Active ingredients: Insulin (Insulin Aspart)
NovoRapid FlexPen 100 units / ml solution for injection in pre-filled pen
Novorapid package inserts are available for pack sizes:- NovoRapid FlexPen 100 units / ml solution for injection in pre-filled pen
- NovoRapid Penfill 100 units / ml solution for injection in cartridge
Why is Novorapid used? What is it for?
NovoRapid is indicated for the treatment of diabetes mellitus in adults, adolescents and children from the age of 2 years onwards.
Contraindications When Novorapid should not be used
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Precautions for use What you need to know before you take Novorapid
It is necessary to consult the physician before traveling to countries with a different time zone as this may mean that the patient has to take insulin and meals at different times.
Hyperglycemia
Inadequate dosage or discontinuation of treatment can, especially in type 1 diabetes, can lead to hyperglycemia and diabetic ketoacidosis. The first symptoms of hyperglycaemia usually appear gradually over a few hours or days. These include thirst, polyuria, nausea. , vomiting, drowsiness, dry and red skin, xerostomia, loss of appetite and acetoneemic breath In type 1 diabetes, untreated hyperglycaemia could lead to diabetic ketoacidosis, which is life-threatening.
Hypoglycemia
Missing a meal or unexpected strenuous physical activity can lead to hypoglycemia. Hypoglycemia can occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or suspicion of hypoglycaemia, NovoRapid must not be injected. Dose adjustment should be considered after stabilization of the patient's blood glucose (see sections 4.8 and 4.9).
Patients who have experienced marked improvement in blood glucose control, for example with intensive insulin treatment, should be advised that they may experience a change in their ability to sense the warning symptoms of hypoglycaemia. Common alarm symptoms may not present themselves. more in patients with long-lasting diabetes.
A consequence of the pharmacodynamic properties of fast-acting insulin analogs is that in the case of hypoglycaemia, it may present earlier after injection than with soluble human insulin.
Since NovoRapid must be administered in the immediate vicinity of a meal, consideration must be given to the speed with which the medicine acts in the presence of concomitant diseases or pharmacological treatments that slow down the absorption of food.
Concomitant illnesses, especially infections and febrile states, generally increase the patient's need for insulin. Concomitant diseases of the kidney, liver or affecting the adrenal gland, pituitary or thyroid may require a change in the insulin dose.
When patients change the type of insulin medicines used, the initial symptoms of hypoglycaemia may change or be less pronounced than those experienced during previous treatment.
Transfer from other insulin medicines
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal, human insulin or human insulin analogue) and / or method of manufacture (recombinant DNA or animal insulin) may require dose modification. transferred to NovoRapid from another type of insulin, there may be a need to increase the number of injections per day or to change the dose from that used with the insulins they used previously. or during the first few weeks or months.
Injection site reactions
As with any insulin therapy, injection site reactions may occur including pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within the same area reduces or prevents these reactions. Reactions usually resolve within a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of NovoRapid.
Combination of NovoRapid with pioglitazone
Cases of heart failure have been reported during use of pioglitazone in combination with insulin, especially in patients with risk factors for developing heart failure. This should be borne in mind when considering treatment with pioglitazone and NovoRapid in combination. combination treatment is used, patients should be monitored for signs and symptoms of heart failure, weight gain and edema Pioglitazone should be discontinued if symptoms worsen.
Insulin antibodies
The administration of insulin can cause the formation of anti-insulin antibodies. In rare cases, the presence of such insulin antibodies may require adjustment of the insulin dose in order to correct a tendency to hyperglycemia or hypoglycemia.
Interactions Which drugs or foods may change the effect of Novorapid
Numerous medicines are known to affect glucose metabolism.
The following substances may reduce the patient's insulin requirements: oral antidiabetic drugs, monoamine oxidase inhibitors (MAOIs), beta blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), salicylates, anabolic steroids and sulfonamides.
The following substances may increase the patient's need for insulin: oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetic drugs, growth hormone and danazol.
Beta blockers can mask the symptoms of hypoglycemia.
Octreotide and lanreotide can both increase and decrease insulin requirements.
Alcohol can intensify or reduce the blood glucose lowering effect of insulin.
Warnings It is important to know that:
Pregnancy
NovoRapid (insulin aspart) can be used during pregnancy. Data from two randomized clinical trials (322 and 27 exposed pregnancies, respectively) indicate no undesirable effects of insulin aspart on pregnancy or fetal / newborn health compared to human insulin (see section 5.1).
