NovoMix 30 FlexPen, 100 me/ml syringe pens 3 ml, 5 pcs.

Composition

Active ingredient:

insulin aspart — soluble insulin aspart (30%) and crystals of insulin aspart protamine (70%)100 units (3.5 mg);

Auxiliary substances:

glycerol — 16 mg;

phenol — 1.5 mg;

metacresol — 1,72 mg;

zinc chloride to 19.6 mg;

sodium chloride 0,877 mg;

sodium hydrogen phosphate dihydrate — 1.25 mg;

Protamine sulfate is about 0.33 mg;

sodium hydroxide of about 2.2 mg;

hydrochloric acid — approximately 1.7 mg;

water for injection — up to 1 ml

Pharmacological action

NovoMix 30 FlexPen – hypoglycemic.

Pharmacodynamics

NovoMix ® 30 FlexPen® is a two-phase suspension consisting of soluble insulin aspart (30% short-acting insulin analog) and insulin crystals aspart protamine (70% medium – acting insulin analog). The Active ingredient of NovoMix ® 30 FlexPen® is insulin aspart, produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain.

Insulin aspart is equipotential to soluble human insulin based on molarity indicators.

A decrease in the concentration of glucose in the blood occurs due to an increase in its intracellular transport after binding of insulin aspart to insulin receptors in muscle and adipose tissues and simultaneous inhibition of glucose production by the liver. After subcutaneous administration of NovoMix ® 30 FlexPen®, the effect develops within 10-20 minutes. The maximum effect is observed in the range from 1 to 4 hours after the injection. The duration of action of the drug reaches 24 hours.

In a three-month comparative clinical trial involving patients with type 1 and 2 diabetes mellitus who received NovoMix 30 FlexPen and biphasic human insulin 30 twice daily before breakfast and dinner, NovoMix 30 FlexPen significantly reduced postprandial blood glucose concentrations (after breakfast and dinner).

A meta-analysis of data from 9 clinical trials involving patients with type 1 and 2 diabetes mellitus showed that NovoMix ® 30 FlexPen®, when administered before breakfast and dinner, provides better control of postprandial blood glucose concentration (average increase in prandial glucose concentration after breakfast, lunch and dinner), compared with human biphasic insulin 30. Although fasting glucose concentrations were higher in patients using NovoMix 30 FlexPen, in general NovoMix 30 FlexPen It has the same effect on the concentration of glycosylated hemoglobin (HbA1c) as biphasic human insulin 30.

In a clinical trial involving 341 patients with type 2 diabetes mellitus, patients were randomly assigned to NovoMix 30 FlexPen alone, NovoMix 30 FlexPen in combination with metformin, and metformin in combination with a sulfonylurea derivative. The HbA1c concentration after 16 weeks of treatment did not differ in patients receiving NovoMix® 30 FlexPen® in combination with metformin and in patients receiving metformin in combination with a sulfonylurea derivative. In this study,57% of patients had a baseline HbA1c concentration above 9%; in these patients, NovoMix 30 FlexPen therapy in combination with metformin resulted in a more significant reduction in HbA1c concentrations than in patients receiving metformin in combination with a sulfonylurea derivative.

In another study, patients with type 2 diabetes mellitus with poor glycemic control who received oral hypoglycemic drugs were randomly assigned to the following groups: NovoMix 30 twice daily (117 patients) and insulin glargine once daily (116 patients). After 28 weeks of drug administration, the average decrease in HbA1c concentration in the NovoMix 30 FlexPen group was 2.8% (the initial mean value was 9.7%). In 66% and 42% of patients treated with NovoMix 30 FlexPen, HbA1c values were below 7 and 6.5%, respectively, at the end of the study. Mean fasting plasma glucose decreased by approximately 7 mmol / l (from 14 mmol / l at the start of the study to 7.1 mmol/L).

