Humalog® mix 50
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HUMALOGâ MIX 50 (HUMALOGâ MIX 50)
Composition:
Active substance: insulin lispro;
1 ml of suspension contains 100 IU insulin lispro (50 % insulin lispro and 50 % insulin lispro protamine suspension);
Excipients: glycerol; sodium hydrogen phosphate dihydrate; metacresol; zinc oxide; phenol; protamine sulfate; water for injections; hydrochloric acid 10 %; sodium hydroxide 10 %.
Pharmaceutical form. Suspension for subcutaneous administration.
Main physicochemical properties: white-colored suspension.
Pharmacotherapeutic group. Antidiabetic agents. Combinations of short- and intermediate-acting insulins. ATC code A10AD04.
Pharmacological Properties.
Pharmacodynamics.
Humalog® Mix 50 – a DNA-recombinant human insulin analogue – is a mixture consisting of 50% insulin lispro (a rapid-acting human insulin analogue) and 50% insulin lispro protamine suspension (an intermediate-acting human insulin analogue).
The primary action of insulin lispro is the regulation of glucose metabolism.
In addition, all insulins exert anabolic and anticatabolic effects on various body tissues. In muscles and other tissues (except the brain), insulin increases levels of glycogen, fatty acids, and glycerol, enhances protein synthesis and amino acid uptake, while in the liver, insulin suppresses glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid production.
Insulin lispro has been shown to be equivalent to human insulin.
Insulin lispro acts rapidly, reaches its peak effect earlier than regular human insulin, and has a shorter duration of glucose-lowering action compared to regular human insulin following subcutaneous administration. The earlier onset of action of insulin lispro, approximately 15 minutes after injection, is directly related to its more rapid absorption. This allows insulin lispro to be administered closer to mealtime (0–15 minutes before a meal) compared to regular soluble insulin (30–45 minutes before a meal).
The activity profile of Humalog basal is similar to that of basal insulin (NPH) over a time period of approximately 15 hours.
| Glucose infusion rate (mg/min/kg) |
Humalog®
Humalog® Mix 25
|
Time (hours)
Figure. Mean insulin activity profiles over time after administration of 0.3 IU/kg of Humalog®, Humalog® Mix 50, Humalog® Mix 25, and protamine-suspended insulin lispro to 30 healthy volunteers.
In a glucose clamp study conducted in 30 healthy volunteers, the onset of action and glucose-lowering activity of Humalog®, Humalog® Mix 50, Humalog® Mix 25, and protamine-suspended insulin lispro were compared (see figure). The mean glucose infusion rate profiles over time demonstrated distinct insulin activity profiles for each product. The characteristic rapid onset of glucose-lowering activity observed with Humalog® was preserved in Humalog® Mix 25. The median time to maximum pharmacological effect of Humalog® Mix 25 following administration of 0.3 IU/kg to healthy subjects was approximately 2 hours (range: 1 to 6 hours). Glucose-lowering activity was observed on average for 22 hours (range: 13 to 22 hours), which corresponded to the end of the clamp test.
Renal or hepatic impairment does not affect the glucodynamic response to insulin lispro. The glucodynamic difference between insulin lispro and soluble human insulin, as determined during the glucose clamp procedure, was maintained across varying levels of renal function. Insulin lispro was equipotent to human insulin on a molar basis, but had a faster onset and shorter duration of action.
Pharmacokinetics.
The onset of action of insulin lispro occurs approximately 15 minutes after subcutaneous injection; peak effect develops within 30–70 minutes. The rate of absorption of insulin lispro, and consequently the onset of action, depends on the injection site. The pharmacokinetics of insulin lispro reflect those of a rapidly absorbed component. The pharmacokinetics of protamine-suspended insulin lispro correspond to those of intermediate-acting insulin, such as NPH. The pharmacokinetics of Humalog® Mix 50 reflect the combined pharmacokinetic properties of its two individual components.
In patients with renal impairment, absorption of insulin lispro is faster compared to soluble human insulin preparations. In patients with type 2 diabetes and varying degrees of renal function, the pharmacokinetics of insulin lispro and soluble human insulin were approximately equivalent and independent of renal functional status. In patients with hepatic impairment, absorption of insulin lispro is faster compared to soluble human insulin preparations.
Clinical Characteristics.
Indications.
