Protopan nm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROTAHANE® NM (PROTAPHANE® NM)

Composition:

Active substance: human insulin (rDNA);

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

1 vial contains 10 ml, equivalent to 1000 IU;

1 IU (International Unit) equals 0.035 mg of anhydrous human insulin;

Excipients: zinc chloride; glycerol; m-cresol; phenol; sodium hydrogen phosphate dihydrate; sodium hydroxide; hydrochloric acid diluted; protamine sulfate; water for injections.

Pharmaceutical form. Suspension for injection.

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.

Pharmacotherapeutic group. Antidiabetic agents. Insulins and analogues for injection, intermediate-acting insulin (human). ATC code A10AC01.

Pharmacological Properties

Pharmacodynamics. The glucose-lowering effect of insulin results from promoting 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.

Protaphane® NM is a prolonged-action insulin.

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

onset of action – within 1.5 hours;

peak effect – between 4 and 12 hours after administration;

duration of action – approximately 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 adipose tissue, type of diabetes mellitus), resulting in considerable variability in insulin effect both within the same patient and among different patients.

Absorption. Peak insulin concentration in plasma occurs 2–18 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 are believed to exist. None of the metabolites formed after hydrolysis are biologically active.

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

Preclinical Safety Data

Preclinical safety studies (repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity) revealed no specific risks associated with the use of Protaphane® NM in humans.

Clinical characteristics.

Indications.

Treatment of diabetes mellitus.

Contraindications.

Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

It is known that various medicinal products affect glucose metabolism.

Medicinal products that may decrease insulin requirements

Oral hypoglycemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective β-adrenergic blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulfonamides.

Medicinal products that may increase insulin requirements

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

β-adrenergic blockers may mask the symptoms of hypoglycemia and slow 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.

Before traveling across time zones, patients should consult their physician, as this alters the schedule of insulin injections and meal times.

Hyperglycemia

Inadequate dosing or discontinuation of treatment (especially in type 1 diabetes) may lead to hyperglycemia and diabetic ketoacidosis. Typically, the first symptoms of hyperglycemia develop gradually over several hours or days. These include thirst, frequent urination, nausea, vomiting, drowsiness, skin flushing and dryness, dry mouth, loss of appetite, and acetone odor on the breath.

In type 1 diabetes, untreated hyperglycemia leads to diabetic ketoacidosis, which is potentially life-threatening.

Hypoglycemia

Hypoglycemia may occur if the insulin dose is too high relative to insulin requirements. Do not administer the medication if hypoglycemia is present or suspected.

Skipping meals or unexpected physical exertion may lead to hypoglycemia.

Patients who have significantly improved glycemic control due to intensive insulin therapy may experience changes in the usual warning signs of hypoglycemia and should be warned accordingly. Typical warning symptoms may diminish or disappear in patients with long-standing diabetes. Concomitant diseases, particularly infections and febrile conditions, generally increase insulin requirements. Renal, hepatic, or adrenal disorders, as well as disorders of the pituitary or thyroid gland, may necessitate adjustment of insulin dosage.

When a patient is switched to another type of insulin, symptoms of hypoglycemia 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 delay insulin absorption and impair glycemic control. Cases of hypoglycemia have been reported following sudden changes from injecting into affected areas to unaffected sites. Monitoring of blood glucose levels and adjustment of antidiabetic medication dosage are recommended after switching injection sites from affected to unaffected areas.

Avoidance of accidental administration errors

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

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), species (human or human insulin analog), and/or production method (recombinant DNA technology or animal-sourced insulin) may require insulin dose adjustments. Patients switching to Protaphane® NM from another insulin may require an increased number of daily injections or changes in dosage compared to their previous insulin regimen. Dose adjustments may be necessary both at initiation of the new insulin and during the first weeks or months of treatment.

Injection site reactions

With any insulin therapy, injection site reactions may occur, including pain, redness, itching, urticaria, swelling, bruising, and inflammation. Rotating injection sites within an area may reduce or prevent these reactions. Such reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Protaphane® NM.

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

Combination of Protaphane® 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 edema. If cardiac function worsens, treatment with pioglitazone should be discontinued.

Special populations

Elderly patients (≥65 years)

Protaphane® NM can be used in elderly patients.

Increased glucose monitoring and individualized insulin dose adjustments are recommended in elderly patients.

Renal and hepatic impairment

Renal and hepatic impairment may reduce insulin requirements. Increased glucose monitoring and individualized insulin dose adjustments are recommended in patients with renal or hepatic impairment.

Children

The medication can be used in children and adolescents.

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

Use during pregnancy or breastfeeding

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 monitoring of blood glucose levels and close supervision of treatment are recommended throughout pregnancy and whenever pregnancy is suspected in women with diabetes.

