose selector will not deliver insulin.
Fig. J. Keep the injection button fully pressed and leave the needle under the skin for at least 6 seconds. This ensures the full dose of medicine is delivered. Remove the needle from the skin and release the injection button. Always ensure that the dose indicator has returned to "0" after injection. If the dose indicator stops before returning to "0", the full dose has not been delivered, which may affect blood sugar levels.
Fig. K. Cover the needle with the large outer cap without touching it. Once the needle is completely covered by the large outer cap, gently press the cap and then unscrew the needle. Dispose of the needle carefully and replace the cap on the pen-injector.
Always remove the needle after each injection and store the Actrapid® NM FlexPen® without a needle attached. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and inaccurate dosing.
Additional important information Healthcare providers, family members, and others assisting the patient must be very careful with used needles to reduce the risk of accidental needlestick injury and cross-infection. Dispose of the used pen-injector without the needle. Never give your pen-injector or needles to other people. This may lead to cross-infection. Never give your pen-injector to other people. Your medicine may be harmful to their health. Store your pen-injector and needles in places inaccessible to others, especially children.

Children.

Biosynthetic human insulin preparations are effective and safe medicinal products for the treatment of diabetes mellitus in children of various age groups. Daily insulin requirements in children depend on the stage of the disease, body weight, age, diet, physical activity, degree of insulin resistance, and glycemia dynamics.

Overdose.

Although a specific definition of overdose for insulin has not been established, administration of doses significantly higher than the patient's requirements may lead to the development of hypoglycemia, progressing through sequential stages.

• Mild hypoglycemia can be treated by oral administration of glucose or sweet foods. Therefore, diabetic patients are advised to always carry several sources of sugar.
• In cases of severe hypoglycemia, when the patient is unconscious, individuals who have received appropriate training should administer glucagon intramuscularly or subcutaneously (0.5 to 1.0 mg). A healthcare professional may administer intravenous glucose. Intravenous glucose should be administered if the patient does not respond to glucagon within 10–15 minutes. After the patient regains consciousness, carbohydrate-containing food should be administered to prevent recurrence.

Adverse Reactions

The most common adverse effect of therapy is hypoglycaemia. The frequency of hypoglycaemia depends on the patient population, dosage regimen, and level of glycaemic control (see description of individual adverse reactions below).

At the initiation of insulin therapy, transient refractive disturbances, oedema, and injection site reactions (pain, erythema, urticaria, inflammation, bruising, swelling, and pruritus at the injection site) may occur. These reactions are usually transient. Rapid improvement in blood glucose control may cause a reversible condition of acute painful neuropathy. Intensification of insulin therapy with rapid improvement in glycaemic control may lead to a temporary worsening of diabetic retinopathy, whereas long-term, well-established glycaemic control reduces the risk of progression of diabetic retinopathy.

Based on clinical trials, the adverse reactions listed below are classified by frequency and organ system classes according to MedDRA.

By frequency of occurrence, these reactions were categorized as very common (≥1/10), common (≥1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Immune system disorders

Urticaria, pruritus – uncommon.

Anaphylactic reactions* – very rare.

Metabolism and nutrition disorders

Hypoglycaemia* – very common.

Nervous system disorders

Peripheral neuropathies (painful neuropathies) – uncommon.

Eye disorders

Refractive disturbances – uncommon.

Diabetic retinopathy – very rare.

Skin and subcutaneous tissue disorders

Lipodystrophy* – uncommon.

Cutaneous amyloidosis*† – frequency not known.

General disorders and administration site conditions

Injection site reactions – uncommon.

Oedema – uncommon.

* See section "Description of individual adverse reactions".

† Adverse reactions known from post-marketing experience (see section "Description of individual adverse reactions").

Description of individual adverse reactions

Anaphylactic reactions

Symptoms of generalized hypersensitivity (including generalized skin rash, pruritus, sweating, gastrointestinal disturbances, angioedema, dyspnoea, tachycardia, hypotension, and dizziness/loss of consciousness) are very rare but potentially life-threatening.

Hypoglycaemia

Hypoglycaemia is the most common adverse effect. It may occur when the insulin dose significantly exceeds the patient's insulin requirement. Severe hypoglycaemia can lead to loss of consciousness and/or seizures, resulting in temporary or permanent impairment of brain function, and even fatal outcomes. Symptoms of hypoglycaemia usually appear suddenly. They may include cold sweat, pallor and cold skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, visual disturbances, headache, nausea, and tachycardia.

In clinical trials, the frequency of hypoglycaemia varied depending on the patient population, dosage regimens, and level of glycaemic control.

Skin and subcutaneous tissue reactions

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may develop at injection sites and delay insulin absorption from the injection site. Regular rotation of injection sites within a given area may reduce the occurrence or prevent the development of these reactions (see section "Special instructions").

Children

Based on post-marketing surveillance and clinical trials, adverse reactions in children do not differ in frequency, type, or severity from those observed in the general population.

Other special patient groups

Based on post-marketing surveillance and clinical trials, adverse reactions in elderly patients and patients with impaired renal or hepatic function do not differ in frequency, type, or severity from those observed in the general population.

Reporting of suspected adverse reactions and lack of drug efficacy

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

Shelf life. 2.5 years.

Storage conditions.

Store in the original packaging at 2 °C – 8 °C (in a refrigerator, but not near the freezer compartment). Do not freeze.

To protect from light, store the pen with the cap on.

After first opening: use within 6 weeks. Do not store in the refrigerator. Store at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Incompatibilities.

In general, insulin may be mixed with substances with which its compatibility is known. Medicinal products added to insulin may cause its degradation, for example, preparations containing thiols or sulfites.

Packaging. The product is contained in a 3 mL cartridge made of type 1 glass, sealed on one side with a bromobutyl rubber plunger and on the other side with a bromobutyl/polyisoprene rubber stopper. The cartridge is placed in a multidose disposable pen device made of plastic.

1 or 5 pen devices per cardboard box.

Prescription category. Prescription only.

Manufacturers. A/T Novo Nordisk, Denmark.

Novo Nordisk A/S, Denmark.

Novo Nordisk Production SAS, France.

Manufacturers' locations and addresses of places of business.

Novo Allé, 2880, Bagsværd, Denmark.

Novo Alle, 2880 Bagsvaerd, Denmark.

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

45 avenue d'Orleans, 28000 Chartres, France.