NovoMix 30 FlexPen, 100 iu/ml suspension 3 ml cartridges in syringe pens 5 pcs

NovoMix 30 FlexPen is hypoglycemic.

Pharmacodynamics

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

Aspart insulin is equipotential to soluble human insulin based on molarity values.

The decrease in blood glucose concentration is due to increased intracellular transport after insulin aspart binds to insulin receptors of muscle and adipose tissues and simultaneously inhibition of glucose production by the liver. After subcutaneous administration of NovoMix® 30 FlexPen® the effect develops within 10-20 min. Maximum effect is observed within 1 to 4 hours after injection. The duration of action of the drug is up to 24 hours.

In a three-month comparative clinical study involving patients with type 1 and type 2 diabetes who received NovoMix® 30 FlexPen® and biphasic human insulin 30 twice daily before breakfast and supper it was shown that NovoMix® 30 FlexPen® was stronger in reducing postprandial blood glucose concentration (after breakfast and supper).

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

In a clinical trial involving 341 patients with type 2 diabetes, patients were randomized to treatment groups of NovoMix® 30 FlexPen® alone, NovoMix® 30 FlexPen® in combination with metformin and metformin in combination with a sulfonylurea derivative. HbA1c concentrations after 16 weeks of treatment did not differ between patients who received NovoMix® 30 FlexPen® in combination with metformin and those who received metformin in combination with a sulfonylurea derivative. In this study, 57% of patients had baseline HbA1c concentrations above 9%; in these patients, therapy with NovoMix® 30 FlexPen® in combination with metformin resulted in a greater reduction in HbA1c concentration than patients who received metformin in combination with a sulfonylurea derivative.

In another study, patients with type 2 diabetes with poor glycemic control who were taking oral hypoglycemic medications were randomized to the following groups: those receiving NovoMix® 30 twice daily (117 patients) and those receiving insulin glargine once daily (116 patients). After 28 weeks of treatment the average decrease of HbA1c concentration in NovoMix® 30 FlexPen® group was 2.8% (initial average was 9.7%). In 66% and 42% of patients who used NovoMix®30 FlexPen® the HbA1c values were lower than 7 and 6.5% at the end of the study, respectively. The average fasting plasma glucose value decreased by approximately 7 mmol/L (from 14 mmol/L at the beginning of the study to 7.1 mmol/L).

The results of a meta-analysis of data from clinical trials involving patients with type 2 diabetes demonstrated a reduction in total episodes of nocturnal hypoglycemia and severe hypoglycemia with NovoMix® 30 FlexPen® compared to biphasic human insulin 30. The overall risk of daytime hypoglycemia was higher in patients receiving NovoMix® 30 FlexPen®.

Children and adolescents. A 16-week clinical study was conducted comparing blood glucose levels after meals on NovoMix® 30 (before meals), human insulin/biphasic human insulin 30 (before meals) and isophane insulin (administered before bedtime). The study included 167 patients aged 10 to 18 years. The mean HbA1c values in both groups remained close to the initial values throughout the study. There were also no differences in the incidence of hypoglycemia when using NovoMix® 30 FlexPen® or biphasic human insulin 30.

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

Elderly patients. The pharmacodynamics of NovoMix® 30 FlexPen® has not been studied in elderly patients. However, a randomized, double-blind, cross-over study conducted in 19 patients with type 2 diabetes mellitus aged 65-83 years (mean age 70 years) compared pharmacodynamics and pharmacokinetics of insulin aspart and soluble human insulin. The relative differences in pharmacodynamic values (maximum glucose infusion rate – GIRmax and area under the glucose infusion rate curve for 120 min after insulin administration – AUCGIR, 0-120 min) between asparte insulin and human insulin in older patients were similar to those in healthy volunteers and in younger diabetic patients.

Preclinical safety data

Preclinical studies have not shown any risk to humans based on data from generally accepted studies of pharmacological safety, repeat use toxicity, genotoxicity and reproductive toxicity.