It is recommended that blood glucose control and monitoring of diabetic women be intensified during pregnancy (type 1 diabetes, type 2 diabetes or gestational diabetes) and during pregnancy planning. Insulin requirements typically decrease in the first trimester and increase thereafter in the second and third trimesters. After delivery, insulin requirements usually quickly return to pre-pregnancy values.
Feeding time
There are no restrictions on NovoRapid therapy during breastfeeding. Insulin therapy in breastfeeding women does not pose a risk to the baby. However, the NovoRapid dose may need to be adjusted.
Fertility
Reproduction studies in animals did not indicate any difference between insulin aspart and human insulin with regard to fertility. 4.7
Effects on ability to drive and use machines
The patient's ability to concentrate and react may be reduced as a result of hypoglycaemia.This fact can pose a risk in situations where these skills are of particular importance (for example when driving a vehicle or operating machinery).
Patients should be advised of the need to take the necessary precautions to avoid the occurrence of a hypoglycaemic episode while they are driving. This is particularly important for those who have little or no awareness of the warning symptoms of hypoglycemia or who have frequent episodes of hypoglycemia. Driving should be discouraged in these circumstances.
Dosage and method of use How to use Novorapid: Dosage
Dosage
The potency of insulin analogues, including insulin aspart, is expressed in units, while the potency of human insulin is expressed in international units.
The dosage of NovoRapid varies from patient to patient and should be determined by the physician based on the patient's needs. Generally this medicine should be used in combination with administered intermediate or long-acting insulin. In addition, NovoRapid can be used for continuous subcutaneous insulin infusion (CSII) with insulin pumps or can be administered intravenously by healthcare professionals. Optimal glycemic control Blood glucose monitoring and dose adjustments are recommended.
The individual insulin requirement in adults and children is usually between 0.5 and 1.0 units / kg / day. In a basal-bolus regimen, 50-70% of this requirement can be provided by NovoRapid and the rest by intermediate or long-acting insulin.
Dosage adjustment may be necessary when patients increase physical activity, change their usual diet or during a concomitant illness.
Special populations
Older people (≥ 65 years old)
NovoRapid can be used in older patients. In older patients, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.
Renal and hepatic insufficiency
Renal or hepatic insufficiency may reduce the patient's need for insulin. In patients with renal or hepatic insufficiency, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.
Pediatric population
NovoRapid can be used in children 2 years of age and older and adolescents in preference to soluble human insulin when a rapid onset of action could be beneficial (see sections 5.1 and 5.2). For example, at the time of injections at the meals.
The safety and efficacy of NovoRapid in children below 2 years of age has not been established. No data are available.
Transfer from other insulin medicines
When transferring from other insulin medicinal products, adjustment of the NovoRapid dose and basal insulin may be required. NovoRapid starts to work faster and has a shorter duration of action than soluble human insulin. When the solution is injected subcutaneously into the abdominal wall, it will begin to act within 10-20 minutes of injection. The maximum effect is seen between 1 and 3 hours after injection. The duration of action is between 3 hours. and 5 hours.
Close monitoring of blood glucose is recommended during and in the first few weeks following the transfer (see section 4.4).
Method of administration
NovoRapid is a fast-acting insulin analogue.
NovoRapid is administered subcutaneously by injection into the abdominal wall, thigh, upper arm, deltoid region or buttock. The injection site must always be rotated within the same area to reduce the risk of lipodystriphy. Subcutaneous administration into the abdominal wall ensures faster absorption than other injection sites. Compared to soluble human insulin, the faster rate is faster. of action of NovoRapid is maintained regardless of the injection site. The duration of action varies according to the dose, injection site, blood flow, temperature and level of physical activity.
Due to its faster action, NovoRapid should generally be administered immediately before a meal. When needed, it can be given immediately after a meal.
Administration with FlexPen:
NovoRapid FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to 8 mm in length. FlexPen releases 1 to 60 units in 1 unit increments.
The NovoRapid FlexPen pack is color-coded and contains a package leaflet with detailed instructions for use.
Continuous subcutaneous insulin infusion (CSII)
NovoRapid can be used for CSII with pumps suitable for insulin infusion. CSII should be delivered in the abdominal wall. The infusion site should be rotated.
When NovoRapid is used with insulin pumps, it must not be mixed with other insulin medicinal products.
Patients practicing CSII should receive complete instructions on the use of insulin pumps and on the correct use of the reservoir and tubing for the pump (see section 6.6). The infusion set (tube and cannula) must be changed following the instructions enclosed with the infusion set.
