Expiration date: 06/2025

The composition and form of issue:

Solution for subcutaneous and intravenous injection. 1 ml contains:

insulin aspart 100 U

100 U corresponds to 3.5 mg of anhydrous insulin aspart 

excipients: glycerol, phenol, metacresol zinc chloride sodium hydrogen phosphate dihydrate sodium chloride sodium hydroxide 2M 2M hydrochloric acid water for injections 

for 3 ml glass cartridge, closed with a disk of bromatology rubber/polyisoprene with one hand and sealed in plastic multidose disposable syringe-pen for multiple injections on the other in cardboard pack of 5 syringe pens.

Description pharmaceutical form:

Clear colorless solution.

Pharmacokinetics:

After p/to the introduction of insulin aspart Tmax in plasma is on average 2 times less than after administration of soluble human insulin. Cmax in plasma is on average (492±256) pmol/l and is reached in 40 min after s/to the dose of 0.15 U/kg of body weight in patients with diabetes mellitus type 1. The insulin concentration returned to baseline levels after 4-6 h after drug administration. The absorption rate is slightly lower in patients with type 2 diabetes, leading to lower maximum concentration (352±240) pmol/l and later Tmax (60 min). Vnutricinovialnoe variability in Tmax is significantly lower when using insulin aspart compared to soluble human insulin, whereas the mentioned variability in Cmax for insulin aspart more.

Pharmacokinetics in children (6-12 years) and adolescents (13-17 years) with diabetes mellitus type 1. Absorption of insulin aspart is fast in both age groups with Tmax, similar to that in adults. However, there are differences in Cmax for the two age groups, highlighting the importance of individual dosages of the drug.

Elderly patients: the relative differences in pharmacokinetics between insulin aspart and soluble human insulin in elderly patients (65-83 years, mean age 70 years) with diabetes mellitus type 2 were similar to those seen in healthy volunteers and in younger patients with diabetes. Elderly patients were observed decrease in the rate of removals that have led to lower Tmax — 82 (variability 60-120) min, whereas Cmax was similar to that observed in younger patients with diabetes type 2 and slightly smaller than in patients with diabetes mellitus type 1.

Failure of liver function. A study was conducted in the pharmacokinetics with the introduction of a single dose of insulin aspart in 24 patients, the liver function which is in the range from normal to severe forms of violations. Patients with hepatic impairment the absorption rate of insulin aspart was reduced and more erratic, the result of which was the slowdown in Tmax from about 50 minutes in patients with normal hepatic function to about 85 min in subjects with hepatic impairment moderate and severe severity. AUC, Cmax in plasma and total clearance (CL/F) was similar in individuals with reduced and normal liver function.

Failure of kidney function. A study was conducted in the pharmacokinetics of insulin aspart in 18 patients, renal function varying from normal to severe violations. It was not revealed clear effect of creatinine clearance values on AUC, Cmax, Tmax of insulin aspart. Data were limited to the indicators for persons with impaired renal function moderate and severe forms. Persons with renal failure requiring dialysis were not included in the study.

Description pharmacological action:

Insulin aspart, like human insulin short-acting, produced by the method of biotechnology recombinant DNA using a strain of Saccharomyces cerevisiae, in which the amino acid Proline in position B28 replaced by aspartic acid.

Interacts with the specific receptor zitoplazmaticescoy external cell membrane of cells to form insulin-receptor complex stimulates intracellular processes, including synthesis of several key enzymes (geksokinazoj, pyruvate kinase, glikogensintetaza, etc.). The decrease in the content glucose in the blood due to its increase of intracellular transport, increased assimilation of tissues, stimulation of lipogenesis, glikogenogeneza, a decrease in the rate of glucose production by the liver, etc.

The substitution of Proline at position B28 on the aspartic acid in insulin aspart reduces the tendency of the molecules to the formation of hexamers, which is observed in a solution of regular insulin. In this regard, insulin aspart is much faster absorbed from the subcutaneous fat and starts acting much faster than soluble human insulin. Insulin aspart stronger reduces the level of blood glucose in the first 4 hours after a meal than soluble human insulin.

The duration of action of insulin aspart after subcutaneous injection is shorter than soluble human insulin.

