Mixtard® 30 nm flexpen®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MІXTARD® 30 HM FLEXPEN® (MIXTARD® 30 HM FLEXPEN®)
Composition:
Active substance: human insulin (rDNA);
1 ml of injection suspension contains 100 IU of biosynthetic human insulin (recombinant DNA obtained from Saccharomyces cerevisiae);
1 IU (international unit) equals 0.035 mg of anhydrous human insulin;
1 multi-dose disposable pen contains 3 ml of injection suspension, equivalent to 300 IU;
Mixtard® 30 HM FlexPen® is a mixture of soluble insulin and isophane insulin (NPH), containing 30% soluble insulin and 70% isophane insulin;
Excipients: zinc chloride; glycerol; metacresol; phenol; sodium dihydrogen phosphate, dihydrate; sodium hydroxide (for pH adjustment); hydrochloric acid, diluted (for pH adjustment); protamine sulfate; water for injections.
Pharmaceutical form. Injection suspension.
Main physicochemical properties: white-colored suspension, which upon standing forms a white sediment and a colorless or almost colorless supernatant liquid; the sediment readily resuspends upon gentle shaking. Under microscopic examination, particles appear as elongated crystals, most of which are 1–20 μm in length.
Pharmacotherapeutic group. Antidiabetic agents. Insulins and analogues. Combinations of intermediate- and long-acting insulins with short-acting insulins. Human insulin.
ATC code A10AD01.
Pharmacological properties.
Pharmacodynamics.
The blood 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 suppression of glucose release from the liver.
Mixtard® 30 NM FlexPen® is an insulin preparation with two components.
On average, the profile of action after subcutaneous injection is as follows:
onset of action – within 0.5 hours;
maximum effect – from 2 to 8 hours;
duration of action – approximately 24 hours.
Pharmacokinetics.
The half-life of insulin in blood is several minutes; therefore, the action profile of insulin preparations is determined solely by the characteristics of their absorption. This process depends on a number of factors (e.g., insulin dose, method and site of injection, thickness of subcutaneous tissue, type of diabetes), resulting in considerable variability of insulin effect both within an individual and between different patients.
Absorption. The absorption profile is determined by the fact that this insulin is a mixture of insulin components characterized by rapid and prolonged absorption. The peak plasma concentration of short-acting insulin occurs within 1.5–2.5 hours after subcutaneous injection.
Distribution. No significant binding of insulin to plasma proteins has been observed, except for circulating antibodies against insulin (if present).
Metabolism. Human insulin is cleaved by insulin proteases or insulin-degrading enzymes, and possibly by protein disulfide isomerase. Several cleavage (hydrolysis) sites within the human insulin molecule have been identified. None of the metabolites formed after hydrolysis possess biological activity.
Elimination. The elimination half-life of insulin is determined by the rate of its absorption from the subcutaneous tissue. Therefore, the elimination half-life (t½) reflects the rate of absorption rather than elimination per se of insulin from plasma (the t½ of insulin in circulation is only several minutes). According to available study data, t½ ranges from 5 to 10 hours.
Non-clinical safety data
In experimental studies (repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity), no hazard to humans from administration of Mixtard® 30 NM FlexPen® was identified.
Clinical characteristics.
Indications.
Treatment of diabetes mellitus.
Contraindications.
Hypersensitivity to human insulin or to any component of the medicinal product.
Hypoglycemia.
Interaction with other medicinal products and other forms of interactions.
It is known that a number of medicinal products affect glucose metabolism.
Substances that may decrease the patient's insulin requirements:
oral hypoglycemic agents (OHA), monoamine oxidase inhibitors (MAOI), β-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulfonamides.
Substances that may increase the patient's insulin requirements:
- oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, and danazol;
- β-blockers may mask symptoms of hypoglycemia;
- octreotide/lanreotide may either decrease or increase insulin requirements;
- alcohol may potentiate and prolong the hypoglycemic effect of insulin.
Special precautions for use.
Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administered product must be clearly recorded.
Patients should consult their physician before traveling across time zones, as this may require adjustments to the insulin injection and meal schedules.
