Rayzodeg^® Penphill (Solution) Instructions for Use

ATC Code

A10AD06 (Insulin degludec + insulin aspart)

Active Substances

Insulin aspart (Rec.INN registered by WHO)

Insulin degludec (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combination of intermediate-acting or long-acting and short-acting human insulin analogues

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; insulins and their analogues; intermediate-acting or long-acting insulins and their analogues in combination with short-acting insulins for injectable administration.

Pharmacological Action

Hypoglycemic agent, an insulin preparation consisting of a soluble ultra-long-acting human insulin analogue (Insulin degludec) and a rapid-acting soluble human insulin analogue (Insulin aspart), produced by recombinant DNA biotechnology using a Saccharomyces cerevisiae strain.

Insulin degludec and insulin aspart specifically bind to the receptor of human endogenous insulin and, by interacting with it, exert their pharmacological effect similarly to that of human insulin. The hypoglycemic effect of insulin is due to an increase in glucose utilization by tissues after insulin binds to receptors on muscle and fat cells, and a simultaneous decrease in the rate of glucose production by the liver.

The pharmacodynamic effects of the combination components are distinctly different, and the overall action profile of the drug reflects the action profiles of the individual components: rapid-acting Insulin aspart and ultra-long-acting Insulin degludec.

The basal component of the combination, which has an ultra-long action (insulin degludec), after subcutaneous injection forms soluble multihexamers in the subcutaneous depot, from where a continuous slow release of Insulin degludec into the circulation occurs, providing a flat action profile and a stable hypoglycemic effect of the drug.

This effect is maintained in combination with insulin aspart and does not affect the absorption rate of the rapid-acting Insulin aspart monomers.

The combination starts to act rapidly, meeting prandial insulin needs shortly after injection, while the basal component has a flat, stable, and ultra-long action profile that provides basal insulin requirements. The duration of action of a single dose is more than 24 hours.

A linear relationship has been demonstrated between the increase in the dose of this combination and the overall and maximum hypoglycemic effect. Steady-state concentration is achieved after 2-3 days of administration.

Pharmacokinetics

After subcutaneous injection, soluble stable multihexamers of Insulin degludec are formed, which create an insulin depot in the subcutaneous adipose tissue, and this does not prevent the rapid release of Insulin aspart monomers into the bloodstream.

The multihexamers gradually dissociate, releasing Insulin degludec monomers, resulting in a slow continuous entry of the drug into the blood. The steady-state concentration of the ultra-long-acting component (Insulin degludec) in the blood plasma is reached 2-3 days after administration of the combination.

The well-known parameters of rapid absorption of Insulin aspart are preserved when using this combination. The pharmacokinetic profile of Insulin aspart appears 14 minutes after injection, with C_max observed at 72 minutes.

The affinity of Insulin degludec for serum albumin corresponds to a plasma protein binding capacity of > 99% in human plasma. Insulin aspart has a lower plasma protein binding capacity (<10%), as does human insulin.

The degradation of Insulin degludec and Insulin aspart is similar to that of human insulin; all metabolites formed are inactive.

The T_1/2 of the combination after subcutaneous injection is determined by its absorption rate from the subcutaneous tissue. The T_1/2 of Insulin degludec is approximately 25 hours and is dose-independent.

Indications

Diabetes mellitus in adults.

ICD codes

Dosage Regimen

Solution

Administered subcutaneously 1-2 times/day before main meals.

In patients with type 2 diabetes mellitus, it can be used both as monotherapy and in combination with oral hypoglycemic agents or with bolus insulin.

In patients with type 1 diabetes mellitus, it is used in combination with short/ultra-short-acting insulin before other meals.

The dose is determined individually according to the patient’s needs. To optimize glycemic control, it is recommended to adjust the dose of the drug based on fasting plasma glucose levels.

As with the use of any insulin preparations, dose adjustment of the drug may be required with increased physical activity of the patient, changes in their usual diet, or in case of concomitant illness.

