Composition, form of production and packaging
The solution for the sc administration is clear, colorless.
1 ml
a mixture of insulin degludec and insulin aspart in a ratio of 70/30 (equivalent to 2.56 mg insulin degludec and 1.05 mg insulin aspart) 100 units *
[PRING] glycerol 19 mg, phenol 1.5 mg, metacresol 1.72 mg, zinc 27.4 Ојg (zinc acetate 92 Ојg), sodium chloride 0.58 mg, hydrochloric acid or sodium hydroxide (for pH correction), water d / and - up to 1 ml.
3 ml (300 units) - Penfill В® glass cartridges (5) - Al / PVC blisters (1) - cardboard packs.
The pH of the solution is 7.4.
* 1 ED contains 0.0256 mg of anhydrous saltless insulin degludec and 0.0105 mg of anhydrous salt-free insulin aspart that corresponds to 1 IU of human insulin, 1 ED of insulin detemir, insulin glargine or biphasic insulin aspart.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Rhizodeg В® Penfill В® is a combined preparation consisting of a soluble analog of human insulin of superlative action (insulin degludec) and a fast acting soluble analog of human insulin (insulin aspart), produced by the method of biotechnology of recombinant DNA using the strain of Saccharomyces cerevisiae.
Mechanism of action
Insulin degludec and insulin aspart bind in a specific way to the human endogenous insulin receptor and interact with it, realizing their pharmacological effect similar to the effect of human insulin. The hypoglycemic action of insulin is due to the increased utilization of glucose by tissues after binding of insulin to the receptors of muscle and fat cells, and a simultaneous decrease in the rate of production of glucose by the liver.
Pharmacodynamics
The pharmacodynamic effects of the components of the preparation RhizodegВ® PenfillВ® differ distinctly and the general profile of the action of the preparation reflects the profiles of the action of individual components: high-speed insulin aspart and insulin degludec of long-acting action.
The basal component of the preparation RhizodegВ® PenphillВ®, which has a super-long action (insulin degludec), after subcutaneous injection forms soluble multiexameres in the subcutaneous depot, from which the insulin degludec enters the circulation slowly, providing a flat action profile and a stable hypoglycemic effect of the drug. This effect is preserved in combination with insulin aspart and does not affect the rate of absorption of fast-acting insulin aspart monomers.
The preparation RhizodegВ® PenphillВ® begins to act quickly, providing a prandial insulin requirement shortly after injection, while the basal component has a flat, stable and ultra-long action profile that provides a basal insulin requirement. The duration of a single dose of RhizodegВ® Penphill В® is more than 24 hours.
A linear relationship between an increase in the dose of Raizodeg В® Penfnill В® and its overall and maximum hypoglycemic effect was demonstrated. The equilibrium concentration of the preparation Rhizodeg В® Penfill В® is achieved after 2-3 days of the drug administration.
Differences in the pharmacodynamics of RaizodegВ® Penphill В® in elderly and senile patients and younger patients were not revealed.
Clinical efficacy and safety
Five international randomized, controlled, open-label clinical trials of the Raizodeg В® preparation were performed in the Treatment to Goal mode for 26 or 52 pedules involving 1,360 patients with diabetes mellitus (362 patients with type 1 diabetes and 998 patients with type 2 diabetes). Two comparisons were made of gelmy studies of a single dose of RazodegВ® in combination with oral hypoglycemic drugs (PGHP) and single administration of insulin glargine in combination with PGHP in patients with type 2 diabetes. The administration of RaizodegВ® twice a day in combination with PGHP was compared with the administration of biphasic insulin aspart 30 twice a day in combination with PGHP in two studies in patients with type 2 diabetes mellitus. The introduction of Raizodeg В® once a day in combination with insulin aspart was also compared with the administration of insulin detirim alone or two times daily in combination with insulin aspartate in patients with type 1 diabetes mellitus.
It has been shown that the absence of superiority in comparative drugs has been reduced by Raizodeg В® with respect to the reduction of HbA 1c in all studies in the treatment of patients to the target.
