Expiration date: 02/2026

The composition and form of issue:

Suspension for subcutaneous injection. 1 ml contains:

active substance: insulin aspart biphasic soluble insulin aspart (30%) and crystals of insulin aspart Protamine (70%) — 100 UNITS 

1 IU corresponds to 0,035 mg or 6 nmol of anhydrous insulin aspart 

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

1 cartridge (3 ml) contains 300 UNITS 

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

Description pharmaceutical form:

Homogeneous suspension of white color containing no lumps.

The sample may appear flakes.

During storage, the suspension is stratified, forming a white precipitate and a colorless or almost colorless supernatant.

While stirring the content of the pen according to the methods described in the instructions for medical use and should form a homogenous suspension.

Pharmacokinetics:

In insulin aspart substitution of amino acid Proline at position B28 on the aspartic acid reduces the tendency of the molecules to the formation of hexamers in the soluble fraction NovoMix 30 Flexpen that is observed in the soluble human insulin. In this regard, insulin aspart (30%) absorbed from the subcutaneous fat quicker than soluble insulin, contained in two-phase human insulin. Insulin aspart Protamine (70%), as well as human isophane insulin, absorbed longer.

When using NovoMix 30 Flexpen insulin Cmax in the serum on average 50% higher than when using a two-phase human insulin. The average Tmax in 2 times less than that of biphasic human insulin. In healthy volunteers when s/to the introduction of the drug in a dose of 0.2 U/kg mean C Max were (140±32) pmol/l and was achieved 60 min after injection. The average T1/2 NovoMix 30 Flexpen, reflecting the absorption rate preteenvaginas fraction, was about 8-9 h. the insulin Concentration in serum returns to baseline levels after 15-18 h after s/to the introduction. In patients with diabetes mellitus type 2 insulin Cmax in serum is reached after 95 min and maintained at a level significantly above 0 for at least 14 h after drug administration.

Children and adolescents

Pharmacokinetic properties NovoMix 30 Flexpen in children and adolescents has not been studied. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been studied in children (6-12 years) and adolescents (13 to 17 years) with diabetes type 1. Patients of both age groups insulin aspart has rapid absorption and Tmax values similar to those seen in adults. However, the values of C Max in the two age groups were different, indicating the importance of individual selection of doses of insulin aspart.

In older patients, and patients with impaired liver function or renal the pharmacokinetics of the drug NovoMix 30 Flexpen was conducted.

Description pharmacological action:

NovoMix 30 Flexpen is a two-phase suspension consisting of soluble insulin aspart (30% insulin analogue short-acting) and crystals of insulin aspart Protamine (70% of analogue insulin average duration). Active substance NovoMix 30 Flexpen is insulin aspart produced by the method of biotechnology recombinant DNA using a strain of Saccharomyces cerevisiae.

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. Compared to soluble human insulin, insulin aspart (fast-acting analog of human insulin) begins to act more quickly, so it can be entered directly before the meal (0 to 10 min before meal). Crystalline phase (70%) consists of insulin aspart Protamine (analog of human insulin average duration), which is similar to the human insulin isophane. After p/to the introduction NovoMix 30 Flexpen effect develops within 10-20 min and the Maximum effect is observed within 1 to 4 h after injection. The duration of action of the drug up to 24 h.

Three-month clinical study involving patients with diabetes type 1 and 2 showed that NovoMix 30 Flexpen has the same effect on the concentration of glycosylated haemoglobin (HbA1c), and biphasic human insulin. Insulin aspart has the same activity with human insulin in a molar equivalent.

In a clinical study involving 341 patients with diabetes mellitus type 2 patients were randomized to a treatment group only drug NovoMix 30 Flexpen a drug NovoMix  30 Flexpen in combination with the drug Metformin a drug Metformin in combination with sulfonylureas. Variable primary efficacy — HbA1c after 16 weeks of treatment — did not differ in patients receiving NovoMix 30 Flexpen in combination with the drug Metformin, and in patients treated with Metformin in combination with sulfonylureas. In this study, 57% of patients had a baseline HbA1c level above 9% in these patients, therapy with the drug NovoMix 30 Flexpen in combination with Metformin led to a greater reduction in HbA1c than patients who received Metformin in combination with sulfonylureas.