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 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 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, which may pose a risk in situations where such abilities are critical (e.g., driving a vehicle or operating machinery).

Patients should be advised to take preventive measures against hypoglycemia before driving. This is particularly important for patients with diminished or absent hypoglycemia warning symptoms or those experiencing frequent hypoglycemic episodes. In such cases, the appropriateness of driving should be carefully evaluated.

Administration and Dosage

Protafan® NM is a prolonged-acting insulin preparation and may be used either alone or in combination with short-acting insulin. In intensified insulin therapy, the suspension can be used as basal insulin (injections in the evening and/or morning) supplemented with short-acting insulin at meal times.

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

Dosing

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

The individual daily insulin requirement usually 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.

Dose Adjustment

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

Dose adjustments may also be required when patients change their level of physical activity or usual diet. Dose titration may also be necessary when patients are switched to different insulin preparations.

Administration

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

Protafan® NM is usually injected subcutaneously into the thigh. It may also be administered in the abdominal wall, buttocks, or deltoid region of the upper arm. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated, even within the same body area.

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

Subcutaneous injections in the thigh result in slower insulin absorption compared to injections in other body sites.

The duration of action depends on the dose, injection site, temperature of the insulin preparation, and the patient's level of physical activity.

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

To reduce the risk of lipodystrophy, injection sites should always be rotated, even within the same body area.

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

Do not use Protafan® NM if the protective plastic cap is loose or missing. (Each vial has a tamper-evident plastic cap; if the cap is loose or missing upon receipt, the vial should be returned to the pharmacy.)

Immediately before use, roll the vial of Protafan® NM between the palms until the liquid appears uniformly white and cloudy. Mixing is more effective when the insulin has reached room temperature.

Before use, remove the protective plastic cap from the vial of Protafan® NM.

Draw into the syringe an amount of air equal to the required insulin dose and inject it into the vial.

Handling and Disposal Precautions

Upon first use, after removing Protafan® NM from the refrigerator, it is recommended to warm the vial to room temperature before mixing.

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 Protafan® NM are intended for individual use only.

Children. Biosynthetic human insulin preparations are effective and safe medicinal products for the treatment of diabetes mellitus in children and adolescents of various age groups. Daily insulin requirements in children and adolescents depend on the stage of the disease, body weight, age, diet, physical activity, degree of insulin resistance, and glycemic dynamics.

Overdose.

Although a specific definition of insulin overdose is not established, hypoglycemia may develop in successive stages if doses exceeding the patient's requirements are administered.

• Mild hypoglycemia can be treated by oral intake of glucose or sugary products. Therefore, diabetic patients are advised to always carry several sugar-containing products.
• 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 intravenous glucose. Intravenous glucose should also 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 hypoglycaemia. According to clinical trial data and post-marketing surveillance, 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, redness, urticaria, inflammation, bruising, swelling, and itching 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.

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 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 frequency not known (cannot be estimated based on available data).

Immune system disorders.

Urticaria, rash – uncommon.

Anaphylactic reactions* – very rare.

Metabolism and nutrition disorders.

Hypoglycaemia* – very common.

Nervous system disorders.

Peripheral neuropathies (painful neuropathies) – uncommon.

Eye disorders.

Refractive disturbances – very rare.

Diabetic retinopathy – uncommon.

Skin and subcutaneous tissue disorders.

Lipodystrophy* – uncommon.

Cutaneous amyloidosis*† – frequency not known.

General disorders and administration site conditions.

Injection site reactions – uncommon.

Oedema – uncommon.

* see section "Description of selected adverse reactions".

† post-marketing adverse reactions are described in the section "Description of selected adverse reactions".

Description of selected adverse reactions

Anaphylactic reactions

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

Hypoglycaemia

The most common adverse effect is hypoglycaemia. 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 even death. Symptoms of hypoglycaemia usually appear suddenly. They may include cold sweat, pallor, cold skin, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, visual changes, headache, nausea, and tachycardia.

Skin and subcutaneous tissue disorders

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous 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.

Reporting suspected adverse reactions

After marketing authorization, it is important to report suspected adverse reactions. 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. 2.5 years (30 months).

Storage conditions.

Unopened vials of Protaphane® NM should be stored in a refrigerator at 2–8°C (not too close to the freezer compartment). Do not freeze.

Store in the original packaging, protected from light and out of reach of children. Avoid exposure to heat and 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.

In-use vials of Protaphane® NM should not be stored in the refrigerator. They may be stored at temperatures up to 25°C for up to 6 weeks after first opening, or up to 4 weeks at temperatures up to 30°C.

Insulin that has been frozen must not be used.

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

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

Incompatibility. Insulin suspensions must not be mixed with infusion solutions.

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

Prescription status. 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.