Hyperglycemia
Inadequate dosing or discontinuation of treatment (particularly in type 1 diabetes) may lead to hyperglycemia and diabetic ketoacidosis. The first symptoms of hyperglycemia usually develop gradually over several hours or days. They include thirst, frequent urination, nausea, vomiting, drowsiness, skin flushing and dryness, dry mouth, loss of appetite, and acetone breath odor.
In type 1 diabetes, untreated hyperglycemia leads to diabetic ketoacidosis, which is potentially life-threatening.
Hypoglycemia
Skipping meals or unexpected physical exertion may lead to hypoglycemia.
Hypoglycemia may occur if the insulin dose is too high relative to insulin requirements. Insulin should not be administered in case of hypoglycemia or suspected hypoglycemia. After blood glucose stabilization, the patient's insulin dose should be reevaluated (see sections "Adverse Reactions" and "Overdose").
Patients who have significantly improved glycemic control due to intensive insulin therapy may experience changes in the usual warning signs of hypoglycemia, which should be explained to them in advance. Typical warning symptoms may disappear in patients with long-standing diabetes.
Concomitant illnesses, particularly infections and febrile conditions, generally increase insulin requirements. Concomitant kidney, liver, or adrenal, pituitary, or thyroid gland disorders may necessitate insulin dose adjustments.
When a patient is switched to another type of insulin, the symptoms of hypoglycemia may change or become less pronounced compared to those experienced with the previous insulin.
Switching from other insulins
Switching a patient to another type or brand of insulin must be done under strict medical supervision. Changes in insulin concentration, type (manufacturer), kind, origin (animal insulin, human insulin, or human insulin analog), and/or production method (rDNA technology or animal insulin) may require insulin dose adjustments. Patients switching to Mixtard® 30 NM FlexPen® from another insulin may require an increased number of daily injections or changes in dosing compared to their previous insulin regimen. Dose adjustments may be necessary both at the initiation of the new product and during the first weeks or months of treatment.
Injection site reactions
With any insulin therapy, injection site reactions may occur, including pain, redness, urticaria, inflammation, bruising, swelling, and pruritus. Regularly rotating the injection site within an area may reduce these reactions or prevent their occurrence. Reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Mixtard® 30 NM FlexPen®.
Skin and subcutaneous tissue disorders
Patients should be instructed to rotate injection sites regularly to reduce the risk of lipodystrophy and cutaneous amyloidosis. Injecting insulin into areas with such reactions may lead to delayed insulin absorption and impaired glycemic control. Cases of hypoglycemia have been reported after sudden switching of injection sites from affected to unaffected areas. Blood glucose monitoring and dose adjustments of antidiabetic medications are recommended after changing injection sites from affected to unaffected areas.
Combination of Mixtard® 30 NM FlexPen® with pioglitazone
Cases of congestive heart failure have been reported when pioglitazone is used in combination with insulin, particularly in patients with predisposing risk factors. This should be considered when prescribing combination therapy with pioglitazone and insulin. Patients receiving this combination should be monitored for signs and symptoms of congestive heart failure, weight gain, and edema. If cardiac function worsens, pioglitazone therapy should be discontinued.
Prevention of accidental medication errors
Patients should be instructed to always check the label on the insulin packaging before each injection to avoid accidentally confusing Mixtard® 30 NM FlexPen® with other insulin products.
Mixtard® 30 NM FlexPen® contains less than 1 mmol of sodium (23 mg) and can therefore be considered essentially sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
Since insulin does not cross the placental barrier, there are no restrictions on insulin treatment during pregnancy.
Both hypoglycemia and hyperglycemia, which may occur with inadequate diabetes management, increase the risk of congenital malformations or fetal death. Therefore, intensified blood glucose monitoring and medical supervision are recommended throughout pregnancy and whenever pregnancy is suspected in women with diabetes.
Insulin requirements usually decrease during the first trimester and significantly increase during the second and third trimesters. After delivery, insulin requirements typically return rapidly to pre-pregnancy levels.
Breastfeeding period
There are no restrictions on insulin treatment for diabetes during breastfeeding, as maternal insulin therapy poses no risk to the infant. However, dose adjustments 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 particularly important (e.g., driving a car or operating machinery).
Patients should be advised to take preventive measures against hypoglycemia before driving. This is especially important for patients with diminished or absent hypoglycemia warning symptoms or those who experience frequent hypoglycemic episodes. In such cases, the advisability of driving should be carefully considered.
