Insulin® n
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INSUVIT® H (INSUVIT® H)
Composition:
Active substance: insulin (human);
1 ml of solution contains 100 IU of human insulin (recombinant DNA);
Excipients: metacresol, zinc oxide, glycerol, diluted hydrochloric acid or sodium hydroxide solution, water for injections.
Pharmaceutical form. Solution for injection.
Main physicochemical properties: clear, colorless solution. A fine-dispersed precipitate may form during storage.
Pharmacotherapeutic group. Antidiabetic agents. Insulins and short-acting analogues. ATC code A10AB01.
Pharmacological properties.
Pharmacodynamics.
The 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.
Clinical study results in the treatment of hyperglycemia (blood glucose levels above 10 mmol/L) in patients with diabetes mellitus who underwent major surgical procedures showed that normoglycemia (glucose level 4.4–6.1 mmol/L), induced by intravenous administration of short-acting human insulin, reduced mortality.
Insubit® N 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 (t1/2) of insulin from blood is 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, subcutaneous tissue thickness, type of diabetes), which leads to considerable variability in the effect of insulin preparations among patients.
Absorption. Peak plasma concentration occurs within 1.5–2.5 hours after subcutaneous injection.
Distribution. Significant binding of insulin to plasma proteins, except circulating antibodies against it (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 of hydrolysis of the human insulin molecule have been identified. None of the metabolites formed after hydrolysis possess biological activity.
Elimination. The terminal t1/2 of insulin is determined by the rate of its absorption from the subcutaneous tissue. Therefore, the terminal t1/2 reflects the absorption rate rather than the actual elimination of insulin from plasma (the t1/2 of insulin in circulation is only several minutes). According to available study data, t1/2 ranges from 2 to 5 hours.
Children and adolescents. The pharmacokinetic profile of short-acting human insulin has been studied in a small number of children (6–12 years) and adolescents (13–17 years) with diabetes mellitus. Limited data indicate that the pharmacokinetic profile of insulin in children, adolescents, and adults is nearly identical. However, maximum concentration (Cmax) varied among different age groups, indicating the importance of individual dose adjustment.
Preclinical safety data
Preclinical studies on pharmacological safety (repeated-dose toxicity, genotoxicity, carcinogenicity, toxic effects on fertility and fetal development) did not reveal any safety concerns associated with the administration of short-acting human insulin.
Clinical characteristics.
Indications.
Treatment of diabetes mellitus.
Contraindications.
Hypoglycemia.
Hypersensitivity to human insulin or to any component of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
A number of medicinal products are known to 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 hypoglycemic effect of insulin.
Special precautions for use.
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, as well as acetone odor on the breath.
In untreated type 1 diabetes, hyperglycemia leads to diabetic ketoacidosis, which is potentially life-threatening.
Hypoglycemia
Hypoglycemia may occur when using an insulin dose that is too high relative to insulin requirements. Do not administer the medication during hypoglycemia or if hypoglycemia is suspected.
Skipping meals or unexpected increased physical activity may lead to hypoglycemia.
When patients are switched to another type of insulin, symptoms of hypoglycemia may change or become less pronounced compared to those experienced during previous insulin therapy.
Patients in whom glycemic control has significantly improved due to intensive insulin therapy may experience altered typical warning symptoms of hypoglycemia; such patients should be informed in advance.
Usual warning symptoms may diminish or disappear in patients with long-standing diabetes. Concomitant illnesses, particularly infections and febrile conditions, generally increase insulin requirements.
Concomitant kidney, liver, or adrenal gland disorders, as well as disorders of the pituitary or thyroid gland, may necessitate adjustment of insulin dosage.
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), source, and/or method of production may require insulin dose adjustments.
Patients switching to Insuvit® N from another type of 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 several weeks or months of its use.
Injection site reactions
Reactions at the injection site may occur with any insulin therapy and may include pain, redness, itching, urticaria, swelling, bruising, and inflammation. Regularly changing the injection site, even within the same anatomical region, may reduce or prevent these reactions. Such reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Insuvit® N therapy. 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 areas with such reactions. Switching injection sites to unaffected skin areas has been reported to cause hypoglycemia. Monitoring of blood glucose levels is recommended after changing injection sites, and dose adjustments of antidiabetic medications may be necessary.
Patients traveling across time zones should consult their physician, as this may alter the insulin injection and meal schedules.
Insuvit® N should not be used in insulin pumps for continuous subcutaneous infusion due to the risk of precipitation in the tubing.
Combination of Insuvit® N with pioglitazones
Cases of congestive heart failure have been reported when pioglitazones are used in combination with insulin, particularly in patients with risk factors. This should be considered when prescribing combination therapy with pioglitazones and insulin. Patients receiving this combination should be monitored closely for signs and symptoms of congestive heart failure, weight gain, and edema. If any deterioration in cardiac function occurs, treatment with pioglitazones should be discontinued.
