Mixtard® 30 nm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİXSTARD® 30 NM (MIXTARD® 30 NM)

Composition:

Active substance: human insulin (rDNA);

1 ml of injectable suspension contains 100 IU (3.5 mg) of biosynthetic human insulin, 30% soluble insulin, 70% isophane insulin crystals, produced by rDNA technology in Saccharomyces cerevisiae;

1 vial contains 10 ml, equivalent to 1000 IU;

1 IU (international unit) corresponds to 0.035 mg of anhydrous human insulin;

Excipients: zinc chloride; glycerol; metacresol; phenol; sodium dihydrogen phosphate dihydrate; sodium hydroxide; hydrochloric acid, diluted; protamine sulfate; water for injections.

Pharmaceutical form. Suspension for injection.

Main physicochemical properties: neutral, cloudy, white aqueous suspension of human insulin.

Pharmacotherapeutic group. Antidiabetic agents. Insulins and analogues for injection, intermediate- and long-acting in combination with short-acting insulin (human). 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 inhibition of glucose release from the liver.

Mixtard® 30 NM is an intermediate-acting insulin with a dual action profile.

On average, the action profile after subcutaneous injection is as follows:

onset of action – within 0.5 hours;

maximum effect – occurs 2–8 hours after administration;

duration of action – up to 24 hours.

Pharmacokinetics.

The half-life of insulin in blood is only several minutes; therefore, the insulin action profile is determined exclusively by the characteristics of its absorption.

This process depends on a number of factors (e.g., insulin dose, injection method and site, thickness of subcutaneous fat tissue, type of diabetes mellitus), 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 insulins characterized by rapid and prolonged absorption. The peak plasma concentration of short-acting insulin occurs 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 proteindisulfide isomerase. It is believed that several cleavage (hydrolysis) sites exist on the human insulin molecule. None of the metabolites formed after hydrolysis are active.

Elimination. The half-life of insulin is determined by the rate of its absorption from the subcutaneous tissue. Therefore, the elimination half-life (t½) reflects the absorption rate rather than the actual elimination of insulin from plasma (the t½ of insulin in the bloodstream is only several minutes). According to available study data, t½ is 5–10 hours.

Preclinical safety data.

Preclinical studies on pharmacological safety (repeated-dose toxicity, genotoxicity, carcinogenicity, toxic effects on reproductive function and fetal development) revealed no safety concerns regarding the use of Mixtard® 30 NM in humans.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus.

Contraindications.

Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients (see section "Composition").

Interaction with other medicinal products and other forms of interaction.

It is known that certain medicinal products affect glucose metabolism.

Medicinal products that may decrease insulin requirements

Oral hypoglycemic agents, monoamine oxidase inhibitors, non-selective β-blockers, angiotensin-converting enzyme inhibitors, salicylates, anabolic steroids, and sulphonamides.

Medicinal products that may increase insulin requirements

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, and danazol.

β-blockers may mask the symptoms of hypoglycemia and delay recovery from hypoglycemia.

Octreotide/lanreotide may either decrease or increase insulin requirements.

Alcohol may potentiate or weaken the blood glucose-lowering effect of insulin.

Special precautions for use.

Tracking.

The name and batch number of the medicinal product used should be clearly documented to improve traceability of the biological medicinal product.

Patients should consult their physician before travelling across time zones, as this may alter the schedule for insulin injections and meals.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment (particularly in type 1 diabetes) may lead to hyperglycaemia and diabetic ketoacidosis. The first symptoms of hyperglycaemia usually develop gradually over several hours or days. They include thirst, frequent urination, nausea, vomiting, drowsiness, skin redness and dryness, dry mouth, loss of appetite, and acetone breath.

In type 1 diabetes, untreated hyperglycaemia leads to diabetic ketoacidosis, which may be potentially life-threatening.

Hypoglycaemia

Hypoglycaemia may occur if the insulin dose is too high relative to insulin requirements. Do not administer the product in case of hypoglycaemia or suspected hypoglycaemia.

Skipping meals or unexpected physical exertion may lead to hypoglycaemia.

Patients who have significantly improved glycaemic control due to intensive insulin therapy should be warned in advance that their usual warning symptoms of hypoglycaemia may change. Typical warning symptoms may diminish or disappear in patients with long-standing diabetes.

Concomitant illnesses, particularly infections and febrile conditions, generally increase insulin requirements. Concomitant kidney, liver, or adrenal gland disorders, as well as disorders of the pituitary or thyroid gland, may necessitate insulin dose adjustments.

When patients are switched to another type of insulin, symptoms of hypoglycaemia may change or become less pronounced compared to those experienced with the previous insulin.

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 result in delayed insulin absorption and impaired glycaemic control. Cases of hypoglycaemia have been reported after sudden switching from affected to unaffected injection sites. Monitoring of blood glucose levels and dose adjustment of antidiabetic medicinal products are recommended after changing injection sites from affected to unaffected areas.

