Gensulin n

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GENSULIN N (GENSULIN N)

Composition:

Active substance: recombinant isophane insulin human 100 IU;

1 ml of suspension contains recombinant isophane insulin human 100 IU;

Excipients: m-cresol; phenol; glycerol; protamine sulfate; zinc oxide; sodium dihydrogen phosphate dihydrate; hydrochloric acid (diluted); water for injections.

Pharmaceutical form: Injection suspension.

Main physicochemical characteristics: white suspension, which upon standing separates into a white sediment and a colorless or almost colorless liquid.

Pharmacotherapeutic group: Antidiabetic agents. Intermediate-acting insulin and analogues for injection. Human insulins.

ATC code: A10A C01.

Pharmacological properties.

Pharmacodynamics.

Gensulin N is a recombinant human isophane insulin medicinal product obtained by genetic engineering using a genetically modified, but non-pathogenic, strain of E. coli. Insulin is a hormone produced by the pancreatic beta cells. Insulin participates in the metabolism of carbohydrates, proteins and fats, particularly promoting a reduction in blood glucose concentration. Insulin exhibits several anabolic and anti-catabolic properties depending on the tissue type. In muscle tissue, insulin enhances the synthesis of glycogen, fatty acids, glycerol and proteins. This increases amino acid uptake and simultaneously reduces the rate of glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid utilization. Insulin deficiency in the body is the cause of diabetes mellitus. Insulin administered by injection acts in the same way as the hormone produced by the body.

Pharmacokinetics.

Gensulin N begins to act within 30 minutes after administration; peak effect is observed between 2 and 8 hours, and duration of action lasts up to 24 hours and depends on the dose administered. In healthy individuals, up to 5% of insulin is bound to blood proteins. Insulin has been detected in cerebrospinal fluid at concentrations approximately 25% of those found in blood serum.

Insulin is metabolized in the liver and kidneys. Small amounts are metabolized in muscle and adipose tissue. In patients with diabetes mellitus, metabolism proceeds as in healthy individuals. Insulin is excreted by the kidneys. Trace amounts are excreted in bile. The elimination half-life of human insulin is approximately 4 minutes. Renal and hepatic diseases may delay insulin elimination. In elderly individuals, insulin elimination is slower and the duration of hypoglycemic action of the drug is prolonged.

Clinical characteristics

Indications.

Treatment of patients with diabetes mellitus requiring insulin therapy.

Contraindications.

Hypoglycemia. Hypersensitivity to the medicinal product Gensulin N or to any of its components, except in cases where it is used as desensitizing therapy. Do not administer intravenously.

Special precautions

Do not use the medicinal product Gensulin N:

• if the cartridge or pen has been dropped or subjected to external pressure, as this may damage the device and cause insulin leakage;
• if it has been stored improperly or has been frozen;
• if the liquid contained in it is not uniformly cloudy;
• the vial or cartridge must not be used if, after mixing, the suspension remains clear or if a white sediment forms at the bottom;
• do not use the product if, after mixing, white flakes or white particles float in the vial or cartridge, or remain on the container walls, giving the preparation an appearance similar to that of a frozen product.

Alcohol consumption may lead to dangerous reduction in blood glucose levels.

Interaction with other medicinal products and other types of interactions.

Patients should inform their physician about any concomitant therapy administered together with human insulin.

Gensulin N should not be mixed with animal insulin or biosynthetic insulins from other manufacturers. Many medicinal products (including certain antihypertensive and cardiac agents, lipid-lowering drugs, medications used in pancreatic disorders, certain antidepressants, antiepileptic agents, salicylates, antibiotics, oral contraceptives) may affect insulin action and the effectiveness of insulin therapy.

Medicinal products and substances that enhance insulin action: β-adrenergic blockers, chloroquine, angiotensin-converting enzyme inhibitors, monoamine oxidase inhibitors (antidepressants), methyldopa, clonidine, pentamidine, salicylates, anabolic steroids, cyclophosphamide, sulfonamides, tetracyclines, quinolone antibiotics, and ethanol.

Medicinal products that reduce insulin action: diltiazem, dobutamine, estrogens (including oral contraceptives), phenothiazines, phenytoin, pancreatic hormones, heparins, calcitonin, corticosteroids, antiviral drugs used in the treatment of HIV infection, niacin, thiazide diuretics.

Insulin requirements may increase when using drugs with hyperglycemic activity, such as glucocorticoids, thyroid hormones and growth hormone, danazol, β2-sympathomimetics (e.g., ritodrine, salbutamol, terbutaline), thiazides.

