Active ingredients: Insulin (Insulin detemir)
Levemir 100 units / ml solution for injection in pre-filled pen
Indications Why is Levemir used? What is it for?
Levemir is a long-acting modern "insulin analogue". Modern insulin medicines are an improved version of human insulin.
Levemir is used to reduce the high blood sugar level in adults, adolescents and children from 1 year of age with diabetes mellitus (diabetes). Diabetes is a disease in which the body does not produce enough insulin to control the blood. blood sugar level.
Levemir can be used with fast-acting mealtime insulin medicines. In the treatment of type 2 diabetes mellitus, Levemir can also be used in combination with diabetes tablets and / or injectable antidiabetic medicines, other than insulin.
Levemir has a prolonged and constant action in reducing the level of sugar present in the blood within 3-4 hours after injection. Levemir provides up to 24 hours of baseline insulin coverage.
Contraindications When Levemir should not be used
Do not use Levemir
- If you are allergic to insulin detemir or any of the other ingredients of this medicine see section 6, Contents of the pack and other information).
- If you get the warning symptoms of a hypo (low blood sugar) see a) Summary of serious and very common side effects in section 4.
- In insulin pumps.
- If FlexPen drips, it is damaged or cracked.
- If it has not been stored correctly or been frozen see section 5, How to store Levemir.
- If the insulin does not appear as clear, colorless and aqueous water.
Do not use Levemir if any of these apply to you. Talk to your doctor, nurse or pharmacist for advice.
Precautions for use What you need to know before taking Levemir
Before using Levemir
- Check the label to make sure it is the right type of insulin.
- Always use a new needle for each injection to prevent contamination.
- Needles and Levemir FlexPen should not be shared with others.
Warnings and Precautions
Certain conditions and activities can affect your need for insulin. These include:
- If you have kidney or liver problems, adrenal gland, pituitary or thyroid abnormalities.
- If there has been an increase in physical activity or a change in your usual diet, as this could cause your blood sugar level to vary.
- If you get sick: keep taking your insulin and consult your doctor.
- If you intend to travel abroad, traveling to countries with a different time zone may cause your insulin requirement and the time of your injection to vary.
- If you have very low albumin levels, you should carefully monitor your blood sugar level. Talk to your doctor.
Children and adolescents
Levemir can be used in adolescents and children from 1 year of age.
The safety and efficacy of Levemir in children below 1 year of age has not been established. Data not available.
Interactions Which drugs or foods may change the effect of Levemir
Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines. Some medicines affect your blood sugar level and can change your insulin requirement. The most important medicines in the blood are listed below. able to influence insulin treatment.
Your blood sugar level may drop (hypoglycaemia) if you take:
- other medicines to treat diabetes
- monoamine oxidase inhibitors (MAOIs), used to treat depression
- beta blockers (used to treat high blood pressure)
- angiotensin converting enzyme inhibitors (ACE inhibitors, used to treat certain heart conditions or high blood pressure)
- salicylates (used to relieve pain and lower fever)
- anabolic steroids (such as testosterone)
- sulfonamides (used to treat infections).
Your blood sugar level may rise (hyperglycaemia) if you take:
- oral contraceptives (birth control pills)
- thiazides (used to treat high blood pressure or excessive water retention)
- glucocorticoids (such as "cortisone" used to treat inflammation)
- thyroid hormones (used to treat thyroid disease)
- sympathomimetics, such as epinephrine (adrenaline), salbutamol, terbutaline, used to treat asthma
- growth hormone (medicine used to stimulate skeletal and somatic growth and which significantly affects the metabolic processes in the body)
- danazol (medicine that acts on ovulation).
Octreotide and lanreotide (used to treat acromegaly, a rare hormonal disorder that usually occurs in middle-aged adults caused by "excessive production of pituitary growth hormone" may increase or decrease your sugar level. in the blood.
Beta blockers (used to treat high blood pressure) can completely weaken or suppress the warning symptoms that can help you recognize low blood sugar.
Pioglitazone (tablets used to treat type 2 diabetes)
Some patients with long-standing type 2 diabetes and heart disease or previous stroke who were treated with pioglitazone and insulin experienced heart failure. Tell your doctor immediately if you experience signs of heart failure such as unusual shortness of breath or rapid weight gain or localized swelling (edema).
If you have taken any of the medicines listed, please tell your doctor, nurse or pharmacist.