In in vitro tests involving binding to insulin and IGF-1 receptors and effects on cell growth, the properties of Aspart insulin were shown to be similar to those of human insulin. The results also showed that the dissociation of insulin asparte binding 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 asparagic acid reduces the tendency of the molecules to form hexamers in the soluble fraction of NovoMix® 30 FlexPen® that is observed in soluble human insulin. As a result, aspart insulin (30%) is absorbed from the subcutaneous fat tissue faster than soluble insulin contained in biphasic human insulin. The remaining 70% is from the crystalline form of protamine-insulin aspart, which has the same absorption rate as human NPH insulin.

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

In healthy volunteers after subcutaneous administration of NovoMix® 30 at a rate of 0.2ED/kg, serum insulin aspart Cmax was reached after 60 minutes and was (140±32) pmol/L. T1/2 duration of NovoMix® 30, which reflects absorption rate of prothamine-bound fraction, was 8-9 h. Serum insulin levels returned to baseline 15-18 h after subcutaneous administration of the drug. In patients with type 2 diabetes Cmax was reached 95 min after injection and remained higher than the baseline for at least 14 h.

Patients of elderly and old age. Pharmacokinetics of NovoMix® 30 has not been studied in elderly and senile patients. However, the relative differences of pharmacokinetic values between insulin aspart and human soluble insulin in elderly patients with type 2 diabetes (aged 65-83 years, mean age – 70 years) were similar to those in healthy volunteers and in younger patients with diabetes. In elderly patients, a decreased absorption rate was observed, resulting in a slower T1/2 (82 min (interquartile range, 60-120 min), whereas the meanCmax was similar to that observed in younger type 2 diabetic patients and slightly lower than in type 1 diabetic patients.

Patients with impaired renal and hepatic function. No study of the pharmacokinetics of NovoMix® 30 FlexPen® has been performed in patients with impaired renal and hepatic function. However, no change in the pharmacokinetics of soluble insulin aspart was observed with increasing the dose of the drug in patients with various degrees of renal and hepatic impairment.

Children and adolescents. The pharmacokinetic properties of NovoMix® 30 FlexPen® have not been studied in children and adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been studied in children (6 to 12 years old) and adolescents (13 to 17 years old) with type 1 diabetes. In both age groups, insulin aspart was characterized by rapid absorption and Tmax values similar to those of adults. However, Cmax values in the two age groups were different, indicating the importance of individual selection of insulin aspart doses.

Indications

Type 1 diabetes, Type 2 diabetes

Diabetes mellitus.

Active ingredient

Insulin aspart biphasic

Composition

Active ingredient:

Insulin aspart – soluble insulin aspart (30%) and insulin aspart protamine crystals (70%)100 IU (3.5 mg);

Associates:

Glycerol, 16 mg;

Phenol, 1.5 mg;

Methacresol, 1.72 mg;

p> zinc chloride – 19.6 mg;

sodium chloride – 0.877 mg;

sodium hydrophosphate dihydrate – 1.25 mg;

protamine sulfate – about 0.33 mg;

sodium hydroxide – about 2.2 mg;

hydrochloric acid – about 1.7 mg;

water for injection – up to 1 ml

How to take, the dosage

The dose of the drug is adjusted individually, under the supervision of a doctor. It is administered subcutaneously before meals

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Interaction

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

The hypoglycemic effects of insulin are impaired by oral contraceptives, GCS, thyroid hormones, thiazide diuretics, heparin, tricyclic antidepressants, sympathomimetics, somatropin, danazol, clonidine, calcium channel blockers, diazoxide, morphine, phenytoin, nicotine.

Beta-adrenoblockers may mask symptoms of hypoglycemia.

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

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

Special Instructions

Patients should consult with their physician before traveling for an extended period of time because a time zone change means the patient must eat and inject insulin at a different time.

Hyperglycemia. An insufficient dose of medication or discontinuation of treatment, especially in type 1 diabetes, can lead to the development of hyperglycemia and diabetic ketoacidosis. Typically, symptoms of hyperglycemia appear gradually over a period of hours or days. Symptoms of hyperglycemia include a feeling of thirst, increased urine output, nausea, vomiting, drowsiness, red and dry skin, dry mouth, loss of appetite, and the smell of acetone in the exhaled air. Without appropriate treatment, hyperglycemia in patients with type 1 diabetes can lead to diabetic ketoacidosis, a condition that is potentially fatal.