Insulin requirements may decrease when using drugs with hypoglycemic activity, such as oral hypoglycemic agents, salicylates (e.g., acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin-converting enzyme inhibitors (captopril, enalapril), non-selective beta-blockers, or alcohol. Somatostatin analogs (octreotide, lanreotide) may either increase or decrease insulin requirements.

When Gensulin N is used concomitantly with pioglitazone, cases of heart failure may occur, particularly in patients with risk factors for heart failure. When this combination is used, patients should be monitored for the development of signs and symptoms of heart failure, weight gain, and edema. Pioglitazone therapy should be discontinued if cardiac symptoms worsen.

Special precautions for use.

Decisions regarding changes in insulin dosage regimen, mixing insulin products, or switching from one insulin product to another must be made solely by a physician. Such decisions must be made under direct medical supervision and may affect the required dose of the drug. If dose adjustment is needed, it may be initiated with the first dose or later over several weeks or months. During insulin therapy, monitoring of blood serum and urine glucose concentrations, glycosylated hemoglobin (HbA1c), and fructosamine levels should be performed. Patients should be trained to self-monitor blood and urine glucose levels using simple tests (e.g., test strips). Hypoglycemia symptoms may appear at different times and vary in intensity among individuals. Therefore, patients should be educated to recognize their individual hypoglycemic symptoms. For patients switching from animal-sourced insulin to human insulin, a reduction in insulin dose may be necessary (due to the risk of hypoglycemia). In some patients, early symptoms of hypoglycemia after switching to recombinant human insulin may be milder than when using animal-sourced insulin. Early signs of hypoglycemia may also be less pronounced in patients with long-term diabetes, diabetic neuropathy, or when concomitantly using β-adrenergic blocking agents. Both untreated hypoglycemia and hyperglycemia can lead to loss of consciousness, coma, or even death.

Insulin requirements may change due to high fever, severe infection (which may significantly increase insulin needs), emotional stress, illness, or gastrointestinal disorders associated with nausea and vomiting, diarrhea, constipation, or malabsorption. The presence of such conditions always requires medical intervention. In these cases, blood and urine glucose levels should be monitored frequently. In renal insufficiency, insulin excretion is reduced and its duration of action prolonged.

Patients whose diabetes is associated with pancreatic disorders or coexisting Addison’s disease or pituitary insufficiency are highly sensitive to insulin and usually require very low doses.

Insulin requirements may change in patients with disorders of the pituitary gland, pancreas, adrenal glands, thyroid gland, or in hepatic or renal insufficiency.

Antibody production may occur during treatment with human insulin, although at lower concentrations than with purified animal-sourced insulin.

With prolonged insulin therapy, insulin resistance may develop. In cases of insulin resistance, higher insulin doses may be required.

Incorrect dosing or discontinuation of treatment (especially in patients with insulin-dependent diabetes) may lead to hyperglycemia and potentially fatal diabetic ketoacidosis. Dose adjustments may be necessary when there are changes in the intensity of physical activity or usual dietary patterns.

Patients planning long journeys across multiple time zones should consult their physician regarding adjustments to their insulin administration schedule.

Patients should be advised to rotate injection sites regularly to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and impaired glycemic control following insulin injections into affected areas. It has been reported that switching injection sites to unaffected skin areas may lead to hypoglycemia. Monitoring of blood glucose levels after changing injection sites is recommended, and dose adjustments of antidiabetic medications may need to be considered.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Insulin does not cross the placental barrier.

For pregnant women with pre-existing diabetes or gestational diabetes, maintaining adequate carbohydrate metabolism control throughout pregnancy is essential. Insulin requirements may decrease during the first trimester and increase during the second and third trimesters. Insulin needs drop sharply immediately after delivery, increasing the risk of hypoglycemia. Therefore, careful blood glucose monitoring is crucial.

There are no restrictions on the use of GenSulin N during breastfeeding. However, women during lactation may require dose and dietary adjustments, as insulin requirements during lactation fall below pre-pregnancy levels. Insulin requirements return to pre-pregnancy levels within 6–9 months after delivery.

Ability to influence reaction speed when driving or operating machinery.

The ability to drive may be impaired due to hypoglycemia, which may cause peripheral nervous system disturbances and symptoms such as headache, anxiety, diplopia, and impaired judgment and distance perception. During the initial phase of insulin therapy, when changing insulin products, or during stress or excessive physical exertion (when significant fluctuations in blood glucose occur), the ability to drive vehicles or operate moving machinery may be impaired. Blood glucose monitoring is recommended during prolonged travel.

