Instructions Protaphan NM suspension for injection 100 IU/ml bottle 10 ml No. 1
Composition
active ingredient: human insulin (rDNA);
1 ml of suspension for injection 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, which is equivalent to 1000 IU;
1 IU (International Unit) is equal to 0.035 mg of anhydrous human insulin;
Excipients: zinc chloride; glycerin; metacresol; phenol; sodium hydrogen phosphate, dihydrate; sodium hydroxide; diluted hydrochloric acid; protamine sulfate; water for injections.
Dosage form
Suspension for injection.
Main physicochemical properties: white suspension, in which a white precipitate forms upon settling and a colorless or almost colorless liquid above the precipitate; the precipitate is easily resuspended by gentle shaking.
Pharmacotherapeutic group
Antidiabetic drugs. Insulin and analogues for injection, intermediate-acting insulin (human). ATC code A10A C01.
Pharmacological properties
Pharmacodynamics. The blood sugar-lowering effect of insulin consists in promoting the absorption of glucose by tissues after binding of insulin to receptors of muscle and fat cells, as well as in the simultaneous inhibition of glucose release from the liver.
Protaphane® NM is a long-acting insulin.
On average, the action profile after subcutaneous injection is as follows:
onset of action – within 1.5 hours;
the maximum effect lasts from 4 to 12 hours after administration;
The duration of action is approximately 24 hours.
Pharmacokinetics.
The half-life of insulin from the blood is several minutes, so the action profile of an insulin drug is determined solely by its absorption characteristics.
This process depends on a number of factors (for example, the dose of insulin, the method and site of injection, the thickness of subcutaneous fat, the type of diabetes mellitus), which causes significant variability in the effect of an insulin drug both in the same and in different patients.
Absorption: Peak plasma insulin concentrations occur within 2–18 hours after subcutaneous injection.
Distribution: No significant binding of insulin to plasma proteins has been observed, except for circulating antibodies to it (if present).
Metabolism: Human insulin is cleaved by insulin proteases or insulin-degrading enzymes and possibly by protein disulfide isomerase. It is believed that there are a number of sites at which cleavage (hydrolysis) of the human insulin molecule occurs. None of the metabolites formed after hydrolysis are active.
Elimination. The terminal half-life of insulin is determined by the rate of absorption from the subcutaneous tissue. Therefore, the terminal half-life (t½) indicates the rate of absorption, not the elimination (as such) of insulin from the blood plasma (the t½ of insulin from the bloodstream is only a few minutes). Studies have shown that t½ is 5–10 hours.
Preclinical safety data
Preclinical safety pharmacology studies (repeated dose toxicity, genotoxicity, carcinogenicity, toxicity to reproduction and fetal development) also did not reveal any hazard of administering Protaphane® NM to humans.
Indication
Diabetes treatment.
Contraindication
Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients.
Interaction with other medicinal products and other types of interactions
As is known, a number of medications affect glucose metabolism.
Medicines that may reduce insulin requirements
Oral hypoglycemic agents (OHAs), monoamine oxidase inhibitors (MAOIs), non-selective beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulfonamides.
Medicines that may increase insulin requirements
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blockers may mask the symptoms of hypoglycemia and slow recovery from hypoglycemia.
Octreotide/lanreotide may either decrease or increase insulin requirements.
Alcohol can enhance or weaken the blood sugar-lowering effect of insulin.
Application features
Before traveling with a change in time zones, patients should consult a doctor, as this changes the schedule of insulin injections and meals.
Hyperglycemia
Inadequate dosage or discontinuation of treatment (especially in type 1 diabetes) may lead to hyperglycemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycemia develop gradually, over several hours or days. They include thirst, frequent urination, nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, loss of appetite, and the smell of acetone on the exhaled air.
In type 1 diabetes, untreated hyperglycemia leads to diabetic ketoacidosis, which is potentially fatal.
Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement. Do not administer if hypoglycemia occurs or is suspected.
