Protafan® nm flexpen®

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

Composition:

Active substance: human insulin (rDNA);

1 ml of injectable suspension contains 100 IU of biosynthetic human insulin (recombinant DNA produced in Saccharomyces cerevisiae);

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

1 multidose disposable pen contains 3 ml of injectable suspension, equivalent to 300 IU.

Protaphane® NM FlexPen® is an isophane (NPH) insulin suspension.

Excipients: zinc chloride; glycerol; metacresol; phenol; sodium hydrogen phosphate, dihydrate; sodium hydroxide (for pH adjustment); hydrochloric acid, diluted (for pH adjustment); protamine sulfate; water for injections.

Pharmaceutical form. Injectable suspension.

Main physicochemical properties: a white suspension, which upon standing forms a white sediment and a colorless or almost colorless supernatant liquid; the sediment readily resuspends upon gentle agitation. When examined under a microscope, the particles appear as elongated crystals, most of which are 1–20 μm in length.

Pharmacotherapeutic group. Antidiabetic agents. Intermediate-acting insulin and analogues for injection, human insulin.

ATC code A10AC01.

Pharmacological properties.

Pharmacodynamics.

The 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.

Protafan® NM FlexPen® is an intermediate-acting insulin.

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

onset of action – within 1.5 hours;

maximum effect – from 4 to 12 hours;

duration of action – approximately 24 hours.

Pharmacokinetics.

The elimination half-life of insulin from the blood is several minutes; therefore, the insulin action profile is determined solely by the characteristics of its absorption. This process depends on a number of factors (e.g., insulin dose, injection method and site, subcutaneous tissue thickness, type of diabetes), resulting in considerable variability in insulin effect both within the same patient and among different patients.

Absorption. Peak plasma concentration occurs within 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 have been identified. None of the metabolites formed after hydrolysis possess biological activity.

Elimination. The duration of the terminal elimination half-life of insulin is determined by the rate of its absorption from the subcutaneous tissue. Therefore, the terminal 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.

Preclinical safety data.

Preclinical studies (repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity) revealed no specific hazard associated with administration of Protafan® NM FlexPen® to humans.

Clinical characteristics.

Indications

Treatment of diabetes mellitus.

Contraindications

Hypersensitivity to human insulin or to any excipient of the product. Hypoglycemia.

Interaction with other medicinal products and other forms of interactions

It is known that various medicinal products affect glucose metabolism.

Substances that may decrease the patient's insulin requirements:

oral hypoglycemic agents (OHAs), monoamine oxidase inhibitors (MAOIs), β-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulphonamides.

Substances that may increase the patient's insulin requirements:

• oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, and danazol;
• β-blockers may mask the symptoms of hypoglycemia;
• octreotide/lanreotide may either decrease or increase insulin requirements;
• alcohol may potentiate or weaken 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 documented.

Patients should consult their physician before travelling across time zones, as this may require adjustment of insulin injection and meal schedules.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment (especially 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 flushing and dryness, dry mouth, loss of appetite, as well as acetone breath.

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

Hypoglycaemia

Skipping meals or unexpected physical exertion may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high relative to insulin requirements. In case of hypoglycaemia or suspected hypoglycaemia, the product should not be administered. After stabilizing blood glucose levels, dose adjustment should be considered (see sections "Adverse reactions" and "Overdose").

Patients who have significantly improved glycaemic control due to intensive insulin therapy may experience changes in the usual warning symptoms of hypoglycaemia, which should be explained to them in advance. Typical warning symptoms may disappear in patients with long-standing diabetes.

Concomitant diseases, especially infections and fever, generally increase insulin requirements. Concomitant kidney, liver, or adrenal, pituitary, or thyroid gland disorders may necessitate insulin dose adjustments.

When switching a patient to another type of insulin, symptoms of hypoglycaemia 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 should be done under strict medical supervision. Changes in insulin concentration, type (manufacturer), species (animal insulin, human insulin, or human insulin analogue), and/or method of production (recombinant DNA technology or animal insulin) may require insulin dose adjustments. Patients switching to Protaphane® NM FlexPen® 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 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. Regular rotation of injection sites within a single area may reduce or prevent these reactions. Reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Protaphane® NM FlexPen®.