Patients taking NovoRapid for CSII must have another method of insulin delivery available to use in the event of a pump failure.
Intravenous use
If necessary, NovoRapid can be administered intravenously by healthcare professionals.
For intravenous use, NovoRapid 100 units / ml infusion systems at insulin aspart concentrations of 0.05 units / ml to 1.0 units / ml in 0.9% sodium chloride, 5% sodium chloride infusion solutions dextrose or 10% dextrose, at 40 mmol / l potassium chloride, are stable at room temperature for 24 hours using polypropylene infusion bags.
Although stable over time, some insulin will initially be absorbed by the infusion bag material. Blood glucose should be monitored during the insulin infusion.
Overdose What to do if you have taken too much Novorapid
It is not possible to define a specific overdose level for insulin, however, hypoglycaemia can develop in sequential stages if doses that are too high compared to the patient's needs have been administered:
- Mild hypoglycemic episodes can be treated by oral administration of glucose or sugary products. Diabetic patients are therefore advised to always carry sugary products with them
- Severe hypoglycaemic episodes, in which the patient loses consciousness, can be treated with glucagon (0.5 to 1 mg) administered intramuscularly or subcutaneously by an experienced person or with glucose administered intravenously by a healthcare professional. Also administer intravenous glucose if the patient does not react to glucagon within 10-15 minutes. When the patient regains consciousness, administration of oral carbohydrates is recommended to avoid
Side Effects What are the side effects of Novorapid
Summary of the safety profile
Adverse reactions observed in patients receiving NovoRapid are mainly attributable to the pharmacological effect of insulin.
Hypoglycaemia is the most frequently reported adverse reaction during treatment. The frequencies of hypoglycaemia vary with patient population, dose regimen and blood glucose level control (see section 4.8 Description of selected adverse reactions).
Impaired refraction, edema and injection site reactions (pain, redness, itching, inflammation, bruising, swelling and itching at the injection site) may occur upon initiation of insulin treatment. These reactions are usually transient in nature. Rapid improvement in blood glucose control may be associated with acute painful neuropathy which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycemic control may be associated with a temporary worsening of diabetic retinopathy, while long-term improvement in glycemic control decreases the risk of progression of diabetic retinopathy.
Table of adverse reactions
Adverse reactions listed below are based on clinical data and classified by frequency and MedDRA System Organ Class. Frequency categories are defined according to the following convention: very common (≥1 / 10); common (≥1 / 100 e
* see section 4.8 Description of selected adverse reactions.
Description of selected adverse reactions
Anaphylactic reactions:
The occurrence of generalized hypersensitivity reactions (including generalized skin rash, itching, sweating, gastrointestinal upset, angioneurotic edema, difficulty in breathing, palpitations and hypotension) is very rare but can be potentially life-threatening.
Hypoglycemia:
Hypoglycaemia is the most frequently reported adverse reaction. It can occur if the insulin dose is too high in relation to insulin requirement. Severe hypoglycaemia can induce loss of consciousness and / or seizures and can lead to temporary brain damage or permanent or even death. Symptoms of hypoglycemia usually come on suddenly. They may include cold sweats, cold pale skin, fatigue, nervousness or tremor, anxiety, tiredness or weakness, confusion, difficulty concentrating, sleepiness, excessive hunger, visual disturbances, headache, nausea and palpitations.
During clinical trials, the frequency of hypoglycaemia varies with patient population, dose regimen, and glycemic control. In clinical trials, the total number of hypoglycemia does not differ between patients treated with insulin aspart compared with insulin. Human.
Lipodystrophy:
Lipodystrophy (including lipohypertrophy, lipoatrophy) can occur at the injection site. Continuous rotation of the injection site within the particular injection area reduces the risk of developing these reactions.
Pediatric population
Based on post-marketing data and those from clinical trials, the frequency, type and severity of adverse reactions observed in the pediatric population indicate no difference to the broader experience in the general population.
Other special populations
Based on post-marketing data and data from clinical trials, the frequency, type and severity of adverse reactions observed in older patients and in patients with renal or hepatic impairment indicate no difference to the broader experience in the population. general.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the reporting system listed in the "Annex V
Expiry and Retention
Period of validity
Before opening: 30 months.
After first opening or when carried as a spare: the product should be stored for a maximum of 4 weeks. Store below 30 ° C.
Special precautions for storage
Before opening: Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
After first opening or when carried as a spare: Store below 30 ° C. Do not refrigerate. Do not freeze.