Hypoglycemia. Skipping a meal or unplanned strenuous exercise can lead to hypoglycemia. Hypoglycemia can also occur if a dose of insulin too high relative to the patient’s need is administered (see Side Effects, Overdose).

In comparison to biphasic human insulin, administration of NovoMix® 30 FlexPen® has a more pronounced hypoglycemic effect within 6 hours of administration. In this regard, in individual cases, it may be necessary to adjust the dose of insulin and/or dietary patterns. After compensation of carbohydrate metabolism, e.g. with intensified insulin therapy, patients may change typical precursor symptoms of hypoglycemia, and the patients should be informed about it. Typical precursor symptoms may disappear in the long-term course of diabetes mellitus. Stricter control of glycemic levels in patients may increase the risk of hypoglycemia; therefore, increasing the dose of NovoMix® 30 FlexPen® should be done under close medical supervision (see “Dosage and administration”).

Since NovoMix® 30 FlexPen® must be used directly in conjunction with food intake, the high rate of onset of the drug effect should be considered when treating patients who have comorbidities or are taking medications that delay food absorption.

Concomitant diseases, especially infectious and accompanied with fever, usually increase the body’s need for insulin. Correction of the drug dose may also be necessary if the patient has concomitant kidney, liver, adrenal, pituitary, or thyroid disorders.

If the patient is switched to other types of insulin, the early precursor symptoms of hypoglycemia may change or become less severe than with the previous type of insulin.

Transferring a patient from other insulin medications. Transfer of a patient to a new type of insulin or another manufacturer’s insulin must be done under strict medical supervision. A change in concentration, type, manufacturer and type (human insulin, human insulin analogues) of insulin preparations and/or method of manufacture may require a change in 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 may be made as early as the first administration of the drug or during the first weeks or months of treatment.

Injection site reactions. As with other insulin drugs, injection site reactions may develop, as manifested by pain, redness, urticaria, inflammation, bruising, swelling, and itching. Regularly changing the injection site in the same anatomical area may reduce symptoms or prevent the development of these reactions. Reactions usually disappear within a few days to a few weeks. In rare cases, NovoMix® 30 FlexPen® may need to be withdrawn due to injection site reactions.

The concomitant use of thiazolidinedione and insulin drugs has been reported in patients treated with thiazolidinedione in combination with insulin drugs, especially if these patients have risk factors for chronic heart failure. This fact should be taken into account when prescribing combined therapy with thiazolidinediones and insulin drugs. When prescribing such combination therapy, medical examination of patients should be carried out to detect signs and symptoms of chronic heart failure, weight gain and edema. If patients have worsening symptoms of heart failure, treatment with thiazolidinedione should be discontinued.

Impact on ability to drive vehicles and operate machinery.Patients’ ability to concentrate and reaction speed may be impaired during hypoglycemia, which may pose a hazard in situations where these abilities are particularly needed (e.g., driving or operating machinery and machines).

Patients should be advised to take steps to prevent hypoglycemia during driving. This is particularly important for patients with the absence or reduced severity of symptom precursors of developing hypoglycemia or who suffer from frequent episodes of hypoglycemia. In these cases, consideration should be given to the appropriateness of driving and performing such activities.

Contraindications

Individual hypersensitivity to insulin aspart or any of the ingredients of the drug.

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Overdose

Symptoms. No specific dose required for insulin overdose has been established, but hypoglycemia may develop gradually if doses too high relative to the patient’s need are administered.

Treatment. Mild hypoglycemia can be managed by the patient himself by ingesting glucose or sugary foods. Therefore, it is recommended that diabetics carry sugary foods with them at all times.

In case of severe hypoglycemia, when the patient is unconscious, 0.5 mg to 1 mg of glucagon should be administered either by injection or by injection (can be administered by a trained person), or an intravenous glucose (dextrose) solution (can only be administered by a healthcare professional). Dextrose should also be administered intravenously if the patient does not regain consciousness 10-15 minutes after glucagon administration. After recovery of consciousness, the patient is advised to take carbohydrate-rich food to prevent recurrence of hypoglycemia.

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