Humalog

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HUMALOG® (HUMALOG®)

Composition:

Active substance: 1 ml of solution contains 100 IU of insulin lispro (recombinant DNA), equivalent to 3.5 mg;

Excipients: glycerol, m-cresol, zinc oxide, sodium hydrogen phosphate heptahydrate, hydrochloric acid 10% solution, sodium hydroxide 10% solution, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antidiabetic agents. Fast-acting insulins and analogues. Insulin lispro. ATC code A10AB04.

Pharmacological properties.

Pharmacodynamics.

The primary action of insulin lispro is the regulation of glucose metabolism. In addition, all insulins exert anabolic and anticatabolic effects on various tissues of the body. In muscle tissues, these effects include enhanced synthesis of glycogen, fatty acids, glycerol, and protein, as well as increased amino acid uptake, simultaneously with inhibition of glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid excretion.

Insulin lispro is characterized by a rapid onset of action (approximately 15 minutes after injection), allowing it to be administered closer to mealtime (0–15 minutes before a meal) compared to regular insulin (30–45 minutes before a meal). Insulin lispro acts quickly and has a shorter duration of action (2 to 5 hours) compared to regular human insulin.

As with all insulin preparations, the duration of action of insulin lispro may vary between different individuals or at different times in the same individual, and also depends on dose, injection site, blood supply, temperature, and physical activity. The glucodynamic response to insulin lispro is not affected by renal or hepatic dysfunction.

Pharmacokinetics.

The onset of action of insulin lispro occurs within 15 minutes after subcutaneous administration; peak effect is reached within 30–70 minutes; duration of action is 2–5 hours. Some studies with human insulin have shown increased levels of circulating insulin in patients with renal and/or hepatic impairment. Careful glucose monitoring and appropriate insulin dose adjustment, including insulin lispro, are necessary in such cases. In patients with type 2 diabetes mellitus, the pharmacokinetics of insulin lispro and soluble human insulin are approximately equivalent and do not depend on renal functional status.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus in children and adults who require insulin administration to maintain normal blood glucose levels.

Primary stabilization of diabetes mellitus.

Contraindications.

Hypersensitivity to insulin lispro or to any of the other components of the product.

Hypoglycemia.

Interaction with other medicinal products and other forms of interaction.

Insulin requirements may increase when taking medicinal products with hyperglycemic activity, such as oral contraceptives, corticosteroids, thyroid hormones, danazol, beta-2-agonists (e.g., ritodrine, salbutamol, terbutaline).

Insulin requirements may decrease in the presence of medicinal products with hypoglycemic activity, such as oral hypoglycemic agents, salicylates (e.g., acetylsalicylic acid), sulfonamides, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), certain angiotensin-converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor antagonists, beta-blockers, octreotide, or alcohol.

Prior to using other medicinal products in combination with Humalog®, consult a physician.

Special precautions for use.

Tracking.

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

Switching a patient to another type or brand of insulin.

Switching a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular/soluble, NPH/isophane, etc.), species origin (animal, human, human insulin analogue), and/or method of production (recombinant DNA insulin or animal-sourced insulin) may require a dosage adjustment. When using short-acting insulins in patients who are also receiving basal insulin, doses of both insulins should be adjusted to achieve optimal blood glucose control throughout the day, particularly during the night and fasting periods.

Hypoglycemia and hyperglycemia.

Conditions in which early warning symptoms of hypoglycemia may be less specific or less pronounced include long-standing diabetes mellitus, intensive insulin therapy, diabetic neuropathy, or concomitant use of medications such as beta-blockers.

Several patients who experienced hyperglycemic reactions after switching from animal-sourced insulin to human insulin have reported that early warning symptoms of hypoglycemia were less pronounced or different from those experienced with the previous insulin. Untreated hypoglycemic or hyperglycemic reactions can lead to loss of consciousness, coma, or death.

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

Injection technique.

Patients should be instructed to rotate injection sites regularly to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and deterioration in glycemic control following insulin injections into areas affected by such reactions. Cases of hypoglycemia have been reported following sudden changes in injection site to areas not affected by amyloidosis or lipodystrophy. After changing the injection site, blood glucose monitoring is recommended, and dose adjustments of antidiabetic medications may need to be considered.

