LEVEMIR FLEXPEN 100U / ml injection for pre-filled pen medication leaflet

Levemir Penfill 100 units/ml solution for injection in cartridge.

Levemir FlexPen 100 units/ml solution for injection in pre-filled pen.

Levemir InnoLet 100 units/ml solution for injection in pre-filled pen.

Levemir FlexTouch 100 units/ml solution for injection in pre-filled pen.

Levemir Penfill1 ml of the solution contains 100 units insulin detemir* (equivalent to 14.2 mg). 1 cartridge contains3 ml equivalent to 300 units.

Levemir FlexPen/Levemir InnoLet/Levemir FlexTouch1 ml of the solution contains 100 units insulin detemir* (equivalent to 14.2 mg). 1 pre-filled pencontains 3 ml equivalent to 300 units.

*Insulin detemir is produced in Saccharomyces cerevisiae by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is clear, colourless and aqueous.

Levemir is indicated for treatment of diabetes mellitus in adults, adolescents and children aged 1 yearand above.

The potency of insulin analogues, including insulin detemir, is expressed in units, whereas the potencyof human insulin is expressed in international units. 1 unit insulin detemir corresponds to1 international unit of human insulin.

Levemir can be used alone as the basal insulin or in combination with bolus insulin. It can also be usedin combination with oral antidiabetic medicinal products and/or GLP-1 receptor agonists.

When Levemir is used in combination with oral antidiabetic medicinal products or when added to

GLP-1 receptor agonists it is recommended to use Levemir once daily, initially at a dose of 0.1-0.2 units/kg or of 10 units in adult patients. The dose of Levemir should be titrated based on theindividual patient’s needs.

When a GLP-1 receptor agonist is added to Levemir, it is recommended to reduce the dose of Levemirby 20% to minimise the risk of hypoglycaemia. Subsequently, dosage should be adjusted individually.

For individual dose adjustments, the following two titration guidelines are recommended for adults:

Adult type 2 diabetes titration guideline:

Average pre-breakfast SMPG* Levemir dose adjustment>10.0 mmol/l (180 mg/dl) +8 units9.1-10.0 mmol/l (163-180 mg/dl) +6 units8.1-9.0 mmol/l (145-162 mg/dl) +4 units7.1-8.0 mmol/l (127-144 mg/dl) +2 units6.1-7.0 mmol/l (109-126 mg/dl) +2 units4.1-6.0 mmol/l (73-108 mg/dl) No change in dose (target)

If one SMPG measurement3.1-4.0 mmol/l (56-72 mg/dl) -2 units<3.1 mmol/l (<56 mg/dl) -4 units

*Self-Monitored Plasma Glucose

Adult type 2 diabetes simple self-titration guideline:

Average pre-breakfast SMPG* Levemir dose adjustment>6.1 mmol/l (>110 mg/dl) +3 units4.4-6.1 mmol/l (80-110 mg/dl) No change in dose (target)<4.4 mmol/l (<80 mg/dl) -3 units

*Self-Monitored Plasma Glucose

When Levemir is used as part of a basal-bolus insulin regimen, Levemir should be administered onceor twice daily depending on patients’ needs. The dose of Levemir should be adjusted individually.

Adjustment of dose may be necessary if patients undertake increased physical activity, change theirusual diet or during concomitant illness.

When adjusting dose in order to improve glucose control, patients should be advised to be aware ofsigns of hypoglycaemia.

Levemir can be used in elderly patients. In elderly patients, glucose monitoring should be intensifiedand the Levemir dose adjusted on an individual basis.

Renal or hepatic impairment may reduce the patient’s insulin requirements.

In patients with renal or hepatic impairment, glucose monitoring should be intensified and the Levemirdose adjusted on an individual basis.

Levemir can be used in adolescents and children from the age of 1 year (see section 5.1). Whenchanging basal insulin to Levemir, dose reduction of basal and bolus insulin needs to be considered onan individual basis, in order to minimise the risk of hypoglycaemia (see section 4.4).

In children and adolescents, glucose monitoring should be intensified and the Levemir dose adjustedon an individual basis.

The safety and efficacy of Levemir in children below the age of 1 year have not been established.

No data are available.

Transfer from other insulin medicinal products

When transferring from other intermediate or long-acting insulin medicinal products, adjustment ofthe dose and timing of administration may be necessary (see section 4.4).

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (seesection 4.4).

Concomitant antidiabetic treatment may need to be adjusted (dose and/or timing of oral antidiabeticmedicinal products or concurrent short/rapid-acting insulin medicinal products).