Keep the cap on the FlexPen to protect it from light.
For storage conditions of the medicinal product see section 6.3.
Special precautions for disposal and handling
Needles and NovoRapid FlexPen should not be shared with others. The pen does not need to be refilled.
Do not use this medicine if the solution is not clear, colorless and aqueous.
NovoRapid that has been frozen must not be used.
The patient should be advised to discard the needle after each injection.
NovoRapid can be used in insulin pumps (CSII) as described in section 4.2. Tubes whose internal surface is made of polyethylene or polyolefin have been evaluated and found compatible with the use of insulin pumps.
In case of an emergency in regular NovoRapid users (hospitalization or pen malfunction), NovoRapid can be withdrawn from a FlexPen with a 100 U insulin syringe.
Any unused medicine and waste should be disposed of according to local regulations
Composition and pharmaceutical form
QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 100 units of insulin aspart * (equivalent to 3.5 mg), 1 pre-filled pen contains 3 ml equivalent to 300 units.
* Insulin aspart produced by Saccharomyces cerevisiae by recombinant DNA technology.
For the full list of excipients, see section 6.1.
List of excipients
Glycerol Phenol Metacresol Zinc chloride Disodium phosphate dihydrate Sodium chloride Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections 6.2
Incompatibility
Substances added to NovoRapid may cause degradation of insulin aspart eg medicinal products containing thiols or sulphites. This medicinal product must not be mixed with other medicinal products except NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.
PHARMACEUTICAL FORM
Injectable solution.
The solution is clear, colorless and aqueous.
Nature and contents of the container
3 ml of solution in a cartridge (type I glass) with a plunger (bromobutyl) and a rubber stopper (bromobutyl / polyisoprene) contained in a pre-filled, disposable, multidose, polypropylene pen.
Packs of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NOVORAPID FLEXPEN 100 U / ML SOLUTION FOR INJECTION IN A PRE-FILLED PEN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 100 U insulin aspart * (equivalent to 3.5 mg), 1 pre-filled pen contains 3 ml equivalent to 300 U.
* The insulin aspart produced by Saccharomyces cerevisiae with recombinant DNA technology.
Excipients with known effects: 100 U of NovoRapid contains approximately 30 mcmol sodium, ie NovoRapid contains less than 1 mmol sodium (23 mg) per dose and is therefore considered essentially "sodium-free".
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection in pre-filled pen. FlexPen.
The solution is clear, colorless and aqueous.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of diabetes mellitus in adults, adolescents and children from the age of 2 years onwards
04.2 Posology and method of administration
Dosage
The potency of insulin analogues, including insulin aspart, is expressed in units (U), while the potency of human insulin is expressed in international units (IU).
The dosage of NovoRapid varies from patient to patient and should be determined by the physician based on the patient's needs. Generally this medicine should be used in combination with the administered intermediate or long-acting insulin.Furthermore, NovoRapid can be used for continuous subcutaneous insulin infusion (CSII) with insulin pumps or can be administered intravenously by healthcare professionals. To achieve optimal glycemic control, glucose monitoring and dose adjustments are recommended.
The individual insulin requirement in adults and children is usually between 0.5 and 1.0 U / kg / day. In a basal-bolus regimen, 50-70% of this requirement can be provided by NovoRapid and the rest by intermediate or long-acting insulin.
Dosage adjustment may be necessary when patients increase physical activity, change their usual diet or during a concomitant illness.
Special populations
Senior citizens (≥ 65 years old)
NovoRapid can be used in elderly patients.
As with all insulin medicinal products, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis in elderly patients.
Renal and hepatic insufficiency
Renal or hepatic insufficiency can reduce the patient's need for insulin.
As with all insulin medicinal products, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis in patients with renal or hepatic impairment.
Pediatric population
NovoRapid can be used in children 2 years of age and older and adolescents in preference to soluble human insulin when a rapid onset of action could be beneficial (see sections 5.1 and 5.2). For example, at the time of injections at the meals.
No studies have been conducted with NovoRapid in children less than 2 years of age.
In this age group NovoRapid should only be used under strict medical supervision.
Transfer from other insulin medicines
When transferring from other insulin medicinal products, adjustment of the NovoRapid dose and basal insulin may be required. NovoRapid starts to work faster and has a shorter duration of action than soluble human insulin. When the solution is injected subcutaneously into the abdominal wall, it will begin to act within 10-20 minutes of injection. The maximum effect is seen between 1 and 3 hours after injection. The duration of action is between 3 hours. and 5 hours.