Insulin requirements and dose adjustment.

Insulin requirements may increase during illness or emotional stress.

Dose adjustments may also be necessary with increased physical activity or changes in normal diet. Exercising immediately after meals increases the risk of hypoglycemia. Due to the pharmacodynamic profile of fast-acting insulin analogues, hypoglycemia may occur earlier after injection compared to soluble human insulin.

Concomitant use 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 Humalog® in combination with pioglitazone. When using this combination, patients should be monitored for signs and symptoms of heart failure, weight gain, and edema. Pioglitazone therapy should be discontinued if cardiac symptoms worsen.

Concomitant use with thiazolidinediones.

There is a risk of developing edema and heart failure when thiazolidinediones are used concomitantly with insulin, particularly in patients with a history of cardiovascular disease.

Prevention of medication errors.

Patients should check the insulin label before each injection to avoid accidental mix-ups with other insulin products. Patients should visually confirm the number of units drawn into the dose on the KwikPen autoinjector. It is mandatory for patients to visually verify the dose counter value in the dose window of the KwikPen when self-administering a dose. Patients with complete vision loss or impaired vision should be instructed to always receive assistance from another person with good eyesight who is trained in the use of the KwikPen.

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.

Pregnancy

There is substantial data on the use of Humalog® during pregnancy. No adverse effects of insulin lispro on pregnancy or fetal/neonatal health have been observed. Pregnant patients with insulin-dependent diabetes or gestational diabetes receiving insulin therapy require careful monitoring.

Insulin requirements typically decrease during the first trimester and increase during the second and third trimesters of pregnancy. Patients with diabetes should consult their physician if they become pregnant or are planning pregnancy. Close monitoring of blood glucose levels and overall health is essential for diabetic patients during pregnancy.

Breastfeeding

Patients with diabetes who are breastfeeding may require adjustments in dosage and/or diet.

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 constitute a risk factor when such ability is of particular importance (including driving a vehicle or operating machinery). Patients should take preventive measures to avoid hypoglycemia while driving or operating machinery. 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 cases, the appropriateness of driving or operating machinery should be evaluated.

Method of Administration and Dosage.

Doses.

The dose should be determined by a physician according to the individual needs of the patient.

Humalog® may be administered immediately before meals. If necessary, Humalog® may be administered shortly after eating. Humalog® should be administered subcutaneously. The KwikPen pen device is intended for subcutaneous injections only. Humalog® in cartridges is intended for subcutaneous use only, via a reusable pen injector or compatible subcutaneous infusion pump systems.

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

Care should be taken during Humalog® injection to avoid intravascular injection. The injection site should not be massaged after administration. Patients must be trained in proper injection technique.

After subcutaneous injection, the effect of Humalog® begins more rapidly and lasts for a shorter duration (2 to 5 hours) compared to regular human insulin. The rapid onset of action of Humalog® allows administration (or, in the case of continuous subcutaneous infusion, bolus delivery of Humalog®) immediately before meals. The duration of action of any insulin may vary between different patients or at different times in the same patient. The faster onset of action compared to soluble human insulin is maintained regardless of the injection site. As with all insulin products, the duration of action of Humalog® depends on dose, injection site, blood supply, body temperature, and physical activity.

As directed by a physician, Humalog® may be used in combination with long-acting insulin or oral sulfonylurea agents.

Special Patient Groups.

Patients with Renal Impairment.

Insulin requirements may be reduced in patients with renal impairment.

Patients with Hepatic Impairment.

Insulin requirements may be reduced in patients with impaired liver function due to decreased gluconeogenesis and insulin metabolism. However, in patients with chronic hepatic insufficiency, increased insulin resistance may lead to increased insulin requirements.

Use of Humalog® with Insulin Infusion Pumps

Some insulin infusion pumps are compatible with cartridges that can be inserted whole into the pump.

For insulin infusions, insulin lispro can only be used with specific CE-marked insulin pump models. Before initiating infusions, the manufacturer's instructions for the pump must be carefully reviewed to confirm the suitability of each individual pump model. Use the pump-specific reservoir and infusion set. When filling the pump reservoir, avoid damaging it and use a filling needle of appropriate length.

