Pharmasulin® n 30/70

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FARMASULIN® H 30/70 (Farmasulin® H 30/70)

Composition:

Active substance: human biosynthetic insulin (recombinant DNA);

1 ml of suspension consisting of 30% human insulin solution and 70% isophane human insulin suspension contains 100 IU of biosynthetic human insulin (recombinant DNA);

Excipients: m-cresol; glycerol; phenol liquefied; protamine sulfate; disodium hydrogen phosphate heptahydrate (sodium phosphate dibasic heptahydrate); zinc oxide; diluted hydrochloric acid or sodium hydroxide solution; water for injections.

Pharmaceutical form. Injection suspension.

Main physicochemical properties: white-colored suspension, which upon standing separates into a white precipitate and a colorless or almost colorless supernatant liquid. The precipitate readily resuspends upon shaking.

Pharmacotherapeutic group. Antidiabetic agents. Insulins and analogues for injection, intermediate- or long-acting in combination with short-acting insulins. Human insulin. ATC code A10AD01.

Pharmacological properties.

Pharmacodynamics.

Pharmasulin® H 30/70 is an intermediate-acting insulin preparation.

The primary action of insulin is regulation of glucose metabolism. In addition, insulin affects various anabolic and anticatabolic processes in different tissues. In muscle tissues, these effects include enhanced synthesis of glycogen, fatty acids, glycerol, and protein, as well as increased amino acid uptake, along with simultaneous suppression of glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and release of amino acids.

Below, the figure shows the typical insulin activity profile (glucose utilization curve) for subcutaneous injections as a bold line. The possible variability in duration and/or intensity of insulin activity among different patients is illustrated by the shaded area on the graph. Individual variability depends on factors such as dose volume, injection site temperature, and the patient's level of physical activity.

Pharmacokinetics.

Pharmasulin® H 30/70 is human insulin produced using recombinant DNA technology.

Insulin pharmacokinetics do not reflect the hormone's metabolic activity. Therefore, when considering insulin activity, analysis of glucose utilization curves (shown above) is more appropriate.

No serious adverse effects associated with the use of the drug were observed during toxicological studies.

Clinical characteristics.

Indications.

Treatment of patients with diabetes mellitus who require insulin administration to maintain normal glucose homeostasis.

Contraindications.

Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients of the product, except in cases where desensitization therapy is applied. Intravenous administration is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Some medicinal products affect glucose metabolism; therefore, medical advice should be sought regarding the concomitant use of any other medicinal products with human insulin. The physician should consider possible interactions if the patient is taking any medicinal products.

Insulin requirement 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 requirement may decrease when using medicinal products 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), angiotensin II receptor blockers, non-selective β-blockers, or alcohol.

Somatostatin analogs (octreotide, lanreotide) may either increase or decrease insulin requirement.

Special precautions for use.

Patients should be advised to regularly rotate injection sites to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsening glycemic control following insulin injections at sites of these reactions. It has been reported that changing the injection site to an unaffected area of skin may lead to hypoglycemia. Monitoring of blood glucose levels is recommended after changing the injection site, and adjustment of antidiabetic medication dosage may be considered.

Any substitution of insulin type or brand must be carried out under strict medical supervision. Changes in concentration, brand (manufacturer), type (soluble, NPH, mixed), species (animal-sourced insulin, human insulin, human insulin analog), and/or method of production (recombinant DNA insulin or animal-sourced insulin) may require dosage adjustments.

Dosage when treating patients with human insulin may differ from that used with animal-sourced insulins. Dose adjustments may be necessary starting from the first dose or during the first several weeks or months of treatment.

In some patients who experienced hypoglycemic reactions after switching from animal-sourced insulin to human insulin, early warning symptoms of hypoglycemia were less pronounced or different from those previously observed during treatment with animal insulin. Patients who achieve significantly improved blood glucose levels (e.g., due to intensified insulin therapy) may no longer experience some or any of the early warning symptoms of hypoglycemia, and they should be informed accordingly. Conditions in which early warning symptoms of hypoglycemia may be less specific or less pronounced include long-standing diabetes, diabetic neuropathy, or concomitant use of medications such as β-adrenergic blockers.

Untreated hypoglycemic or hyperglycemic reactions may lead to loss of consciousness, coma, or death.