Drink alcohol and take Levemir
- If you drink alcohol, your insulin requirements may change as your blood sugar level may rise or fall. Careful inspection is recommended.
Warnings It is important to know that:
Pregnancy and breastfeeding
- If you are pregnant or planning to become pregnant ask your doctor for advice before taking this medicine. Your insulin dose may need to be adjusted during pregnancy and after delivery. It is important to carefully control diabetes, especially to prevent hypoglycemic episodes for the health of the child.
- If you are breastfeeding, consult your doctor as you may need insulin dose adjustments.
Consult your doctor, nurse or pharmacist before taking any medicine during pregnancy or breastfeeding.
Driving and using machines
Contact your doctor about driving or using machines:
- If you have frequent episodes of hypoglycaemia.
- If you find it difficult to recognize the warning signs of a low blood sugar.
If your blood sugar is high or low, it can affect your ability to concentrate and react and consequently also your ability to drive a car or use machines. Keep in mind that it could endanger yourself or others.
Important information about some of the ingredients of Levemir
Levemir contains less than 1 mmol sodium (23 mg) per dose, meaning that Levemir is essentially "sodium-free".
Dose, Method and Time of Administration How to use Levemir: Posology
Dose and when to take insulin
Always use insulin and adjust the dose exactly as your doctor has told you. If you are not sure, ask your doctor, nurse or pharmacist.
Levemir can be used with fast-acting mealtime insulin medicines. In the treatment of type 2 diabetes mellitus, Levemir can also be used in combination with diabetes tablets and / or injectable antidiabetic medicines, other than insulin.
Do not change your insulin unless your doctor tells you to.
Your doctor may need to adjust your dose if:
- if your doctor has changed your insulin type or brand, or
- your doctor has added another medicine to treat diabetes in combination with Levemir treatment.
Use in children and adolescents
Levemir can be used in adolescents and children from 1 year of age.
No clinical studies with Levemir have been conducted in children under 1 year.
Use in special patient groups
If you have kidney or liver failure, or if you are over 65, you should monitor your blood sugar regularly and talk to your doctor about adjusting your insulin dose.
How often to inject
Levemir should be administered once daily when used in combination with diabetes tablets and / or in combination with injectable antidiabetic medicines, other than insulin. When Levemir is used as part of a basal-bolus insulin regimen, it should be administered once or twice daily as needed. The dose of Levemir must be individually adjusted. The injection can be given at any time of the day, but at the same time each day. In cases where two daily doses are needed to optimize blood sugar control, the evening dose can be given in the evening or before going to bed. read.
How and where to inject
Levemir is given by injection under the skin (subcutaneous use). You must never inject Levemir directly into a vein (intravenously) or muscle (intramuscularly).
With each injection, you vary the injection site within the particular area of the skin you usually use. This may reduce the risk of developing skin lumps and pits (see section 4, Possible side effects). The best areas to inject yourself are: the front of the thigh, the abdomen, or the upper arm. It is recommended that you check your blood sugar regularly.
How to use Levemir FlexPen
Levemir FlexPen is a pre-filled, color-coded disposable pen that contains insulin detemir.
Read the instructions for use in this leaflet carefully. You should use the pen as described in the "Instructions for use".
Always make sure you are using the correct pen before injecting your insulin.
Overdose What to do if you have taken too much Levemir
If you take more insulin than you should
If you take too much insulin, your blood sugar level drops too low (hypoglycaemia).
Summary of serious and very common side effects in section 4.
If you forget to take insulin
If you forget to take your insulin your blood sugar level becomes too high (hyperglycaemia).
If you stop taking your insulin
Do not stop taking your insulin without talking to your doctor, who will tell you what to do. This could lead to very high blood sugar (severe hyperglycaemia) and ketoacidosis. See c) Effects from diabetes in section 4 .
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Side Effects What are the side effects of Levemir
Like all medicines, this medicine can cause side effects, although not everybody gets them.
a) Summary of serious and very common side effects.
Low blood sugar (hypoglycaemia) is a very common side effect. It may affect more than 1 in 10 people.
You may have low blood sugar if:
- Inject too much insulin.
- Eat too little or skip meals.
- Exercise more than usual.
- Drink alcohol (see Drinking alcohol and taking Levemir in section 2).