In patients with type 2 diabetes mellitus who never received insulin therapy and patients who had previously received insulin therapy, the Rhizodeg В® preparation in combination with PGHP provides a similar glycemic control compared to insulin glargine. Raizodeg В® provides better prandial glycemic control compared to insulin glargine with a lower incidence of nocturnal hypoglycemia (defined as episodes of hypoglycemia occurring between 0 and 6 am, confirmed by a plasma glucose concentration of less than 3.1 mmol / L or evidence The fact that the patient required the help of third parties).
The introduction of Raizodeg® twice daily provides a similar glycemic control (HbA 1c ) compared to the two-phase insulin aspart 30, which was also administered twice daily. The preparation Raizodeg ® provides the best positive dynamics of the decrease in the concentration of glucose in blood plasma on an empty stomach.With the use of Raizodeg ®, the target blood plasma glucose values ​​of 5 mmol / l in patients were achieved faster than patients treated with biphasic insulin aspart 30. The drug Raizodeg ® rarely causes hypoglycemia (including nocturnal). In patients with type 1 diabetes, treatment with Raizodeg ® once a day in combination with insulin aspart before other meals showed similar glycemic control (HbA 1c and fasting plasma glucose) with more rare cases of nocturnal hypoglycemia compared to basal bolus regimen the introduction of insulin dystmir and insulin aspart with each meal.
According to the meta-analysis data of two 26-week open-label studies planned for patients with type 2 diabetes, RizodegВ®, administered twice a day, showed a lower incidence of episodes of confirmed hypoglycemia in general and the confirmed episodes of nocturnal hypoglycemia as compared to insulin aspart biphasic 30. The results showed that the drug Rayzodeg В® reduces plasma fasting glucose concentration with a reduced risk of hypoglycemia in the proce se studies and in maintenance doses from 16 weeks (Table 1)
Table 1. Results of meta-analysis of data on episodes of confirmed hypoglycemia when administered twice a day during the study and during the maintenance of the dose from week 16
Analyzes Established Relative Frequency [95% CI] Study Period Established Relative Frequency [95% CI] Dose Maintenance Period
The total number of confirmed hypoglycemia preparation Raizodeg В® (2 times a day) / biphasic insulin aspart 30 (2 times a day) 0.81 [0.67: 0.9S] 0.43 [0.31: 0.59]
Nocturnally confirmed hypoglycemia preparation Raizodeg В® (2 times a day) / biphasic insulin aspart 30 (2 times a day) 0.69 [0.55: 0.87] 0.38 [0.25, 0.58]
There was no clinically significant formation of antibodies to insulin after treatment with Raizodeg В® for an extended period.
PHARMACOKINETICS
Absorption
After subcutaneous injection, the formation of soluble stable multi-hemeamer insulin degludec. which create a depot of insulin in the subcutaneous fat tissue, and does not hinder the rapid release of insulin aspart monomers into the bloodstream. Multiexameres gradually dissociate, releasing insulin degludec monomers, resulting in a slow continuous flow of the drug into the blood. The equilibrium concentration of the ultra-long-acting (insulin degludec) component in the blood plasma is achieved 2-3 days after the administration of RaizodegВ®.
Well-known indicators of rapid absorption of insulin aspart are preserved in the preparation RaizodegВ®. The pharmacokinetic profile of insulin aspart appears 14 minutes after the injection, the maximum concentration is observed after 72 minutes.
Distribution
The affinity of insulin degludec to serum albumin corresponds to the binding capacity of plasma protein> 99% in human blood plasma. In insulin aspart, the binding capacity of the plasma protein is lower (<10%), as does human insulin.
Metabolism
The breakdown of insulin degludec and insulin aspart is similar to that of human insulin; all formed metabolites are inactive.
Excretion
The half-life of Raizodeg В® after subcutaneous injection is determined by the rate of its absorption from the subcutaneous tissue. The half-life of insulin degludec is approximately 25 hours and does not depend on the dose.
Linearity
The total effect of the preparation Raizodeg В® is proportional to the administered dose of the basal component (insulin degludec) and the prandial component (insulin aspart) in type 1 and type 2 diabetes mellitus.
