Rhizodeg Penfill - instructions for use, dose, side effects, contraindications

Active substanceInsulin degludec + Insulin aspartInsulin degludec + Insulin aspart

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Rhizodeq® Penphill®

solution PC

Novo Nordisk A / S Denmark

Rizodeq® FlexTech®

solution PC

Novo Nordisk A / S Denmark

Dosage form: & nbsphypodermic solution

Composition:

In 1 ml of the drug is contained:

active substance: 100 units of insulin degludec / insulin aspart in a ratio of 70/30 (equivalent to 2.56 mg insulin degludec / 1.05 mg insulin aspart);

Excipients: glycerol 19.0 mg, phenol 1.5 mg, metacresol 1.72 mg, zinc 27.4 μg (as zinc acetate 92.0 μg), sodium chloride 0.58 mg, hydrochloric acid / sodium hydroxide (for pH correction ), water for injection up to 1 ml.

The pH of the solution is 7.4.

One cartridge contains 3 ml of a solution equivalent to 300 units.

One unit of insulin Raizodeg® contains 0.0256 mg of anhydrous insolide deglucose and 0.0105 mg of anhydrous salt-free insulin aspart.

One unit of insulin Raizodeg® (ED) corresponds to one international unit (ME) of human insulin, one unit of insulin glargine, one unit of insulin detemir, or one unit of two-phase insulin aspart.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:hypoglycemic agent - a combination of insulin analogues of medium duration or long and short action

ATX: & nbsp

A.10.A.D.06 Insulin degludec and insulin aspart

Pharmacodynamics:

Rizodeq® Penfill® is a combined preparation consisting of a soluble analog of human super insulin insulin (insulin degludec) and a high-speed soluble analog of human insulin (insulin aspart), produced by biotechnology of recombinant DNA using a strain Saccharomyces cerevisiae.

Insulin Degloodec and insulin aspart specifically bind to the human endogenous insulin receptor and, interacting with it, realize their pharmacological effect similarly 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.

The pharmacodynamic effects of the components of the preparation Rhizodeg® Penfill® differ distinctly (Fig. 1) and the overall profile of the action of the preparation reflects the profiles of the action of the individual components: high-speed insulin aspart and insulin degludec of long-acting action.

The basal component of the preparation Rhizodeg® Penfill®, which has an extremely long-acting effect (insulin degluedek), after subcutaneous injection forms soluble multiexamers in the subcutaneous depot, from which a continuous slow flow of insulin degludec into the circulation, providing a flat action profile and 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 Rhizodeg® Penphill® 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 Raizodeg® Penphill® is more than 24 hours.

See Figure 1. The average profile of the rate of glucose infusion is the equilibrium concentration of the preparation Raizodeg® after the administration of a single dose of 0.8 U / kg for Type 1 diabetes mellitus (study 3539).

A linear relationship between an increase in the dose of Raizodeg® Penphyl® and its overall and maximum hypoglycemic effect was demonstrated.The equilibrium concentration of the preparation Rhizodeg® Penphill® is achieved after 2-3 days of the drug administration.

Differences in the pharmacodynamics of Raizodeg® Penphill® in elderly and senile patients and younger patients have not been revealed.

Clinical efficacy and safety

Five international randomized, controlled, open-label clinical trials of the Raizodeg® preparation were conducted in the Treatment to Goal mode for 26 or 52 weeks with the participation of 1360 patients with diabetes mellitus (362 patients with type 1 diabetes and 998 patients with type 2 diabetes). Two comparative studies of a single administration of Raizodeg® in combination with oral hypoglycemic drugs (PGHP) and single administration of insulin glargine in combination with PGHP in patients with type 2 diabetes have been conducted. The administration of Raizodeq® 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 administration of Raizodeq® once a day in combination with insulin aspart was also compared with the administration of insulin detirim once or twice a day in combination with insulin aspart in patients with type 1 diabetes.

The lack of superiority of the comparative drugs over Raizodeg® with respect to the reduction of the index HbA₁_c in all studies in the treatment of patients to the goal.

