Humulin m3

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HUMULIN M3 (HUMULIN® M3)

Composition:

Active substance: human insulin and isophane human insulin (recombinant DNA) (consisting of 30 IU insulin solution and 70 IU isophane human insulin suspension for injection);

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

Excipients: metacresol; glycerol; phenol; protamine sulfate; sodium dihydrogen phosphate heptahydrate; zinc oxide; hydrochloric acid, 10% solution; sodium hydroxide, 10% solution; water for injections.

Pharmaceutical form. Injection suspension.

Main physicochemical properties: white suspension which, upon standing, settles to form a white precipitate and a colorless or almost colorless supernatant liquid. The sediment is easily resuspended by gentle shaking.

Pharmacotherapeutic group. Antidiabetic agents. Short-acting insulin and analogues in combination with intermediate-acting insulins. ATC code A10AD01.

Pharmacological properties.

Pharmacodynamics.

Humulin M3 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 tissue, these effects include enhanced synthesis of glycogen, fatty acids, glycerol, and protein, as well as increased amino acid uptake, accompanied by suppression of glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid release.

The figure below 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, temperature at the injection site, and the patient's level of physical activity.

Time (hours)

Pharmacokinetics.

Humulin M3 is human insulin produced using recombinant DNA technology.

The pharmacokinetics of insulin do not reflect the metabolic activity of the hormone. 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 medicinal product, except in cases of administration as desensitizing therapy. Intravenous administration is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Some medicinal products affect glucose metabolism; therefore, consultation with a physician is recommended regarding the use of any other medicinal products concomitantly with human insulin. The physician should consider possible interactions if the patient is taking any other medicinal products.

Insulin requirement may increase when using medicinal products 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 beta-blockers, or alcohol.

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

Special precautions for use.

Any change in the type or brand of insulin must be made under close 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 requirements when using human insulin may differ from those when using animal-sourced insulins. Dosage adjustments may be needed starting from the first dose or during the first several weeks or months.

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 compared to those previously observed during treatment with animal insulin. Patients with 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 about this. 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 beta-adrenergic blockers.

Untreated hypoglycemic or hyperglycemic reactions can lead to loss of consciousness, coma, and may be fatal.

The use of inappropriate doses or abrupt discontinuation of treatment, especially in insulin-dependent diabetes, may lead to hyperglycemia and ketoacidosis—conditions that are potentially life-threatening.

Antibody formation may occur during treatment with human insulin, although to a lesser extent than with purified animal-sourced insulin.

Insulin requirements may significantly change 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 the intensity of physical activity or usual dietary patterns.

Patients should be instructed about the necessity of regularly rotating injection sites to minimize the risk of developing lipodystrophy or cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and impaired glycemic control following insulin injections into areas affected by these reactions. Cases of hypoglycemia have been reported after sudden changes in injection sites to areas not affected by amyloidosis or lipodystrophy. After changing injection sites, monitoring of blood glucose levels is recommended, and dosage adjustments of antidiabetic agents may need to be considered.

Combination with pioglitazone

Cases of heart failure have been reported with the concomitant use of pioglitazone and insulin, particularly in patients with risk factors for heart failure. This information should be taken into account when prescribing the combination of Humulin M3 and pioglitazone. When using this combination, patients should be monitored for signs and symptoms of heart failure, weight gain, and edema. Pioglitazone treatment should be discontinued if cardiac symptoms worsen.

Traceability

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

Excipients

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

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. Patients with diabetes should inform their physician if they become pregnant or plan to become pregnant.

During pregnancy, patients 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 influence the speed of reactions while driving or operating machinery

The ability of insulin-treated patients 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 specific precautionary measures necessary to avoid hypoglycemia while driving. This is especially important for patients who have reduced or absent awareness of hypoglycemic warning symptoms or who frequently experience episodes of hypoglycemia. In such circumstances, the appropriateness of driving should be evaluated.

Method of Administration and Dosage

The dosage is determined by the physician according to the individual needs of the patient.

Humulin M3 should be administered only by subcutaneous injection, using a reusable pen-injector (for the cartridge formulation) or a pre-filled pen-injector (for the pen formulation, such as the KwikPen). Humulin M3 must not be administered intravenously.

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

Care must be taken during administration of Humulin M3 to avoid intravascular injection. The injection site should not be massaged after injection. Patients must be trained in the correct injection technique.

Humulin M3 is a ready-to-use mixture of soluble insulin and isophane insulin, developed to eliminate the need for patients to mix insulin preparations manually. The treatment regimen should be based on the individual metabolic requirements of the patient.

Instructions for Use

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

Humulin M3 in cartridges must be used with reusable pen-injectors manufactured by Eli Lilly and Company and its affiliates. It should not be used with other reusable pen-injectors, as the accuracy of dosing has not been established for such devices.

a) Preparing the Dose

Immediately before use, Humulin M3 in cartridges must be resuspended by rolling the cartridge between the palms 10 times and then inverting it 180° 10 times, until the suspension becomes uniformly cloudy or milky. If the liquid in the cartridge does not achieve the proper appearance, repeat the procedure until the contents are fully mixed. The cartridge contains a small glass ball to aid in 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 checked regularly. Do not use the cartridge if the suspension contains clumps or if white particles adhere to the bottom or sides of the cartridge, making the glass appear cloudy.

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

To load the cartridge into the pen-injector, attach the needle, and administer the insulin injection, refer to the manufacturer's instructions for the pen-injector.

b) Administration of the Medication

Administer the prescribed insulin dose as directed by the physician.