The infusion set (tubing and cannula) should be changed according to the manufacturer's recommendations. Insertion of the infusion set must be performed under aseptic conditions. In the event of hypoglycemia, the infusion should be stopped until the hypoglycemic episode resolves. If hypoglycemia recurs or if blood glucose levels drop significantly, consideration should be given to reducing or stopping the infusion. Pump malfunction or occlusion may lead to rapid hyperglycemia. In case of suspected interruption of insulin delivery, follow the pump's instructions. When Humalog® is used in an insulin infusion pump, it must not be mixed with other insulins.

Special Warnings for Use of Humalog®.

Unused medication or waste materials must be disposed of in accordance with applicable legal requirements.

The Humalog® solution should be inspected visually before administration. It should be clear and colorless. Humalog® should not be used if it appears cloudy, viscous, discolored, or contains visible particles.

Each pen injector/cartridge must be used by only one patient, even if the needle is changed, to prevent transmission of infectious agents. The patient should discard the needle after each injection.

Instructions for Preparation and Administration of Humalog® in Cartridges.

Humalog® in cartridges should be used with reusable pen injectors manufactured by Eli Lilly and Company and its affiliates and should not be used with other reusable pen injectors, as dosing accuracy has not been established for such devices.

Follow the instructions provided with each specific pen injector regarding cartridge insertion, needle attachment, and insulin injection.

A. Preparing the Dose.

The following are general recommendations. Refer to the manufacturer's instructions for each specific pen injector for details on cartridge loading, needle attachment, and injection technique.

B. Administering the Dose:

1. Wash your hands.
2. Select an injection site.
3. Clean the skin at the injection site.
4. Remove the needle cap.
5. Stabilize the skin by pinching or forming a skin fold. Insert the needle according to the pen injector's instructions.
6. Press the injection button.
7. Withdraw the needle and gently press on the injection site for several seconds. Do not rub the injection site.
8. Using the needle's protective cap, remove the needle and dispose of it according to safety regulations.
9. Rotate injection sites so that injections at the same site are not performed more frequently than approximately once per month.

Instructions for Preparation and Administration of Humalog® with the KwikPen Pen Injector.

A. Use of the Pre-filled Pen Injector.

Before using the KwikPen pen injector, carefully read the instructions for preparation and administration. The pen injector should be used as described below.

Instructions for Use of the KwikPen Pen Injector.

The KwikPen pen injector delivers a dose of Humalog® ranging from 1 to 60 units per injection, with a dose increment of 1 unit. The number of insulin units is displayed in the dose window of the KwikPen pen injector.

Each time a new KwikPen pen injector is used, the instructions for use should be read carefully, as they may contain updated information. Additionally, you should discuss your health condition and prescribed treatment with your physician.

The KwikPen pen injector is a single-use pen containing 3 mL (300 IU, 100 IU/mL) of insulin. The pen allows multiple injections. The dose increment is 1 unit. Doses from 1 to 60 units of insulin can be administered per injection. If a dose exceeding 60 units is required, two or more injections are necessary. After each injection, the plunger moves slightly, and movement may not be easily noticeable. The plunger reaches the end of the cartridge only after all 300 IU have been used.

Use of the pen injector is not recommended for patients with complete vision loss or impaired vision unless assisted by someone trained in proper pen injector use.

Schematic illustration of the KwikPen pen injector

Description of the KwikPen pre-filled pen with Humalog® medication

Color of the pen body: blue.

Color of the dose button: burgundy.

Color of the label: white with a burgundy stripe.

Use of the KwikPen is recommended only with Becton, Dickinson and Company (BD) needles.

Preparing the KwikPen

• Wash your hands with soap.
• Read the label on the pen to make sure you are using the correct type of insulin. This is especially important if you are using more than one type of insulin.
• Do not use the pen after the expiration date printed on the label. Do not use the pen 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 insulin pen must be performed before each injection.

• Checking the KwikPen insulin pen 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 you do not perform the insulin flow check before each injection, you may receive either too low or too high a dose of insulin.