In patients with type 2 diabetes mellitus who never received insulin therapy and patients who had previously received insulin therapy, Rhizodeg® in combination with PGHP provides similar glycemic control compared to insulin glargine. Raizodeg® provides superior 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 measuring plasma glucose concentrations below 3.1 mmol / L or by evidence The fact that the patient required the help of third parties).

The introduction of Raizodeg® twice daily provides a similar glycemic control (HbA₁_c) in comparison with the two-phase insulin aspart 30, which was also administered twice a day. The drug Raizodeg® provides the best positive dynamics in reducing fasting plasma glucose.With the use of Raizodeg®, the target blood plasma glucose values of 5 mmol / L were achieved more quickly in patients than in patients treated with biphasic insulin aspart 30. The drug Raizodeg® less often causes hypoglycemia (including nocturnal). In patients with type 1 diabetes, treatment with Raizodeq® once a day in combination with insulin aspart before other meals showed similar glycemic control (HbA₁_c and fasted plasma glucose) with more rare cases of nocturnal hypoglycemia compared with the basal bolus regimen of insulin detemir 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, Rizodeq®, administered twice a day, showed a lower incidence of episodes of confirmed hypoglycemia in general (Figure 2) and episodes of confirmed nocturnal hypoglycemia (Figure 3) compared with the two-phase insulin aspart 30. Results showed that the preparation Raizodeg® lowers plasma glucose concentration in the fasting plasma with less risk of hypoglue kemy both during study and in maintenance doses from 16 weeks (Table 1).

Table 1.The results of the 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] dosing period
The total number of confirmed hypoglycemia preparation Rayzodeg® (2 times daily) / insulin-phase ac desks 30 (2 times daily)	0,81	0,69
	[0,67; 0,98]	[0,55; 0,87]
Nocturnal confirmed hypoglycemia preparation Raizodeg® (2 times a day) / biphasic insulin aspart 30 (2 times a day)	0,43	0,38
	[0,31; 0,59]	[0,25; 0,58]

See Figure 2. Confirmed hypoglycemia preparation Rayzodeg® (2 times a day) versus biphasic insulin aspart 30 (2 times a day), a cumulative value of the function for two 26-week, open-designed studies on the principle of "treat to target" patients with type 2 diabetes mellitus

See Figure 3. Night confirmed hypoglycemia preparation Rayzodeg® (2 times a day) versus biphasic insulin aspart 30 (2 times a day), a cumulative value of the function for two 26-week, open-designed studies on the principle of "treat to target" in patients with type 2 diabetes mellitus.

There was no clinically significant formation of antibodies to insulin after treatment with Raizodeg® for an extended period.

Pharmacokinetics:

Absorption

After subcutaneous injection, the formation of soluble stable multi-hexamers insulin degludec, which create a depot of insulin in the subcutaneous fat, while not hindering 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 blood plasma is achieved 2-3 days after the administration of the Raizodeg® preparation.

Well-known indicators of the rapid absorption of insulin aspart are preserved in the preparation Raizodeg®. 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® 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® 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 pharmacokinetic properties of the preparation Rhizodeg®, depending on sex of patients.

Patients of advanced age, patients of different ethnic groups, patients with impaired renal or hepatic function

There were no clinically significant differences in the pharmacokinetics of Raizodeg® 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 pharmacokinetic properties of Raizodeg® in studies in children (6-11 years) and adolescents (12-18 years) with type 1 diabetes are comparable to those in adult patients with 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 are comparable to those in adult patients. Against the background of a single administration to patients with diabetes mellitus type 1 dose of insulin degludec, it was demonstrated that the total dose effect of the drug in children and adolescentswe compared with that in adult patients.

Pre-clinical safety data

Preclinical data based on studies of pharmacological safety, toxicity of repeated doses, 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 mellitus in adults.

Contraindications:

Increased individual sensitivity to active substances or any of the auxiliary components of the drug.

Children under the age of 18, the period of pregnancy and breastfeeding (clinical experience of the drug in children, women during pregnancy and breastfeeding is absent).