To prevent accidental medication errors, patients should be instructed to always check the product label before each injection to avoid confusing Insuvit® N with other insulin products.
Special populations
Elderly patients (≥ 65 years)
Insuvit® N can be used in elderly patients.
Increased blood glucose monitoring and individualized insulin dose adjustments are recommended in elderly patients.
Renal and hepatic impairment
Renal and hepatic impairment may reduce insulin requirements. Enhanced blood glucose monitoring and individualized insulin dose adjustments are recommended in patients with renal or hepatic impairment.
Children
Insuvit® N can be used in children and adolescents.
Content of excipients
Insuvit® N contains less than 1 mmol sodium (23 mg) per dose, i.e., it is practically 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. Enhanced monitoring of blood glucose levels and diabetes management is recommended throughout pregnancy and in case of suspected pregnancy, as inadequate glycemic control—both hypoglycemia and hyperglycemia—increases the risk of fetal malformations and fetal death.
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 therapy 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 affect reaction speed when driving or operating machinery
A patient's reaction and ability to concentrate may be impaired during hypoglycemia. This may pose a risk in situations where such abilities are critical (e.g., driving a car or operating machinery).
Patients should be advised to take preventive measures against hypoglycemia before driving. This is particularly important for patients with diminished or absent hypoglycemia warning symptoms or those experiencing frequent hypoglycemic episodes. Under such circumstances, the advisability of driving should be carefully considered.
Administration and Dosage
Inzuvit® N 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).
Dosing
The 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.
Dose Adjustment
Concomitant diseases, especially infections and febrile conditions, generally increase the patient's insulin requirements. Concomitant kidney or liver disease, or disorders of the adrenal glands, pituitary gland, or thyroid gland, may require adjustments in insulin dosage.
Dose adjustments may also be necessary when there are changes in the patient's level of physical activity or usual diet. Dose re-titration may also be required when switching patients to different insulin preparations.
Administration
Inzuvit® N is intended for subcutaneous or intravenous administration.
Inzuvit® N is usually administered subcutaneously into the abdominal wall, thigh, buttocks, or deltoid muscle of the shoulder. Injection into a lifted skin fold significantly reduces the risk of intramuscular injection.
Following subcutaneous injection into the abdominal wall, insulin is absorbed more rapidly than when administered into other body areas.
After injection, the needle should remain under the skin for at least 6 seconds to ensure delivery of the full dose.
To reduce the risk of lipoatrophy and cutaneous amyloidosis, injection sites should always be rotated, even within the same body area (see sections of the instruction "Special Warnings and Precautions for Use" and
«Side effects»).
Intramuscular injections may only be administered under medical supervision.
Insuvit® N may also be administered intravenously. Such injections must be performed only by a physician.
Use for intravenous administration
Insuvit® N, containing human insulin at a concentration of 0.05 IU/mL to 1.0 IU/mL in an infusion solution consisting of 0.9% sodium chloride, 5% or 10% glucose, and 40 mmol/L potassium chloride, and stored in polypropylene infusion containers, is 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.
Insuvit® N is not intended for use in insulin pumps for prolonged subcutaneous infusion.
Do not use Insuvit® N:
- in infusion pumps;
- in patients with allergy (hypersensitivity) to human insulin or any other ingredient of Insuvit® N;
- when hypoglycemia (low blood sugar) is suspected;
- if the cartridge or the device containing the cartridge has been dropped, damaged, or dented;
- if the product has been improperly stored or has been frozen;
- if the insulin is not clear and colorless.
Before using Insuvit® N:
- check the label to ensure the insulin type matches the prescribed one;
- always inspect the cartridge, including the rubber plunger (stopper); do not use the cartridge if there are any visible damages.
How to use this insulin product
Insuvit® N is administered by subcutaneous injection. Injection sites should always be rotated, even within the same body area, to reduce the risk of developing lipoatrophy or skin pitting. The best sites for self-injection are the front of the abdomen, buttocks, front of the thighs, or upper arms. Insulin acts faster when injected into the abdominal area.
If necessary, Insuvit® N may be administered intravenously; such injections must be performed only by a physician.
Insuvit® N (in vials) should be administered using special insulin syringes with appropriate calibration. When using two types of insulin, they must be mixed in the same order each time.
Before administration, ensure that the syringe calibration corresponds to the insulin concentration indicated on the vial label: 100 IU/mL. Use only syringes with calibration matching the insulin concentration in this vial.
Before drawing insulin from the vial, check the solution for clarity. The product must not be used if flakes appear, if the solution becomes cloudy, if a precipitate forms, or if there is any deposit on the glass of the vial.