After subcutaneous injection, the drug action begins within 10-20 min after injection. The maximum effect is observed after 1-3 hours after injection. The duration of action of the drug is 3-5 h.

Clinical studies involving patients with diabetes type 1 diabetes showed a reduced risk of nocturnal hypoglycaemia when using insulin aspart compared to soluble human insulin. The risk of daytime hypoglycaemia was not significantly increased.

Insulin aspart is an equipotential soluble human insulin on the basis of indicators, molarity.

Adults. Clinical studies involving patients with diabetes type 1 demonstrated a lower postprandial blood glucose concentrations when insulin aspart compared to soluble human insulin.

Elderly. It was a randomized, double-blind crossover study of the pharmacokinetics and pharmacodynamics (PK/PD) of insulin aspart and soluble human insulin in elderly patients with diabetes type 2 diabetes (19 patients aged 65-83 years, mean age 70 years). The relative differences in the pharmacodynamic properties between insulin aspart and soluble human insulin in elderly patients were similar to those seen in healthy volunteers and in younger patients with diabetes.

Children and adolescents. The use of insulin aspart in children showed similar results of long-term glycemic control when compared with soluble human insulin.

Clinical study using soluble human insulin before meals and insulin aspart after the meal was spent in small children (26 patients aged 2 to 6 years) as well as pharmacokinetic/pharmacodynamic (PK/PD) study using a single dose was conducted in children (6-12 years) and adolescents (13-17 years). Pharmacodynamic profile of insulin aspart in children was similar to that in adult patients.

Pregnancy. Clinical studies of the comparative safety and efficacy of insulin aspart and human insulin in the treatment of pregnant women with diabetes mellitus type 1 (322 surveyed pregnant women, of whom 157 were receiving insulin aspart, 165 — human insulin) have not revealed any negative effects of insulin aspart on pregnancy or health of the fetus/newborn.

Additional clinical study of 27 women with gestational diabetes treated with insulin aspart and human insulin (insulin aspart, there were 14 women, human insulin, and 13) indicate comparability of safety profiles along with a significant improvement of glucose control after meals in the treatment of insulin aspart.

Preclinical safety data.

Preclinical studies have not revealed any risk for humans based on conventional studies of pharmacological safety, repeated use toxicity, genotoxicity and reproductive toxicity.

In tests in vitro, including the receptors of insulin and insulin-like growth factor-1, and the impact on cell growth, the nature of the behaviour of insulin aspart is very similar to that of human insulin. The research results also showed that the dissociation of binding of insulin aspart with insulin receptor equivalent to that of human insulin.

Indications:

Diabetes.

Contraindications:

• individual hypersensitivity to insulin aspart or any component of the drug
  
• hypoglycemia.
  

It is not recommended to use the drug Novorapid Flexpen in children under 2 years, because clinical studies in children under 2 years of age was conducted.

Application of pregnancy and breast-feeding:

Novorapid Flexpen can be administered during pregnancy. Data from two randomized controlled clinical trials (157 + 14 surveyed pregnant women) have not revealed any adverse effect of insulin aspart on pregnancy or health of the fetus/newborn compared to human insulin (see section "Pharmacodynamics").

We recommend careful monitoring of glucose levels in the blood and monitoring of pregnant women with diabetes (type 1 diabetes, type 2 diabetes or gestational diabetes) during pregnancy and in the period of pregnancy. The need for insulin usually decreases in the first trimester and gradually rises in the II and III trimester of pregnancy. Shortly after birth the need for insulin quickly returns to the level it was before pregnancy.

In lactation Novorapid Flexpen may be used, since the introduction of insulin to a nursing mother do not pose a threat to the child. However, you may need to adjust the dose of the drug.

Side effects:

Adverse reactions observed in patients using the drug Novorapid are mainly dose dependent and due to the pharmacological effect of insulin. The most common adverse event with insulin is hypoglycemia. Hypoglycemia develops when, if too high a dose of insulin relative to the needs of the body. Symptoms of hypoglycaemia usually occur suddenly. They can include: cold sweat, pale skin, nervousness or tremor, anxiety, unusual tiredness or weakness, violation of orientation, concentration, dizziness, feeling of hunger, temporary blurred vision, headache, nausea, tachycardia. Severe hypoglycemia may lead to unconsciousness and/or seizures, temporary or permanent impairment of the brain and death.