Pregnancy and lactation:Pregnancy

Application of the drug Rhizodeg® Penfill® is contraindicated during pregnancy, as there is no clinical experience with its use during pregnancy. Studies of reproductive function in animals showed no difference between insulin degludec and human insulin in terms of embryotoxicity and teratogenicity.

Breastfeeding period

Application of the drug Rhizodeg® Penfill® during the period of breastfeeding is contraindicated, since there is no clinical experience of its use in lactating women.

Studies in animals have shown that in rats insulin degluedek is excreted in breast milk, the concentration of the drug in breast milk is lower than in blood plasma. It is not known whether insulin degluedek with breast milk of women.

Fertility

In studies on animals, there was no adverse effect of insulin degludec on fertility.

Dosing and Administration:

The drug Raizodeq® Penfill® is a combination of soluble insulin analogs - basal insulin of super-long-acting action (insulin degluedek) and 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, Rhizodeg® Penphill® can be used either as monotherapy or in combination with PGHP or bolus insulin.

Patients with type 1 diabetes mellitus are prescribed Rhizodeg® Penphill® in combination with short / ultrashort insulin before other meals.

The dose of Rhizodeg® Penphill® is determined individually according to the patient's needs. To optimize the control of glycemia, it is recommended to correct the dose of the drug based on 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 Rhizodeg® Penphyl®

Patients with type 2 diabetes mellitus

The recommended initial daily dose of Raizodeg® Penfill® 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 Rhizodeg® Penphyl® is 60-70% of the total daily insulin requirement.

The preparation Rhizodeg® Penfill® is prescribed once a day during the main meal in combination with fast / short insulin injected 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 weeks of the appointment of the new drug. It may be necessary to correct the concomitant hypoglycemic 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 who receive basal insulin therapy or biphasic insulin therapy once a day, the dose of Raizodeg® Penphill® should be calculated on a unit-by-unit 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 Raizodeg® Penphill® should be calculated on the basis of the "unit per unit" principle, with a two-fold introduction of Rizodeq® Penfill® at the same total daily dose insulin, which the patient received before the transfer to a new type of insulin.

When transferring patients on a baseline-bolus insulin regimen, the dose of Raizodeg® Penphill® 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 Raizodeg® Penfill® 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 administration of the preparation Rhizodeg® Penfill® can vary if the time of the main meal changes.

If the dose of Raizodeg® Penphyl® is missed, the patient may enter the next dose on the same day with the next main meal, and then return to his usual time of drug administration. Do not administer an additional dose to compensate for the missed dose.

Special patient groups

Patients of advanced age (over 65 years)

The drug Rhizodeg® Penphill® can be used in elderly patients. You should carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see section "Pharmacokinetics ").

Patients with kidney and liver failure

The drug Raizodeq® Penfill® can be used in patients with kidney and liver failure. It is necessary to carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see subsection Pharmacokinetics).

Children and teens

Existing pharmacokinetic data are presented in subsection Pharmacokinetics, However, the efficacy and safety of Raizodeg® Penphill® in children and adolescents under the age of 18 have not been studied, and recommendations on the dose of the drug in children have not been developed.

Mode of application

The preparation Rhizodeg® Penfill® is intended only for subcutaneous administration.

The drug Raizodeg® Penfill® can not be administered intravenously, as this can lead to the development of severe hypoglycemia. The preparation of Rhizodeg® Penphyl® can not be administered intramuscularly, since in this case the absorption of the drug changes.

The preparation Rhizodeg® Penfill® can not be used in insulin pumps.

The preparation Rhizodeg® Penphyl® is administered subcutaneously to the thigh area, anterior abdominal wall or to the shoulder area. You should constantly change injection sites within the same anatomical area to reduce the risk of developing lipodystrophy. The Penfill® cartridge is designed for use with injection systems for the introduction of Novo Nordisk insulin and disposable needles NovoFine® or NovoTvist®.

Side effects:

The most common side effect reported during treatment is hypoglycemia (see below). Description of individual adverse reactions).