Dose Setting

• You can set doses from 1 to 60 units of insulin per single injection.
• If you need to administer a dose exceeding 60 units, you must perform 2 or more injections.
  • If you need help deciding how exactly to divide your dose, consult your doctor.
  • For each separate injection, use a new needle and repeat the pen check for insulin flow.

• The pen will not allow you to set a dose higher than the number of units remaining in the pen.
• If you need to inject a dose that is greater than the number of units remaining in the pen, you may inject the remaining units, then complete your dose using a new pen, or you may administer the full dose using a new pen.
• It is normal if a small amount of insulin remains in the pen that you are unable to inject.

Administering the dose

• Use the injection technique recommended by your doctor.
• Always rotate your injection sites.
• Never attempt to adjust the dose while injecting insulin.

After injection.

Storage of the Pen

• Keep the pen and needles out of the reach of children.
• Do not store the pen with a needle attached.
• DO NOT USE the pen if any of its parts are damaged or broken.
• Always keep a spare pen available in case your pen is lost or damaged.

Children

Humalog® can be used in adolescents and children.

Overdose

Insulin preparations have no defined upper limit of overdose, since blood glucose concentration results from a complex interaction between insulin levels, glucose availability, and other metabolic processes. Hypoglycemia may occur as a result of excessive insulin activity relative to food intake and energy expenditure. Hypoglycemia is accompanied by symptoms including 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 has stabilized. Patients who do not respond to glucagon administration require intravenous glucose infusion. If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. In the absence of glucagon or if there is no response to glucagon, intravenous glucose solution must be administered. The patient should be fed as soon as consciousness is regained.

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

Adverse reactions.

Summary of safety profile

Hypoglycaemia is the most common adverse effect of insulin therapy occurring 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 dietary composition and level of physical activity.

Tabulated list of adverse reactions.

The adverse reactions listed below were observed during clinical trials. They are presented in the table below according to the Medical Dictionary for Regulatory Activities (MedDRA) organ system classes and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10000 to < 1/1000), and frequency not known (cannot be estimated from the available data).

Within each group, adverse reactions are listed in order of decreasing frequency.

Description of individual adverse reactions

Local allergic reaction.

Local allergic reactions may frequently occur. At the injection site, redness, swelling, or itching may be observed. This condition usually resolves within a few days or weeks. In some cases, this condition is not related to insulin, but rather to other factors, such as irritants in the skin cleansing agent or improper injection technique.

Systemic allergic reaction.

Systemic allergic reaction is less common but potentially represents a more serious adverse effect and constitutes a generalized form of allergy to insulin. It may manifest as a rash over the entire body, dyspnea, difficulty breathing, hypotension, tachycardia, or increased sweating. Severe cases of systemic allergic reactions may be life-threatening.

Skin and subcutaneous tissue disorders.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site, which may delay local absorption of insulin. Regularly rotating injection sites within a specific injection area may help reduce or prevent these reactions (see section "Instructions for use").

Edema.

Cases of edema have been reported during insulin therapy, particularly when poor prior metabolic control was improved by intensive insulin therapy.

Shelf life.

3 years.

Duration of use after first opening – 28 days.

Storage conditions. Store in a refrigerator at 2–8°C. Do not freeze. During use, the medicinal product should be stored at a temperature not exceeding 30°C for no more than 28 days. Protect from direct sunlight and heat. During use, the cartridge or prefilled pen must not be kept in the refrigerator. The prefilled pen must not be stored with an attached needle. Keep out of reach of children.

Incompatibility.

Humalog® in cartridge, Humalog® in prefilled pen KwikPen.

These medicinal products must not be mixed with any other insulins or with any other medicinal products.

Packaging. 3 ml of solution for injection in a glass cartridge sealed with a rubber stopper and aluminum seal. 5 cartridges per cardboard box. 3 ml in a glass cartridge contained in a prefilled pen KwikPen; 5 prefilled pens per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Full-cycle manufacturing:

Lilly France.

Lilly France.

Manufacturers' locations and addresses of their business operations.

Zone Industrielle, 2 rue du Colonel Lilly, 67640 Fegersheim, France.
Zone Industrielle, 2 rue du Colonel Lilly, 67640 Fegersheim, France.