Administration and Dosage
Dosing
The potency of human insulin is expressed in International Units (IU).
The dosage of insulin is individual and must be determined by a physician according to the patient's needs. Combined insulin is usually administered once or twice daily when a rapid initial effect is required along with a longer-lasting subsequent effect. To achieve optimal glycemic control, regular monitoring of blood glucose levels is recommended.
The individual daily insulin requirement usually ranges from 0.3 to 1.0 IU/kg/day. Dose adjustments may be necessary for patients during periods of increased physical activity, changes in diet, or during concomitant illnesses.
Special Populations
Elderly Patients (≥ 65 years of age)
The product Mixtard® 30 NM FlexPen® can be used in elderly patients.
In elderly patients, enhanced monitoring of glucose levels and individual dose adjustment of insulin are recommended.
Renal and Hepatic Impairment
Renal and hepatic impairment may reduce insulin requirements. In patients with renal or hepatic impairment, intensified glucose monitoring and individual dose adjustment of insulin are recommended.
Children
Mixtard® 30 NM FlexPen® can be used in children.
Switching from Other Insulin Preparations
Changing from previous intermediate- or long-acting insulin regimens to Mixtard® 30 NM FlexPen® requires careful adjustment of dosage and timing of administration.
Careful blood glucose monitoring is recommended during the transition to Mixtard® 30 NM FlexPen® and throughout the first several weeks of treatment (see section "Special Warnings and Precautions for Use").
Administration
Mixtard® 30 NM FlexPen® is a human insulin with dual action. It is a biphasic insulin preparation containing both short- and long-acting insulin.
Mixtard® 30 NM FlexPen® is usually administered subcutaneously by injection into the thigh, abdominal wall, buttocks, or deltoid region of the upper arm. To reduce the risk of developing lipodystrophy or cutaneous amyloidosis, injection sites should always be rotated within the same region (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").
Insulin suspension must never be administered intravenously. Injecting into a skin fold significantly reduces the risk of intramuscular injection.
After injection, the needle should remain under the skin for at least 6 seconds to ensure delivery of the full dose. Absorption of insulin is faster when administered subcutaneously into the abdominal wall compared to other injection sites. Duration of action may vary depending on dose, injection site, blood flow, body temperature, and level of physical activity.
The injection should be given 30 minutes before a main or supplemental meal containing carbohydrates.
The insulin suspension must not be used in insulin infusion pumps.
The pre-filled pen Mixtard® 30 NM FlexPen® is intended for use with disposable NovoFine® or NovoTwist® needles up to 8 mm in length.
The FlexPen® device allows administration of doses from 1 to 60 units in 1-unit increments. Mixtard® 30 NM FlexPen® is intended for subcutaneous injection only.
If insulin administration via syringe is required, the vial formulation of the medicinal product should be used.
The detailed instructions for use of these medical devices must be strictly followed.
Handling and Disposal Precautions
Upon first use, after removing Mixtard® 30 NM FlexPen® from the refrigerator, it is recommended to allow the pen to warm to room temperature before mixing the suspension.
Do not use the medicinal product if, after mixing, the suspension does not appear uniformly white and cloudy.
Do not use after freezing.
Patients should be advised to dispose of the needle after each injection.
Any unused medicinal product or waste material must be disposed of in accordance with local requirements.
Needles and pre-filled insulin pens containing Mixtard® 30 NM FlexPen® are intended for individual patient use only.
Refilling the cartridge is strictly prohibited.
Instructions for Using Mixtard® 30 NM FlexPen®
Before using the FlexPen®, carefully read these instructions. Failure to follow these instructions precisely may result in administering too little or too much insulin, which could lead to a sudden increase or decrease in blood glucose levels.
FlexPen® is a pre-filled insulin pen with a dose selector allowing doses from 1 to 60 units of insulin in 1-unit increments. FlexPen® is used with NovoFine® or NovoTwist® needles up to 8 mm in length. Always keep a spare pen available in case your FlexPen® is damaged or lost.
Mixtard® 30 NM FlexPen®
Pen Care
Handle the FlexPen® with care. If the pen is dropped or deformed, insulin leakage may occur, which could lead to incorrect dosing and result in either high or low blood sugar levels.