All of the side effects presented below, based on data from clinical trials, are grouped 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 (impossible to estimate based on available data).

Immune system disorders	Rarely - Hypersensitivity reactions
Immune system disorders	Rarely - Hives
Disorders from the metabolism and nutrition	Often - Hypoglycaemia
Disturbances from the skin and subcutaneous tissues	Infrequently - Lipodystrophy
General disorders and disorders at the site of administration	Often - Reactions at the site of administration
	Infrequently - Peripheral edema

Description of individual adverse reactions

Immune system disorders

With the use of insulin preparations, it is possible to develop allergic reactions. Allergic reactions of immediate type to insulin or ancillary components that make up the drug may potentially threaten the patient's life.

With the use of the preparation Rhizodeg® Penfill®, hypersensitivity reactions (including swelling of the tongue or lips, diarrhea, nausea, fatigue and pruritus) and hives are rarely noted.

Hypoglycaemia

Hypoglycemia can develop if the dose of insulin is too high in relation to the patient's need for it.Severe hypoglycemia can lead to loss of consciousness and / or convulsions, temporary or irreversible impairment of brain function up to a lethal outcome. Symptoms of hypoglycemia, as a rule, develop suddenly. They include cold sweats, paleness of the skin, increased fatigue, nervousness or tremor, anxiety, unusual fatigue or weakness, disorientation, decreased concentration, drowsiness, severe hunger, visual impairment, headache, nausea, palpitations.

Lipodystrophy

Lipodystrophy (including lipohydrophy, lipoatrophy) can develop at the injection site. Adherence to the rules of changing the injection site within one anatomical area helps reduce the risk of this side reaction.

Reactions at the site of administration

Patients treated with Rhizodeg® Penphill® showed reactions at the injection site (hematoma, pain, local hemorrhage, erythema, connective tissue nodules, swelling, discoloration, itching, irritation and compaction at the injection site). Most of the reactions at the site of administration are insignificant and temporary, and usually disappear when the treatment is continued.

Children and teens

The pharmacokinetic properties of the preparation Rhizodeg® Penfill® have been studied in children and adolescents under the age of 18 (see subsection Pharmacokinetics). Studies of efficacy and safety in children and adolescents have not been conducted.

Special patient groups

In clinical trials, no difference in frequency, type, or severity of adverse reactions between patients elderly, patients with impaired renal or hepatic function and the general population of patients was not revealed.

Overdose:

A certain dose necessary for an overdose of insulin has not been established, however hypoglycemia can develop gradually if the dose of the drug has been introduced too high in comparison with the patient's need (see section Special instructions).

- Light hypoglycemia the patient can eliminate himself by taking glucose or sugar-containing foods inside. Therefore, patients with diabetes are encouraged to constantly carry with them sugar-containing foods.

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

Interaction:

There are a number of drugs that affect the need for insulin.

The need for insulin can reduce: oral hypoglycemic agents, glucagon-like peptide-1 receptor agonists (GLP-1), monoamine oxidase inhibitors, non-selective beta-blockers, angiotensin converting enzyme inhibitors, salicylates, anabolic steroids and sulfonamides.

The need for insulin can increase: oral hormonal contraceptives, thiazide diuretics, glucocorticosteroids, thyroid hormones, sympathomimetics, somatropin and danazol.

Beta-blockers can mask symptoms of hypoglycemia.

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

Ethanol can both enhance and reduce the hypoglycemic effect of insulin.

Incompatibility

Some medicinal substances, when added to the Raizodeg® Penphyl® preparation, can cause the destruction of insulin degludec and / or insulin aspart.

Do not add Raizodeg® Penfill® to infusion solutions.

Do not mix this drug with other medications.

Special instructions:

Hypoglycaemia

If you miss a meal or an unplanned intensive physical exertion, the patient may develop hypoglycemia. Hypoglycemia can also develop if the insulin dose is too high in relation to the patient's need (see "Side effect" and "Overdose").

