Actrapid® nm

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

Composition:

Active substance: human insulin (rDNA);

1 ml of injectable solution contains 100 IU (3.5 mg) of biosynthetic human insulin (produced using rDNA technology in Saccharomyces cerevisiae);

1 vial contains 10 ml, equivalent to 1000 IU;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: neutral, clear, colorless, aqueous solution.

Pharmacotherapeutic group. Antidiabetic agents. Short-acting insulins and analogues.

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 inhibition of glucose release from the liver.

Results from a clinical study conducted in an intensive care unit treating hyperglycemia (blood glucose levels above 10 mmol/L) in 204 patients with diabetes mellitus and 1344 patients without diabetes who underwent major surgery showed that normoglycemia (blood glucose levels of 4.4–6.1 mmol/L), induced by intravenous administration of Actrapid® NM, reduced mortality by 42% (8% vs. 4.6%).

Actrapid® NM is a short-acting insulin preparation.

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

Pharmacokinetics

The elimination half-life of insulin from blood is only several minutes. Therefore, the action profile of insulin preparations is determined exclusively by the characteristics of their absorption. This process depends on a number of factors (e.g., insulin dose, injection method and site, thickness of subcutaneous adipose tissue, type of diabetes mellitus), resulting in considerable variability in insulin effect both within individual patients and among different patients.

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

Distribution. Significant binding of insulin to plasma proteins, apart from circulating antibodies against insulin (if present), has not been observed.

Metabolism. Human insulin is cleaved by insulin proteases or insulin-degrading enzymes and possibly by protein disulfide isomerase. Several sites are believed to be involved in the hydrolysis of the human insulin molecule. None of the metabolites formed after hydrolysis are pharmacologically active.

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

Children and adolescents. The pharmacokinetic profile of Actrapid® NM has been studied in a small number of children (n=18), including children aged 6–12 years and adolescents aged 13–17 years, with diabetes mellitus. Limited data indicate that the pharmacokinetic profile of insulin in children, adolescents, and adults is practically similar. However, Cmax (maximum concentration) levels varied across different age groups, highlighting the importance of individual dose adjustment.

Non-clinical safety data.

Non-clinical pharmacological safety studies (repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity) revealed no specific hazards associated with the use of Actrapid® NM.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus.

Contraindications.

Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

It is known that various medicinal products affect glucose metabolism.

Medicinal products that may decrease insulin requirements.

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

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 and delay recovery from hypoglycemia.

Octreotide/lanreotide may either decrease or increase insulin requirements.

Alcohol may potentiate or weaken the blood glucose-lowering effect of insulin.

Special precautions for use.

Before traveling across time zones, patients should consult their doctor, as this alters the schedule of insulin injections and meal times.

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 flushing 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 potentially life-threatening.

Hypoglycemia

Hypoglycemia may occur if the insulin dose is too high relative to insulin requirements. Do not administer the drug if hypoglycemia is present or suspected.

Skipping meals or unexpected physical exertion may lead to hypoglycemia.

Patients in whom blood glucose control has significantly improved due to intensive insulin therapy may experience changes in the usual warning symptoms of hypoglycemia, and they should be warned about this in advance.

Typical warning symptoms may disappear in patients with long-standing diabetes.

Concomitant diseases, particularly infections and febrile conditions, generally increase insulin requirements. Renal, hepatic, or adrenal, pituitary, or thyroid gland disorders may necessitate insulin dose adjustments.

When patients are 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 (human or human insulin analog), and/or production method (recombinant DNA technology or animal-sourced insulin) may necessitate insulin dose adjustments. Patients switched to Actrapid® NM 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 drug and during the first weeks or months of treatment.

Injection site reactions

With any insulin therapy, injection site reactions may occur, including pain, redness, itching, urticaria, swelling, bruising, and inflammation. 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.

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

Skin and subcutaneous tissue disorders

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

Combination of Actrapid® NM with pioglitazone

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

Actrapid® NM contains metacresol, which may cause allergic reactions.

Prevention of accidental medication errors

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

Special populations

Elderly patients (≥65 years)

Actrapid® NM may be used in elderly patients.

Enhanced glucose monitoring and individual insulin dose adjustments are recommended in elderly patients.

Renal and hepatic impairment

Renal and hepatic impairment may reduce insulin requirements. Enhanced glucose monitoring and individual insulin dose adjustments are recommended in patients with renal or hepatic impairment.

Children

Actrapid® NM may be used in children and adolescents.

Actrapid® NM contains less than 1 mmol of sodium (23 mg), so the medicinal product can be considered "sodium-free."

Use during pregnancy or breastfeeding

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 treatment are recommended throughout pregnancy and whenever pregnancy is suspected in women with diabetes.

Insulin requirements usually decrease during the first trimester of pregnancy and significantly increase during the second and third trimesters.

After delivery, insulin requirements rapidly return to pre-pregnancy levels.

There are no restrictions on insulin treatment for diabetes during breastfeeding, as maternal treatment poses no risk to the infant. However, dose adjustments and/or dietary modifications for the mother may be necessary.

Fertility

Reproductive toxicity studies in animals using human insulin have shown no 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 hypoglycemia, which may pose a risk in situations where such abilities are critical (e.g., driving a vehicle or operating machinery).

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

Dosage and Administration

Actrapid® NM is a short-acting insulin preparation; therefore, it is often used in combination with long-acting insulin.

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

Dosage

The insulin dosage is individual and must be determined by a physician according to the patient's needs.