The results of a meta-analysis of data obtained from clinical trials involving patients with type 2 diabetes mellitus showed a decrease in the total number of episodes of nocturnal hypoglycemia and severe hypoglycemia when using NovoMix ® 30 FlexPen®, compared with biphasic human insulin 30. At the same time, the overall risk of daytime hypoglycemia in patients treated with NovoMix 30 FlexPen was higher.

Children and teenagers. A 16-week clinical trial was conducted that compared blood glucose levels after meals with NovoMix® 30 (pre-meal), human insulin/biphasic human insulin 30 (pre-meal), and isofan-insulin (administered before bedtime). The study involved 167 patients aged 10-18 years. The mean values of HBA1C in both groups remained close to the initial values throughout the study. Also, when using NovoMix ® 30 FlexPen® or biphasic human insulin 30, there were no differences in the incidence of hypoglycemia.

A double-blind cross-sectional study was also conducted in a population of patients aged 6-12 years (a total of 54 patients,12 weeks for each type of treatment). The incidence of hypoglycemia and increased glucose levels after meals in the group of patients treated with NovoMix ® 30 FlexPen® were significantly lower compared to the values in the group of patients treated with biphasic human insulin 30. HbA1c values at the end of the study in the biphasic human insulin 30 group were significantly lower than in the NovoMix 30 FlexPen group.

Elderly patients. Pharmacodynamics of NovoMix ® 30 FlexPen® It was not studied in elderly and senile patients. However, the pharmacodynamics and pharmacokinetics of insulin aspart and soluble human insulin were compared in a randomized double — blind cross-sectional study conducted on 19 patients with type 2 diabetes mellitus aged 65-83 years (mean age-70 years). The relative differences in pharmacodynamic parameters (maximum glucose infusion rate — GIRmax and area under the curve of its infusion rate within 120 minutes after administration of insulin preparations-AUCGIR,0-120 min) between insulin aspart and human insulin in elderly patients were similar to those in healthy volunteers and in younger diabetic patients.

Preclinical safety data sheet

In the course of preclinical studies, no danger to humans was identified, based on data from generally accepted studies of pharmacological safety, repeated use toxicity, genotoxicity and reproductive toxicity.

In vitro tests that included binding to insulin and IGF-1 receptors and influencing cell growth showed that the properties of insulin aspart are similar to those of human insulin. The results also showed that the dissociation of the binding of insulin aspart to insulin receptors is equivalent to that of human insulin.

Pharmacokinetics

In insulin aspart, the substitution of the amino acid proline at position B28 for aspartic acid reduces the tendency of molecules to form hexamers in the soluble fraction of NovoMix ® 30 FlexPen®, which is observed in soluble human insulin. In this regard, insulin aspart (30%) is absorbed from subcutaneous adipose tissue faster than soluble insulin contained in biphasic human insulin. The remaining 70% is accounted for by the crystalline form of protamine-insulin aspart, the absorption rate of which is the same as that of human NPH insulin.

The Cmax of insulin in the blood serum after administration of NovoMix ® 30 FlexPen® is 50% higher than that of biphasic human insulin 30. and the Tmax is twice as short as that of biphasic human insulin 30.

In healthy volunteers, after subcutaneous administration of NovoMix® 30 at the rate of 0.2 U/kg, the Cmax of insulin aspart in the blood serum was reached in 60 minutes and amounted to (140±32) pmol/l. The T1/2 duration of NovoMix 30, which reflects the rate of absorption of the protamine-bound fraction, was 8-9 hours. Serum insulin levels returned to baseline 15-18 hours after subcutaneous administration of the drug. In patients with type 2 diabetes mellitus, Cmax was reached 95 minutes after administration and remained higher than the initial value for at least 14 hours.