Close monitoring of blood glucose is recommended during and in the first few weeks following the transfer (see section 4.4).
Method of administration
NovoRapid is a fast-acting insulin analogue.
NovoRapid is administered subcutaneously by injection into the abdominal wall, thigh, upper arm, deltoid region or buttock. The injection site should always be rotated within the same area to reduce the risk of lipodystrophy. As with all insulin medicinal products, subcutaneous administration into the abdominal wall ensures faster absorption than other injection sites.
Compared to soluble human insulin, the faster speed of action of NovoRapid is maintained regardless of the injection site. As with all insulin medicinal products, the duration of action varies according to dose, injection site, blood flow, temperature. and the level of physical activity.
Administration with FlexPen
NovoRapid FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to 8 mm in length. FlexPen releases 1 to 60 units in 1 unit increments.
The NovoRapid FlexPen pack is color-coded and contains a package leaflet with detailed instructions for use.
Continuous subcutaneous infusion of insulin (CSII)
NovoRapid can be used for CSII with pumps suitable for insulin infusion. CSII should be delivered in the abdominal wall. The infusion site should be rotated.
When NovoRapid is used with insulin pumps, it must not be mixed with other insulin medicinal products.
Patients practicing CSII should receive complete instructions on the use of insulin pumps and on the correct use of the reservoir and tubing for the pump (see section 6.6). The infusion set (tube and cannula) must be changed following the instructions enclosed with the infusion set.
Patients taking NovoRapid for CSII must have another method of insulin delivery available to use in the event of a pump failure.
Intravenous use
If necessary, NovoRapid can be administered intravenously by healthcare professionals.
For intravenous use, NovoRapid 100 U / mL infusion systems at insulin aspart concentrations of 0.05 U / mL to 1.0 U / mL in 0.9% sodium chloride, 5% sodium chloride infusion solutions dextrose or 10% dextrose, at 40 mmol / l potassium chloride, are stable at room temperature for 24 hours using polypropylene infusion bags.
Although stable over time, some insulin will initially be absorbed by the infusion bag material. Blood glucose should be monitored during the insulin infusion.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
04.4 Special warnings and appropriate precautions for use
It is necessary to consult the doctor before traveling to countries with a different time zone as this may mean that the patient has to take insulin and meals at different times.
Hyperglycemia
Inadequate dosage or discontinuation of treatment can, especially in type 1 diabetes, can lead to hyperglycemia and diabetic ketoacidosis.
The first symptoms of hyperglycemia usually appear gradually over a few hours or days. These include thirst, polyuria, nausea, vomiting, drowsiness, dry and flushed skin, xerostomia, loss of appetite and acetoneemic breath. In type 1 diabetes, untreated hyperglycemia could lead to diabetic ketoacidosis, which is life-threatening.
Hypoglycemia
Missing a meal or unexpected strenuous physical activity can lead to hypoglycemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or hypoglycaemia is suspected, NovoRapid should not be injected. After stabilization of the patient's blood glucose, dose adjustment should be considered (see paragraphs 4.8 and 4.9).
Patients who have experienced marked improvement in blood glucose control, for example with intensive insulin treatment, should be advised that they may experience a change in their ability to sense the warning symptoms of hypoglycaemia. Common alarm symptoms may not present themselves. more in patients with long-lasting diabetes.
A consequence of the pharmacodynamic properties of fast-acting insulin analogs is that in the case of hypoglycaemia, it may present earlier after injection than with soluble human insulin.
Since NovoRapid must be administered in the immediate vicinity of a meal, consideration must be given to the speed with which the medicine acts in the presence of concomitant diseases or pharmacological treatments that slow down the absorption of food.
Concomitant illnesses, especially infections and febrile states, generally increase the patient's need for insulin. Concomitant diseases of the kidney, liver or affecting the adrenal gland, pituitary or thyroid may require a change in the insulin dose.
When patients change the type of insulin medicines used, the initial symptoms of hypoglycaemia may change or be less pronounced than those experienced during previous treatment.
Transfer from other insulin medicines
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal, human insulin or human insulin analogue) and / or method of manufacture (recombinant DNA or animal insulin) may require dose modification. transferred to NovoRapid from another type of insulin, there may be a need to increase the number of injections per day or to change the dose from that used with the insulins they used previously. or during the first few weeks or months.
Injection site reactions
As with any insulin therapy, injection site reactions may occur including pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within the same area can help reduce or prevent these reactions. Reactions usually resolve within a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of NovoRapid.