Warning symptoms of low blood sugar: cold sweats; cold, pale skin; headache; rapid heartbeat; feeling unwell; very hungry; temporary visual disturbances; drowsiness; unusual tiredness and weakness; nervousness or tremor; anxiety; confusional state; difficulty concentrating.
Severe hypoglycemia can lead to loss of consciousness. If prolonged severe hypoglycaemia is not treated, it can cause brain damage (temporary or permanent) and even death. You can regain consciousness faster with an "injection" of the hormone glucagon given by someone who knows how to use it. If you are given glucagon you will need glucose or a sweet snack as soon as you regain consciousness. If he does not respond to glucagon treatment he will have to be transported to the hospital.
What to do if your blood sugar is low:
- If your blood sugar is too low, eat sugar cubes or another high-sugar snack (candy, cookies, fruit juice). Measure your blood sugar if possible and then rest. Always carry sugar cubes, candies, biscuits or fruit juices with you, to be used in case of need.
- When the symptoms of hypoglycaemia have disappeared or when your blood sugar has stabilized, continue your insulin treatment.
- If you have low blood sugar, you may lose consciousness, if you have needed glucagon injection, or if you have many episodes of low blood sugar, talk to your doctor. insulin, food and physical activity times.
Tell those close to you that you are diabetic and what the consequences may be, including the risk of fainting from a hypo. Explain that if you faint, they should turn you on your side and seek immediate medical attention. You should not be given any food or drink as they could choke you.
Serious allergic reaction to Levemir or one of its ingredients (called a systemic allergic reaction) is a side effect that can be potentially life threatening. It may affect less than 1 in 10,000 people.
Contact your doctor immediately:
- if the signs of allergy spread to other parts of the body
- if you suddenly feel unwell, and: start sweating; you start to feel sick (vomiting); have breathing difficulties; the heartbeat is rapid; Are you dizzy.
If you notice any of these signs, contact your doctor immediately.
b) List of other undesirable effects
Uncommon side effects
They may affect less than 1 in 100 people.
Signs of allergy: Local allergic reactions (pain, redness, hives, inflammation, bruising, swelling and itching) at the injection site. These symptoms usually disappear within a few weeks of treatment. If symptoms do not go away or spread to other parts of the body, see your doctor immediately. See also Severe allergic reaction.
Visual disturbances: Visual disturbances may occur at the start of insulin treatment, however this is usually a temporary reaction.
Changes at the injection site (lipodystrophy): The subcutaneous fatty tissue at the injection site may shrink (lipoatrophy) or thicken (lipohypertrophy). Changing the injection site within the same area can help reduce the risk of developing these disorders. If you notice a skin pitting or thickening at the injection site, please tell your doctor or nurse. These reactions may worsen or may cause insulin absorption to vary if injected at this point.
Swollen Joints: Fluid retention can cause swelling around your ankles and other joints at the start of insulin treatment. This soon disappears. If not, contact your doctor.
Diabetic retinopathy (a diabetes-related eye disorder that can lead to loss of vision): If you have diabetic retinopathy and your blood sugar improves very quickly, your retinopathy may get worse. Ask your doctor.
Rare side effects
They may affect less than 1 in every 1000 people.
Peripheral neuropathy (pain due to nerve damage): A rapid improvement in the blood sugar level can lead to nerve pain, this is called peripheral neuropathy and disappears spontaneously.
Reporting of side effects
If any of the side effects appear, please tell your doctor, nurse or pharmacist. This also includes any side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
c) Effects of diabetes
High blood sugar level (hyperglycemia)
You may have a high blood sugar level if:
- If you haven't injected enough insulin.
- If you have forgotten to take insulin or have stopped taking it.
- If you repeatedly take less insulin than you need.
- If you have an infection or fever.
- If you eat more than usual.
- If you exercise less than usual.
Warning symptoms of high blood sugar:
warning symptoms appear gradually. They include: passing more urine than normal; thirst; loss of appetite; feeling sick (nausea or vomiting); feeling sleepy or tired; dry, reddened skin; dry mouth and fruity breath (acetone).
What to do if your blood sugar is high:
- If you get any of these symptoms: Check your blood sugar, if you can, check your urine for ketones and contact a doctor immediately.
- These can be symptoms of a very serious condition called diabetic ketoacidosis (buildup of acid in the blood because the body is breaking down fat instead of sugar). If left untreated, it could lead to diabetic coma and eventually death.
