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..

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.

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.

Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

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:

* 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 ( 65 years old)

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 region in order to reduce the risk of 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.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

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.

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.

Pregnancy

Treatment with Levemir can be considered during pregnancy, but any potential benefit must be weighed against a possibly increased risk of an adverse pregnancy outcome.

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.

In an open-label randomised controlled clinical trial pregnant women with type 1 diabetes (n=310) were treated in a basal-bolus treatment regimen with Levemir (n=152) or NPH insulin (n=158) as basal insulin, both in combination with NovoRapid. Primary objective of this study was to assess the effect of Levemir on blood glucose regulation in pregnant women with diabetes (see section 5.1).

The overall rates of maternal adverse events were similar for Levemir and NPH insulin treatment groups; however, a numerically higher frequency of serious adverse events in the mothers (61 (40%) vs. 49 (31%)) and in the newborn children (36 (24%) vs. 32 (20%)) was seen for Levemir compared to NPH insulin. The number of live born children of women becoming pregnant after randomisation were 50 (83%) for Levemir and 55 (89%) for NPH. The frequency of congenital malformations was 4 (5%) for Levemir and 11 (7%) for NPH with 3 (4%) major malformations for Levemir and 3 (2%) for NPH.

Post-marketing data from an additional 250 outcomes from pregnant women exposed to Levemir indicate no adverse effects of insulin detemir on pregnancy and no malformative or feto/neonatal toxicity of insulin detemir.

Animal data do not indicate reproductive toxicity (see section 5.3).

Breast-feeding

It is unknown whether insulin detemir is excreted in human milk. No metabolic effects of ingested insulin detemir on the breast-fed newborn/infant are anticipated since insulin detemir, as a peptide, is digested into amino acids in the human gastrointestinal tract.

Breast-feeding women may require adjustments in insulin dose and diet.

Fertility

Animal studies do not indicate harmful effects with respect to fertility.

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.

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 ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

* 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 (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduce the risk of developing these reactions.

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.

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.

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

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 (HbA_1c) 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

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 HbA_1c <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 HbA_1c 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

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 (HbA_1c) 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.

Pregnancy

Levemir was studied in an open-label randomised controlled clinical trial pregnant women with type 1 diabetes (n=310) were treated in a basal-bolus treatment regimen with Levemir (n=152) or NPH insulin (n=158) as basal insulin, both in combination with NovoRapid (see section 4.6).

Levemir was non-inferior to NPH insulin as measured by HbA_1c at gestational week (GW) 36, and the reduction in mean HbA_1c through pregnancy was similar, see table 4.

Table 4. Maternal 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 (HbA_1c) 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.

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 ( 65 years old)

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.

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.

Glycerol

Phenol

Metacresol

Zinc acetate

Disodium phosphate dihydrate

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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.

30 months.

After first opening: A maximum of 6 weeks when stored below 30°C.

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.

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.

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.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Date of first authorisation: 01 June 2004

Date of last renewal: 16 April 2009

12/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.