The incidence of side effects on treatment with Novorapid Flexpen is presented below. The incidence of side effects was defined as infrequent (>1/1000, <1/100) and rare (>1/10000, <1/1000). Separate spontaneous cases are presented as very rare defined as and <1/10000, including individual cases.

The immune system: rare — urticaria, rash very rare — anaphylactic reactions.

Generalized allergic reactions can include skin rash, itching of the skin, increased sweating, disorders of the gastrointestinal tract, angioedema, difficulty breathing, tachycardia, decrease in blood pressure. Generalized allergic reactions are potentially life-threatening.

From the nervous system: rarely — peripheral neuropathy. With the rapid improvement in glycemic control may develop a condition called acute painful neuropathy, which are normally reversible.

On the part of the organ of vision: infrequent — refractive error (can occur at the beginning of insulin therapy. These symptoms are usually transient in nature), diabetic retinopathy (sustained improvement in glycemic control reduces the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may cause temporary increased severity of diabetic retinopathy).

Local reactions: rare — allergic local reaction (the treatment with insulin may experience redness, swelling, itching of the skin at the injection site. These reactions are usually temporary and pass as you continue treatment), lipodystrophy (if you do not change the injection site within the anatomical region may develop lipodystrophy at the injection site of insulin).

System disorders: infrequent — edema (may occur at the beginning of insulin therapy. These symptoms are usually temporary).

Drug interactions:

There are a number of drugs that affect insulin requirements.

Hypoglycemic effect of insulin increase the oral hypoglycemic drugs, MAO inhibitors, ACE inhibitors, carbonic anhydrase inhibitors, nonselective beta-blockers, bromocriptine, sulfonamides, anabolic steroids, tetracyclines, clofibrate, ketoconazole, mebendazole, pyridoxine, theophylline, cyclophosphamide, fenfluramine, lithium preparations, drugs containing ethanol.

Hypoglycemic effect of insulin to weaken oral contraceptives, corticosteroids, tireoidnye hormones, tiazidnye dioretiki, heparin, tricyclic antidepressants, sympathomimetics, danazol, clonidine, calcium channel blockers, diazoxide, morphine, phenytoin, nicotine.

Under the influence of rezerpina and salicylates may as weakening, and strengthening actions of the drug.

Beta-adrenoblokatora may mask symptoms gipoglikemii. Octreotide and lanreotide may both increase and decrease insulin requirements

Pharmaceutical interaction. Drugs, containing thiols or sulphites, when added to insulin cause its destruction.

Method of application and dose:

P/K, V/V. Novorapid Flexpen has a more rapid onset and shorter duration of action than soluble human insulin. Due to the more rapid onset of action, Novorapid Flexpen, you must enter, as a rule, immediately before meals and, if necessary, you can enter shortly after eating.

The dose is determined individually in each case, on the basis of the level of glucose in the blood. Novorapid Flexpen is usually used in combination with drugs insulin average duration or long-acting, which is administered at least 1 time a day. Usually the total daily insulin requirement is 0.5–1 U/kg of body weight. When the drug is administered before a meal, insulin requirements may be provided by the drug Novorapid Flexpen 50-70%, the remaining need for insulin provided by insulin of the prolonged action.

Temperature of insulin must correspond to room. Novorapid Flexpen is injected subcutaneously in the anterior abdominal wall, hip, shoulder or buttocks. Injection sites within the same area of the body need to be regularly changed. As with any other insulin preparations, the duration of action of Novorapid Flexpen is dependent on dose, site of injection, intensity of flow, temperature and level of physical activity.

Subcutaneous administration into the abdominal wall ensures a faster absorption than administration in other places. However, a more rapid onset of action compared to soluble human insulin is maintained regardless of the location of the injection site.

If necessary, Novorapid Flexpen may be administered in/in, but only qualified medical personnel.