Instructions for Use

Each time a new KwikPen pre-filled with Humulin M3 is used, carefully read the accompanying instructions for use, as they may contain updated information. This information does not replace the necessity of discussing your health condition and prescribed treatment with your physician.

The pre-filled KwikPen containing Humulin M3 is a single-use pen-injector containing 300 IU (3 mL) of insulin. Multiple injections can be administered using one pen-injector. The dose increment is 1 unit. Doses from 1 to 60 units of insulin can be set for a single injection. If a dose greater than 60 units is required, two or more injections must be administered. After each injection, the plunger moves slightly, and this movement may not be easily noticeable. The plunger will reach the end of the cartridge only after all 300 units have been used.

It is not recommended for patients with complete vision loss or impaired vision to use the pen-injector without assistance from individuals trained in its proper use.

Schematic illustration of the KwikPen pen-injector

Description of the Humulin M3 KwikPen device

The body of the KwikPen is beige, and the button is brown.

The label is white with a brown stripe.

The KwikPen device is recommended to be used only with needles from Becton, Dickinson and Company (BD).

Preparing the KwikPen device

• Wash hands with soap.
• Read the label text on the KwikPen to ensure the patient is using the correct type of insulin. This is especially important if the patient uses more than one type of insulin.
• Do not use the KwikPen after the expiration date stated on the label. Do not use the KwikPen for more than 28 days, even if insulin remains in it.
• Always use a new needle for each injection to prevent infection and needle blockage.

Checking the KwikPen insulin pen for insulin flow

The insulin flow check for the KwikPen should be performed before each injection.

• Checking the KwikPen for insulin flow is necessary to remove any air that may have accumulated in the needle or insulin cartridge during normal use, and to ensure that the pen is working properly.
• If the patient does not perform the insulin flow check before each injection, they may receive either too low or too high a dose of insulin.

Dose Setting

• Doses from 1 to 60 units of insulin can be set for a single injection.
• If a dose greater than 60 units is required, two or more injections must be administered.
  • If assistance is needed in deciding how exactly to divide the dose, consult your doctor.
  • For each separate injection, use a new needle and repeat the insulin flow check.

• The pen will not allow you to administer a dose exceeding the number of units remaining in the pen.
  • If a dose greater than the number of units remaining in the pen is required, you may administer the remaining units, then complete the dose using a new pen, or administer the full dose using a new pen.
• It is normal for a small amount of insulin to remain in the pen that cannot be administered.

Administering the dose

• Use the injection technique recommended by your doctor.
• Always rotate injection sites.
• Never attempt to change the dose during insulin administration.

After injection.

Children.

The dosage, administration schedule, and number of injections for children must be determined by a physician based on individual patient needs and according to each specific case.

Overdose.

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

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

Mild hypoglycemia can usually be corrected 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 has stabilized. For patients who do not respond to glucagon administration, intravenous glucose solution must be administered. In comatose patients, glucagon should be given intramuscularly or subcutaneously. If glucagon is unavailable or if there is no response to glucagon, intravenous glucose must be administered. The patient should be fed as soon as he or she regains consciousness.

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

Adverse Reactions

Hypoglycemia is the most common adverse effect of insulin therapy in patients with diabetes mellitus. Severe hypoglycemia may lead to loss of consciousness and, in some cases, to fatal outcomes. The exact frequency of hypoglycemic episodes cannot be determined, as it results from the combined influence of insulin dose and other factors, such as the patient's diet and level of physical activity.

Local allergic reactions may occur frequently (frequency from 1/100 to <1/10), including injection site reactions: erythema, swelling, and pruritus. These reactions usually resolve within a period of several days to several weeks. Sometimes, such reactions are not related to insulin itself but to other factors, for example, irritant substances in skin cleansing agents or inadequate injection technique.

Systemic allergic reactions occur very rarely (<1/10,000), but represent a potentially more serious adverse effect and constitute a generalized form of allergy to insulin. Symptoms may include generalized rash, dyspnea, wheezing, hypotension, tachycardia, and increased sweating. Severe cases of generalized allergy can be life-threatening. In some exceptional cases of severe allergy to Humulin M3, immediate appropriate measures should be taken. Insulin replacement or desensitization therapy may be required.

Lipodystrophy at the injection site occurs infrequently (frequency from 1/1,000 to <1/100).

Skin and subcutaneous tissue disorders: cutaneous amyloidosis, occurring at unknown frequency.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site, delaying local insulin absorption. Regular rotation of injection sites within a given injection area may help reduce or prevent these reactions (see section "Special Instructions").

Edema has been reported during insulin therapy, particularly when intensive insulin therapy improves previously poor metabolic control.

Shelf life. 3 years.

Storage conditions. Store out of reach and sight of children, in a cool place at a temperature of 2°C to 8°C. Do not freeze.

During use, store at room temperature of 15–25°C for up to 28 days, protected from excessive heat and direct sunlight.

Incompatibility. Humulin M3 must not be mixed with insulins from other manufacturers or with animal-sourced insulins.

Packaging. Glass cartridges of 3 ml; 5 cartridges per cardboard pack. Glass cartridges of 3 ml in QuickPen injection pens; 5 injection pens per cardboard pack.

Prescription category. Prescription only.

Manufacturer. Eli Lilly France, France.

Manufacturer's address and place of business.

Zone Industrielle 2, Rue Colonel Lilly, 67640 Fegersheim, France.