Special patient groups
There were no differences in the pharmacokiptic properties of the preparation Rhizodeg В® , depending on the sex of the patients.
Patients of advanced age, patients of different ethnic groups, patients with impaired function of nochek or liver
There were no clinically significant differences in the pharmacokinetics of Raizodeg В® between elderly and young patients, between patients of different ethnic groups, between patients with impaired renal and hepatic function and healthy patients.
Children and teens
The pharmacokinist properties of the preparation Raizodeg В® in a study in children (6-11 years) and adolescents (12-18 years) with type 1 diabetes mellitus are comparable to those of adult patients on a background of a single injection.
The total concentration and maximum concentration of insulin aspart are higher in children than in adults and are the same in adolescents and adults.
The pharmacokinetic properties of insulin degludec in children and adolescents with type 1 diabetes mellitus are comparable to those of adult patients. Against the background of a single administration to patients with diabetes mellitus type 1 of insulin degludec dose it was demonstrated that the total dose effect of the drug in children and adolescents is higher than that of adult patients.
Pre-clinical safety data
Preclinical data based on pharmacological safety studies, repeated dose toxicity. carcinogenic potential, toxic effect on reproductive function, did not reveal any danger to humans. The ratio of metabolic and mitogenic activity of insulin degludec is similar to that of human insulin.
INDICATIONS
- diabetes in adults.
DOSING MODE
The preparation Rhizodeg В® Penfill В® is a combination of soluble insulin analogs - an ultra-long-acting basal insulin (insulin degludec) and a rapid-acting prandial insulin (insulin aspart).
The drug is administered subcutaneously 1 or 2 times a day before the main meals. If necessary, patients have the opportunity to independently change the time of administration of the drug, but it must be tied to the main meal.
In patients with type 2 diabetes mellitus, RhizodegВ® PenphillВ® can be used either as monotherapy or in combination with PGHP or bolus insulin.
Patients with type 1 diabetes are prescribed RhizodegВ® PenphillВ® in combination with short / ultrashort insulin before other meals.
The dose of Rhizodeg В® Penfill В® is determined individually according to the patient's needs. To optimize glycemic control, it is recommended to correct the drug vine on the basis of fasting plasma glucose.
As with any form of insulin, correction of the dose of the drug may be required with increased physical activity of the patient, a change in his usual diet or with concomitant disease.
The initial dose of RhizodegВ® PenphillВ®
Patients with type 2 diabetes mellitus
The recommended initial daily dose of Raizodeg В® Penfill В® is 10 units, with the subsequent selection of an individual dose of the drug.
Patients with type 1 diabetes mellitus
The recommended initial dose of RhizodegВ® PenphillВ® is 60-70% of the total daily insulin requirement.
The preparation Rhizodeg В® Penfill В® is prescribed once a day during the main meal in combination with fast / short-acting insulin administered before the rest of the meals, followed by the selection of an individual dose of the drug.
Translation from other insulin preparations
It is recommended that the blood glucose concentration be closely monitored during the transfer and in the first prescription medication guide. It may be necessary to correct concomitant gnopglankemicheskoy therapy (dose and time of administration of insulin preparations of short and ultrashort action or dose of PGHP).
Patients with type 2 diabetes mellitus:
When transferring patients receiving basal insulin therapy or biphasic insulin therapy once per laziness, the dose of RaizodegВ® Penphill В® should be calculated on a "one-on-one" basis from the total daily insulin dose that the patient received before switching to a new type of insulin.
When transferring patients who are in more than a single mode of administration of basal or biphasic insulin, the dose of RaizodegВ® PenphillВ® should be calculated on a "one-on-one" basis, with a double injection of Rhizodeg! * PenfillВ® at the same total daily dose of insulin , which the patient received before the transfer to a new type of insulin.
When translating patients who are on a basal-bolus regimen of ipulsipotherapy. the dose of RhizodegВ® PenfillВ® should be calculated on the basis of the patient's individual needs. As a rule, patients start with the same dose of basal insulin.
