1. Name Of The Medicinal Product
Levemir 100 U/ml solution for injection in cartridge.
Levemir 100 U/ml solution for injection in pre-filled pen.
Levemir 100 U/ml solution for injection in pre-filled pen.
2. Qualitative And Quantitative Composition
1 ml of the solution contains 100 U insulin detemir* (equivalent to 14.2 mg).
1 cartridge contains 3 ml equivalent to 300 U.
1 pre-filled pen contains 3 ml equivalent to 300 U.
*Insulin detemir is produced by recombinant DNA technology in Saccharomyces cerevisiae.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection in cartridge. Penfill.
Solution for injection in pre-filled pen. FlexPen.
Solution for Injection in pre-filled pen. InnoLet
Clear, colourless, neutral solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.
4.2 Posology And Method Of Administration
Posology
The potency of insulin analogues, including insulin detemir, is expressed in units (U), whereas the potency of human insulin is expressed in international units (IU). 1 unit (U) insulin detemir corresponds to 1 international unit (IU) of human insulin.
Levemir can be used alone as the basal insulin or in combination with bolus insulin. It can also be used in combination with oral antidiabetic medicinal products or as add-on therapy to liraglutide treatment.
In combination with oral antidiabetic medicinal products and as add-on to liraglutide it is recommended to use Levemir once daily, initially at a dose of 10 U or 0.1-0.2 U/kg. The dose of Levemir should be titrated based on individual patients' needs.
Based on study results, the following titration guideline is recommended for adult diabetes patients:
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* Self Monitored Plasma Glucose
When Levemir is used as part of a basal-bolus insulin regimen Levemir should be administered once or twice daily depending on patients' needs. Dose of Levemir should be adjusted individually.
Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.
Special populations
Elderly (
Levemir can be used in elderly patients. As with all insulin medicinal products, in elderly patients, glucose monitoring should be intensified and the Levemir dose adjusted on an individual basis.
Renal and hepatic impairment
Renal or hepatic impairment may reduce the patient's insulin requirements.
As with all insulin medicinal products, in patients with renal or hepatic impairment, glucose monitoring should be intensified and the Levemir dose adjusted on an individual basis.
Paediatric population
The efficacy and safety of Levemir were demonstrated in adolescents and children aged 2 years and above in studies up to 12 months (see section 5.1).
As with all insulin medicinal products, in children and adolescents, glucose monitoring should be intensified and the Levemir dose adjusted on an individual basis.
Levemir has not been studied in children below the age of 2 years.
Transfer from other insulin medicinal products
When transferring from other intermediate or long-acting insulin medicinal products adjustment of the dose and timing of administration may be necessary (see section 4.4).
As with all insulin medicinal products, close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).
Concomitant antidiabetic treatment may need to be adjusted (dose and/or timing of oral antidiabetic medicinal products or concurrent short/rapid-acting insulin medicinal products).
Method of administration
Levemir is a long-acting insulin analogue used as a basal insulin. Levemir is for subcutaneous administration only. Levemir must not be administered intravenously, as it may result in severe hypoglycaemia. Intramuscular administration should also be avoided. Levemir is not to be used in insulin infusion pumps.
Levemir is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same anatomic region in order to avoid lipodystrophy. As with all insulin medicinal products the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. The injection can be given at any time during the day, but at the same time each day. For patients who require twice daily dosing to optimise blood glucose control, the evening dose can be administered in the evening or at bedtime.
Levemir Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. The patient should be advised not to use any counterfeit needles.
Levemir Penfill is accompanied by a package leaflet with detailed instructions for use to be followed.
Levemir FlexPen are pre-filled pens designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. FlexPen delivers 1-60 units in increments of 1 unit. The patient should be advised not to use any counterfeit needles.
Levemir FlexPen is colour-coded and accompanied by a package leaflet with detailed instructions for use to be followed.
Levemir InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. InnoLet delivers 1-50 units in increments of 1 unit. The patient should be advised not to use any counterfeit needles.
Levemir InnoLet is accompanied by a package leaflet with detailed instructions for use to be followed.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
4.4 Special Warnings And Precautions For Use
Before travelling between different time zones, the patient should seek the doctor's advice since this may mean that the patient has to take the insulin and meals at different times.
Hyperglycaemia
Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.
Hypoglycaemia
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see sections 4.8 and 4.9).
Patients, whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.
Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in insulin dose.
When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.
Transfer from other insulin medicinal products
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, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dose. Patients transferred to Levemir from another type of insulin may require a change in dose from that used with their usual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.
Injection site reactions
As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Levemir.
Hypoalbuminaemia
There are limited data in patients with severe hypoalbuminaemia. Careful monitoring is recommended in these patients.
Combination of Levemir with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and Levemir is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirements:
Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.
The following substances may increase the patient's insulin requirements:
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blockers may mask the symptoms of hypoglycaemia.