For I/V administration used the infusion system with the drug Novorapid 100 U/ml with a concentration of from 0.05 to 1 U/ml insulin aspart in 0.9% sodium chloride solution 5 or 10% dextrose solution containing 40 mmol/l potassium chloride, using polypropylene containers for infusion. These solutions are stable at room temperature for 24 h During infusion of insulin needed to control blood glucose levels.

Novorapid Flexpen may also be used for continuous subcutaneous insulin infusion (PII) in insulin pumps designed for infusion of insulin. PII should be made in the abdominal wall. Places of the infusion should be changed periodically.

When using an insulin pump for infusion Novorapid Flexpen must not be mixed with other types of insulin. Patients using PII should be trained to use the pump, the relevant reservoir and tubing for the pump. Infusion set (tubing and catheter) should be replaced in accordance with the user manual attached to the infusion set.

Patients receiving Novorapid Flexpen with PII should have additional insulin required in case of failure of the infusion system.

Novorapid Flexpen is a pre-filled pen and is intended for use with needles Novofine® or Novotwist. Packing needles Novofein marked with the symbol “S”. Flexpen offers the ability to enter from 1 to 60 UNITS of the drug with an accuracy of 1 ED. You must follow the exact instructions for use provided with the device.

Novorapid Flexpen is designed for individual use only and may not be re-filled.

Instructions for use:

Before you use Novorapid Flexpen:

check the label to make sure that you select the correct type of insulin

always use a new needle for each injection to prevent contamination.

Do not use Novorapid Flexpen if:

Flexpen has been dropped or damaged, or crushed, because there is a risk of leakage of insulin

the conditions of storage of insulin do not match those specified, or preparation was frozen

insulin has ceased to be transparent and colorless.

Novorapid Flexpen for subcutaneous injection or continuous infusion insulin pump system (PPII). Novorapid Flexpen may also be used intravenously under strict medical supervision.

You should always change injection sites to avoid lipodystrophy. The best places for injection are the anterior abdominal wall, buttocks, front of the thigh or shoulder. Insulin will act faster if it is put in the region of the anterior abdominal wall.

How to make an injection

Follow the instructions and doctor's recommendations on the technique of injection Novorapid Flexpen.

For use in an insulin pump system for continuous infusion

When used in a pump system Novorapid Flexpen® should never be mixed with other insulin preparations. Follow the instructions and doctor's recommendations on the use of Flexpen Novorapid® in a pump system. Before you use Novorapid Flexpen® in a pump system you should carefully read the full instructions on how to use this system and information on any action to be taken in case of illness, too high or too low blood sugar or when a system fault for PPII. Before you insert the needle, wash your hands and the skin at the injection needle with soap and water to avoid any infection at the site of infusion.

When filling a new tank, check out if there are any large air bubbles in the syringe or tube.

Replacement of infusion set (tubing and needle) must be done by following the user instructions attached to the infusion set.

For optimal compensation of carbohydrate metabolism disorders and timely detection of possible malfunction of the insulin pump, it is recommended to regularly monitor the content of glucose in the blood.

What to do if an insulin pump system not working

You should always have extra insulin for subcutaneous injection in the event of failure of the system to PPII.

General information

Read these instructions carefully before using Novorapid Flexpen

Novorapid Flexpen is a unique insulin syringe-pen dispenser.

The administered dose of insulin in the range from 1 to 60 units can be changed in increments of 1 unit. Novorapid Flexpen is designed for use with needles Novofine® and Novotwist® up to 8 mm. In as a precautionary measure, always carry a back-up system for insulin in case you lose or damage your pen, Novorapid Flexpen

Overdose:

Symptoms: may develop hypoglycemia.

Treatment: mild hypoglycemia, the patient can remove the, taking into glucose, sugar or carbohydrate-rich foods. Therefore, patients with diabetes are advised to constantly carry around a sugar, sweets, biscuits or sugary fruit juice.

In severe cases, the loss of patient consciousness/injected a 40% solution of dextrose (glucose)/m or p/to — glucagon (0.5–1 mg). After recovering consciousness, the patient is recommended to take food rich in carbohydrates, to prevent recurrence of hypoglycemia.

Precautions:

Novorapid Flexpen should be used only with those products that are compatible with it and ensure the safe and efficient operation of the pen, Novorapid Flexpen. Novorapid Flexpen is designed for individual use only.