Inappropriate dosing or abrupt discontinuation of treatment, especially in insulin-dependent diabetes, may lead to hyperglycemia and ketoacidosis—conditions that are potentially fatal.

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

Insulin requirements may change significantly in the presence of adrenal, pituitary, or thyroid gland disorders, as well as in renal or hepatic insufficiency.

Insulin requirements may also increase during illness or emotional stress.

Dosage adjustments may be necessary when there are changes in physical activity levels or usual dietary patterns.

This medicinal product contains no more than 29 mmol/L (100 IU) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Combination with pioglitazone.

Cases of heart failure have been reported with concomitant use of pioglitazone and insulin, particularly in patients with risk factors for heart failure. This information should be considered when prescribing the combination of Pharmasulin® H 30/70 with pioglitazone. When using this combination, patients should be monitored for signs and symptoms of heart failure, weight gain, and edema. Treatment with pioglitazone should be discontinued if cardiac symptoms worsen.

Use during pregnancy or breastfeeding.

Pregnant women with insulin-dependent diabetes or gestational diabetes require careful monitoring throughout pregnancy. Insulin requirements typically decrease during the first trimester and then increase during the second and third trimesters. Women with diabetes should inform their physician if they become pregnant or plan to become pregnant.

During pregnancy, women with diabetes require close monitoring of blood glucose levels and overall health status.

Breastfeeding women with diabetes may require adjustments in insulin dosage and/or dietary regimen.

Ability to affect reaction speed when driving or operating machinery.

The ability of patients using insulin to concentrate and react may be impaired as a result of hypoglycemia. This may represent a risk factor when such abilities are of particular importance (e.g., while driving a vehicle or operating machinery).

Patients should be informed about the necessary preventive measures to avoid hypoglycemia while driving. This is especially important for patients with diminished or absent awareness of hypoglycemic warning symptoms or those who frequently experience episodes of hypoglycemia. In such cases, the appropriateness of driving should be evaluated.

Method of Administration and Dosage

The dose is determined by a physician according to the patient's individual needs.

Pharmasulin® H 30/70 must be administered only by subcutaneous injection, using a reusable pen device for cartridges or insulin syringes—for vials.

Pharmasulin® H 30/70 must not be administered intravenously.

Subcutaneous injections should be administered into the abdominal wall, thigh, buttocks, or upper arm. Injection sites should be rotated to avoid using the same site more than once a month, in order to reduce the risk of developing lipodystrophy and cutaneous amyloidosis (see sections "Special Instructions" and "Adverse Reactions").

Care must be taken during injection of Pharmasulin® H 30/70 to avoid intravascular injection. The injection site should not be massaged after administration. Patients must be trained in the correct injection technique.

Pharmasulin® H 30/70 is a ready-to-use mixture of soluble and isophane insulin, designed to eliminate the need for patients to mix insulin preparations themselves. The treatment regimen should be based on the patient's individual metabolic requirements.

1. Instructions for Use of the Medicinal Product

Cartridges

The 3 mL suspension for injection in cartridges must be used with an insulin pen device bearing the "CE" marking, in accordance with the pen manufacturer's recommendations.

Immediately before use, Pharmasulin® H 30/70 in cartridges must be resuspended by rolling the cartridge between the palms 10 times and inverting it 180° 10 times until the suspension becomes uniformly cloudy or uniformly milky. If the liquid in the cartridge does not achieve the proper appearance, the procedure should be repeated until the contents are completely mixed. Cartridges contain a small glass ball to facilitate mixing. Do not shake the cartridge vigorously, as this may cause foaming, which can interfere with accurate dose measurement.

The appearance of the cartridge contents should be regularly checked. Do not use if the suspension contains clumps or if white particles adhere to the bottom or sides of the cartridge, making the glass appear frosted.

Cartridges are not intended for mixing different insulins. Empty cartridges must not be reused.

For instructions on loading the cartridge into the pen, attaching the needle, and administering the insulin injection, refer to the manufacturer's instructions for the insulin pen device.

Each pen/cartridge must be used by only one patient, even if the needle is changed, to prevent the possible transmission of infectious agents.

Vials

The appearance of the vial contents should be regularly checked. Do not use the product if, after shaking, the suspension contains flakes or if white particles adhere to the bottom or sides of the vial, creating a frost-like appearance.

Use a syringe with markings corresponding to the insulin dose prescribed by the physician. It is recommended to use the same type and brand of syringe consistently. Inattention when using a syringe may lead to incorrect insulin dosing.