The individual daily insulin requirement usually ranges from 0.3 to 1.0 IU/kg/day. Daily insulin requirements may increase in patients with insulin resistance (e.g., during puberty or in obesity) and may decrease in patients with residual endogenous insulin production.

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

Dosage Adjustment

Concomitant diseases, particularly infections and fever, generally increase the patient's insulin requirements. Diseases of the kidneys, liver, or adrenal glands, as well as disorders of the pituitary or thyroid gland, may require insulin dosage adjustments.

Dosage adjustments may also be necessary when patients change their level of physical activity or usual diet. Dose titration may also be required when switching patients to different insulin preparations.

Administration

Actrapid® NM is intended for subcutaneous or intravenous injection.

Actrapid® NM is usually administered subcutaneously by injections into the abdominal wall, thigh, buttocks, or deltoid region of the upper arm. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated, even within the same body area. Injection into a skin fold significantly reduces the risk of intramuscular injection.

Insulin absorption after subcutaneous injection into the abdominal wall is faster than after injection into other body areas.

After injection, the needle should remain under the skin for at least 6 seconds to ensure complete delivery of the dose.

Intramuscular injections may be performed under medical supervision.

Actrapid® NM may also be administered intravenously. Such injections must be performed only by a physician.

Actrapid® NM in vials should be administered using special insulin syringes with appropriate calibration. When using two types of insulin, they must be mixed sequentially.

Intravenous Administration

Infusion systems containing Actrapid® NM with human insulin concentrations ranging from 0.05 IU/mL to 1.0 IU/mL in an infusion solution containing 0.9% sodium chloride, 5% or 10% glucose, and 40 mmol/L potassium chloride, stored in polypropylene infusion containers, are stable for 24 hours at room temperature. Even with demonstrated stability over prolonged periods, some insulin may adsorb onto the inner surface of the infusion container. Blood glucose levels must be monitored during infusions.

Actrapid® NM is not intended for use in insulin pumps for continuous subcutaneous infusion.

Children

Biosynthetic human insulin preparations are effective and safe medicinal products for the treatment of diabetes mellitus in various pediatric and adolescent age groups.

The daily insulin requirement in children and adolescents depends on the stage of the disease, body weight, age, diet, physical activity, degree of insulin resistance, and glycemic dynamics.

Overdose

Although a specific definition of insulin overdose is not established, hypoglycemia may develop following insulin administration, particularly when doses exceed patient requirements.

• Mild hypoglycemia can be treated by oral administration of glucose or sugary products. Therefore, diabetic patients are advised to always carry several carbohydrate-containing products.
• In cases of severe hypoglycemia with loss of consciousness, individuals who have received appropriate training should administer glucagon subcutaneously or intramuscularly (0.5 to 1.0 mg). A healthcare professional may administer glucose intravenously. Intravenous glucose should also 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. According to clinical trial data and post-marketing surveillance, the frequency of hypoglycaemia varies among different patient groups, different dosage regimens, and levels of glycaemic control (see information below).

At the initiation of insulin therapy, the following may occur: refractive disturbances, oedema, and injection site reactions (pain, erythema, urticaria, inflammation, bruising, swelling, and pruritus at the injection site). These reactions are usually transient. Rapid improvement in blood glucose control may cause a generally reversible condition of acute painful neuropathy.

Rapid improvement in glycaemic control due to intensification of insulin therapy may be accompanied by a temporary worsening of diabetic retinopathy, whereas long-term, well-maintained glycaemic control reduces the risk of progression of diabetic retinopathy.

Based on clinical trial data, the adverse reactions listed below 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 from available data).

Immune system disorders

Urticaria, rash – uncommon.

Anaphylactic reactions* – very rare.

Metabolism and nutrition disorders

Hypoglycaemia* – very common.

Nervous system disorders

Peripheral neuropathies (painful neuropathies) – uncommon.

Eye disorders

Refractive disturbances – very rare.

Diabetic retinopathy – uncommon.

Skin and subcutaneous tissue disorders

Lipodystrophy* – uncommon. Cutaneous amyloidosis*† – frequency not known.

General disorders and administration site reactions

Injection site reactions – uncommon.

Oedema – uncommon.

* – See information below.

†See information from post-marketing surveillance data.

Description of selected 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 may be potentially life-threatening.

Hypoglycaemia

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

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.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after a medicinal product has been authorized. This enables continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions to the local pharmacovigilance authorities.

Shelf life. 30 months.

Storage conditions.

Unopened vials of Actrapid® NM should be stored in a refrigerator at 2 °C – 8 °C (not too close to the freezer compartment). Do not freeze. Store in the original packaging and keep out of reach of children.

Do not expose to heat or direct sunlight.

Each vial has a protective, colour-coded plastic cap. If the safety plastic cap is loose or missing, the vial should be returned to the pharmacy.

Actrapid® NM vials in use should not be stored in the refrigerator. They may be stored for up to 6 weeks at temperatures up to 30 °C after first opening.

Insulin that has been frozen must not be used.

Never use insulin after the expiry date stated on the packaging. Only clear, colourless solutions of Actrapid® NM should be used.

Incompatibilities

Insulin may generally be mixed with medicinal products with which compatibility has been established. However, medicinal products added to insulin may cause its degradation; for example, products containing thiols or sulfites.

Packaging

10 ml in a vial; 1 vial in a cardboard box.

Prescription status

Prescription only.

Manufacturer

A/T Novo Nordisk

Novo Nordisk Production SAS

Manufacturer's name and address of the place of business

Novo Allé, Bagsværd, 2880, Denmark

45, avenue d'Orléans, 28000 Chartres, France