Avoiding accidental administration errors

Patients must be instructed and should always check the label on the insulin packaging before each injection to avoid accidentally confusing Mixtard® 30 NM with other insulin products.

Switching from other insulins

Switching a patient to another type or brand of insulin should be done under strict medical supervision. Changes in concentration, type (manufacturer), kind, source (human insulin or human insulin analogue), and/or method of production (rDNA technology or animal-sourced insulin) may necessitate insulin dose adjustments. Patients switched to Mixtard® 30 NM from another insulin type may require an increased number of daily injections or changes in dosage compared to their previous insulin regimen. Dose adjustments may be needed both at the initiation of the new product and during the first several weeks or months of treatment.

Injection site reactions

Reactions at the injection site may occur with any insulin therapy, including pain, redness, itching, urticaria, swelling, bruising, and inflammation. Regular rotation of injection sites within an area may reduce or prevent these reactions. Reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Mixtard® 30 NM.

Insulin suspensions should not be used in insulin pumps for continuous subcutaneous insulin infusion.

Combination of Mixtard® 30 NM 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 oedema. If cardiac function worsens, treatment with pioglitazone should be discontinued.

Special populations

Elderly patients (≥65 years of age)

Mixtard® 30 NM can be used in elderly patients.

Enhanced monitoring of blood glucose levels and individual insulin dose adjustments are recommended in elderly patients.

Renal and hepatic impairment

Renal and hepatic impairment may reduce insulin requirements. Enhanced monitoring of blood glucose and individual insulin dose adjustments are recommended in patients with renal or hepatic impairment.

Mixtard® 30 NM contains less than 1 mmol sodium (23 mg) per dose and can therefore be considered essentially sodium-free.

Use during pregnancy or breastfeeding

As insulin does not cross the placental barrier, there are no restrictions on insulin treatment for diabetes during pregnancy.

Both hypoglycaemia and hyperglycaemia resulting from inadequate diabetes management may increase the risk of congenital malformations or fetal death. Therefore, intensified monitoring of blood glucose levels and close supervision of diabetic pregnant women are recommended throughout pregnancy and whenever pregnancy is suspected.

Insulin requirements usually decrease during the first trimester of pregnancy and increase significantly during the second and third trimesters.

After delivery, insulin requirements rapidly return to pre-pregnancy levels.

There are no restrictions on insulin treatment for diabetes during breastfeeding, as maternal insulin therapy poses no risk to the infant. However, dose adjustments and/or dietary modifications for the mother may be necessary.

Fertility

Reproductive toxicity studies in animals using human insulin have not shown any 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 hypoglycaemia, which may pose a risk in situations where such abilities are critical (e.g., driving a car or operating machinery).

Patients should be advised to take preventive measures against hypoglycaemia before driving. This is particularly important for patients with diminished or absent hypoglycaemic warning symptoms or those who experience frequent episodes of hypoglycaemia. In such cases, the appropriateness of driving should be carefully considered.

Method of Administration and Dosage

Mixtard® 30 NM is a biphasic human insulin. It contains both short-acting insulin and long-acting insulin. Biphasic insulin preparations are usually administered 1 or 2 times daily when a rapid initial effect followed by a prolonged effect is required.

Dosage

The potency of human insulin is expressed in International Units (IU).

Insulin dosage is individual and must be determined by a physician according to the patient's needs.

Individual insulin requirement generally ranges from 0.3 to 1.0 IU/kg/day. Daily insulin requirements may increase in patients with insulin resistance (e.g., during puberty or in obesity) and decrease in patients with residual endogenous insulin production.

The injection should be administered 30 minutes before a main or supplemental meal containing carbohydrates.

Dosage Adjustment

Concomitant diseases, especially infections and febrile conditions, generally increase the patient's insulin requirements. Diseases of the kidneys, liver, or disorders of the adrenal glands, pituitary, or thyroid gland may necessitate insulin dosage adjustments.

Dosage adjustments may also be required when patients increase their physical activity, change their usual diet, or develop concomitant illness. Dose titration may also be necessary when switching patients to other insulin preparations.

Administration

Mixtard® 30 NM is intended for subcutaneous injection only. Insulin suspension must never be administered intravenously.

Mixtard® 30 NM is usually administered by subcutaneous injection into the thigh, the abdominal wall, the buttocks, or the deltoid region of the upper arm. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated within the same region.

Injection into a skin fold significantly reduces the risk of intramuscular injection.

Subcutaneous injections into the abdominal wall result in faster insulin absorption compared to injections into other body areas.

The duration of action depends on the dose, injection site, temperature, and level of physical activity.

After injection, the needle should remain under the skin for at least 6 seconds to ensure full dose delivery.