Levemir is a long-acting insulin analogue used as a basal insulin. Levemir is for subcutaneousadministration only. Levemir must not be administered intravenously, as it may result in severehypoglycaemia. Intramuscular administration should also be avoided. Levemir is not to be used ininsulin 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 regionin order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8). Theduration of action will vary according to the dose, injection site, blood flow, temperature and level ofphysical 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 beadministered in the evening or at bedtime.

For detailed user instructions, please refer to the package leaflet.

Levemir Penfill

Administration with an insulin delivery system

Levemir Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or

NovoTwist needles. Levemir Penfill is only suitable for subcutaneous injections from a reusable pen.

If administration by syringe is necessary, a vial should be used.

Levemir FlexPen

Administration with FlexPen

Levemir FlexPen is a pre-filled pen (colour-coded) designed to be used with NovoFine or NovoTwistdisposable needles up to a length of 8 mm. FlexPen delivers 1-60 units in increments of 1 unit.

Levemir FlexPen is only suitable for subcutaneous injections. If administration by syringe isnecessary, a vial should be used.

Levemir InnoLet

Administration with InnoLet

Levemir InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposableneedles up to a length of 8 mm. InnoLet delivers 1-50 units in increments of 1 unit. Levemir InnoLetis only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should beused.

Levemir FlexTouch

Administration with FlexTouch

Levemir FlexTouch is a pre-filled pen (colour-coded) designed to be used with NovoFine or

NovoTwist disposable needles up to a length of 8 mm. FlexTouch delivers 1-80 units in increments of1 unit. Levemir FlexTouch is only suitable for subcutaneous injections. If administration by syringe isnecessary, a vial should be used.

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 thismay mean that the patient has to take the insulin and meals at different times.

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead tohyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia developgradually 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 ispotentially lethal.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

In children, care should be taken to match insulin doses (especially in basal-bolus regimens) with foodintake and physical activities in order to minimise the risk of hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In caseof hypoglycaemia or if hypoglycaemia is suspected, Levemir must not be injected. After stabilisationof the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.8 and 4.9).

Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia, and should be advisedaccordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

Concomitant illness, especially infections and feverish conditions, usually increases the patient'sinsulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary orthyroid gland can require changes in insulin dose.

When patients are transferred between different types of insulin medicinal products, the early warningsymptoms of hypoglycaemia may change or become less pronounced than those experienced withtheir previous insulin.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin orinsulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) mayresult in the need for a change in dose. Patients transferred to Levemir from another type of insulinmay require a change in dose from that used with their usual insulin medicinal products. If anadjustment is needed, it may occur with the first dose or during the first few weeks or months.

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 givenarea may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a fewweeks. On rare occasions, injection site reactions may require discontinuation of Levemir.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.

Blood glucose monitoring is recommended after the change in the injection site from an affected to anunaffected area, and dose adjustment of antidiabetic medications may be considered.

Hypoalbuminaemia

There are limited data in patients with severe hypoalbuminaemia. Careful monitoring is recommendedin 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 inmind if treatment with the combination of pioglitazone and Levemir is considered. If the combinationis 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.

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between Levemir and other insulin products.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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, GLP-1 receptor agonists, monoamine oxidase inhibitors(MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroidsand sulphonamides.

The following substances may increase the patient’s insulin requirements:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growthhormone 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.

The use of Levemir in pregnant women with diabetes has been investigated in a clinical trial and in aprospective non-interventional post-authorisation safety study (see section 5.1). Post-marketing data inpregnant women using Levemir, with more than 4,500 pregnancy outcomes do not indicate anyincreased risk of malformative or feto/neonatal toxicity. Treatment with Levemir can be consideredduring pregnancy, if clinically needed.

In general, intensified blood glucose control and monitoring of pregnant women with diabetes arerecommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usuallyfall in the first trimester and increase subsequently during the second and third trimester. Afterdelivery, insulin requirements normally return rapidly to pre-pregnancy values.

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

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

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 mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

Adverse reactions observed in patients using Levemir are mainly due to the pharmacologic effect ofinsulin. The overall percentage of treated patients expected to experience adverse reactions isestimated to be 12%.

The most frequently reported adverse reaction during treatment is hypoglycaemia, please see section4.8, Description of selected adverse reactions.

From clinical investigations, it is known that major hypoglycaemia, defined as requirement for thirdparty intervention, occurs in approximately 6% of the patients treated with Levemir.