Expiry and Retention
Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the "FlexPen label and carton after 'EXP". The expiry date refers to the last day of the month shown. When not in use, always keep the FlexPen cap on the pen in order to protect it from light. Levemir must be protected from excessive heat and light.
Before opening: Levemir FlexPen that is not being used is to be stored in the refrigerator at 2 ° C - 8 ° C, away from the cooling elements. Do not freeze.
During use or when carried as a spare: Levemir FlexPen that is being used or carried as a spare is not to be kept in the refrigerator. You can carry it with you and keep it at room temperature (below 30 ° C) for up to 6 weeks.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to dispose of unused medicines. This will help protect the environment.
Composition and pharmaceutical form
What Levemir contains
- The active ingredient is insulin detemir. Each ml contains 100 units of insulin detemir. Each pre-filled pen contains 300 units of insulin detemir in 3 ml of solution for injection. 1 unit of insulin detemir corresponds to 1 international unit (IU) of human insulin.
- The other ingredients are: glycerol, phenol, metacresol, zinc acetate, disodium phosphate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
What Levemir looks like and contents of the pack
Levemir comes as a solution for injection.
Pack sizes of 1 (with or without needles), 5 (without needles) and 10 (without needles) 3ml 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
LEVEMIR 100 UNITS / ML SOLUTION FOR INJECTION IN PRE-FILLED PEN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of the solution contains 100 units of insulin detemir * (equivalent to 14.2 mg). 1 pre-filled pen contains 3 ml equivalent to 300 units.
* Insulin detemir is produced by Saccharomyces cerevisiae with recombinant DNA technology.
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
Levemir is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.
04.2 Posology and method of administration
Dosage
The potency of insulin analogues, including insulin detemir, is expressed in units, while the potency of human insulin is expressed in international units. 1 unit of insulin detemir corresponds to 1 international unit of human insulin.
Levemir can be used alone as a basal insulin or in combination with a "bolus insulin. It can also be used in combination with oral antidiabetic medicines and / or GLP-1 receptor agonists.
When Levemir is used in combination with oral antidiabetic medicinal products or in addition to GLP-1 receptor agonists, it is recommended to use Levemir once daily, initially at a dose of 10 units or 0.1-0.2 units / kg. . Levemir dosage should be determined based on the individual needs of the patients.
When a GLP-1 receptor agonist is added to Levemir, it is recommended that the dose of Levemir be reduced by 20% to minimize the risk of hypoglycaemia. Thereafter, the dose can be adjusted individually.
The following two guidelines are recommended for individual dose adjustments:
Dose Adjustment Guideline for Adults with Type 1 and Type 2 Diabetes:
* Self-monitoring of blood glucose
Simplified Self-Adjustment Dose Guideline for Adults with Type 2 Diabetes
* Self-monitoring of blood glucose
When Levemir is used on a basal / bolus insulin regimen, it should be administered once or twice daily as needed by patients. Levemir dosage should be adjusted based on individual needs.
Dosage adjustment may be necessary if patients increase physical activity, change their usual diet or during a concomitant illness.
During a dose adjustment to improve glucose control, patients should be made aware of the signs of hypoglycaemia.
Special populations
Older patients (≥ 65 years old)
Levemir can be used in older patients. In older patients, glucose monitoring should be intensified and Levemir dosage adjusted on an individual basis.
Renal and hepatic insufficiency
Renal or hepatic insufficiency can reduce the patient's need for insulin.
In patients with renal or hepatic insufficiency, glucose monitoring should be intensified and the Levemir dosage adjusted on an individual basis.
Pediatric population
The efficacy and safety of Levemir have been demonstrated in studies of up to 12 months duration in adolescents and children aged 2 years and above (see section 5.1).
In children and adolescents, glucose monitoring should be intensified and the Levemir dosage adjusted on an individual basis.
Levemir has not been studied in children less than 2 years of age.
Transfer from other insulin medicines
When transferring from other intermediate or long-acting insulin medicinal products, adjustment of the dosage and timing of administration may be necessary (see section 4.4).
Constant monitoring of blood glucose is recommended during the transition period and the first few weeks thereafter (see section 4.4).
Any concomitant hypoglycemic treatments may require dosage adjustment (dosage and / or timing of administration of oral antidiabetic drugs or other short / fast acting insulin drugs).