After compensating for carbohydrate metabolism (for example, with intensified insulin therapy), the symptoms typical for them can be changed in patients-precursors of hypoglycemia, which patients should be informed about. Common symptoms-precursors can disappear with prolonged course of diabetes. Concomitant diseases, especially infectious and accompanied by fever, usually increase the body's need for insulin. Correction of the dose of the drug may also be required if the patient has concomitant diseases of the kidneys, liver or disorders of the adrenal, pituitary or thyroid gland function.

As with the use of other basal insulin preparations or preparations with a basal component, recovery from hypoglycemia with the use of Raizodeg® Penphill® can be delayed.

Hyperglycaemia

An 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 diseases, can promote the development of hyperglycemic conditions and, accordingly, increase the body's need for insulin.

Typically, the first symptoms of hyperglycemia appear gradually, within a few hours or days. These symptoms include: thirst, rapid urination, nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, loss of appetite, odor of acetone in the exhaled air. With type 1 diabetes mellitus without appropriate treatment, hyperglycemia leads to the development of diabetic ketoacidosis and can lead to death.

For the treatment of severe hyperglycemia, it is recommended that high-speed insulin be administered.

Transfer of the patient from other insulin preparations

Transfer of the patient to a new type or preparation of insulin of a new brand or other manufacturer should occur under strict medical supervision. The translation may require a dose adjustment.

The simultaneous use of drugs of the thiazolidinedione group and insulin preparations

Cases of chronic heart failure in the treatment of patients with thiazolidinediones in combination with insulin preparations have been reported, especially if such patients have risk factors for developing chronic heart failure. Keep in mind this fact when assigning patients to combination therapy with thiazolidinediones and drug Rayzodeg® Penfill®. In the appointment of such combination therapy, it is necessary to conduct medical examinations of patients to identify signs and symptoms of chronic heart failure, increase in body weight and the presence of peripheral edema. If the symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Disturbances on the part of the organ of sight

Intensification of insulin therapy with a sharp improvement in the control of carbohydrate metabolism can lead to a temporary deterioration in the state of diabetic retinopathy,at the same time, a prolonged improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

Prevention of accidental entanglement of insulin preparations

The patient should be instructed to check the labeling on each label before each injection to avoid accidental entanglement of Rhizodeg® Penfill® with other insulin preparations.

Patients should check the dose on the injector dose counter.

It is necessary to inform visually impaired or visually impaired people that they always need help from those who do not have vision problems and are trained to work with the injector.

Antibodies to insulin

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

Instructions for use

Cartridge Rhizodep® Penfill® is designed for use with Novoin® or NovoTvist® needles up to 8 mm in length and Novo Nordisk insulin injection systems. Follow the detailed instructions for use attached to the injector.

Rayzodeg® Penfill® and needles are intended only for personal use. Do not refill the cartridge.

Do not use the drug if the solution has ceased to be clear and colorless. Do not use if it has been frozen.

Discard the needle after each injection.

Effect on the ability to drive transp. cf. and fur:

The ability of patients to concentrate and respond to the reaction may be impaired during hypoglycemia, which can be dangerous in situations where this ability is particularly necessary (for example, in the management of vehicles or working with mechanisms).

Patients should be advised to take measures to prevent the development of hypoglycemia in the management of vehicles. 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, the desirability of driving a vehicle should be considered.

Form release / dosage:Solution for subcutaneous administration, 100 units / ml.

Packaging:

In the Penfill® cartridge.

3 ml in cartridges of glass I of hydrolytic class, sealed with stoppers with discs of halobutyl rubber / polyisoprene on one side and pistons of halobutyl rubber on the other side.

5 cartridges per blister of PVC / aluminum foil.

1 blister with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of 2 to 8 ° C (in the refrigerator), but not next to the freezer. Do not freeze.

Store the cartridges in a cardboard box to protect them from light.

For use or as a replacement cartridge: do not store in the refrigerator. Store at a temperature of no higher than 30 ° C for 4 weeks.

Keep out of the reach of children.

Shelf life:

30 months.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002316