The recommended initial daily dose is 10 units, followed by individual dose titration.

Adverse Reactions

Immune system disorders rarely – hypersensitivity reactions, urticaria.

Metabolism and nutrition disorders: very common – hypoglycemia.

Skin and subcutaneous tissue disorders unknown – lipodystrophy.

General disorders and administration site conditions common – reactions at the injection site; uncommon – peripheral edema.

Contraindications

Children under 18 years of age; pregnancy, breastfeeding period, hypersensitivity to the components of the combination.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

The drug Rayzodeg^® Penphill^® can be used in patients with renal insufficiency. Blood glucose concentration should be carefully monitored and the insulin dose adjusted individually (see the Pharmacokinetics subsection).

Use in Renal Impairment

The drug Rayzodeg^® Penphill^® can be used in patients with renal insufficiency. Blood glucose concentration should be carefully monitored and the insulin dose adjusted individually (see the Pharmacokinetics subsection).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Blood glucose concentration should be carefully monitored and the insulin dose adjusted individually.

Special Precautions

If a meal is missed or during unplanned intense physical exertion, the patient may develop hypoglycemia. Hypoglycemia can also develop if a dose of insulin that is too high relative to the patient’s needs is administered. After compensation of carbohydrate metabolism (for example, during intensive insulin therapy), the typical warning symptoms of hypoglycemia for patients may change, and patients should be informed about this.

Usual warning symptoms may disappear with long-term diabetes. Concomitant diseases, especially infectious ones accompanied by fever, usually increase the body’s need for insulin. Dose adjustment of the drug may also be required in the presence of concomitant kidney or liver diseases, or impaired function of the adrenal glands, pituitary gland, or thyroid gland.

As with the use of other basal insulin preparations or preparations with a basal component, recovery from hypoglycemia when using this combination may be delayed.

Insufficient dose of the drug or discontinuation of treatment can lead to the development of hyperglycemia or diabetic ketoacidosis. In addition, concomitant diseases, especially infectious ones, can contribute to the development of hyperglycemic conditions and, accordingly, increase the body’s need for insulin.

Switching a patient to a new type or brand of insulin or insulin from a different manufacturer should occur under strict medical supervision. Dose adjustment may be required when switching.

Cases of chronic heart failure have been reported during treatment of patients with thiazolidinediones in combination with insulin preparations, especially in such patients with risk factors for the development of chronic heart failure. When prescribing such combination therapy, medical examinations of patients should be conducted to identify signs and symptoms of chronic heart failure, weight gain, and the presence of peripheral edema. If symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Intensification of insulin therapy with a sharp improvement in carbohydrate metabolism control can lead to a temporary worsening of diabetic retinopathy, while long-term improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

Formation of antibodies is possible with the use of insulin. In rare cases, antibody formation may require adjustment of the insulin dose to prevent cases of hyperglycemia or hypoglycemia.

Effect on ability to drive vehicles and operate machinery

The ability of patients to concentrate and the speed of reactions may be impaired during hypoglycemia, which can be dangerous in situations where this ability is especially necessary (for example, when driving vehicles or working with machinery). Patients should be advised to take measures to prevent the development of hypoglycemia when driving vehicles.

This is especially important for patients with absent or reduced severity of warning symptoms of developing hypoglycemia or with frequent episodes of hypoglycemia. In these cases, the advisability of driving a vehicle should be considered.

Drug Interactions

There are a number of medicinal products that affect the need for insulin. The need for insulin can be reduced by: oral hypoglycemic agents, glucagon-like peptide-1 (GLP-1) receptor agonists, MAO inhibitors, non-selective beta-blockers, ACE inhibitors, salicylates, anabolic steroids, and sulfonamides.

The need for insulin can be increased by: oral hormonal contraceptives, thiazide diuretics, glucocorticosteroids, thyroid hormones, sympathomimetics, somatropin, and danazol. Beta-blockers can mask the symptoms of hypoglycemia. Octreotide/lanreotide can either increase or decrease the body’s need for insulin.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.