Treatment of diabetes mellitus in patients requiring insulin administration to maintain normal glucose homeostasis.
Contraindications.
Hypersensitivity to insulin lispro or to any of the excipients.
Hypoglycemia.
Intravenous administration is contraindicated.
Interaction with other medicinal products and other forms of interactions.
Insulin requirements may increase when used concomitantly with medicinal products having hyperglycemic activity, such as oral contraceptives, corticosteroids, thyroid hormones, danazol, beta2-agonists (e.g., ritodrine, salbutamol, terbutaline).
Insulin requirements may decrease when used concomitantly with medicinal products having 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.
The use of Humalog® Mix 50 in combination with other insulins has not been studied.
Prior to taking other medications in combination with Humalog® Mix 50, consult a physician.
Special precautions.
Humalog® Mix 50 must not be administered intravenously.
Switching 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 analog), and/or method of manufacture (recombinant DNA insulin or animal insulin) may require a dosage adjustment.
Hypoglycemia and hyperglycemia
Conditions in which early warning symptoms of hypoglycemia may be less specific or less pronounced include long-standing diabetes, 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 their previous insulin. Untreated hypoglycemic or hyperglycemic reactions can lead to loss of consciousness, coma, and fatal outcomes.
Inappropriate dosing or abrupt discontinuation of treatment, especially 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 minimize the risk of developing lipodystrophy or cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and deterioration of 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, blood glucose monitoring is recommended, and dose adjustments of antidiabetic medications may need to be considered.
Insulin requirements and dose adjustments
Insulin requirements may increase during illness or emotional stress.
Dose adjustments may also be necessary with increased physical activity or changes in usual diet. Exercising immediately after meals increases the risk of hypoglycemia.
Use of Humalog® Mix 50 in children under 12 years of age is possible if benefits are expected compared to using regular human insulin.
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 Humalog® Mix 50 in combination 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.
Avoiding medication errors
Patients should check the insulin label before each injection to avoid accidental confusion with other insulin products. Patients should visually confirm the number of units drawn up on the dose counter of the KwikPen. Therefore, it is mandatory for patients to visually verify the dose counter reading in the dose window of the KwikPen when self-administering insulin. Patients with complete vision loss or impaired vision should be instructed to always receive assistance from a person with adequate vision who is trained in using 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
Use during pregnancy
Extensive data on the use of Humalog® Mix 50 during pregnancy have not shown any adverse effects of insulin lispro on pregnancy outcomes or fetal or neonatal health. Close monitoring is required for pregnant patients with insulin-dependent diabetes mellitus or gestational diabetes receiving insulin therapy.
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 plan to become pregnant. During pregnancy, patients with diabetes require careful monitoring of blood glucose levels and overall health.
Breastfeeding
Patients with diabetes who are breastfeeding may require adjustments in dosage and/or diet.
Effect on ability to drive and use machines
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 abilities are of particular importance (e.g., when 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 with reduced or absent awareness of hypoglycemic warning symptoms or those who frequently experience hypoglycemic episodes. In such circumstances, the appropriateness of driving or operating machinery should be carefully evaluated.
Method of Administration and Dosage.
Doses
The dose is determined by the physician according to the individual needs of the patient. Humalog® Mix 50 may be administered immediately before a meal. If necessary, Humalog® Mix 50 may be administered shortly after a meal. Humalog® Mix 50 must be administered only subcutaneously. The medication must not be administered intravenously.
After subcutaneous injection of Humalog® Mix 50, a rapid onset of action and early peak activity of Humalog® itself is observed. This allows administration immediately before meals. The duration of action of insulin lispro protamine suspension (Humalog Basal), a component of Humalog® Mix 50, is similar to that of NPH basal insulin. The duration of action of any insulin may vary among 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® Mix 50 depends on dose, injection site, blood supply, body temperature, and physical activity.
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 liver disease, increased insulin resistance may lead to increased insulin requirements.
Method of Administration.
Subcutaneous injections should be administered in the upper arm, thigh, buttock, 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 must be taken during injection of Humalog® Mix 50 to avoid intravascular injection. The injection site should not be massaged after injection. Patients must be trained in the correct injection technique.
Special Warnings on Use.
Any unused materials or waste must be disposed of in accordance with applicable legal requirements.
Each pen device/cartridge must be used by only one patient, even if the needle is changed, to prevent the possible transmission of infectious agents. Patients should discard the needle after each injection.