Combination of NovoRapid with pioglitazone
Cases of heart failure have been reported during use of pioglitazone in combination with insulin, especially in patients with risk factors for developing heart failure. This should be borne in mind when considering treatment with pioglitazone and NovoRapid in combination. combination treatment is used, patients should be monitored for signs and symptoms of heart failure, weight gain and edema Pioglitazone should be discontinued if symptoms worsen.
04.5 Interactions with other medicinal products and other forms of interaction
Numerous medicines are known to affect glucose metabolism.
The following substances can reduce the patient's need for insulin:
oral antidiabetic drugs, monoamine oxidase inhibitors (MAOIs), beta blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), salicylates, anabolic steroids and sulphonamides.
The following substances may increase the patient's need for insulin: oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetic drugs, growth hormone and danazol.
Beta blockers can mask the symptoms of hypoglycemia.
Octreotide and lanreotide can both increase and decrease insulin requirements.
Alcohol can intensify or reduce the blood glucose lowering effect of insulin.
04.6 Pregnancy and lactation
Pregnancy
NovoRapid (insulin aspart) can be used during pregnancy. Data from two randomized clinical trials (322 and 27 exposed pregnancies, respectively) indicate no undesirable effects of insulin aspart on pregnancy or fetal / newborn health compared to human insulin (see section 5.1).
It is recommended that blood glucose control and monitoring of diabetic women be intensified during pregnancy (type 1 diabetes, type 2 diabetes or gestational diabetes) and during pregnancy planning. Insulin requirements typically decrease in the first trimester and increase thereafter in the second and third trimesters. After delivery, insulin requirements usually quickly return to pre-pregnancy values.
Feeding time
There are no restrictions on NovoRapid therapy during breastfeeding. Insulin therapy in breastfeeding women does not pose a risk to the baby. However, the NovoRapid dose may need to be adjusted.
Fertility
Reproduction studies in animals did not indicate any difference between insulin aspart and human insulin with regard to fertility.
04.7 Effects on ability to drive and use machines
The patient's ability to concentrate and react may be reduced as a result of hypoglycaemia. This fact can pose a risk in situations where these skills are of particular importance (for example when driving a vehicle or operating machinery).
Patients should be advised of the need to take the necessary precautions to avoid the occurrence of a hypoglycaemic episode while they are driving. This is particularly important for those who have little or no awareness of the warning symptoms of hypoglycemia or who have frequent episodes of hypoglycemia. Driving should be discouraged in these circumstances.
04.8 Undesirable effects
to. Summary of the safety profile
Adverse reactions observed in patients receiving NovoRapid are mainly attributable to the pharmacological effect of insulin.
Hypoglycaemia is the most frequently reported adverse reaction during treatment. The frequencies of hypoglycaemia vary with patient population, dose regimen and blood glucose level control, see section c below.
Impaired refraction, edema and injection site reactions (pain, redness, itching, inflammation, bruising, swelling and itching at the injection site) may occur upon initiation of insulin treatment. These reactions are usually transient in nature. Rapid improvement in blood glucose control may be associated with acute painful neuropathy which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycemic control may be associated with a temporary worsening of diabetic retinopathy, while long-term improvement in glycemic control decreases the risk of progression of diabetic retinopathy.
b. Table of adverse reactions
Adverse reactions listed below are based on clinical data and classified by frequency and MedDRA System Organ Class. Frequency categories are defined according to the following convention: very common (≥1 / 10); common (≥1 / 100 e
* see paragraph c
c. Description of selected adverse reactions
Anaphylactic reactions
The occurrence of generalized hypersensitivity reactions (including generalized skin rash, itching, sweating, gastrointestinal upset, angioneurotic edema, difficulty in breathing, palpitations and hypotension) is very rare but can be potentially life-threatening.
Hypoglycemia
Hypoglycaemia is the most frequently reported adverse reaction. It can occur if the insulin dose is too high in relation to insulin requirement. Severe hypoglycaemia can induce loss of consciousness and / or seizures and can lead to temporary brain damage or permanent or even death. Symptoms of hypoglycemia usually come on suddenly. They may include cold sweats, cold pale skin, fatigue, nervousness or tremor, anxiety, tiredness or weakness, confusion, difficulty concentrating, sleepiness, excessive hunger, visual disturbances, headache, nausea and palpitations.
During clinical trials, the frequency of hypoglycaemia varies with patient population, dose regimen, and glycemic control. In clinical trials, the total number of hypoglycemia does not differ between patients treated with insulin aspart compared with insulin. Human.