Method of administration
Levemir is a long-acting insulin analog used as a basal insulin. Levemir is for subcutaneous administration only. Levemir should not be administered intravenously, as this may result in severe hypoglycaemia. Intramuscular administration should also be avoided. Levemir should not be administered intravenously. it should be used in insulin pumps.
Levemir is administered subcutaneously by injection into the abdominal wall, thigh, upper arm, deltoid region or buttock. The injection sites should always be rotated within the same area to reduce the risk of lipodystrophy. The duration of action will vary depending on the dose, injection site, blood flow, temperature and level of physical activity. The injection can be given at any time of the day, but at the same time each day. In cases where two daily doses are required to optimize blood glucose control, the evening dose can be given in the evening or before going to bed.
Administration with FlexPen
Levemir FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist needles that are 8 mm or less in length. FlexPen releases 1-60 units in 1 unit increments.
The Levemir FlexPen pack is color-coded and contains a package leaflet with detailed instructions for use.
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, 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 red skin, xerostomia, loss of appetite and acetoneemic breath In type 1 diabetics, untreated hyperglycaemia can lead to diabetic ketoacidosis, a life-threatening event.
Hypoglycemia
Failure to eat a strenuous and unscheduled meal or exercise 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 suspected hypoglycaemia, Levemir should not be injected. After stabilization of the patient's blood glucose, a dose adjustment should be considered (see sections 4.8 and 4.9).
Patients who have experienced a marked improvement in glycemic control, for example due to intensified insulin therapy, should be advised that they may experience a change in the common initial symptoms of hypoglycemia. Common initial symptoms may not appear in patients with long-standing diabetes.
The onset of concomitant diseases, particularly infections and febrile states, usually increases the patient's insulin requirements. Concomitant diseases of the kidney, liver or affecting the adrenal gland, pituitary or thyroid may require dosage adjustments of insulin.
When patients are transferred from a different type of insulin, the initial symptoms of hypoglycemia 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 insulin, human insulin or insulin analogue) and / or method of manufacture (from recombinant DNA or animal insulin) may require dose adjustment. Patients transferred to Levemir from another type of insulin may need a change in dosage from that used with their previously used insulin medicines. If a dose adjustment is required this can be done on the first dose or during the first few weeks or months.
Reactions at the injection site
As with any insulin therapy, reactions around the injection site 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 over a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Levemir.
Hypoalbuminemia
Limited data are available in patients with severe hypoalbuminaemia. It is recommended that these patients be closely monitored.
Combination of Levemir 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 Levemir 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 drugs interact with glucose metabolism.
The following substances can reduce the patient's insulin requirement:
Oral hypoglycemic medicinal products, GLP-1 receptor agonists, monoamine oxidase inhibitors (MAOIs), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.
The following substances may increase the patient's insulin requirement:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blocking agents can mask the symptoms of hypoglycemia.
Octreotide and lanreotide can increase or decrease insulin requirements.
Alcohol can intensify or reduce the hypoglycemic effects of insulin.
04.6 Pregnancy and lactation
Pregnancy
Levemir treatment can be considered in pregnancy, but any potential benefit must be weighed against a possible increased risk of a negative pregnancy outcome.
In general, intensified blood glucose monitoring and monitoring of women with diabetes is recommended both during pregnancy planning and during pregnancy.
Insulin requirements usually decrease during the first trimester and increase later in the second and third trimester of pregnancy. After delivery, insulin requirements quickly return to pre-pregnancy values.
In an open-label, randomized controlled clinical trial, pregnant women with type 1 diabetes (n = 310) were treated on a basal-bolus regimen with Levemir (n = 152) or NPH insulin (n = 158) as basal insulin. both in combination with NovoRapid. The primary objective of this study was to evaluate the effect of Levemir on blood glucose regulation in pregnant women with diabetes (see section 5.1).
The total rate of maternal adverse events was similar for the Levemir and NPH insulin groups; however, a numerically higher frequency of serious adverse events was observed for Levemir in mothers (61 (40%) vs 49 (31%)) and neonates (36 (24%) vs 32 (20%) compared to NPH insulin. . The number of live births to women who became pregnant after randomization was 50 (83%) for Levemir and 55 (89%) for NPH. The frequency of congenital malformations was 4 (5%) for Levemir and of 11 (7%) for NPH including 3 (4%) severe malformations for Levemir and 3 (2%) for NPH.
Post-marketing data from an additional 250 outcomes of pregnant women receiving Levemir show no adverse effects of insulin detemir on pregnancy and no malformation or fetal / neonatal toxicity of insulin detemir.