Elderly and senile patients. The pharmacokinetics of NovoMix 30 in elderly and senile patients have not been studied. However, the relative differences in the pharmacokinetic values between insulin aspart and human soluble insulin in elderly patients with type 2 diabetes mellitus (aged 65-83 years, mean age-70 years) were similar to those in healthy volunteers and in younger patients with diabetes mellitus. In elderly patients, a decrease in the absorption rate was observed, which led to a slow T1/2 (82 min (interquartile range — 60-120 min), while the average MAX was similar to that observed in younger patients with type 2 diabetes mellitus, and slightly less than in patients with type 1 diabetes mellitus.

Patients with impaired renal and hepatic function. Study of the pharmacokinetics of NovoMix ® 30 FlexPen® No studies have been performed in patients with impaired renal and hepatic function. However, when increasing the dose of the drug in patients with varying degrees of impaired renal and hepatic function, there were no changes in the pharmacokinetics of soluble insulin aspart.

Children and teenagers. Pharmacokinetic properties of NovoMix 30 FlexPen They were not studied in children and adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart were studied in children (from 6 to 12 years) and adolescents (from 13 to 17 years) with type 1 diabetes mellitus. In patients of both age groups, insulin aspart was characterized by rapid absorption and Tmax values similar to those in adults. However, the Cmax values in the two age groups were different, which indicates the importance of individual selection of insulin aspart doses.

Indications

Diabetes mellitus.

Contraindications

Increased individual sensitivity to insulin aspart or any of the components of the drug.

Interaction

There are a number of drugs that affect the need for insulin. The hypoglycemic effect of insulin is enhanced by oral hypoglycemic drugs, MAO inhibitors, ACE inhibitors, carbonic anhydrase inhibitors, non-selective beta-blockers, bromocriptine, sulfonamides, anabolic steroids, tetracyclines, clofibrate, ketoconazole, mebendazole, pyridoxine, theophylline, cyclophosphamide, fenfluramine, lithium preparations, salicylates.

The hypoglycemic effect of insulin is weakened by oral contraceptives, corticosteroids, thyroid hormones, thiazide diuretics, heparin, tricyclic antidepressants, sympathomimetics, somatropin, danazol, clonidine, calcium channel blockers, diazoxide, morphine, phenytoin, nicotine.

Beta-blockers can mask the symptoms of hypoglycemia.

Octreotide / lanreotide can both increase or decrease the body’s need for insulin.

Alcohol can either increase or decrease the hypoglycemic effect of insulin.

How to take, course of administration and dosage

The dose of the drug is selected individually, under the supervision of a doctor. Injected subcutaneously before meals

Overdose

Symptoms. The exact dose required for an insulin overdose has not been established, but hypoglycemia may develop gradually if too high doses are administered in relation to the patient’s needs.

Treatment. The patient can eliminate mild hypoglycemia by taking glucose or sugar-containing foods inside. Therefore, patients with diabetes are advised to carry sugar-containing products at all times.

In the case of severe hypoglycemia, when the patient is unconscious,0.5 mg to 1 mg of glucagon should be administered intravenously or subcutaneously (can be administered by a trained person), or intravenously glucose (dextrose) solution (can only be administered by a medical professional). It is also necessary to inject dextrose intravenously if the patient does not regain consciousness 10-15 minutes after glucagon administration. After regaining consciousness, the patient is recommended to take a carbohydrate-rich diet to prevent the recurrence of hypoglycemia.

Special instructions

Before a long trip involving jet lag, the patient should consult with their healthcare provider, as jet lag means that the patient must eat and administer insulin at a different time.

Hyperglycemia. Insufficient dosage of the drug or discontinuation of treatment, especially in patients with type 1 diabetes, can lead to the development of hyperglycemia and diabetic ketoacidosis. As a rule, the symptoms of hyperglycemia appear gradually, over several hours or days. Symptoms of hyperglycemia include a feeling of thirst, increased urine output, nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, loss of appetite, and the appearance of an acetone smell in the exhaled air. Without appropriate treatment, hyperglycemia in patients with type 1 diabetes can lead to diabetic ketoacidosis — a potentially fatal condition.