Injection site reactions are seen more frequently during treatment with Levemir than with humaninsulin products. These reactions include pain, redness, hives, inflammation, bruising, swelling anditching 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 reactionsare usually of transitory nature. Fast improvement in blood glucose control may be associated withacute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abruptimprovement in glycaemic control may be associated with temporary worsening of diabeticretinopathy, while long-term improved glycaemic control decreases the risk of progression of diabeticretinopathy.

Adverse reactions listed below are based on clinical trial data and classified according to MedDRAfrequency and System Organ Class. Frequency categories are defined according to the followingconvention: 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 availabledata).

Immune system disorders Uncommon - Allergic reactions, potentially allergic reactions,urticaria, rash, eruptions*

Very rare - Anaphylactic reactions*

Metabolism and nutrition Very common - Hypoglycaemia*disorders

Nervous system disorders Rare - Peripheral neuropathy (painful neuropathy)

Eye disorders Uncommon - Refraction disorders

Uncommon - Diabetic retinopathy

Skin and subcutaneous tissue Uncommon - Lipodystrophy*disorders

Not known - Cutaneous amyloidosis*†

General disorders and Common - Injection site reactionsadministration site conditions

Uncommon - Oedema

* see section 4.8, Description of selected adverse reactions.† ADR from postmarketing sources.

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 antidiabeticmedicinal products, three clinical studies have shown a frequency of common (2.2% of allergicreactions 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 andreduction in blood pressure) is very rare but can potentially be life threatening.

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is toohigh in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/orconvulsions 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 paleskin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficultyin concentrating, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at theinjection site and delay local insulin absorption. Continuous rotation of the injection site within thegiven injection area may help to reduce or prevent these reactions (see section 4.4).

Based on post-marketing sources and clinical trials, the frequency, type and severity of adversereactions observed in the paediatric population do not indicate any differences to the broaderexperience in the general diabetes population.

Based on post-marketing sources and clinical trials, the frequency, type and severity of adversereactions observed in elderly patients and in patients with renal or hepatic impairment do not indicateany differences to the broader experience in the general population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop oversequential 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 sugaryproducts. It is therefore recommended that the diabetic patient always carries sugar-containingproducts.

* Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated withglucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or withglucose 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 regainingconsciousness, administration of oral carbohydrates is recommended for the patient in order toprevent a relapse.

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting:

ATC code: A10AE05.

Mechanism of action and pharmacodynamic effects

Levemir is a soluble, long-acting insulin analogue with a prolonged duration of effect used as a basalinsulin.

The blood glucose lowering effect of Levemir is due to the facilitated uptake of glucose followingbinding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucoseoutput from the liver.

The time action profile of Levemir is statistically significantly less variable and therefore morepredictable 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

Pharmacodynamic Endpoint Levemir NPH insulin

CV (%) CV (%)

AUCGIR,0-24h* 27 68

GIRmax** 23 46

*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 detemirmolecules at the injection site and albumin binding via the fatty acid side-chain. Insulin detemir isdistributed more slowly to peripheral target tissues compared to NPH insulin. These combinedmechanisms of protraction provide a more reproducible absorption and action profile of insulindetemir compared to NPH insulin.

Pharmacodynamic Parameters for Levemir and NPH

U/kg U/kg U/kg IU/kg

Duration of action (hr)

GIRmax (mg/kg/min)†estimated values

Time Since Insulin Injection (hours)

Levemir ….. 0.2 U/kg 0.3 U/kg . . . .0.4 U/kg

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 twicedaily administration. If administered twice daily, steady state will occur after 2-3 doseadministrations. For doses in the interval of 0.2-0.4 units/kg (U/kg), Levemir exerts more than 50% ofits 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 antidiabeticmedicinal products demonstrated that glycaemic control (HbA1c) with Levemir is comparable to NPHinsulin and insulin glargine and associated with less weight gain, see Table 2 below. In the studyversus insulin glargine, Levemir was allowed to be administered once or twice daily whereas insulinglargine was to be administered once a day, 55% of the Levemir treated patients completed the52 weeks of treatment on the twice daily regimen.