Skipping a meal or unexpectedly exercising can lead to hypoglycemia.
Patients who have significantly improved blood glucose control with intensive insulin therapy may experience changes in the usual warning symptoms of hypoglycemia, and should be warned about this in advance. The usual warning symptoms may disappear in patients with long-standing diabetes. Concomitant diseases, especially infections and fever, usually increase insulin requirements. Concomitant diseases of the kidneys, liver, or damage to the adrenal, pituitary, or thyroid glands may require a change in insulin dosage.
When a patient is transferred to another type of insulin, the symptoms of hypoglycemia may change or become less severe compared to those experienced by the patient on the previous insulin.
Skin and subcutaneous tissue disorders
Patients should be instructed to rotate injection sites to reduce the risk of lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsening glycemic control when injected into sites with these reactions. Hypoglycemia has been reported after abrupt change of injection site to an unaffected site. Blood glucose monitoring and dose adjustment of antidiabetic medications are recommended after changing injection sites from an affected to an unaffected site.
Avoiding accidental input errors.
Patients should be instructed and always check the label on the insulin package before each injection to avoid accidentally confusing Protaphane® NM with other insulin preparations.
Transfer from other insulins
Transferring a patient to another type or type of insulin should be done under strict medical supervision. Changing the concentration, type (manufacturer), type, origin of insulin (human or human insulin analogue) and/or method of production (rDNA technology or animal insulin) may require a dose adjustment. Patients transferred to Protaphane® NM from another type of insulin may require an increase in the number of daily injections or a change in dosage compared to the insulin they were usually taking. The need for dose adjustment may arise both when a new drug is first introduced and during the first few weeks or months of its use.
Injection site reactions
Injection site reactions, including pain, redness, itching, hives, swelling, bruising and inflammation, may occur with any insulin therapy. Changing the injection site within the same area may reduce or prevent these reactions. The reactions usually resolve within a few days or weeks. Rarely, injection site reactions may require discontinuation of Protaphane® NM treatment.
Insulin suspensions should not be used in insulin pumps for long-term subcutaneous insulin administration.
Combination of Protaphane® NM with pioglitazone
Cases of congestive heart failure have been reported with pioglitazone in combination with insulin, especially in patients with associated risk factors. This should be considered when prescribing pioglitazone in combination with insulin. Patients should be monitored for symptoms of congestive heart failure, weight gain and oedema when these drugs are used in combination. In the event of any deterioration in cardiac function, pioglitazone treatment should be discontinued.
Special populations
Elderly patients (≥65 years).
The drug Protaphan® NM can be used in elderly patients.
In elderly patients, glucose monitoring should be intensified and the insulin dose should be adjusted individually.
Renal and hepatic failure
Renal and hepatic impairment may reduce insulin requirements. In patients with renal and hepatic impairment, glucose monitoring should be intensified and the insulin dose adjusted individually.
Children
The drug can be used in children and adolescents.
Protaphane® HM contains less than 1 mmol sodium (23 mg), therefore the medicinal product can be considered as sodium-free.
Use during pregnancy or breastfeeding
Since insulin does not cross the placental barrier, there are no restrictions on treating diabetes with insulin during pregnancy.
Both hypoglycemia and hyperglycemia, which can occur with inadequate treatment of diabetes mellitus, increase the risk of congenital malformations or fetal death. Therefore, increased blood glucose control and monitoring of treatment of pregnant women with diabetes mellitus are recommended throughout pregnancy and when pregnancy is suspected.
Insulin requirements usually decrease in the first trimester of pregnancy and increase significantly in the second and third trimesters.
There are also no restrictions on the treatment of diabetes with insulin during breastfeeding, as the treatment of the mother does not pose any risk to the child. However, it may be necessary to adjust the dose and/or diet for the mother.