Lipodystrophy
Lipodystrophy (including lipohypertrophy, lipoatrophy) can occur at the injection site. Continuous rotation of the injection site within the particular injection area can help reduce the risk of developing these reactions.
d. Pediatric population
Based on post-marketing data and those from clinical trials, the frequency, type and severity of adverse reactions observed in the pediatric population indicate no difference to the broader experience in the general population.
And. Other special populations
Based on post-marketing data and those from clinical trials, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic insufficiency indicate no difference to the broader experience in the general population. .
04.9 Overdose
It is not possible to define a specific overdose level for insulin, however, hypoglycaemia can develop in sequential stages if doses that are too high compared to the patient's needs have been administered:
• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. Diabetic patients are therefore advised to always carry sugary products with them
• Severe hypoglycaemic episodes, in which the patient loses consciousness, can be treated with glucagon (0.5 to 1 mg) administered intramuscularly or subcutaneously by an experienced person or with glucose administered intravenously by a healthcare professional. Also administer intravenous glucose if the patient does not react to glucagon within 10-15 minutes. When the patient regains consciousness, administration of oral carbohydrates is recommended to avoid a relapse.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes. Insulins and analogues for fast-acting injections: ATC code: A10AB05.
Mechanism of action and pharmacodynamic effects
The hypoglycemic effect of insulin aspart is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and the simultaneous inhibition of glucose release from the liver.
NovoRapid has a greater rapidity of action than soluble human insulin and results in a lower concentration of glucose, based on assessments made in the first four hours after meals. NovoRapid has a shorter duration of action than soluble human insulin after the meal. "subcutaneous injection.
When injected subcutaneously, NovoRapid will start to work within 10-20 minutes after injection. The maximum effect occurs between 1 and 3 hours after injection. The duration of action is between 3 and 5 hours. .
Clinical efficacy
Clinical trials in patients with type 1 diabetes have shown a lower blood glucose level after meals with NovoRapid than soluble human insulin (Fig. I). In two long-term open-label trials on 1070 and 1070 respectively. 884 patients with type 1 diabetes, NovoRapid showed a decrease in glycosylated hemoglobin by a percentage of 0.12 [95% CI 0.03; 0.22] and 0.15 [95% C.I. 0.05; 0.26] compared to human insulin: this is a difference of dubious clinical significance.
Clinical trials in patients with type 1 diabetes have shown a lower risk of nocturnal hypoglycaemia with insulin aspart than with soluble human insulin. The risk of daytime hypoglycaemia does not significantly increase.
Special populations
Elderly (≥ 65 years old)
A randomized, double-blind, cross-over pharmacokinetic and pharmacodynamic study comparing insulin aspart and human insulin was conducted in elderly patients with type 2 diabetes (19 patients aged 65 to 83 years, mean age 70 years). . The relative differences in pharmacodynamic properties (GIRmax, AUCGIR, 0-120 min) between insulin aspart and human insulin in the elderly were similar to those observed in healthy subjects and in younger subjects with diabetes.
Pediatric population
A clinical study was performed which compared pre-prandial soluble human insulin with post-prandial insulin aspart in young children (20 patients aged 2 to less than 6 years, studied for 12 weeks of which four were less than 4 years) and a single dose pharmacodynamic / pharmacokinetic study in children (6-12 years) and adolescents (13-17 years). The pharmacodynamic profile of insulin aspart in children was similar to that observed in adults.
Pregnancy
A clinical study comparing the safety and efficacy of insulin aspart and human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies (insulin aspart: 157; human insulin: 165) indicate the absence of undesirable effects with insulin aspart on pregnancy or on the health of the fetus / newborn.
Additionally, data from a clinical trial including 27 women with gestational diabetes randomized to treatment with insulin aspart versus human insulin (insulin aspart: 14; human insulin: 13) showed similar safety profiles between treatments.
At the same concentration (molarity) insulin aspart is equipotent to soluble human insulin.
05.2 "Pharmacokinetic properties
Absorption, distribution and elimination
In NovoRapid, replacing the amino acid proline with aspartic acid in position B28 reduces the tendency to form hexamers as occurs with soluble human insulin. NovoRapid is therefore absorbed more rapidly from the subcutaneous layer than soluble human insulin.