Insulin pens/cartridges should be inspected frequently. The product should not be used if the suspension contains clumps or if white particles adhere to the bottom or sides of the cartridge, making the glass appear cloudy.
Instructions for Preparation and Administration of Humalog® Mix 50 in Cartridges.
Humalog® Mix 50 in 3 ml cartridges must be used with reusable pen injectors manufactured by Eli Lilly and Company and should not be used with other reusable pen injectors, as dosing accuracy has not been established for them.
The instructions provided with each individual pen injector must be followed regarding cartridge insertion, needle attachment, and insulin injection.
Preparation of Dose.
Before using Humalog® Mix 50 in cartridges, the insulin mixture must be resuspended by rolling the cartridge between the palms 10 times and inverting it 10 times through 180° until the suspension becomes uniformly cloudy or uniformly milky. If this does not occur, the procedure should be repeated until complete mixing is achieved. The cartridges contain a glass ball to facilitate mixing. The cartridge should not be shaken vigorously, as this may cause foaming, which could interfere with accurate dose measurement.
The cartridges are not designed for mixing different insulins. Empty cartridges must not be reused.
The following are general recommendations. Refer to the manufacturer's instructions for each individual pen injector regarding cartridge loading, needle attachment, and insulin injection.
Administration of Dose
- Wash your hands.
- Select an injection site.
- Clean the skin at the injection site.
- Remove the needle cap.
- Stabilize the skin by stretching or pinching it. Insert the needle according to the pen injector's instructions.
- Press the injection button.
- Withdraw the needle and gently press on the injection site for several seconds. Do not rub the injection site.
- Using the needle's protective cap, remove the needle and dispose of it according to safety requirements.
- Rotate injection sites so that the same site is not used more than once a month.
Instructions for Preparation and Administration of Humalog® Mix 50 in the QuickPen Pre-filled Pen.
Before using Humalog® Mix 50 in the QuickPen, the insulin mixture must be resuspended by rolling the pen between the palms 10 times and inverting it 10 times through 180° until the suspension becomes uniformly cloudy or uniformly milky. If this does not occur, the procedure should be repeated until complete mixing is achieved. The cartridges contain a glass ball to facilitate mixing. The pen should not be shaken vigorously, as this may cause foaming in the cartridge, which could interfere with accurate dose measurement.
Use of the Pre-filled Pen.
Before using the QuickPen, carefully read the instructions for preparation and administration. The pen must be used as described below.
Instructions for Use.
The QuickPen delivers from 1 to 60 units per injection, with a dose increment of 1 unit. The number of units is displayed in the dose window of the QuickPen.
Each time a new QuickPen is used, the instructions for use should be read carefully, as they may contain updated information. This information does not replace the need to discuss your health condition and prescribed treatment with your physician.
The QuickPen is a single-patient-use pen containing 3 ml (300 IU, 100 IU/mL) of insulin. One 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 must be performed. After each injection, the plunger moves slightly, and movement may not be noticeable. The plunger will reach the end of the cartridge only after all 300 IU have been used.
Use of the pen is not recommended for patients with complete vision loss or impaired vision unless assisted by someone trained in the correct use of the pen.
Schematic Diagram of the QuickPen
| Parts of the pen needle (needles are not included in the package) |
Parts of the QuickPen pen device |
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| Paper insert |
Cap holder |
Cartridge holder |
Pen device label |
Dose indicator |
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| Injection button |
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| Needle outer cap |
Needle inner cap |
Needle |
Pen cap |
Rubber disk |
Plunger |
Pen body |
Dose window |
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Description of the KwikPen insulin pen with Humalog® Mix 50 medication
Color of the pen body – blue
Color of the injection button – red
Color of the label – white label with a red stripe
The KwikPen insulin pen is recommended for use only with needles from Becton, Dickinson and Company (BD).
Preparing the KwikPen insulin pen
- Wash your hands with soap.
- Read the label on the insulin pen to make sure you are using the correct type of insulin. This is especially important if you use more than one type of insulin.
- Do not use the insulin pen after the expiration date printed on the label. Do not use the insulin pen for more than 28 days, even if there is still insulin remaining in it.
- Always use a new needle for each injection to prevent infection and needle blockage.
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Mixing is important to ensure you receive the correct dose. The insulin should appear uniformly mixed. |
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Checking the KwikPen insulin pen for insulin flow.