Fertility
Animal reproductive toxicity studies with human insulin
did not reveal any negative effect on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
The patient's reaction and ability to concentrate may be impaired during hypoglycemia, which may become a risk factor in situations where this ability is of particular importance (for example, when driving a car or working with other mechanisms).
Patients should be advised to take precautions to prevent hypoglycemia before driving. This is especially important for patients who have reduced or absent symptoms of hypoglycemia or who have frequent episodes of hypoglycemia. In such circumstances, the question of whether driving is appropriate should be considered.
Method of administration and doses
Protaphane® NM is a long-acting insulin preparation, so it can be used 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) with the addition of short-acting insulin during meals.
The potency of human insulin is expressed in international units (IU).
Dosage
The dosage of insulin is individual and is determined by the doctor according to the patient's needs.
The individual daily insulin requirement is usually 0.3 to 1.0 IU/kg/day. The daily insulin requirement may increase in patients with insulin resistance (e.g. during puberty or obesity) and decrease in patients with residual endogenous insulin production.
Dose adjustment
Concomitant diseases, especially infections and fever, usually increase the patient's insulin requirements. Concomitant diseases of the kidneys, liver, or damage to the adrenal, pituitary, or thyroid glands require changes in insulin dosage.
Dose adjustment may also be necessary when patients change their physical activity or their usual diet. Dose adjustment may also be necessary when transferring patients to other insulin preparations.
Introduction
Protaphane® NM is intended for subcutaneous injection only. Insulin suspension is never administered intravenously.
Protaphane® NM is usually injected under the skin of the thigh. It can also be injected into the anterior abdominal wall, buttocks or deltoid muscle of the shoulder. To reduce the risk of lipodystrophy and skin amyloidosis, injection sites should always be changed, even within the same area of the body.
Injecting into a retracted skin fold significantly reduces the risk of getting into the muscle.
With subcutaneous injections into the thigh, insulin absorption occurs more slowly than when injected into other areas of the body.
The duration of action depends on the dose, site of administration, temperature of the drug, and the patient's level of physical activity.
After injection, the needle should remain under the skin for at least 6 seconds. This will ensure that the full dose is administered.
To reduce the risk of lipodystrophy, the injection site should always be changed, even within the same area of the body.
Protaphane® NM in vials should be administered with special insulin syringes that have the appropriate graduation.
Do not use Protaphane® NM if the protective plastic cap is loose or missing (each bottle has a protective plastic cap to indicate opening; if the cap is loose or missing upon receipt, the bottle should be returned to the pharmacy);
Immediately before use, roll the vial of Protaphane® HM between your palms until the liquid becomes white and uniformly cloudy. Mixing is best done when the insulin is warmed to room temperature.
Before using Protafan® NM, remove the protective plastic cap.
Draw into the syringe a volume of air equal to the dose of insulin you need and inject it into the vial.
Precautions for handling and disposal.
When first used, after Protaphane® NM has been removed from the refrigerator, it is recommended to warm the vial to room temperature before mixing.
Do not use the medicine if you notice that the suspension does not look uniformly white and cloudy after mixing.
Do not use after freezing.
The patient should be advised to dispose of the needle and syringe after each injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Needles and syringes with the drug Protafan® NM are intended for individual use only.
Children. Biosynthetic human insulin preparations are effective and safe drugs in the treatment of diabetes mellitus in different age groups of children and adolescents. The daily insulin requirement in children and adolescents depends on the stage of the disease, body weight, age, diet, physical activity, degree of insulin resistance and dynamics of glycemia levels.
Overdose
Although there is no specific concept of overdose for insulin, hypoglycemia may develop in successive stages after its administration if doses that are too high compared to the patient's needs are used.
Mild hypoglycemia can be treated with oral glucose or sugary foods. Therefore, diabetics are advised to carry several sugar-containing foods with them at all times.
In severe hypoglycemia, when the patient is unconscious, glucagon should be administered subcutaneously or intramuscularly (0.5 to 1.0 mg) by trained personnel. Glucose may be administered intravenously by a healthcare professional. Glucose should also be administered intravenously if the patient does not respond to glucagon within 10 to 15 minutes.