Skin and subcutaneous tissue disorders

Patients should be instructed on the necessity of regularly rotating injection sites 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 of injection sites from affected to unaffected areas. Monitoring of blood glucose levels and dose adjustment of antidiabetic medicinal products are recommended after changing injection sites from affected to unaffected areas.

Combination of Protaphane® NM FlexPen® with pioglitazone

Cases of congestive heart failure have been reported when pioglitazone is used in combination with insulin, particularly in patients with risk factors for congestive heart failure. This should be considered when prescribing combination therapy with pioglitazone and insulin. Patients receiving these drugs in combination should be monitored for signs and symptoms of congestive heart failure, weight gain, and development of oedema. If any deterioration in cardiac function occurs, treatment with pioglitazone 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 accidental confusion of Protaphane® NM FlexPen® with other insulin products.

Protaphane® 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 of diabetes during pregnancy.

Both hypoglycaemia and hyperglycaemia, which may occur with inadequate diabetes management, increase the risk of congenital malformations or fetal death. Therefore, intensified monitoring of blood glucose levels and medical supervision of pregnant women with diabetes is 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 typically return rapidly to pre-pregnancy levels.

Breastfeeding period

There are no restrictions on the use of Protaphane® NM FlexPen® during breastfeeding, as treatment of the mother does not pose any 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 hypoglycaemia. This may represent a risk factor in situations where these abilities are of particular importance (e.g., driving a car or operating machinery).

Patients should be advised to take precautions to prevent hypoglycaemia before driving. This is especially important for patients with impaired or absent hypoglycaemic warning symptoms or those who experience frequent episodes of hypoglycaemia. In such circumstances, the advisability of driving should be carefully considered.

Method of Administration and Dosage

Dosing

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

The insulin dosage is individual and determined by the physician according to the patient's needs. The physician decides whether one or several daily injections are required. Protaphane® NM FlexPen® may be used alone or in combination with short-acting insulin. In intensive insulin therapy, the suspension can be used as basal insulin (evening and/or morning injection) together with fast-acting insulin at meal times. For 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 increased physical activity, changes in diet, or during concomitant illness.

Special Populations

Elderly patients (≥ 65 years of age)

Protaphane® NM FlexPen® can be used in elderly patients.

For elderly patients, intensified glucose monitoring and individual insulin dose adjustment are recommended.

Renal and hepatic impairment

Renal and hepatic impairment may reduce insulin requirements. For patients with renal or hepatic impairment, intensified glucose monitoring and individual insulin dose adjustment are recommended.

Children

The product can be used in children.

Switching from other insulin products

Changing from previously used intermediate- or long-acting insulin products to treatment with Protaphane® NM FlexPen® requires individual dose adjustment and timing optimization.

Careful blood glucose monitoring is recommended during the transition to Protaphane® NM FlexPen® and during the first few weeks of its use (see section "Special Precautions").

Administration

Protaphane® NM FlexPen® is human insulin with gradual and prolonged action.

Protaphane® NM FlexPen® is administered subcutaneously by injection into the thigh, abdominal wall, buttocks, or deltoid region of the shoulder. To reduce the risk of lipodystrophy and cutaneous amyloidosis, injection sites should always be rotated, even within the same body area (see sections "Special Precautions" and "Adverse Reactions").

Insulin suspension must never be administered intravenously. Injecting into a lifted skin fold significantly reduces the risk of intramuscular injection.

After injection, the needle should remain under the skin for at least 6 seconds. This ensures delivery of the full dose. Absorption of insulin after subcutaneous injection into the thigh area is slower and less variable compared to other injection sites. Duration of action may vary depending on dose, injection site, blood flow, body temperature, and level of physical activity.

Insulin suspension must not be used in infusion pumps. The pre-filled pen device Protaphane® NM FlexPen® is intended for use with NovoFine® or NovoTwist® disposable needles up to 8 mm in length. The FlexPen® device allows administration of doses from 1 to 60 units in increments of 1 unit. Protaphane® NM FlexPen® is intended for subcutaneous injections only.

If insulin administration via syringe is required, the vial formulation of this medicinal product should be used.

Detailed instructions for use of these medical devices must be strictly followed.