Avoid injecting the needle into a blood vessel. After injection, do not rub the injection site.
Aseptic technique must be followed during injection. To prevent infectious complications, do not reuse disposable syringes.
- Disinfect the rubber stopper with an alcohol-soaked cotton swab.
- Draw into the syringe an amount of air equal to the insulin dose to be administered.
- Inject the air from the syringe into the insulin vial.
- Gently shake the vial and draw the required insulin dose into the syringe. Check for air bubbles in the syringe and verify the dose.
- Administer insulin subcutaneously. How to inject insulin:
- pinch the skin with two fingers, insert the needle under the skin, and inject the syringe contents;
- keep the needle under the skin for 6 seconds, ensure complete delivery of insulin, then withdraw the needle;
- if bleeding occurs at the injection site after needle removal, apply firm pressure with a cotton swab.
To administer Insuvit® N, use an insulin pen according to the detailed instructions for its use. Refilling the cartridge is not permitted. The insulin pen is intended for individual use only. Strictly follow the manufacturer's instructions for using the insulin pen.
Like all insulin products, Insuvit® N must not be mixed with solutions containing reducing agents, such as thiols or sulfites.
Children
Biosynthetic human insulin preparations are effective and safe medicinal products for the treatment of diabetes mellitus in children and adolescents of various age groups.
Daily insulin requirements in children and adolescents depend 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 in progressive stages following administration of doses higher than the patient's requirements.
Mild hypoglycemia can be treated by oral intake of glucose or sweet foods. Therefore, diabetic patients are advised to always carry several sugar-containing products.
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 intravenous glucose. 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 hypoglycemia. According to clinical trial data and post-marketing surveillance, the frequency of hypoglycemia varies among different patient groups, dosing regimens, and levels of glycemic control.
At the initiation of insulin therapy, transient refractive disturbances, edema, 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 lead to transient acute painful neuropathy, which is typically reversible.
Rapid improvement in glycemic control due to intensification of insulin therapy may
be accompanied by temporary worsening of diabetic retinopathy, while long-term, well-established glycemic 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 organ system classes according to MedDRA.
Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).
Immune system disorders:
Uncommon – urticaria, rash; very rare – anaphylactic reactions*.
Metabolism and nutrition disorders:
Very common – hypoglycemia*.
Nervous system disorders:
Uncommon – peripheral neuropathies (painful neuropathies).
Eye disorders:
Very rare – refractive disturbances; uncommon – diabetic retinopathy.
Skin and subcutaneous tissue disorders:
Uncommon – lipodystrophy*;
Frequency not known – cutaneous amyloidosis.
General disorders and administration site conditions:
Uncommon – injection site reactions, edema.
*See information below.
Description of selected adverse reactions
Anaphylactic reactions
Generalized hypersensitivity reactions (including generalized skin rash, pruritus, sweating, gastrointestinal disturbances, angioedema, dyspnea, tachycardia, hypotension, and dizziness/loss of consciousness) are very rare but may be life-threatening.
Hypoglycemia
Hypoglycemia is the most common adverse effect. It may occur when the insulin dose significantly exceeds the patient's insulin requirements. Severe hypoglycemia can lead to loss of consciousness, seizures, and subsequent temporary or permanent impairment of brain function, and may even result in death. Symptoms of hypoglycemia usually appear suddenly and 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.
Skin and subcutaneous tissue disorders
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and may delay local insulin absorption. Regular rotation of injection sites within the same anatomical region may help reduce or prevent these reactions (see section "Special precautions").
Reporting suspected adverse reactions
It is important to report suspected adverse reactions after drug authorization. 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. 2 years.
The shelf life of the product in cartridges and vials after first opening is 42 days at a temperature not exceeding 25 °C, protected from overheating and direct sunlight. Used cartridges should not be stored in the refrigerator. Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
Store at a temperature between 2 °C and 8 °C (in the refrigerator). Do not freeze. Keep out of reach of children.
Incompatibilities.
Insulin should only be used with substances proven to be fully compatible with insulin. Do not mix with solutions containing reducing agents – thiols or sulfites.
Packaging.
3 mL in a cartridge. 5 cartridges in a blister, 1 blister per carton. 10 mL in a vial. 1 vial per carton.
Prescription status. Prescription only.
Manufacturer: JSC "Farmak".
Manufacturer's address and location of operations.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.
Marketing Authorization Holder:
LLC "SMARTPHARMA GROUP", Ukraine
"SMARTPHARMA GROUP" LLC, Ukraine
Address of the Marketing Authorization Holder:
26 Peremohy Avenue, Office 52, Kyiv, 04116, Ukraine
Ukraine, 04116, Kyiv, 26 Peremohy Avenue, Office 52