Method of Administration and Dosage

In clinical practice, numerous regimens for human insulin therapy are known. The appropriate individualized regimen for a specific patient must be selected by a physician, based on the patient's insulin requirements. Based on the established blood glucose concentration, the physician determines the required dosage and type of insulin preparation for the particular patient. In type 2 diabetes, the average initial dose is 0.2 IU/kg body weight.

Gensulin N can be used in intensive insulin therapy to provide basal insulin secretion. The medicinal product is also used when initiating insulin therapy in type 2 diabetes. The most common regimen is one injection per day in the evening.

Gensulin N is administered subcutaneously by injection into the abdominal wall, thigh, shoulder, deltoid, or gluteal area. Injection sites should always be rotated within the same region to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). In exceptional cases, it may be administered intramuscularly. Gensulin N should be administered 15–30 minutes before a meal. Approximately 10–20 minutes before the planned injection, the insulin should be removed from the refrigerator to allow it to warm to room temperature.

Before administration, carefully inspect the vial or cartridge containing insulin. The Gensulin N suspension should be uniformly cloudy (homogeneously turbid or milky in appearance). Special attention must be paid to ensure that the needle does not enter the lumen of a blood vessel during insulin injection.

Administration of the drug using syringes.

Special syringes marked with insulin dosage units are available for insulin administration. In the absence of disposable syringes and needles, reusable syringes and needles may be used, provided they are sterilized before each injection. It is recommended to use syringes of the same type and manufacturer. Always check that the syringe used is calibrated according to the dosage of the insulin preparation being administered.

The vial of Gensulin N should be rolled between the palms until the suspension becomes uniformly cloudy or milky in appearance.

Procedure for performing the injection:

• remove the plastic cap, without removing the actual cap of the vial;
• wipe the vial stopper with an alcohol swab; do not remove the cap from the vial!
• draw into the syringe an amount of air equal to the selected insulin dose;
• puncture the rubber stopper and inject the air into the vial;
• invert the vial with the syringe so that it is upside down;
• ensure that the tip of the needle is immersed in the insulin;
• draw the required volume of insulin solution into the syringe;
• remove air bubbles from the syringe by expelling insulin back into the vial;
• recheck the accuracy of the drawn dose and withdraw the needle from the vial;
• disinfect the skin at the planned injection site;
• with one hand, stabilize the skin by pinching it into a fold;
• hold the syringe in the other hand like a pencil. Insert the needle into the skin at a 90° angle. Ensure that the needle is fully inserted and properly positioned in the subcutaneous fat layer, not in deeper tissue layers (in thin individuals, the needle should be inserted not perpendicularly, but at a shallower angle);
• to administer the insulin, push the syringe plunger fully to the end, delivering the dose over at least 5 seconds;
• hold an alcohol-soaked cotton swab close to the needle and withdraw the needle from the skin. Apply the alcohol-soaked swab to the injection site for several seconds. Do not rub the skin at the injection site!
• To avoid tissue damage, it is recommended to change the injection site with each injection. The next injection site should be at least 1–2 cm away from the previous one.

Mixing Gensulin N suspension with Gensulin R solution.

The decision to mix Gensulin N with the above-mentioned solution and suspensions may be made only by a physician.

Use of Gensulin N in cartridges for pen devices.

Gensulin N cartridges can be used with reusable pen-type injection devices ("pens"). When filling the insulin pen, attaching the needle, and administering the injection, strictly follow the manufacturer's instructions for the insulin pen. If necessary, insulin can be drawn from the cartridge into a standard insulin syringe and administered as described above (depending on insulin concentration and product type).

The Gensulin N suspension must be mixed before each injection by inverting the cartridge up and down 10 times or by rolling it between the palms until the suspension becomes uniformly cloudy or milky in appearance.

Children.

There is insufficient experience with the use of this product in children.

Overdose.

In case of insulin overdose, symptoms of hypoglycemia appear, including hunger, apathy, dizziness, muscle tremors, disorientation, anxiety, tachycardia, excessive sweating, vomiting, headache, and confusion. In mild hypoglycemia, oral intake of sweet fluids or carbohydrate-rich food is sufficient. Rest is recommended. Patients should always carry sugar cubes, glucose, or candies. Chocolate consumption is not recommended, as the fat content delays glucose absorption.