Animal data indicate no reproductive toxicity (see section 5.3).
Feeding time
It is not known whether insulin detemir is excreted in human milk. No metabolic effects of ingested insulin detemir are expected on breastfed infants / children as insulin detemir, as a peptide, is digested into amino acids in the human gastrointestinal tract.
During breastfeeding, adjustments in the patient's insulin dose and diet may be required.
Fertility
Animal studies do not indicate harmful effects with respect 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 car 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 using Levemir are mostly due to the pharmacological effect of insulin. The overall percentage of treated patients who may experience adverse drug reactions is estimated to be around 12%.
Hypoglycaemia is the most frequently observed adverse reaction during treatment, see section c below.
Clinical investigations have revealed that major hypoglycaemia, defined as hypoglycaemia requiring the intervention of other people, occurs in approximately 6% of patients treated with Levemir.
Reactions around the injection site are seen more frequently during treatment with Levemir than with human insulin medicines. These reactions include pain, redness, hives, inflammation, bruising, swelling and itching around the injection site. Most reactions around the injection site are minor and transient in nature, in fact, they usually disappear within a few days or weeks with continued treatment.
Refractive abnormalities and edema may occur upon initiation of insulin therapy; these reactions are usually transient in nature.
A rapid fall in blood glucose may be associated with acute painful neuropathy, which is usually transient in nature. Intensification of insulin therapy with a sharp fall in blood glucose may be associated with worsening of diabetic retinopathy, while gradual improvement in glycemic control decreases the risk of progression of diabetic retinopathy.
b. Table of adverse reactions
Adverse reactions listed below are classified according to MedDRA frequency and 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
Allergic reactions, potential allergic reactions, hives, rash, skin rashes
Allergic reactions, potential allergic reactions, urticaria, rash, rash are uncommon when Levemir is used as a basal / bolus insulin regimen. However, 3 clinical studies showed a common frequency (2.2% allergic reactions and potential allergic reactions were observed) when used in combination with oral antidiabetic medicinal products.
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 observed 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 to death. Symptoms of hypoglycemia 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.
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.
d. Pediatric population
In market use and 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
In use in the market and in clinical trials, the frequency, type and severity of adverse reactions observed in older patients and in patients with renal or hepatic insufficiency indicate no difference from the broader experience in the general population.
f. 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 "Annex V.
04.9 Overdose
It is not possible to define a specific level of insulin overdose, however hypoglycaemia can develop in sequential stages if doses that are too high for the patient's insulin requirement are administered:
• Mild hypoglycaemic episodes can be treated with oral administration of glucose or sugar-containing products. Diabetic patients are therefore recommended to carry sugar-containing products with them at all times.
• Severe hypoglycaemic episodes, when the patient has lost consciousness, can be treated with glucagon (0.5 to 1 mg) administered intramuscularly or subcutaneously by a person who has received appropriate education or with intravenous glucose administered by a healthcare professional . Glucose should also be administered intravenously if the patient has not responded within 10-15 minutes to the administration of glucagon. Once the state of consciousness has recovered, it is recommended to administer carbohydrates by mouth in order to prevent a relapse.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs used in diabetes. Long-acting insulins and analogues for injectable use.
ATC code: A10AE05.
Mechanism of action and pharmacodynamic effects
Levemir is a long-acting soluble insulin analog with a prolonged duration of effect, used as a basal insulin.
The hypoglycemic effect of Levemir 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.
The time-of-action profile of Levemir is statistically and significantly less variable and therefore more predictable than that of NPH (Neutral Protamine Hagedorn) insulin, as shown by the coefficients of variation (CV) in the same subject of the total and maximum pharmacodynamic effect. in Table 1.
Table 1. Single-subject variability of the time-of-action profile of Levemir and NPH insulin
* Area under the curve ** Glucose infusion rate p-value
The prolonged action of Levemir is mediated by the marked aggregation of insulin detemir molecules at the injection site and by binding to albumin via the fatty acid side chain. Insulin detemir distributes more slowly to target peripheral tissues than NPH insulin. The combination of these two protraction mechanisms ensures a more reproducible absorption and action profile of insulin detemir than NPH insulin.