The time to maximum concentration is, on average, equal to half that of soluble human insulin. On average, in type 1 diabetic patients, the maximum plasma concentration of 492 ± 256 pmol / l was reached 40 (interquartile range: 30-40) minutes after subcutaneous administration of a dose of 0.15 U / kg body weight. The return of insulin to baseline concentration occurred approximately 4 or 6 hours after administration of the dose. The absorption rate was slightly slower in type 2 diabetic patients, resulting in lower Cmax (352 ± 240 pmol / L) and delay in tmax (60 (interquartile range: 50-90) minutes). Intra-individual variability in time to maximum concentration is significantly lower with NovoRapid than with soluble human insulin, while intra-individual variability in Cmax with NovoRapid is greater.
Special populations
Elderly (≥ 65 years old)
The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly subjects (65-83 years, mean age 70 years) with type 2 diabetes are similar to those observed in healthy subjects and in younger subjects with diabetes. A decrease in the rate of absorption was observed in elderly subjects, with a delayed tmax of 82 (interquartile range: 60-120 minutes), while Cmax is similar to that seen in younger subjects with type 2 diabetes and slightly lower than to that observed in subjects with type 1 diabetes.
Hepatic insufficiency
A single dose pharmacokinetic study of insulin aspart was conducted in 24 subjects with liver function ranging from normal to severely impaired. In subjects with hepatic insufficiency, the rate of absorption was decreased and more variable, with a delayed tmax, from approximately 50 min in subjects with normal hepatic function up to 85 min in subjects with moderate and severe hepatic dysfunction. AUC, Cmax and CL / F values were similar in subjects with impaired hepatic function compared to subjects with normal hepatic function.
Kidney failure
A single dose pharmacokinetic study of insulin aspart was conducted in 18 subjects with renal function ranging from normal to severely impaired. There was no apparent effect of creatinine clearance values on insulin aspart AUC, Cmax, CL / F and tmax. Data in subjects with moderate and severe renal impairment were limited. Subjects with renal impairment who were not studied were not studied. need dialysis treatment.
Pediatric population
The pharmacokinetic and pharmacodynamic properties of NovoRapid were studied in children (6-12 years) and adolescents (13-17 years) with type I diabetes. Insulin aspart was rapidly absorbed in both age groups with a similar tmax. to that of adults. However, the age groups showed a different Cmax, underlining the importance of individualization of the NovoRapid dosage.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, reproductive and developmental toxicity.
In tests in vitro, including binding to insulin and IGF-1 receptor sites and effects on cell growth, the behavior of insulin aspart was very similar to that of human insulin. Studies also show that the dissociation of binding to the insulin aspart receptor is equivalent to that of human insulin. Acute toxicity studies with insulin aspart at one month and 12 months did not provide clinically relevant toxicity data.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycerol
Phenol
Metacresol
Zinc chloride
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
06.2 Incompatibility
Substances added to NovoRapid may cause the degradation of insulin aspart eg medicinal products containing thiols or sulphites.
This medicinal product must not be mixed with other medicinal products except NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.
06.3 Period of validity
Before opening: 30 months.
After first opening or when carried as a spare: the product should be stored for a maximum of 4 weeks. Store below 30 ° C.
06.4 Special precautions for storage
Before opening: Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
After first opening or when carried as a spare: Store below 30 ° C. Do not refrigerate. Do not freeze.
Keep the cap on the FlexPen to protect it from light.
For storage conditions of the medicinal product see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
3 ml solution in a cartridge (type I glass) with a plunger (bromobutyl rubber) and a stopper (bromobutyl / polyisoprene) contained in a pre-filled, disposable, multidose, polypropylene pen.
Packs of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Needles and NovoRapid FlexPen should not be shared with others. The pen does not need to be refilled.
Do not use this medicine if the solution is not clear, colorless and aqueous.
NovoRapid that has been frozen must not be used.
The patient should be advised to discard the needle after each injection.
NovoRapid can be used in insulin pumps (CSII) as described in section 4.2. Tubes whose internal surface is made of polyethylene or polyolefin have been evaluated and found compatible with the use of insulin pumps.
In case of an emergency in regular NovoRapid users (hospitalization or pen malfunction), NovoRapid can be withdrawn from a FlexPen with a 100 U insulin syringe.
Any unused medicine and waste should be disposed of according to local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novo Nordisk A / S
Novo Allè
DK-2880 Bagsværd
Denmark
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/99/119/009 - AIC: 034498093
EU / 1/99/119/010
EU / 1/99/119/011
EU / 1/99/119/017
EU / 1/99/119/018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 7 September 1999
Date of last renewal: 30 April 2009
10.0 DATE OF REVISION OF THE TEXT
07/2012