Octreotide/lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
4.6 Pregnancy And Lactation
Pregnancy
There is no clinical experience with Levemir during pregnancy.
Animal reproduction studies have not revealed any differences between insulin detemir and human insulin regarding embryotoxicity and teratogenicity. Caution should be exercised when prescribing to pregnant women.
In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Breast-feeding
There is no clinical experience with Levemir during breast-feeding. Caution should be exercised when prescribing to breast-feeding women. Breast-feeding women may require adjustments in insulin dose and diet.
Fertility
Animal reproduction studies with insulin detemir have not revealed any adverse effects on fertility.
4.7 Effects On Ability To Drive And Use Machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving or using machines).
Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable Effects
a. Summary of the safety profile
Adverse reactions observed in patients using Levemir are mainly due to the pharmacologic effect of insulin. The overall percentage of treated patients expected to experience adverse reactions is estimated to be 12%.
The most frequently reported adverse reaction during treatment is hypoglycaemia, please see section c below.
From clinical investigations, it is known that major hypoglycaemia, defined as requirement for third party intervention, occurs in approximately 6% of the patients treated with Levemir.
Injection site reactions are seen more frequently during treatment with Levemir than with human insulin products. These reactions include pain, redness, hives, inflammation, bruising, swelling and itching at the injection site. Most of the injection site reactions are minor and of a transitory nature, i.e. they normally disappear during continued treatment in a few days to a few weeks.
At the beginning of the insulin treatment, refraction anomalies and oedema may occur; these reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.
b. Tabulated list of adverse reactions
Adverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (
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* see section c
c. Description of selected adverse reactions
Allergic reactions, potentially allergic reactions, urticaria, rash, eruptions
Allergic reactions, potentially allergic reactions, urticaria, rash and eruptions are uncommon when Levemir is used in basal-bolus regimen. However, when used in combination with oral antidiabetic medicinal products, three clinical studies have shown a frequency of common (2.2% of allergic reactions and potentially allergic reactions have been observed).
Anaphylactic reactions
The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.
Hypoglycaemia
The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.
Lipodystrophy
Lipodystrophy is reported as uncommon. It may occur at the injection site as a consequence of failure to rotate injection sites within an area.
d. Paediatric population
Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the paediatric population do not indicate any differences to the broader experience in the general population.
e. Other special populations
Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.
4.9 Overdose
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirement are administered:
• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar-containing products.
• Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously, by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting: ATC code: A10AE05.
Mechanism of action
Levemir is a soluble, long-acting insulin analogue with a prolonged duration of effect used as a basal insulin.
The blood glucose lowering effect of Levemir is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
The time action profile of Levemir is statistically significantly less variable and therefore more predictable than for NPH (Neutral Protamine Hagedorn) insulin as seen from the within-subject Coefficients of Variation (CV) for the total and maximum pharmacodynamic effect in Table 1.
Table 1. Within-subject variability of the time action profile of Levemir and NPH insulin
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*Area under the curve ** Glucose Infusion Rate p-value < 0.001 for all comparisons with Levemir
The prolonged action of Levemir is mediated by the strong self-association of insulin detemir molecules at the injection site and albumin binding via the fatty acid side-chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to NPH insulin. These combined mechanisms of protraction provide a more reproducible absorption and action profile of insulin detemir compared to NPH insulin.
Figure 1. Activity profiles of Levemir in patients with type 1 diabetes.
The duration of action is up to 24 hours depending on dose providing an opportunity for once or twice daily administration. If administered twice daily, steady state will occur after 2-3 dose administrations. For doses in the interval of 0.2 - 0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours and up to approximately 14 hours after dose administration.
Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after subcutaneous administration.
Lower day-to-day variability in FPG was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials.
Studies in patients with type 2 diabetes treated with basal insulin in combination with oral antidiabetic medicinal products demonstrated that glycaemic control (HbA1c) with Levemir is comparable to NPH insulin and insulin glargine and associated with less weight gain, see Table 2 below. In the study versus insulin glargine, Levemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the Levemir treated subjects completed the 52 weeks of treatment on the twice daily regimen.
Table 2. Change in body weight after insulin treatment
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In trials investigating the use of oral antidiabetic medicinal products, combination therapy with Levemir resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.
An open-label randomised clinical trial in patients with type 2 diabetes not reaching target with oral anti-diabetic medicinal products was conducted. The trial started with a 12 week run-in period with liraglutide+metformin, where 61% reached an HbA1c <7%. The 39% of patients not achieving target were randomised to have Levemir once-daily added or continue on liraglutide+metformin for 52 weeks. Addition of Levemir provided a further reduction of HbA1c from 7.6% to 7.1% after 52 weeks. There were no major hypoglycaemic episodes. A major hypoglycaemic episode is defined as an episode where the subject was not able to treat him/herself and if glucagon or i.v. glucose was needed. See table 3.