In another study, patients with type 2 diabetes, is not effectively monitored by using oral hypoglycemic agents were randomized to the following groups: application NovoMix 30 Flexpen 2 times a day (117 patients) and insulin glargine, 1 per day (116 patients). After 28 weeks of use of drugs, the average decrease in HbA1c in the group of application NovoMix 30 Flexpen was 2.8% (initial average value was 9.7 per cent). 66 and 42% of patients treated NovoMix 30 Flexpen, at the end of the study was characterized by the values of HbA1c lower than 7 and 6.5%, respectively. The mean value of fasting plasma glucose was reduced by about 7 mmol/l (14,0 mmol/l at baseline to 7.1 mmol/l).

Children and adolescents

Held 16-week clinical trial that compared the content of glucose in the blood after a meal due to the introduction NovoMix 30 Flexpen (to food) human insulin/biphasic human insulin 30 (before food) and isophane-insulin (administered at bedtime). The study involved 167 patients aged 10 to 18 years. The average values of HbA1c in both groups remained close to the initial throughout the study. When NovoMix 30 Flexpen or biphasic human insulin showed no significant differences in the incidence of hypoglycemia. Additionally was conducted a double-blind crossover study in a population of patients aged 6 to 12 years (a total of 54 patients, at 12 weeks for each treatment). The incidence of hypoglycemia and improve glucose after the meal in the group treated with NovoMix 30 Flexpen was lower compared with values in the group applied a two-phase human insulin. The values of HbA1c at the end of the study in the group treated biphasic human insulin were significantly lower than in the group treated with NovoMix 30 Flexpen.

Preclinical safety data

In in vitro tests, including binding to insulin receptors and IGF-1 and influence on the growth of cells, it was shown that the properties of insulin aspart are similar to human insulin. In addition, it was found that insulin aspart binds to insulin receptors analogous to human insulin. In the study of acute (1 month) and chronic (12 months) toxicity no data were received about the presence of insulin aspart clinically significant toxic properties.

Indications:

• Diabetes.
  

Contraindications:

• hypoglycemia
  
• individual hypersensitivity to insulin aspart or any component of the drug.
  
• Not recommended for use in children under 6 years, because clinical studies of the use of NovoMix 30 Flexpen they have not been conducted.
  

Application of pregnancy and breast-feeding:

Clinical experience with the drug NovoMix 30 Flexpen during pregnancy is very limited. Animal studies revealed no differences between the embryotoxicity or teratogenicity of insulin aspart and human insulin. In a period of possible pregnancy and throughout its term is necessary to conduct careful monitoring of patients with diabetes and control the glucose level in blood. 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 the period of breast-feeding NovoMix 30 Flexpen can be used without restrictions. Insulin a nursing mother do not pose a threat to the child. However, you may need a dose adjustment NovoMix  30 Flexpen.

Side effects:

Adverse reactions observed in patients using the drug NovoMix 30 Flexpen 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 large a dose of insulin on the body's need for insulin. Symptoms of hypoglycemia may include cold sweat, pale skin, nervousness or tremor, anxiety, unusual fatigue or weakness, disorientation, impaired concentration, dizziness, feeling of hunger, temporary blurred vision, headache, nausea, tachycardia. Severe hypoglycemia can lead to loss of consciousness, temporary or permanent malfunction of the brain or death. When conducting clinical research, as well as after acceptance of the drug sales observed frequency of this complication varied depending on the study populations, dosing regimens, therefore, to specify the frequency of hypoglycemia in patients receiving NovoMix 30 Flexpen is not possible. In clinical studies, no difference was found in frequency of hypoglycemia while taking insulin aspart and human insulin.The incidence of side effects with application of the NovoMix 30 Flexpen (insulin aspart) is shown below and is defined as infrequently (>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.

Disorders of the immune system: seldom — urticaria, rash very rare — anaphylactic reactions.

Symptoms of generalized hypersensitivity reactions may include: generalised skin rash, itching, sweating, gastro-intestinal disorders, angioneurotic edema, shortness of breath, tachycardia and decreased blood pressure. Reactions generalised hypersensitivity is a potentially life-threatening.

Disorders of the nervous system: rare — peripheral neuropathy.

Rapid improvement of glycemic control may be associated with the development of usually reversible acute pain of neuropathy.

Ophthalmic disorders: rarely, refractive error, diabetic retinopathy.

Refractive errors may develop when you start insulin therapy. These symptoms are usually reversible.

Long adequate control of glycemia reduces the risk of progression of diabetic retinopathy. However, the increasing intensity of insulin therapy with abrupt improvement in glycemic control may be associated with transient worsening of diabetic retinopathy.