Preparation of the Dose

1. Immediately before injection, gently roll the vial of insulin suspension between the palms to ensure uniform cloudiness throughout the vial. Do not shake the vial vigorously, as this may cause foaming, which can interfere with accurate dose measurement.
2. Draw up the insulin from the vial by piercing the rubber stopper with a sterile needle after disinfecting it with alcohol. The temperature of the insulin to be injected should be at room temperature.
3. Draw air into the syringe up to the mark corresponding to the required insulin dose, then inject this air into the vial.
4. Invert the syringe together with the vial so that the vial is upside down, and draw up the required insulin dose.
5. Remove the needle from the vial. Expel air from the syringe and verify the correct insulin dose.

Aseptic technique must be followed during injection. To avoid infectious complications, do not reuse disposable syringes.

1. Administration of the Medicinal Product

Administer the prescribed insulin dose as directed by the physician.

Injections should be given in different body areas, ensuring that the same site is not used more than once a month.

The use of an insulin pen is not recommended for patients with complete vision loss or impaired vision unless they are assisted by individuals trained in the proper use of the pen.

Children

Dosage, administration schedule, and number of injections for children are determined by the physician based on individual needs and specific circumstances.

Overdose

There is no specific definition for insulin overdose, as blood glucose levels result from a complex interaction between insulin levels, glucose intake, and other metabolic processes. Hypoglycemia may result from an excess of insulin relative to food intake and energy expenditure.

Symptoms of hypoglycemia include lethargy, confusion, tachycardia, headache, sweating, and vomiting.

Mild hypoglycemia is usually treated by oral administration of glucose or sugar-containing products. Moderate to severe hypoglycemia may be managed by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrates once the patient's condition stabilizes. For patients unresponsive to glucagon, intravenous glucose solution must be administered. If the patient is comatose, glucagon should be given intramuscularly or subcutaneously. In the absence of glucagon or if there is no response to glucagon administration, intravenous glucose solution must be given. The patient should be fed as soon as consciousness is regained.

Continued carbohydrate intake and medical monitoring may be necessary, as recurrence of hypoglycemia may occur after apparent clinical recovery.

Adverse reactions.

Hypoglycaemia is the most common adverse effect of insulin therapy in patients with diabetes mellitus. Severe hypoglycaemia may lead to loss of consciousness and, in extreme cases, to fatal outcome. The exact frequency of hypoglycaemic episodes cannot be established, as it results from the combined influence of insulin dose and other factors, such as the patient's diet composition and level of physical activity.

Local allergic reactions may occur frequently (frequency from 1/100 to < 1/10), including injection site reactions: erythema, swelling, pruritus. These reactions usually resolve within a few days to several weeks. In some cases, such conditions may not be related to insulin itself, but rather to other factors, such as skin irritants in skin-cleansing agents or inadequate injection technique.

Systemic allergic reaction is very rare (< 1/10,000), but potentially more serious, representing a generalized allergic response to insulin. It may manifest as generalized rash, dyspnoea, wheezing, hypotension, tachycardia, and increased sweating. Severe cases of generalized allergy can be life-threatening. In rare exceptional cases of severe allergy to Pharmasulin® H 30/70, appropriate measures should be taken immediately. Insulin substitution or desensitization therapy may be required.

Lipodystrophy at the injection site occurs infrequently (frequency from 1/1000 to < 1/100).

Skin and subcutaneous tissue disorders – frequency unknown: cutaneous amyloidosis.

Disorders of the skin and subcutaneous tissue – 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").

Cases of oedema have been reported during insulin therapy, particularly when previous poor metabolic control is improved by intensive insulin therapy.

Suspected adverse reaction reporting

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

The shelf life of the product in cartridges and vials after first opening is 28 days at a temperature from 15 °C to 25 °C, protected from overheating and direct sunlight. Cartridges in use should not be stored in the refrigerator.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature from 2 °C to 8 °C (in the refrigerator). Do not freeze. Keep out of the reach of children.

Incompatibility. Pharmasulin® H 30/70 must not be mixed with insulins from other manufacturers or with animal-sourced insulins.

Packaging. 3 mL in a cartridge. 5 cartridges in a blister. 1 blister in a carton.

5 mL or 10 mL in a vial. 1 vial in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.