Hypoglycemia. Skipping a meal or doing an unplanned amount of intense physical activity can lead to hypoglycemia. Hypoglycemia can also develop if the dose of insulin is too high relative to the patient’s needs (see “Side effects”, “Overdose”).

Compared to biphasic human insulin, NovoMix 30 FlexPen exerts a more pronounced hypoglycemic effect within 6 hours after administration. In this regard, in some cases, it may be necessary to adjust the dose of insulin and / or the nature of nutrition. After compensation of carbohydrate metabolism, for example, with intensive insulin therapy, patients may change their typical symptoms-harbingers of hypoglycemia, which patients should be informed about. The usual harbinger symptoms may disappear with a prolonged course of diabetes mellitus. More strict control of the level of glycemia in patients may increase the risk of hypoglycemia, so increasing the dose of NovoMix ® 30 FlexPen® should be carried out under strict medical supervision (see “Dosage and administration”).

Since NovoMix ® 30 FlexPen® should be used in direct connection with food intake, it is necessary to take into account the high rate of onset of the drug effect in the treatment of patients with concomitant diseases or taking drugs that slow down the absorption of food.

Concomitant diseases, especially those that are infectious and accompanied by fever, usually increase the body’s need for insulin. Dose adjustment of the drug may also be required if the patient has concomitant diseases of the kidneys, liver, adrenal gland, pituitary gland or thyroid gland.

When a patient is switched to other types of insulin, the early warning signs of hypoglycemia may change or become less pronounced compared to those with the previous type of insulin.

Transfer of the patient from other insulin preparations. The transfer of a patient to a new type of insulin or an insulin preparation from another manufacturer must be carried out under strict medical supervision. If you change the concentration, type, manufacturer, and type (human insulin, human insulin analog) of insulin preparations and/or the method of production, you may need to change the dose. Patients switching from other insulin preparations to treatment with NovoMix 30 FlexPen may need to increase the frequency of injections or change the dose compared to the doses of previously used insulin preparations. If a dose adjustment is necessary, it can be made already at the first administration of the drug or during the first weeks or months of treatment.

Reactions at the injection site. As with other insulin preparations, reactions at the injection site may develop, which is manifested by pain, redness, urticaria, inflammation, hematomas, swelling and itching. Regularly changing the injection site in the same anatomical area can reduce symptoms or prevent the development of these reactions. Reactions usually disappear within a few days to several weeks. In rare cases, discontinuation of NovoMix 30 FlexPen may be necessary due to injection site reactions.

Simultaneous use of drugs of the thiazolidinedione group and insulin preparations. Cases of chronic heart failure have been reported when patients are treated with thiazolidinediones in combination with insulin preparations, especially when these patients have risk factors for developing chronic heart failure. This fact should be taken into account when prescribing combination therapy with thiazolidinediones and insulin preparations to patients. When prescribing such combination therapy, it is necessary to conduct medical examinations of patients for signs and symptoms of chronic heart failure, weight gain and the presence of edema. If the symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Influence on the ability to drive vehicles and work with mechanisms. Patients ‘ ability to concentrate and react quickly may be impaired during hypoglycemia, which can be dangerous in situations where these abilities are particularly necessary (for example, when driving vehicles or working with machines and mechanisms).

Patients should be advised to take measures to prevent the development of hypoglycemia when driving vehicles. This is especially important for patients with the absence or reduction of symptoms-harbingers of developing hypoglycemia or suffering from frequent episodes of hypoglycemia. In these cases, it is necessary to consider the feasibility of driving vehicles and performing such work.

Form of production

Suspension for subcutaneous administration

Storage conditions

At a temperature of 2-8 °C (in the refrigerator)

Shelf life

2 years

Active ingredient

Insulin aspart biphasic

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

Nursing mothers as prescribed by a doctor, Children as prescribed by a doctor, Pregnant women as prescribed by a doctor, Adults as prescribed by a doctor

Indications

Type 2 Diabetes, Type 1 Diabetes

Weight

Weight: 148 g.