The insulin flow check for the KwikPen insulin pen should be performed before each injection.
- Checking the KwikPen insulin pen for insulin flow is necessary to remove any air that may accumulate 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.
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The presence of small air bubbles is normal and will not affect the insulin dose. |
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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.
| Step 10:
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(Example: the dose window shows 12 units) (Example: the dose window shows 25 units) |
- 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 larger than the number of units remaining in the pen, you may inject the remaining units, then complete your dose with a new pen, or administer the full dose using a new pen.
- It is normal if a small amount of insulin remains in the pen that you cannot inject.
Administering the dose
- Use the injection technique recommended by your doctor.
- Always rotate your injection sites.
- Never attempt to change the dose while injecting insulin.
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| Do not attempt to deliver insulin by turning back the injection button. You will not receive the required insulin dose this way. If the injection button is hard to push:
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| Step 13:
After each injection, the plunger moves forward a small distance, and you may not notice its movement. If you see blood after removing the needle from the skin, gently press a piece of gauze or swab against the injection site. Do not rub the injection site. |
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After injection.
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Storage of the pen injector
- Keep the pen injector and needles out of the reach of children.
- Do not store the pen injector with a needle attached.
- DO NOT USE the pen injector if any of its parts are damaged or broken.
- Always keep a spare pen injector available in case your pen injector is lost or damaged.
Children
Use of the product in children under 12 years of age is possible if benefits are expected from its use compared to soluble human insulin.
Overdose
Insulin products do not have a defined overdose limit, since blood glucose concentration results from a complex interaction between insulin levels, glucose input, 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 drowsiness, confusion, tachycardia, headache, sweating, and vomiting.
Mild hypoglycemia can usually be 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 he regains consciousness.
Continued carbohydrate intake and medical monitoring may be necessary, since hypoglycemia may recur after apparent clinical improvement.
Adverse reactions.
Summary of safety profile
Hypoglycemia is the most common adverse effect of insulin therapy occurring in patients with diabetes mellitus. Severe hypoglycemia may lead to loss of consciousness and, in rare cases, to fatal outcome. 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.
Tabulated list of adverse reactions.
The adverse reactions listed below were observed during clinical studies. They are presented in the table below according to MedDRA (Medical Dictionary for Regulatory Activities) system organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000), and frequency not known (cannot be estimated from the available data).
Within each group, adverse reactions are listed in order of decreasing frequency.
| System organ classes according to MedDRA |
Very common |
Common |
Uncommon |
Rare |
Very rare |
Frequency not known |
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| Immune system disorders |
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| Local allergic reaction |
X |
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| Systemic allergic reaction |
X |
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| Skin and subcutaneous tissue disorders |
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| Lipodystrophy |
X |
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| Skin amyloidosis |
X |
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Description of individual adverse reactions
Local allergic reaction.
Local allergic reactions may often 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 skin-cleansing agents or improper injection technique.
Systemic allergic reaction.
Systemic allergic reaction is less common but potentially more serious and represents a generalized form of allergy to insulin. It may manifest as generalized rash, 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 insulin absorption. Regularly rotating injection sites within a single injection area may help reduce or prevent these reactions (see section "Special instructions").
Edema.
Cases of edema have been reported during insulin therapy, particularly when poor prior metabolic control is corrected by intensive insulin treatment.
Shelf life.
3 years.
Duration of use after first opening: 28 days.
Storage conditions. Store at 2–8°C. Do not freeze. During use, the medicinal product may be stored at temperatures not exceeding 30°C for up to 28 days, protected from excessive heat and sunlight. During use, the cartridge or pre-filled pen must not be kept in the refrigerator. The pre-filled pen must not be stored with the needle attached. Keep out of the reach of children.
Incompatibilities.
Humalog® Mix 50 must not be mixed with any other medicinal products.
Packaging. 3 ml of injectable suspension in a glass cartridge sealed with a rubber stopper and aluminum seal. 5 cartridges per cardboard package.
3 ml glass cartridges in KwikPen pre-filled pens, 5 pre-filled pens per cardboard package.
Prescription status. Prescription only.
Manufacturer.
Lilly France
Lilly France
Manufacturer's address and location of operations.
Zone Industrielle, 2 rue du Colonel Lilly, 67640 Fegersheim, France