Table 2. Change in body weight after insulin treatment

Study duration Levemir once Levemir twice NPH insulin Insulindaily daily glargine20 weeks +0.7 kg +1.6 kg26 weeks +1.2 kg +2.8 kg52 weeks +2.3 kg +3.7 kg +4.0 kg

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 oralantidiabetic medicinal products was conducted. The trial started with a 12-week run-in period withliraglutide+metformin, where 61% reached an HbA1c <7%. The 39% of patients not achieving target

Glucose infusion rate (mg/kg/min)were randomised to have Levemir once-daily added or continue on liraglutide+metformin for52 weeks. Addition of Levemir provided a further reduction of HbA1c from 7.6% to 7.1% after52 weeks. There were no major hypoglycaemic episodes. A major hypoglycaemic episode is definedas an episode where the subject was not able to treat him/herself and if glucagon or i.v. glucose wasneeded. See Table 3.

Table 3. Clinical trial data - Levemir add-on to liraglutide+metformin

Study week Randomised Randomised P-value

Levemir + liraglutide +liraglutide + metforminmetformin n=149n=160

Mean change in HbA1c from 0-26 weeks -0.51 0.02 <0.0001baseline (%) 0-52 weeks -0.50 0.01 <0.0001

Proportions of patients 0-26 weeks 43.1 16.8 <0.0001achieving HbA1c <7% targets 0-52 weeks 51.9 21.5 <0.0001(%)

Change in body weight from 0-26 weeks -0.16 -0.95 0.0283baseline (kg) 0-52 weeks -0.05 -1.02 0.0416

Minor hypoglycaemic 0-26 weeks 0.286 0.029 0.0037episodes (per patient year) 0-52 weeks 0.228 0.034 0.0011

A 26-week, double blind, randomised clinical trial was conducted to investigate the efficacy and safetyof adding liraglutide (1.8 mg) vs. placebo in patients with type 2 diabetes inadequately controlled onbasal insulin with or without metformin. The insulin dose was reduced by 20% for patients withbaseline HbA1c ≤8.0% in order to minimise the risk of hypoglycaemia. Subsequently, patients wereallowed to up-titrate their insulin dose to no higher than the pre-randomisation dose. Levemir was thebasal insulin product for 33% (n=147) of the patients (97.3% using metformin). In these patients,addition of liraglutide resulted in a greater decline in HbA1c compared to addition of placebo (to 6.93%vs. to 8.24%), a greater decline in fasting plasma glucose (to 7.20 mmol/l vs. to 8.13 mmol/l), and agreater decline in body weight (-3.47 kg vs. -0.43 kg). Baseline values for these parameters weresimilar in the two groups. Observed rates of minor hypoglycaemic episodes were similar and no severehypoglycaemic episodes were observed in either group.

In long-term trials in patients with type 1 diabetes receiving a basal-bolus insulin therapy, fastingplasma 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 noassociated weight gain.

In clinical trials using basal bolus insulin therapy, the overall rates of hypoglycaemia with Levemirand NPH insulin were similar. Analyses of nocturnal hypoglycaemia in patients with type 1 diabetesshowed a significantly lower risk of minor nocturnal hypoglycaemia (able to self-treat and confirmedby capillary blood glucose less than 2.8 mmol/l or 3.1 mmol/l if expressed as plasma glucose) thanwith 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 tohave any impact on glycaemic control.

In a prospective non-interventional post-authorisation safety study, pregnant women with type 1 ortype 2 diabetes exposed to Levemir (n=727, 680 liveborn infants) or other basal insulins (n=730, 668liveborn infants) were monitored for pregnancy outcomes.

No statistically significant difference was observed between Levemir and other basal insulins for thecomponents of the malformation endpoint (induced abortion due to major congenital malformations,major congenital malformations or minor congenital malformations). The results from the studyindicated that Levemir is not associated with an excess risk of adverse pregnancy outcomes, whencompared to other basal insulins, in women with pre-existing diabetes.

Levemir has been studied in an open-label randomised controlled clinical trial, in which pregnantwomen with type 1 diabetes (n=310) were treated with a basal-bolus treatment regimen with Levemir(n=152) or NPH insulin (n=158) as basal insulin, both in combination with NovoRapid.

Levemir was non-inferior to NPH insulin as measured by HbA1c at gestational week (GW) 36, and thereduction in mean HbA1c through pregnancy was similar.

The efficacy and safety of Levemir has been studied for up to 12 months, in three randomisedcontrolled clinical trials in adolescents and children (n=1,045 in total); the trials included in total 167children aged 1-5 years. The trials demonstrated that glycaemic control (HbA1c) with Levemir iscomparable to NPH insulin and insulin degludec when given as basal-bolus therapy, using a non-inferiority margin of 0.4%. In the trial comparing Levemir vs. insulin degludec, the rate ofhyperglycaemic episodes with ketosis was significantly higher for Levemir, 1.09 and 0.68 episodes perpatient-year of exposure, respectively. Less weight gain (SD score, weight corrected for gender andage) was observed with Levemir than with NPH insulin.