Table 3. Clinical trial data - Levemir add-on to liraglutide+metformin
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In long-term trials in patients with type 1 diabetes receiving a basal-bolus insulin therapy, fasting plasma glucose was improved with Levemir compared with NPH insulin. Glycaemic control (HbA1c) with Levemir was comparable to NPH insulin, with a lower risk of nocturnal hypoglycaemia and no associated weight gain.
In clinical trials using basal bolus insulin therapy, the overall rates of hypoglycaemia with Levemir and NPH insulin were similar. Analyses of nocturnal hypoglycaemia in patients with type 1 diabetes showed a significantly lower risk of minor nocturnal hypoglycaemia (able to self-treat and confirmed by capillary blood glucose less than 2.8 mmol/l or 3.1 mmol/l if expressed as plasma glucose) than with NPH insulin, whereas no difference was seen in type 2 diabetes.
Antibody development has been observed with the use of Levemir. However, this does not appear to have any impact on glycaemic control.
Paediatric population
The efficacy and safety of Levemir has been studied for up to 12 months, in two randomised controlled clinical trials in adolescents and children (n=694 in total); one of the studies included in total 82 children aged 2-5 years. Both trials demonstrated that glycaemic control (HbA1c) with Levemir is comparable to NPH insulin when given as basal-bolus therapy, using a non-inferiority margin of 0.4%. In addition less weight gain (SD score, weight corrected for gender and age) was observed with Levemir than with NPH insulin.
The trial including children above 2 years was extended for an additional 12 months (total of 24 months treatment data) to assess antibody formation after long-term treatment with Levemir. After an increase in insulin antibodies during the first year, the insulin antibodies decreased during the second year to a level slightly higher than pre-trial level. Results indicate that antibody development had no negative effect on glycaemic control and Levemir dose.
5.2 Pharmacokinetic Properties
Absorption
Maximum serum concentration is reached between 6 and 8 hours after administration. When administered twice daily, steady state serum concentrations are reached after 2-3 dose administrations. Within-patient variation in absorption is lower for Levemir than for other basal insulin preparations.
The absolute bioavailability of insulin detemir when administered subcutaneous is approximately 60%.
Distribution
An apparent volume of distribution for Levemir (approximately 0.1 l/kg) indicates that a high fraction of insulin detemir is circulating in the blood.
The results of the in vitro and in vivo protein binding studies suggest that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein bound medicinal products.
Biotransformation
Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are inactive.
Elimination
The terminal half-life after subcutaneous administration is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life is between 5 and 7 hours depending on the dose.
Linearity
Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after subcutaneous administration in the therapeutic dose range.
No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and Levemir when administering a single dose of Levemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.
Special populations
Elderly (
There was no clinically relevant difference in pharmacokinetics of Levemir between elderly and young subjects.
Renal and hepatic impairment
There was no clinically relevant difference in pharmacokinetics of Levemir between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of Levemir has not been studied extensively in these populations, it is advised to monitor plasma glucose closely in these populations.
Gender
There are no clinically relevant differences between genders in pharmacokinetic properties of Levemir.
Paediatric population
The pharmacokinetic properties of Levemir were investigated in children (6–12 years) and adolescents (13–17 years) and compared to adults with type 1 diabetes. There was no clinically relevant difference in pharmacokinetic properties.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. Receptor affinity data and in vitro mitogenicity tests revealed no evidence of an increased mitogenic potential compared to human insulin.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Glycerol
Phenol
Metacresol
Zinc acetate
Disodium phosphate dihydrate
Sodium chloride
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections
6.2 Incompatibilities
Substances added to Levemir may cause degradation of insulin detemir, e.g. if the medicinal product contains thiols or sulphites. Levemir should not be added to infusion fluids.
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
30 months.
After first opening: A maximum of 6 weeks when stored below 30°C.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the cartridge in the outer carton in order to protect from light.
Keep the cap on FlexPen in order to protect from light.
Keep the cap on InnoLet in order to protect from light.
After first opening or carried as a spare: Do not refrigerate. Store below 30°C.
Levemir must be protected from excessive heat and light.
6.5 Nature And Contents Of Container
Levemir Penfill:
3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) in a carton.
Pack sizes of 1, 5 and 10 cartridges. Not all pack sizes may be marketed.
Levemir FlexPen:
3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene in a carton.
Pack sizes of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens. Not all pack sizes may be marketed.
Levemir InnoLet:
3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene in a carton.
Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Needles and Levemir Penfill must not be shared.
Needles and Levemir FlexPen must not be shared.
Needles and Levemir InnoLet must not be shared.
The cartridge must not be refilled.
Levemir must not be used if it does not appear clear and colourless.
Levemir which has been frozen must not be used.
The patient should be advised to discard the needle after each injection.
7. Marketing Authorisation Holder
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 01 June 2004
Date of last renewal: 16 April 2009
10. Date Of Revision Of The Text
10/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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