The maximum duration of action is 24 hours, depending on the dosage. It is possible to perform one or two daily administrations. If given twice daily, steady state will be reached after administration of 2-3 doses. For doses in the range of 0.2 - 0.4 U / kg, Levemir exerts more than 50% of its maximum effect between 3-4 hours and up to 14 hours after dose administration.
After subcutaneous administration (maximum effect, duration of action, total effect) a proportionality between the dosage and the pharmacodynamic response was observed.
In long-term clinical trials, lower day-to-day variability in FPG has been demonstrated during Levemir therapy compared to NPH therapy.
Studies in patients with type 2 diabetes treated with basal insulin in combination with oral antidiabetic medicinal products (OADs) have shown that glycemic control (HbA1c) achieved with Levemir is comparable to that with NPH and that with insulin glargine and is associated with a minor increase weight, see Table 2 below. In the comparison study with insulin glargine, where Levemir could be given once or twice a day while insulin glargine was given once a day, 55% of patients taking Levemir completed 52 weeks of treatment following the regimen of double daily administration.
Table 2. Change in body weight following insulin therapy
In studies evaluating the use of oral antidiabetic medicinal products in combination with Levemir there was a 61-65% lower risk of minor nocturnal hypoglycaemia compared to that with NPH.
An open-label, randomized clinical trial was conducted in patients with type 2 diabetes who failed to target oral antidiabetic medicinal products. The study began with a 12-week run-in period with liraglutide + metformin, in which 61% of patients achieved metformin HbA1c for 52 weeks. The addition of Levemir provided a further reduction in HbA1c from 7.6% to 7.1% after 52 weeks. There were no major hypoglycaemic episodes. A major hypoglycemic episode is defined as an episode in which the subject is unable to perform treatment on their own and in which intravenous glucagon or glucose needs to be administered. See table 3.
Table 3. Clinical data - Levemir in addition to liraglutide + metformin
A 26-week, double-blind, randomized clinical study was conducted to investigate the efficacy and safety of adding liraglutide (1.8 mg) versus placebo in patients with type 2 diabetes inadequately controlled on insulin. with or without metformin. In patients with HbA1c ≤ 8.0% at baseline, the insulin dose was reduced by 20% to minimize the risk of hypoglycaemia. Thereafter, patients were allowed to titrate the insulin dose up to dose not exceeding the pre-randomization dose. Levemir was the basal insulin for 33% (N = 147) of patients (97.3% metformin users). In these patients, the addition of liraglutide resulted in a greater decrease in HbA1c (6.93% vs 8.24%), a greater decrease in fasting glucose (7.20 mmol / l vs 8.13 mmol / l) and greater decrease in body weight (-3.47 kg vs -0.43 kg). Baseline values for these parameters were similar in both groups. The observed rate of minor hypoglycaemic episodes was similar and no severe hypoglycemic episodes was observed in both groups.
In long-term clinical trials in patients with type 1 diabetes on basal / bolus insulin therapy, fasting glucose improved in patients on Levemir compared to patients on NPH insulin. Glycemic control (HbA1c) with Levemir was comparable to NPH insulin, with a lower risk of nocturnal hypoglycaemic events and not associated with weight gain.
In clinical trials using basal / bolus therapy, the total rates of hypoglycemia with Levemir and NPH insulin were similar. The analysis of nocturnal hypoglycemic events in patients with type 1 diabetes showed a significantly lower risk of non-serious hypoglycemic events (confirmed by the finding of capillary blood glucose values below 2.8 mmol / l and 3.1 mmol / l, expressed as plasma glucose, and the patient's ability to self-cure) compared to NPH insulin while no differences were found in patients with type 2 diabetes.
Development of antibodies has been observed with the use of Levemir. However, this does not appear to have any impact on glycemic control.
Pregnancy
Levemir was studied in an open-label, randomized controlled clinical trial in pregnant women with type 1 diabetes (n = 310) treated on a basal-bolus regimen with Levemir (n = 152) or with NPH insulin (n = 158) as basal insulin. , both in combination with NovoRapid (see section 4.6).
Levemir was not inferior to NPH insulin for HbA1c values measured at 36 gestational week (SG), and the reduction in mean HbA1c during pregnancy was similar, see table 4.
Table 4. Maternal glycemic control
Pediatric population
The efficacy and safety of Levemir were studied in two randomized controlled trials of up to 12 months of duration in adolescents and children (n = 694 total); one of the studies included a total of 82 children between the ages of 2 and 5 years. Both studies demonstrated that glycemic control (HbA1c) with Levemir was comparable with NPH insulin when given as basal / bolus therapy, using a 0.4% non-inferiority margin. In addition, a minor increase was observed. weight (SD value, age-corrected body weight) with Levemir versus NPH insulin.