The trial including children above 2 years was extended for an additional 12 months (total of24 months treatment data) to assess antibody formation after long-term treatment with Levemir. Afteran increase in insulin antibodies during the first year, the insulin antibodies decreased during thesecond year to a level slightly higher than pre-trial level. Results indicate that antibody developmenthad no negative effect on glycaemic control and Levemir dose.

Efficacy and safety data for adolescent patients with type 2 diabetes mellitus have been extrapolatedfrom data for children, adolescent and adult patients with type 1 diabetes mellitus and adult patientswith type 2 diabetes mellitus. Results support the use of Levemir in adolescent patients with type 2diabetes mellitus.

Maximum serum concentration is reached between 6 and 8 hours after administration. Whenadministered 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 approximately60%.

An apparent volume of distribution for Levemir (approximately 0.1 l/kg) indicates that a high fractionof 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 relevantinteraction between insulin detemir and fatty acids or other protein bound medicinal products.

Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are inactive.

The terminal half-life after subcutaneous administration is determined by the rate of absorption fromthe subcutaneous tissue. The terminal half-life is between 5 and 7 hours depending on the dose.

Dose proportionality in serum concentrations (maximum concentration, extent of absorption) isobserved after subcutaneous administration in the therapeutic dose range.

No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and Levemirwhen administering a single dose of Levemir 0.5 units/kg with liraglutide 1.8 mg at steady state inpatients with type 2 diabetes.

There was no clinically relevant difference in pharmacokinetics of Levemir between elderly andyoung patients.

There was no clinically relevant difference in pharmacokinetics of Levemir between patients withrenal or hepatic impairment and healthy subjects. As the pharmacokinetics of Levemir has not beenstudied extensively in these populations, it is advised to monitor plasma glucose closely in thesepopulations.

There are no clinically relevant differences between genders in pharmacokinetic properties of

Levemir.

The pharmacokinetic properties of Levemir were investigated in young children (1-5 years), children(6-12 years) and adolescents (13-17 years) and compared to adults with type 1 diabetes. There wereno clinically relevant differences in pharmacokinetic properties between young children, children,adolescents and adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Receptor affinity data and in vitro mitogenicity tests revealed no evidence of an increased mitogenicpotential 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 productcontains thiols or sulphites. Levemir should not be added to infusion fluids.

This medicinal product must not be mixed with other medicinal products.

Before opening: 30 months.

During use or when carried as a spare: The product can be stored for a maximum of 6 weeks.

For storage conditions of the medicinal product, see section 6.3.

Before opening: Store in a refrigerator (2°C-8°C). Keep away from the cooling element. Do notfreeze.

Levemir Penfill

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 in order to protect it from light.

Levemir FlexPen/Levemir FlexTouch

During use or when carried as a spare: Store below 30°C. Can be stored in a refrigerator (2°C-8°C).

Do not freeze.

Keep the pen cap on the pen in order to protect it from light.

Levemir InnoLet

During use or when carried as a spare: Store below 30°C. Do not refrigerate. Do not freeze.

Keep the pen cap on the pen in order to protect it from light.

Levemir Penfill3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene).

Pack sizes of 1, 5 and 10 cartridges. Not all pack sizes may be marketed.

Levemir FlexPen3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

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 InnoLet3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1, 5 and 10 pre-filled pens. Not all pack sizes may be marketed.

Levemir FlexTouch3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) or a multipack with 2 x 5 (withoutneedles) pre-filled pens of 3 ml. Not all pack sizes may be marketed.

Do not use this medicinal product if you notice that the solution is not clear, colourless and aqueous.

Levemir which has been frozen must not be used.

The patient should be advised to discard the needle after each injection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Needles, cartridges and pre-filled pens must not be shared.

The cartridge must not be refilled.

Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

Levemir Penfill

EU/1/04/278/001

EU/1/04/278/002

EU/1/04/278/003

Levemir FlexPen

EU/1/04/278/004

EU/1/04/278/005

EU/1/04/278/006

EU/1/04/278/010

EU/1/04/278/011

Levemir InnoLet

EU/1/04/278/007

EU/1/04/278/008

EU/1/04/278/009

Levemir FlexTouch

EU/1/04/278/012

EU/1/04/278/013

EU/1/04/278/014

EU/1/04/278/015

EU/1/04/278/016

Date of first authorisation: 01 June 2004

Date of last renewal: 16 April 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.