After the patient regains consciousness, he should consume foods containing carbohydrates to prevent relapse.
Side effects
The most common adverse reaction is hypoglycemia. Based on clinical trial data and post-marketing experience, the incidence of hypoglycemia varies across patient populations, dosing regimens, and levels of glycemic control (see below).
At the beginning of insulin therapy, refractive errors, 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 blood glucose control may cause a usually reversible acute painful neuropathy.
A sharp improvement in glycemic control due to intensification of insulin therapy may be accompanied by a temporary exacerbation of diabetic retinopathy, while long-term well-established glycemic control reduces the risk of progression of diabetic retinopathy.
Based on clinical trial data, adverse reactions are listed below, classified by frequency and MedDRA system organ class.
According to the frequency of occurrence, these reactions were divided into those that occur very often (≥1/10), often (≥1/100 to <1/10), infrequently (>1/1000 to <1/100), rarely (>1/10000 to <1/1000), very rarely (<1/10000), with an unknown frequency (cannot be estimated from the available data).
Immune system disorders.
Hives, rash – uncommon.
Anaphylactic reactions* are very rare.
Metabolic and nutritional disorders.
Hypoglycemia* – very common.
Nervous system disorders.
Peripheral neuropathies (painful neuropathies) are uncommon.
Visual impairment.
Refractive errors are very rare.
Diabetic retinopathy is uncommon.
Skin and subcutaneous tissue disorders.
Lipodystrophy* – uncommon.
Cutaneous amyloidosis*† - frequency unknown.
Generalized disorders and injection site reactions.
Injection site reactions are uncommon.
Swelling is uncommon.
* see section “Description of selected adverse reactions”.
† For adverse reactions from post-marketing experience, see section “Description of selected adverse reactions”.
Description of selected adverse reactions
Anaphylactic reactions
Symptoms of generalised hypersensitivity (including generalised skin rash, itching, sweating, gastrointestinal upset, angioedema, difficulty breathing, rapid heart rate, drop in blood pressure and dizziness/loss of consciousness) are very rare but can be potentially life-threatening.
Hypoglycemia
The most common side effect is hypoglycemia. This can occur when the dose is significantly higher than the patient's insulin needs. Severe hypoglycemia can lead to loss of consciousness and/or seizures, followed by temporary or permanent brain damage and even death. Symptoms of hypoglycemia usually come on suddenly. They may include cold sweat, paleness, cool skin, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, vision changes, headache, nausea and rapid heartbeat.
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. Continuous rotation of injection sites within a given area may reduce or prevent the development of this reaction.
Reporting of suspected adverse reactions
Once a medicinal product has been authorised, it is important to report suspected adverse reactions. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Physicians are encouraged to report suspected adverse reactions to their local pharmacovigilance authorities.
Expiration date
2.5 years (30 months).
Storage conditions
Unused vials of Protaphane® NM should be stored in a refrigerator at 2–8°C (not too close to the freezer). Do not freeze.
Store in the original packaging, protected from light and out of reach of children. Keep away from heat and direct sunlight.
Vials of Protaphane® NM in use should not be refrigerated. They can be stored at temperatures up to 25°C for 6 weeks after first opening or for 4 weeks at temperatures up to 30°C.
Insulin preparations that have been frozen cannot be used.
Insulin should not be used after the expiration date stated on the package.
Protaphane® NM should not be used if the liquid does not become uniformly white and uniformly cloudy after mixing the contents of the vial.
Incompatibility
Insulin suspensions should not be mixed with infusion solutions.
Packaging
10 ml in a bottle; 1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
A/T Novo Nordisk.
Novo Nordisk Production SAS.
Location of the manufacturer and its business address.
Novo Alle, Bagsvaerd, 2880, Denmark.
45, Avenue d'Orleans, 28000, Chartres, France.