Mixtard® 30 NM in vials should be administered using special insulin syringes with appropriate calibration.

Patients are advised to dispose of the needle and syringe after each injection.

Precautions for Handling and Disposal

When first used, after Mixtard® 30 NM has been removed from the refrigerator, it is recommended to warm the vial 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 and syringe after each injection.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Needles and syringes containing Mixtard® 30 NM are intended for individual use only.

Children

Mixtard® 30 NM may be used in children and adolescents.

Overdose

Although there is no specific definition of overdose for insulin, hypoglycemia may develop in sequential stages following administration of doses higher than the patient's requirements.

• Mild hypoglycemia can be treated by oral intake of glucose or sweet foods. Therefore, diabetic patients are advised to always carry several sources of sugar with them.
• In cases of severe hypoglycemia when the patient is unconscious, individuals who have received appropriate training should administer glucagon subcutaneously or intramuscularly (0.5 to 1.0 mg). A healthcare professional may administer glucose intravenously. Glucose should also be administered intravenously 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 hypoglycaemia. According to clinical trial data and post-marketing experience, the frequency of hypoglycaemia varies among different patient groups, dosage regimens, and levels of glycaemic control (see information below).

At the beginning of insulin therapy, refractive disturbances, oedema, and injection site reactions (pain, erythema, urticaria, inflammation, bruising, swelling, and pruritus at the injection site) may occur. These reactions are usually transient. Rapid improvement in blood glucose control may cause a generally reversible condition of acute painful neuropathy.

A rapid improvement in glycaemic control due to intensification of insulin therapy may be accompanied by a temporary worsening of diabetic retinopathy, whereas long-term, well-established glycaemic control reduces the risk of progression of diabetic retinopathy.

Based on clinical trial data, the following adverse reactions are listed below, classified by frequency and by system organ classes according to MedDRA.

The reactions are categorized by frequency as follows: 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), very rare (<1/10,000), and frequency not known (cannot be estimated based on available data).

Immune system disorders.

Uncommon – urticaria, rash.

Very rare – anaphylactic reactions*.

Metabolism and nutrition disorders.

Very common – hypoglycaemia*.

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 – oedema.

* See information below.

† Information on adverse reactions from post-marketing experience is provided in the section "Description of selected adverse reactions".

Description of selected adverse reactions.

Anaphylactic reactions.

Symptoms of generalized hypersensitivity (including generalized skin rash, pruritus, sweating, gastrointestinal disorders, angioedema, dyspnoea, tachycardia, hypotension, dizziness/loss of consciousness) are very rare but potentially life-threatening.

Hypoglycaemia.

Hypoglycaemia is the most common adverse effect. It may occur when the insulin dose significantly exceeds the patient's insulin requirements. Severe hypoglycaemia can lead to loss of consciousness and/or seizures, resulting in temporary or permanent impairment of brain function, and may even be fatal. Symptoms of hypoglycaemia usually appear suddenly and may include cold sweat, pallor, cold and clammy skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty in concentrating, drowsiness, excessive hunger, visual disturbances, headache, nausea, and palpitations.

Skin and subcutaneous tissue disorders.

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may develop at injection sites and may 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.

Children

Based on post-marketing surveillance and clinical trial data, the frequency, type, and severity of adverse reactions in children do not differ from those observed in the general population.

Other special patient groups

Based on post-marketing surveillance and clinical trial data, the frequency, type, and severity of adverse reactions in elderly patients and in patients with impaired renal or hepatic function do not differ from those observed in the general population.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions to the local pharmacovigilance authorities.

Shelf life. 30 months.

Storage conditions.

Unused vials of Mixtard® 30 NM should be stored in a refrigerator at 2–8 °C (not near the freezer compartment). Do not freeze.

Store in the original packaging and in a place inaccessible to children.

Avoid exposure to heat or direct sunlight.

Each vial has a protective, colour-coded plastic cap. If the protective plastic cap does not fit tightly on the vial or is missing, the vial should be returned to the pharmacy.

Used vials of Mixtard® 30 NM should not be stored in the refrigerator. They may be stored at room temperature (not above 25 °C) for up to 6 weeks after first opening, or for up to 5 weeks at a temperature not exceeding 30 °C.

Insulin preparations that have been frozen must not be used.

Do not use insulin after the expiry date stated on the packaging.

Do not use Mixtard® 30 NM if, after mixing the contents of the vial, the liquid does not become white and uniformly cloudy.

Incompatibilities.

Insulin suspensions must not be mixed with infusion solutions.

Packaging. 10 ml in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer. A/T Novo Nordisk.

Novo Nordisk Production SAS.

Manufacturer's address.

Novo Allé, Bagsværd, 2880, Denmark.

45, avenue d'Orléans, 28000, Chartres, France.