Patients with type 1 diabetes mellitus:
The recommended initial dose of RaizodegВ® PenfillВ® is 60-70% of the total daily insulin requirement in combination with short / ultrashort insulin with other meals and the subsequent selection of an individual dose of the drug.
Flexible dosing regimen
The time of Rhizodeg В® Penfill В® may change if the time of the main meal changes.
If the dose of RhizodegВ® Penphyl В® is missed, the patient may enter the next dose on the same day with the next main meal, and then return to his usual injection time. Do not administer an additional dose to compensate for the missed dose.
Special patient groups
Patients of advanced age (over 65 years):
The preparation Rhizodeg В® Penfill В® can be used in elderly patients. You should carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see Pharmacokinetics section).
Patients with kidney and liver failure:
The drug Rhizodeg В® Penfill В® can be used in patients with kidney and liver failure. You should carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see subsection Pharmacokinetics).
Children and adolescents:
Existing pharmacokinetic data are presented in the subsection Fircomokinetics, but the efficacy and safety of RaizodegВ® Penphill В® in children and adolescents under 18 years of age have not been studied, and recommendations for the dose of the drug in children have not been developed.
Mode of application
The preparation Rhizodeg В® Penfill В® is intended only for subcutaneous administration. Preparation Rhizodeg В® Penfill В® can not be administered intravenously, as this can lead to the development of severe hypoglycemia. Preparation Rhizodeg В® Penfill В® can not be administered intramuscularly, since in this case the absorption of the drug varies. The preparation Rhizodeg В® Penfill В® can not be used in insulin pumps. The preparation Rhizodeg В® Penfill В® is injected subcutaneously into the thigh area, the anterior abdominal wall or the shoulder region. You should constantly change injection sites within the same anatomical area to reduce the risk of developing lipodystrophy. The PenfillВ® cartridge is designed for use with injection systems for Novo Nordisk insulin and disposable needles NovoFineВ® or NovoTvistВ®.
SIDE EFFECT
The most common side effect reported during treatment is hypoglycemia (see Description of individual adverse reactions).
All of the side effects presented below, based on data from clinical trials, are allocated to groups according to MedDRA and organ systems. The incidence of side effects is defined as: very often (? 1/10): often (? 1/100 to <1/10); infrequently (? 1/1 000 to <1/100); rarely (? 1/10 000 to <1/1000), very rarely (<1/10 000) and unknown (it is impossible to estimate based on available data).
Violations by the immune system rarely - hypersensitivity reactions
Rare - Hives
violations by Metabolism and nutrition Very often - Hypoglycemia
Disorders of the skin and subcutaneous tissue is not known - Lppodistrofiya
General disorders and injection site often - reactions at the injection site
Uncommon - Peripheral edema
Description of the individual side reactions
disorders of immune system
When using insulin preparations may develop allergic reactions. Allergic reactions of immediate type insulin or auxiliary components. make up the drug could potentially threaten the patient's life. In applying the drug Rayzodeg В® PenfillВ® hypersensitivity reactions (including swelling of the lips or tongue, diarrhea, nausea, fatigue and itching) and urticaria have been observed rarely.
Hypoglycemia
Hypoglycemia can develop if the insulin dose is too high in relation to the needs of the patient therein. Severe hypoglycemia may lead to loss of consciousness and / or convulsions, temporary or permanent impairment of brain function or death. Symptoms of hypoglycaemia usually develop suddenly. They include a "cold sweat", pale skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, disorientation, poor concentration, drowsiness, expressed the feeling of hunger, blurred vision, headache, nausea, heart palpitations.
Lipodystrophy
Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Compliance with the rules change the injection site within the same anatomical region helps to reduce the risk of this adverse reaction.
Injection site reactions
in patients receiving the drug Rayzodeg В® Penfill В® , observed reactions in the injection site (hematoma, pain, local bleeding, erythema, nodules of the connective tissue, swelling, changes in skin color, itching, irritation and induration at the injection site). Most injection site reactions are minor and of a temporary nature and usually disappear with continued treatment.