Handling and Disposal Precautions

When first used after removal from the refrigerator, it is recommended that the Protaphane® NM FlexPen® be allowed to warm to room temperature before resuspending 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 (Protaphane® NM FlexPen®) are intended for individual use only.

Refilling the cartridge is prohibited.

Instructions for Use of Protaphane® NM FlexPen®

Before using the FlexPen®, carefully read these instructions.

Failure to follow these instructions carefully may result in administration of too little or too much insulin, which could lead to a sudden increase or decrease in blood glucose levels.

The FlexPen® is a pre-filled insulin pen with a dose selector. It allows setting doses from 1 to 60 units in 1-unit increments. The FlexPen® is used with disposable NovoFine® or NovoTwist® needles up to 8 mm in length. As a precaution, always keep a spare insulin delivery device available in case the FlexPen® is damaged or lost.

Care of the Pen Device

Handle the FlexPen® insulin pen with care. If it has been dropped, damaged, or deformed, insulin leakage may occur. This could result in incorrect dosing, leading to high or low blood sugar levels.

The surface of the FlexPen® may be cleaned by wiping with a cotton swab. Do not immerse, wash, or lubricate the pen, as this may damage it.

Do not refill the pen. If empty, it must be disposed of.

Preparing the FlexPen® for Injection

A. Check the product name and label color to ensure the pen contains the correct type of insulin.

This is especially important if you are using more than one type of insulin. Administering the wrong type of insulin may cause a sudden increase or decrease in your blood sugar level.

Each time you start using a new pen

Before use, insulin should be at room temperature. This facilitates resuspension.

Remove the cap from the pen (Fig. A).

C. Before the first injection with a new pen, the insulin must be resuspended

Turn the pen 20 times up and down between the two positions shown in Figure C, ensuring the glass ball moves from one end of the cartridge to the other. Repeat until the liquid appears uniformly white and cloudy.

Before each subsequent injection, repeat this procedure at least 10 times until the liquid appears uniformly white and cloudy.

Before each injection, ensure the insulin is properly resuspended. This may reduce the risk of sudden blood sugar fluctuations.

After resuspension, proceed immediately with the following steps for injection.

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 pen. The 12-unit mark is indicated on the insulin volume scale (see general pen view in figure above).

Attaching the Needle

C. Remove the protective seal from a new disposable needle.

Screw the needle securely onto the FlexPen®.

D. Remove the outer large needle cap. Do not discard it.

E. Remove the inner needle cap and discard it.

Never attempt to reattach a removed inner needle cap, as needle-stick injury may occur.

Always use a new needle for each injection. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and inaccurate dosing.

Be careful not to bend or damage the needle before use.

Checking Insulin Flow

F. Before each injection, small air bubbles may accumulate in the cartridge during normal use. To prevent injecting air and ensure proper dose delivery, perform the following steps.

Set the dose selector to 2 units.

G. Holding the FlexPen® vertically with the needle pointing upward, gently tap the cartridge several times with your finger to collect air bubbles in the upper part of the cartridge.

H. While holding the pen vertically with needle up, press the injection button fully. The dose selector will return to zero.

A drop of insulin should appear at the needle tip. If not, replace the needle and repeat this procedure up to 6 times.

If no drop appears after 6 attempts, the pen is likely defective and a new pen should be used.

Always confirm a drop appears at the needle tip before injection. This confirms insulin flows through the needle. If no drop appears, you may not deliver any insulin, even if the dose selector moves. This indicates the needle is blocked or damaged.

Always check insulin flow through the needle before injection. Failure to do so may result in under-dosing or no insulin delivery, potentially causing high blood sugar levels.

Setting the Dose

I. Ensure the dose selector is set to "0".

Turn the dose selector to set the required number of units for injection.

The dose can be adjusted up or down by turning the dose selector in the appropriate direction until the required dose aligns with the dose pointer. While turning, avoid accidentally pressing the injection button, as this may cause insulin leakage.

It is not possible to set a dose exceeding the amount remaining in the cartridge.

Always use the dose selector and dose pointer to verify the number of units selected before injection.

Do not count the clicks of the pen when selecting the insulin dose. Selecting or administering an incorrect dose may cause blood sugar levels to rise or fall. Do not use the insulin volume scale, as it only shows an approximate amount of insulin remaining in the pen.