Lesions of the skin and subcutaneous tissue: often — lipodystrophy, local hypersensitivity reactions.

Lipodystrophy may develop at the injection site if it is impossible to change it within the anatomical region.

Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur when using insulin. These are usually transient and disappear with continued treatment.

System disorders: rarely — swelling.

Edema can develop when you start insulin therapy. Usually they are transient. Swelling and weight gain can occur when using NovoMix 30 Flexpen in conjunction with oral hypoglycemic agents.

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, CCB, 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/lanreotide may both increase and decrease insulin requirement.

Alcohol may exacerbate and prolong the hypoglycemic effect of insulin.

Incompatibility

Because of compatibility studies have not been conducted, NovoMix 30 Flexpen should not be mixed with other drugs.

Method of application and dose:

NovoMix 30 Flexpen is designed for p/to the introduction. You should never inject the drug.

The dose is determined individually in each case on the basis of the concentration of glucose in the blood. The average daily dose of the drug in patients with type 1 diabetes ranges from 0.5 to 1 U/kg/day (depends on the individual characteristics of the patient and the concentration of glucose in the blood). In patients with insulin resistance (such as obesity), daily insulin requirements may be increased in patients with residual endogenous insulin secretion — is reduced.

Patients suffering from diabetes type 2, NovoMix 30 Flexpen can be prescribed both as monotherapy and in combination with oral hypoglycemic drugs in cases when the content of glucose in the blood is insufficiently regulated only oral hypoglycemic agents.

For patients with diabetes type 2 diabetes the recommended starting dose NovoMix 30 Flexpen is 6 UNITS morning and 6 evening MEALS (with Breakfast and dinner respectively). It also allowed the introduction of the 12 UNITS of the drug 1 time per day in the evening. In the latter case, it is recommended that after reaching the dose of 30 IU to go to the application NovoMix 30 Flexpen 2 times a day, dividing the dose into two equal parts — morning and evening. Safe transition to the use of NovoMix 30 Flexpen 3 times a day with splitting the morning dose into two equal parts and the introduction of these two parts morning and afternoon. For dose adjustment it is recommended to use the following table:

The concentration of glucose in blood before a meal	Dose adjustment Novomiks 30 Penfill, ED
<4.4 mmol/l (<80 mg/DL)	-2
4.4–6.1 mmol/l (80-110 mg/DL)	0 (not required)
6.2–7.8 mmol/l (111-140 mg/DL)	+2
7.9–10 mmol/l (141-180 mg/DL)	+4
>10 mmol/l (>180 mg/DL)	+6

For adjustment use the lowest value of the concentration of glucose in the blood before eating in the last three days. Should not increase the dose, if in this period, there was hypoglycemia. Dose adjustment can be carried out once a week to achieve target HbA1C values. To assess the adequacy of previous dose using the concentration value of glucose in blood before a meal.

When transferring a patient from biphasic human insulin 30 Flexpen NovoMix should start with the same dose and mode of administration. Then adjust the dose according to the individual needs of the patient (see the above table).

NovoMix 30 Flexpen can be used in elderly patients, but experience of its application in combination with oral hypoglycemic drugs in patients over 75 years of age is limited.

NovoMix 30 Flexpen should be administered immediately before eating. If necessary, you can enter NovoMix 30 Flexpen shortly after the start of the meal. Temperature of insulin must correspond to room. NovoMix 30 Flexpen should enter n/a in the thigh or the anterior abdominal wall. If desired, the drug can be administered into the upper arm or buttocks. It is necessary to change the injection site within the anatomical region to prevent the development of lipodystrophy. As with any other insulin preparations, the duration of the NovoMix  30 Flexpen is dependent on dose, site of injection, intensity of flow, temperature and level of physical activity. The dependence of the absorption NovoMix 30 Flexpen from the site of injection has not been studied.

In patients with renal or hepatic impairment, insulin requirements may be reduced.

NovoMix 30 Flexpen can be used for the treatment of children and adolescents aged 10 years in those cases where it is preferable the use of pre-mixed insulin. There are limited clinical data for children aged 6-9 years. For children under 6 years of clinical studies have not been conducted.