The pharmacokinetic properties of the drug Rayzodeg В® PenfillВ® have been studied in children and adolescents under 18 years of age (see. Farmakokiietika subsection). Research on the effectiveness and safety have not been conducted in children and adolescents.
In clinical trials no differences in the incidence, type, and severity of adverse reactions between elderly patients, patients with impaired renal or hepatic function , and the general population of patients not detected.
CONTRAINDICATIONS
- increased sensitivity of the individual to the active substances or any of the auxiliary components of the formulation;
- children's age till 18 years;
- during pregnancy and breastfeeding (clinical experience with the drug in children, women during pregnancy and breastfeeding is not)
PREGNANCY AND LACTATION
Pregnancy
Use of the drug Rayzodeg В® Penfill В® during pregnancy is contraindicated, as clinical experience with its use during pregnancy is not available. Reproduction studies in animals did not reveal any differences between insulin degludek and human insulin in terms of embryo toxicity and teratogenicity.
Breastfeeding period
Use of the drug Rayzodeg В® Penfill В® in breast-feeding period is contraindicated, as clinical experience with its use in lactating women is not available.
Animal studies have shown that in the rat insulin degludek excreted in breast milk, the drug concentration in breast milk is lower than in blood plasma. It is unknown whether insulin degludek excreted in breast milk of women.
Fertility
In animal studies found no adverse effects of insulin degludek fertility.
APPLICATION FOR FUNCTIONS OF THE LIVER
Preparation Rayzodeg В® Penfill В® can be used in patients with renal insufficiency. One should carefully monitor the concentration of blood glucose and insulin dose adjusted individually (see. Pharmacokinetics subsection).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Preparation Rayzodeg В® Penfill В® can be used in patients with renal insufficiency. One should carefully monitor the concentration of blood glucose and insulin dose adjusted individually (see. Pharmacokinetics subsection).
APPLICATION FOR CHILDREN
Existing pharmacokinetic data presented in subsection Firmakokinetika, but the effectiveness and safety of the drug Rayzodeg В® Penfill В® in children and adolescents under 18 years of age have not been studied, the dose of the drug recommendations for children are not developed.
APPLICATION IN ELDERLY PATIENTS
Preparation Rayzodeg В® Penfill В® may be used in elderly patients. One should carefully monitor the concentration of blood glucose and insulin dose adjusted individually (see. Farmakokiietika section).
SPECIAL INSTRUCTIONS
hypoglycemia
When skipping meals or unplanned intensive exertion of the patient may develop hypoglycemia. Hypoglycemia may also develop if introduced too high in relation to the needs of the patient dose of insulin (see. Side effects sections and overdose). After compensation of carbohydrate metabolism (e.g., intensified iisuliioterapii). patients can vary typical for them-the harbingers of the symptoms of hypoglycemia, as patients should be informed. Conventional-harbingers of the symptoms may disappear with prolonged duration of diabetes. Concomitant diseases, especially infectious and accompanied by fever, usually increase the body's need for insulin. Correction doses may also be necessary if the patient related renal disease,liver disorders or adrenal, pituitary, or thyroid.
As with other drugs or basal insulin preparations with a basal component recovery from hypoglycemia when using the drug Rayzodeg В® Penfill В® can be trapped.
Hyperglycemia
insufficient dose or discontinuation of treatment can lead to the development of hyperglycemia or diabetic ketoacidosis. In addition, co-morbidities. especially infectious, may contribute to the development and hyperglycemic conditions. accordingly, increase the body's need for insulin.
Typically, the first symptoms of hyperglycaemia occur gradually over several hours or days. These symptoms include thirst, frequent urination, nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, loss of appetite, the smell of acetone in exhaled air. In type 1 diabetes without treatment hyperglycemia leads to the development of diabetic ketoacidosis and can lead to death.
It recommended to introduce fast-acting insulin for the treatment of severe hyperglycemia.
Transfer patient from other insulin products
Transfer the patient to a new type of medication or insulin, or a new brand of another manufacturer must be under strict medical supervision. When transferring may require dose adjustment.