Severe hypoglycemia may lead to seizures, loss of consciousness, and even fatal outcomes. If the patient is unconscious, intravenous glucose must be administered. Following insulin overdose, symptoms of hypokalemia (reduced blood potassium concentration) with subsequent myopathy may also occur. In significant hypokalemia, when the patient is unable to take food orally, 1 mg of glucagon should be administered intramuscularly and/or glucose solution intravenously. After regaining consciousness, the patient should consume food. It may also be necessary to continue administering carbohydrates and monitor blood glucose levels, as hypoglycemia may recur after initial clinical recovery.

Adverse Reactions

Hypoglycemia. Hypoglycemia is generally the most common adverse effect observed during insulin therapy. It occurs when the administered insulin dose significantly exceeds the body's requirement. Severe episodes of hypoglycemia, especially if recurrent, may lead to nervous system damage. Prolonged or severe hypoglycemia can be life-threatening.

Symptoms of moderate hypoglycemia: excessive sweating, dizziness, tremor, hunger sensation, anxiety, tingling in palms, feet, lips, or tongue, difficulty concentrating, drowsiness, sleep disturbances, confusion, mydriasis, blurred vision, speech disturbances, depression, irritability. Symptoms of severe hypoglycemia: disorientation, loss of consciousness, seizures.

In many patients, symptoms indicating insufficient glucose supply to brain tissue (neuroglycopenia) are preceded by signs of adrenergic counter-regulation. Generally, the greater and faster the decline in blood glucose level, the more pronounced the counter-regulatory response and the more intense the associated symptoms.

Eye disorders. Significant changes in blood glucose levels may cause temporary visual disturbances due to transient changes in lens turgor and refractive index.

The risk of progression of diabetic retinopathy decreases with achievement of long-term glycemic control. However, intensification of insulin therapy with a sudden drop in blood glucose levels may worsen diabetic retinopathy. In patients with proliferative retinopathy, particularly those not treated with laser photocoagulation, severe hypoglycemic episodes may lead to transient blindness.

Lipodystrophy (incidence from 1/1000 to <1/100).

Skin and subcutaneous tissue disorders. Frequency unknown: cutaneous amyloidosis; lipodystrophy and cutaneous amyloidosis may occur at the injection site and may delay local insulin absorption. Regular rotation of injection sites within the same injection area may help reduce or prevent these reactions (see section "Special precautions for use").

Injection site reactions and allergic reactions – common adverse effect (1/100 to <1/10). Reactions at the injection site and allergic reactions may occur, including erythema, swelling, hematoma, pain, pruritus, urticaria, induration, or inflammation. Most mild reactions to insulin at the injection site usually resolve within a period of several days to several weeks.

Generalized allergic reactions are rare (<1/10,000) but represent a potentially dangerous adverse reaction to insulin. These severe cases may include generalized skin rash, dyspnea, wheezing, hypotension, increased heart rate, and increased sweating.

Immediate-type hypersensitivity reactions occur very rarely. Manifestations may include generalized skin reactions, angioneurotic edema, bronchospasm, arterial hypotension, and shock, which may be life-threatening.

Other reactions. Insulin administration may lead to the formation of insulin antibodies. In isolated cases, the presence of insulin antibodies may necessitate dose adjustments to prevent hypo- or hyperglycemia.

Insulin may cause sodium retention and edema, particularly when improved glycemic control is achieved after intensification of insulin therapy in previously poorly controlled patients. Cases of weight gain, injection site reactions (skin discoloration at injection site, bleeding, induration at injection site, swelling at injection site, injection site nodules, pain, urticaria, and pustules at injection site), localized pruritus, generalized pruritus, and dizziness have also been reported.

Shelf life.

3 years.

Do not use the medication after the expiry date stated on the packaging.

Storage conditions.

After opening the individual package, store for up to 28 days at a temperature not exceeding 25 °C. Store at 2–8 °C in a place protected from light. Do not freeze. Keep out of reach of children.

Incompatibilities.

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

Packaging.

10 ml in glass vials closed with an aluminum cap with a two-layer rubber disc and plastic cap, pack of 1 in a cardboard box; 3 ml in cartridges, pack of 5 in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BIOTON S.A., Poland (BIOTON S.A., Poland).

Manufacturer's address and location of manufacturing site.

Registered address: Poland, 02-516, Warsaw, 5 Staroscinska str. (Poland, 02-516, Warsaw, 5 Staroscinska str.).

Manufacturing address: Macierzysz, 12, Poznanska Street, 05-850 Ozarow Mazowiecki, Poland.