Instructions for use:

NovoMix 30 Flexpen is a unique syringe pen, designed for insulin. The administered dose of insulin ranges from 1 to 60 can be changed in increments of 1 UNIT. NovoMix 30 Flexpen is used with disposable needles or Novofein Novotwist length up to 8 mm. In as a precautionary measure, always carry a back-up system for insulin in case of loss or damage to your NovoMix 30 Flexpen.

Getting started

Check the label to make sure that NovoMix 30 Flexpen contains the required type of insulin. Before the first injection should be resuspendiruetsa insulin.

Always check that the cartridge remains at least 12 UNITS of insulin to ensure uniform mixing. If there are less than 12 UNITS — use the new NovoMix 30 Flexpen.

Care

NovoMix 30 Flexpen is designed for effective and safe applications and requires careful handling. In case of a fall or violent impact may damage the pen and leakage of insulin.

Surface NovoMix 30 Flexpen can be cleaned with a cotton swab dipped in alcohol. Do not immerse the pen in alcohol, do not wash and do not lubricate it, as this may damage the mechanism.

It is not allowed to reseed NovoMix 30 Flexpen.

Overdose:

Specific symptoms of an overdose of insulin available. However, when taking insulin in doses exceeding the demand for it may develop hypoglycemia.

Treatment: mild hypoglycemia, the patient can remove the, taking into glucose, sugar or carbohydrate-rich foods. Therefore, diabetics 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) in/m, 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.

Special instructions:

Lack of dose or discontinuation of treatment, especially in diabetes type 1 (insulin-dependent diabetes mellitus) can lead to the development of hyperglycemia or diabetic ketoacidosis — States that are potentially lethal. 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.

NovoMix 30 Flexpen should be used directly with food. 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.

Skipping meals or unplanned exercise may lead to hypoglycemia. Compared with biphasic human insulin introduction NovoMix 30 Flexpen has a stronger hypoglycemic effect in the first 6 h after injection. In this regard, in some cases, may require correction doses of insulin and/or diet. 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 NovoMix 30 Flexpen, you may need to change the 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. The drug use NovoMix 30 Flexpen in insulin pumps.

When changing insulin preparations may change early warning signs of hypoglycemia, and a reduction in their intensity compared to the observed using the previous formulation of insulin, the patients should be warned. As with other insulin preparations, apply NovoMix 30 Flexpen in combination with pioglitazone should be used with caution, assessing the risk of patients adverse events related to fluid retention. There are also reports of cases of heart failure, the use of pioglitazone in combination with insulin, especially in patients with risk factors for development of heart failure. When using the drug NovoMix 30 Flexpen in combination with pioglitazone to evaluate patient for signs and symptoms of heart failure, increasing body mass and the appearance of edema. Due to increased insulin sensitivity in patients on the background of the use of pioglitazone in combination with insulin may risk of developing dose-dependent hypoglycemia, so you may need a lower dose of insulin.

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 that may be dangerous in situations, when you need it most (such as when driving or working with machines and mechanisms). Patients should be advised to take measures to prevent hypoglycemia when driving a car and operating machinery. This is especially important for patients with no or reduced severity of symptoms — the harbingers of developing hypoglycemia or suffer frequent episodes of hypoglycemia. In these cases, you should consider the appropriateness of performing such work.

Instructions for storage, use and disposal

In the package enclosed instruction for use and storage.

You must emphasize to the patient the importance of mixing the suspension NovoMix 30 Flexpen immediately prior to use. Before the first use remove the pen NovoMix 30 Flexpen from the refrigerator and stand until reaching room temperature to facilitate mixing of the suspension. Properly mixed, the liquid should be uniformly white and cloudy.

NovoMix 30 Flexpen is designed for individual use only. May not be re-filling the pen NovoMix 30 Flexpen.

Needle Novofine and Novotwist designed for use with Flexpen.

Patients should be advised of the need to discard the needle after each injection.

Unused drug supplies should be disposed of in accordance with established requirements.

Instructions for using NovoMix 30 Flexpen that you want to give the patient

Before using the drug you must check the label to make sure you are using the correct type of insulin.

NovoMix 30 Flexpen should not be used:

• in insulin pumps
  
• if the device Flexpen were damaged or destroyed, and if you drop it because there is a risk of leakage of insulin
  
• if the drug was kept in unacceptable conditions or have been frozen
  
• if the insulin is not uniformly white and remains turbid after mixing
  
• if the drug appeared white lumps or white particles stick to the bottom or walls of the cartridge, giving it the appearance of frozen.
  

NovoMix 30 Flexpen is designed for p/to the injections. CTR