It is not allowed to reseed Novorapid Flexpen. Needle Novofine marked S and Novotwist designed for use with Novorapid Flexpen.

Novorapid Flexpen may be used in insulin pumps. The tube, inner surface of which is made of polyethylene or polyolefin, were inspected and found suitable for use in pumps.

Solutions for infusion in polypropylene containers made from Novorapid Flexpen 100 U/ml and containing from 0.05 to 1.0 U/ml insulin aspart in 0.9% sodium chloride solution, 5 or 10% dextrose solution containing 40 mmol/l potassium chloride is stable at room temperature for 24 h. Despite the resistance for some time, a certain amount of insulin initially absorbed by the material of the infusion system. During infusion of insulin necessary to control glucose levels in the blood.

Novorapid Flexpen must not be used if it ceased to be transparent and colorless.

Unused drug and other materials should be disposed of in accordance with local regulations.

Special instructions:

Lack of dose or discontinuation of treatment, especially in diabetes mellitus type 1 can lead to the development of hyperglycemia or diabetic ketoacidosis. Generally, symptoms of hyperglycemia are gradually, for a few hours or days. Symptoms of hyperglycemia include nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, increase urine output, thirst and loss of appetite, as well as the odor of acetone in exhaled air. Without treatment, hyperglycemia can lead to death. After the compensation carbohydrate exchange, for example, when intensified insulin therapy, patients can change their typical symptoms-signs of hypoglycemia, what patients need to be informed.

In patients with diabetes with optimal metabolic control and late complications of diabetes developing later and progressing slower. In this regard, it is recommended to carry out activities aimed at optimizing metabolic control, including the monitoring of the glucose level in blood.

The result of the pharmacodynamic characteristics of insulin analogues short-acting is that the development of hypoglycemia when their application starts earlier than when using soluble human insulin.

Due to shorter duration of action compared with human insulin, the risk of nocturnal hypoglycemia in patients, receiving Novorapid Flexpen, below.

Novorapid Flexpen should be used in direct connection with food intake. Account should be taken of the high speed of onset of effect of the drug in the treatment of patients with concomitant diseases or taking drugs that slow down the absorption of food. In the presence of concomitant diseases, especially infectious nature, the need for insulin, as a rule, increases. Violation of the kidney or liver may lead to a decrease in insulin requirements.

To use Novorapid Flexpen instead of soluble human insulin in children is preferable in the case when you need a fast onset of action of the drug, for example when the child is difficult to observe the interval of time between the injection and meal.

When transferring a patient to other types of insulin early symptoms-signs of hypoglycaemia may change or become less pronounced as compared to those when using the previous type of insulin.

Transfer the patient to a new type of insulin or insulin product from another manufacturer should be under strict medical supervision. When you change the concentration, type, manufacturer and type (human insulin, animal insulin, human insulin analogue) insulin and/or method of manufacture may require change in dose. Patients coming for treatment Novorapid Flexpen, you may need to increase the frequency of injections or changing doses compared with the doses previously used insulin preparations. If necessary, dose adjustment can be made already at the first introduction of the drug, or during the first weeks or months of treatment.

In addition, changes in dose may be required when changing diets and increased physical activities. Performing exercise immediately after a meal, can increase the risk of hypoglycemia. Skipping meals or unplanned exercise may lead to hypoglycemia.

When carrying out insulin therapy can be allergic reactions to the injection of insulin: pain, itching, rash, swelling and inflammation. Usually these symptoms are temporary and disappear within several days to several weeks. The constant change of the injection helps to reduce or prevent these symptoms. In very rare cases may require removal of the drug.

Effects on ability to drive and use machines. The patients ' ability to concentration of attention and speed of reaction can be violated at the time of hypoglycemia and hyperglycemia that may pose a risk in situations where these abilities are especially needed (such as when driving or working with machines and mechanisms). Patients should be advised to take measures to prevent hypoglycemia and hyperglycemia while driving and operating machinery. This is especially important for patients with no or reduced severity of symptoms-the harbingers of developing hypoglycemia or who have frequent episodes of hypoglycemia. In these cases, you should consider C