The surface of the FlexPen® may be cleaned by wiping with a cloth. Do not soak, wash, or lubricate the pen, as this may damage the device.
Do not refill the Mixtard® 30 NM FlexPen®. Once empty, the pen must be disposed of properly.
| Preparing the FlexPen® pen-injector. |
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| A. Check the label for the name and color to ensure that the FlexPen® contains the correct type of insulin. This is especially important if you use more than one type of insulin. If you inject the wrong type of insulin, your blood sugar level may rise or fall sharply. Starting to use a new pen-injector: Before use, insulin should be warmed to room temperature. This facilitates resuspension. Remove the cap from the pen-injector (Fig. A). |
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| B. Before the first injection with a new pen-injector, insulin must be resuspended. Turn the pen-injector upside down 20 times between two positions as shown in the figure, so that the glass bead moves from one end of the cartridge to the other. Repeat until the liquid becomes uniformly white and cloudy. Before each subsequent injection, turn the pen-injector upside down between two positions at least 10 times until the liquid becomes uniformly white and cloudy. Before each injection, ensure that the insulin has been resuspended. This may reduce the risk of sudden increase or decrease in blood sugar levels. After resuspension, proceed immediately to the next steps for injection. |
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| Attaching the needle C. Remove the protective membrane from the new single-use needle. Screw the needle tightly onto the FlexPen®. |
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| D. Remove the large outer needle cap. Do not discard it. |
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| E. Remove the inner needle cap and discard it. Never attempt to re-cover the removed inner needle cap, as you may get a needlestick injury. |
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| Checking insulin flow |
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| F. Before each injection, small amounts of air may normally accumulate in the cartridge. To prevent injecting air and to ensure delivery of the required dose, do the following: Set the dose selector to 2 units. |
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| G. Hold the FlexPen® vertically with the needle pointing upward and gently tap the cartridge several times with your finger to allow air bubbles to rise to the top. |
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| H. While holding the pen-injector vertically with the needle pointing upward, press the injection button. The dose selector will return to zero. A drop of insulin should appear at the needle tip. If it does not, replace the needle and repeat this procedure no more than 6 times. If a drop still does not appear, this indicates that the pen-injector is defective and a new one should be used. |
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| Dose Setting I. Ensure that the dose selector is set to "0". Turn the dose selector to choose the required number of units for injection. The dose can be adjusted either up or down by rotating the dose selector in the appropriate direction. While turning, be careful not to press the injection button accidentally, as this may cause insulin leakage. You cannot set a dose exceeding the amount of insulin remaining in the cartridge. |
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| Injecting insulin |
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| J. Insert the needle under the skin. Follow the injection technique taught to you by your doctor or nurse. Inject the dose by pressing the injection button fully until "0" aligns with the dose indicator. Be careful to press only the injection button during the injection. Rotating the dose selector will not deliver insulin. |
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| K. Keep the injection button fully pressed and leave the needle under the skin for at least 6 seconds. This ensures complete delivery of the dose. Remove the needle from the skin and release the injection button. Always ensure that the dose indicator has returned to "0" after injection. If the dose indicator stops before returning to "0", the full dose was not delivered, which may affect blood sugar levels. |
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| L. Cover the needle with the large outer cap without touching it. Once the needle is fully covered, carefully press on the cap and then unscrew the needle. Dispose of the needle safely and replace the cap on the pen-injector. |
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| Additional important information
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Ensure that at least 12 units of insulin remain in the cartridge to allow proper resuspension. If less than 12 units remain, use a new Mixtard® 30 NM FlexPen®. The 12-unit mark is indicated on the insulin remaining scale (see the overall view of the pen in the figure above).
Children.
Biosynthetic human insulin preparations are effective and safe medicinal products for the treatment of diabetes mellitus in children of various age groups. The daily insulin requirement in children depends on the stage of the disease, body weight, age, diet, physical activity, degree of insulin resistance, and glycemia dynamics.
Overdose.
Although there is no specific definition of overdose for insulin, administration of doses significantly higher than the patient's requirements may lead to the development of hypoglycemia, progressing through sequential stages.