Administering Insulin

J. Insert the needle under the skin. Follow the injection technique taught by your doctor or nurse.

Administer the dose by fully pressing the injection button until "0" aligns with the dose pointer. Be careful to press only the injection button during injection.

Turning the dose selector will not deliver insulin.

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 verify that the dose pointer returns to "0" after injection. If the pointer stops before returning to "0", the full dose was not delivered, which may affect blood sugar levels.

L. Cover the needle with the large outer cap without touching it. Once the needle is fully covered, carefully press the cap on and then unscrew the needle.

Safely dispose of the needle and replace the cap on the pen.

Always remove the needle after each injection and store the Protaphane® NM FlexPen® without an attached needle. This reduces the risk of contamination, infection, insulin leakage, needle blockage, and dosing inaccuracies.

Additional Important Information

Healthcare providers, family members, and others assisting the patient must be extremely careful with used needles to reduce the risk of accidental needle-stick injury and cross-infection.

Dispose of used pens without needles attached.

Never share your pen or needles with others. This may lead to cross-infection.

Never give your pen to other people. Your medication may be harmful to their health.

Store your pen and needles out of reach of others, especially children.

Children

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

Overdose

Although a specific definition of insulin overdose is not established, administration of doses excessively high relative to patient needs may lead to hypoglycemia, progressing through successive stages.

• Mild hypoglycemia can be treated by oral administration of glucose or sugary foods. Therefore, diabetic patients are advised to always carry several sugar-containing products.
• In cases of severe hypoglycemia with unconsciousness, trained individuals should immediately administer glucagon intramuscularly or subcutaneously (0.5–1.0 mg). A healthcare professional may administer intravenous glucose. Intravenous glucose should be given if the patient does not respond to glucagon within 10–15 minutes. After regaining consciousness, the patient should consume carbohydrate-containing food to prevent recurrence.

Adverse Reactions

The most common adverse effect of therapy is hypoglycaemia. The frequency of hypoglycaemia depends on the patient population, dosage regimen, and level of glycaemic control (see description of individual adverse reactions below).

At the beginning of insulin therapy, transient disturbances in refraction, oedema, and injection site reactions (pain, erythema, urticaria, inflammation, bruising, swelling, and pruritus at the injection site) may occur. Rapid improvement in blood glucose control may cause a reversible condition of acute painful neuropathy. Intensification of insulin therapy for rapid improvement in glycaemic control may transiently worsen diabetic retinopathy, whereas prolonged, 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 class 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 available data).

Immune system disorders

Urticaria, pruritus – uncommon.

Anaphylactic reactions* – very rare.

Metabolism and nutrition disorders

Hypoglycaemia* – very common.

Nervous system disorders

Peripheral neuropathies (painful neuropathies) – very rare.

Eye disorders

Refractory 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 individual adverse reactions".

† See section "Description of individual adverse reactions" for adverse reactions from post-marketing experience.

Description of individual adverse reactions

Anaphylactic reactions

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

Hypoglycaemia

Hypoglycaemia is the most common adverse effect. It may occur when the dose significantly exceeds the patient's insulin requirements. Severe hypoglycaemia may lead to loss of consciousness and/or seizures, resulting in temporary or permanent impairment of brain function, and even fatal outcomes. Symptoms of hypoglycaemia 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 hypoglycaemia varied depending on the patient population, dosage regimens, and level of glycaemic control.

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 an injection area may reduce the occurrence or prevent the development of these reactions (see section "Special precautions for use").

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 suspected adverse reactions and lack of drug efficacy

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua.

Shelf life

2.5 years.

Storage conditions

Store in the original packaging at 2°C–8°C (in a 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 reach and sight of children.

Incompatibilities

Insulin suspensions must not be mixed with infusion solutions.

Packaging

The medicinal product is placed 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 contained in a multidose disposable pen made of plastic.

1 or 5 pens per cardboard box.

Prescription status
Prescription only.

Manufacturers
Novo Nordisk A/S, Denmark.

Novo Nordisk Production SAS, France.

Manufacturers' addresses

Novo Allé, 2880 Bagsværd, Denmark.

45 avenue d’Orléans, 28000 Chartres, France.