The simultaneous use of drugs of the thiazolidinedione and insulin preparations
have been reported cases of congestive heart failure in patients giazolidindionami in combination with insulin preparations, especially in the presence of such risk factors for patients with chronic heart failure. Keep in mind this fact when assigning patients to combination therapy and drug tiazolidindiopami Rayzodeg В® PenfillВ®. In the appointment of such combination therapy is necessary to conduct medical examination of patients to identify their signs and symptoms of congestive heart failure, weight gain and the presence of peripheral edema. In case of deterioration of the patients symptoms of heart failure, treatment with thiazolidinediones should be discontinued.
Disturbances on the part of the organ of sight
Intensification ipsuliioterapii with a sharp improvement in carbohydrate metabolism control can cause a temporary worsening of diabetic retinopathy status, while at the same time, long-term improvement in glycemic control reduces the risk of diabetic retinopathy progress.
Preventing accidental entanglement insulin preparations
should instruct the patient about the necessary before each injection check mark on the label in order to avoid accidental entanglement preparation Rayzodeg В® PenfillВ® with other drugs of insulin.
Patients should check the dialed dose on the counter dose injector. Patients should be informed of blind or visually impaired people that they always need help individuals who do not have vision problems and trained to use the injector.
Antibodies to insulin
When using insulin possible formation of antibodies. In rare cases, the formation of antibodies may require insulin for correction of the dose prevent the occurrence of hyperglycemia or hypoglycemia.
Impact on the ability to drive vehicles and mechanisms
And capable of, to the ends of patients radios and reaction rate can be violated during hypoglycemia that may constitute a danger in situations where this ability is particularly necessary (e.g., when driving or operating machinery).
Patients should be advised to take measures to prevent the development of hypoglycemia when driving. This is especially important for patients with absence or reduction in the severity of symptoms-harbingers of developing hypoglycemia or frequent episodes of hypoglycaemia. In these cases, you should consider the advisability of driving.
OVERDOSE
Particular dose required for insulin overdose is not established, but may develop hypoglycemia gradually if too high compared to the need of the patient the dose has been introduced (see. Specific guidance section).
Easy hypoglycaemia the patient can remove himself. taking into glucose or sugar products. Therefore, patients with diabetes are advised to routinely carry sugar products.
In the case of severe hypoglycemia when the patient is unconscious, he should enter glucagon (0.5 to 1 mg) intramuscularly or subcutaneously (can enter a trained person) or intravenous dextrose (glucose) (can only enter a medical worker). It is also necessary to introduce intravenous dextrose in the case, sat down after 10-15 minutes after administration of glucagon, the patient did not regain consciousness. After recovery of consciousness the patient is advised to take writing, rich in carbohydrates, for profilakshki recurrence of hypoglycemia.
DRUG INTERACTION
There are a number of drugs that affect the need for insulin. The need for insulin can reduce: oral hypoglycemic agents, receptor agonists, glucagon-like peptide-1 (GLP-1), inhibitors of
MAO, selective beta-blockers, ACE inhibitors, salicylates, anabolic steroids and sulfonamides.
Insulin requirements may increase: oral hormonal contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and daiazol. Beta-blockers may mask the symptoms of hypoglycemia. Octreotide / lanreotide may either increase or decrease the body's need for insulin.
Ethanol can both enhance and decrease the hypoglycemic effect of insulin.
Incompatibility
Some drugs, when added to a preparation Rayzodeg В® Penfill В® can cause destruction degludek insulin and / or insulin aspart. Preparation Rayzodeg В® Penfill В® can not be added in iifuzionnye solutions. It is impossible to mix the drug with Druts drugs.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store at 2 to 8 В° C (in a refrigerator) but not close to the freezing chamber. Do not freeze.
Store cartridges in a carton box to protect from light.
To be used or carried as a spare cartridge: not stored in the refrigerator. Store at a temperature not higher than 30 В° C for 4 weeks.
Keep out of the reach of children.
Shelf life - 30 months.