- Mild hypoglycemia can be treated by oral administration of glucose or sweetened products. Therefore, diabetic patients are advised to always carry several sugar-containing products with them.
- In cases of severe hypoglycemia, when the patient is unconscious, individuals who have received appropriate training should administer glucagon intramuscularly or subcutaneously (0.5 to 1.0 mg). A healthcare professional may administer glucose intravenously. Intravenous glucose should 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. The frequency of hypoglycemia depends on the patient population, dosage regimen, and level of glycemic control (see description of individual adverse reactions below).
At the beginning of insulin therapy, transient refractive disturbances, edema, and injection site reactions (pain, redness, urticaria, inflammation, bruising, swelling, and itching at the injection site) may occur. These reactions are usually transient. Rapid improvement in glucose control may cause a reversible condition of acute painful neuropathy.
Rapid improvement in glycemic control due to intensified insulin therapy may be accompanied by temporary worsening of diabetic retinopathy, whereas long-term, well-established glycemic control reduces the risk of progression of diabetic retinopathy.
Based on clinical trials, the adverse reactions listed below are classified by frequency and by system organ classes according to MedDRA.
By frequency of occurrence, these reactions were categorized as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the 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 – skin amyloidosis*†.
General disorders and administration site reactions
Uncommon – injection site reactions.
Uncommon – edema.
* See section "Description of individual adverse reactions".
† Information on adverse reactions from post-marketing experience is provided in the section "Description of individual adverse reactions".
Description of individual adverse reactions
Anaphylactic reactions
Symptoms of generalized hypersensitivity (including generalized skin rash, itching, sweating, gastrointestinal disturbances, angioedema, dyspnea, tachycardia, decreased blood pressure, and dizziness/loss of consciousness) are very rare but potentially life-threatening.
Hypoglycemia
Hypoglycemia is the most common adverse effect. It may occur when the dose significantly exceeds the patient's insulin requirements. Severe hypoglycemia may lead to loss of consciousness and/or seizures, followed by temporary or permanent impairment of brain function, and even to fatal outcome. Symptoms of hypoglycemia usually appear suddenly. They 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.
In clinical trials, the frequency of hypoglycemia varied depending on the patient population, dosage regimens, and level of glycemic control.
Skin and subcutaneous tissue reactions
Lipodystrophy (including lipohypertrophy, lipoatrophy) and skin amyloidosis may develop at injection sites and delay insulin absorption from the injection site. Regular rotation of injection sites within a given area may reduce the occurrence or prevent the development of these reactions (see section "Special precautions").
Children
Based on post-marketing surveillance and clinical trial data, adverse reactions in children do not differ in frequency, type, or severity from those observed in the general population.
Other special patient groups
Based on post-marketing surveillance and clinical trial data, adverse reactions in elderly patients and patients with impaired renal or hepatic function do not differ in frequency, type, or severity from those observed in the general population.
Reporting of adverse reactions and lack of drug efficacy
Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk profile of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Information System for Pharmacovigilance at https://aisf.dec.gov.ua.
Shelf life. 2.5 years.
Storage conditions.
Store in the original packaging at 2°C – 8°C (in the refrigerator, not too close to the freezer element). Do not freeze.
To protect from light, store the pen with the cap on.
After first opening: use within 6 weeks. Do not store in the refrigerator. Store at a temperature not exceeding 30°C.
Keep out of the reach and sight of children.
Incompatibility.
Insulin suspensions must not be mixed with infusion solutions.
Packaging.
The medicinal product is contained in a 3 ml cartridge made of type 1 glass, sealed on one side with a bromobutyl rubber plunger and on the other side with a bromobutyl/polyisoprene rubber stopper.
The cartridge is placed in a multidose disposable pen injector made of plastic.
1 or 5 pen injectors per cardboard box.
Prescription category. Prescription only.
Manufacturers. A/T Novo Nordisk, Denmark.
Novo Nordisk A/S, Denmark.
Novo Nordisk Production SAS, France.
Manufacturers' locations and addresses of places of business.
Novo Allé, 2880, Bagsværd, Denmark.
Novo Allé, 2880 Bagsværd, Denmark.
45, avenue d’Orléans, 28000, Chartres, France.
45 avenue d’Orléans, 28000 Chartres, France.