The study, which included children over 2 years of age, was extended for an additional 12 months (data for a total of 24 months of treatment) to evaluate antibody formation after long-term treatment with Levemir. After an increase in insulin antibodies during the first year, the insulin antibodies decreased after the second year reaching a slightly higher level than the pre-study level. The results indicate that the development of antibodies had no negative effect on glycemic control and the dosage of Levemir.
05.2 "Pharmacokinetic properties
Absorption
The maximum serum concentration is reached 6 - 8 hours after administration. If given twice daily, steady state serum concentrations will be achieved after administration of 2-3 doses.
The intra-individual variation in absorption is lower for Levemir than for other basal insulin preparations.
The absolute bioavailability of insulin detemir for subcutaneous administration is approximately 60%.
Distribution
An apparent volume of distribution of Levemir (approximately 0.1 L / kg) indicates that a "high fraction of insulin detemir is circulating in the blood.
The results of the studies on protein bonds in vitro And in vivo indicate that there are no clinically significant interactions between insulin detemir and fatty acids or other protein-bound medicinal products.
Biotransformation
The degradation of insulin detemir is similar to that of human insulin; none of the metabolites formed are active.
Elimination
The half-life after subcutaneous administration is determined by the degree of absorption from the subcutaneous tissues. The half-life varies from 5 to 7 hours, depending on the dosage.
Linearity
After subcutaneous administration (maximum concentration, level of absorption) a proportionality between the serum concentration and the therapeutic dosage range was observed.
No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and Levemir when a single dose of Levemir 0.5 U / kg and 1.8 mg liraglutide was administered at steady state in patients with type 2 diabetes.
Special populations
Older people (≥ 65 years)
There was no clinically significant difference between the pharmacokinetics of Levemir for elderly versus young subjects.
Renal and hepatic insufficiency
There was no clinically relevant difference in Levemir pharmacokinetics between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of Levemir have not been extensively studied in these patient populations, it is advisable to intensify the monitoring of these populations.
Sex
There are no clinically relevant gender differences in the pharmacokinetic properties of Levemir.
Pediatric population
The pharmacokinetic properties of Levemir in children (6 - 12 years) and adolescents (13 - 17 years) were analyzed and compared with those of adults with type 1 diabetes. There was no clinically relevant difference in pharmacokinetic properties.
05.3 Preclinical safety data
Non-clinical data reveal no hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, reproductive and developmental toxicity. Data on receptor affinity and mythogenicity experiments conducted in vitro they did not provide evidence of a greater mitogenic potential than human insulin.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycerol
Phenol
Metacresol
Zinc acetate
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
06.2 Incompatibility
Substances added to Levemir may cause degradation of insulin detemir, eg medicinal products containing thiols or sulphites. Levemir must not be mixed with infusion fluids.
This medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
Before opening: 30 months.
During use or when carried as a spare: The product can be stored for up to 6 weeks.
06.4 Special precautions for storage
Before opening: Store in a refrigerator (2 ° C - 8 ° C). Keep away from cooling elements. Do not freeze.
During use or when carried as a spare: Store below 30 ° C. Do not refrigerate. Do not freeze.
Keep the cartridge in the outer carton 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 of solution in cartridge (type 1 glass), with a plunger (bromobutyl) and a rubber stopper (bromobutyl / polyisoprene) contained in a disposable, pre-filled, multidose, polypropylene pen in a carton.
Pack sizes: 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 Levemir FlexPen should not be shared with others. The cartridge does not need to be refilled.
Do not use the medicine if you notice that the solution does not appear clear, colorless and aqueous.
If Levemir has been frozen it must not be used.
The patient should be advised to discard the needle after each injection.
Any unused medicine and waste should be disposed of according to local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novo Nordisk A / S, Novo Allé, DK-2880 Bagsvaerd, Denmark
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/04/278/004
036850042
EU / 1/04/278/005
036850055
EU / 1/04/278/006
036850067
EU / 1/04/278/010
EU / 1/04/278/011
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 1 June 2004
Date of last renewal: April 16, 2009
10.0 DATE OF REVISION OF THE TEXT
D.CCE May 2015
