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Novo Nordisk Limited
Broadfield Park, Brighton Road, Crawley, West Sussex, RH11 9RT
Telephone: +44 (0)1293 613555
Fax: +44 (0)1293 613535
Medical Information Direct Line: +44 (0)845 600 5055
Medical Information e-mail: ukmedicalinfo@novonordisk.com
Customer Care direct line: +44 (0)845 600 5055
Medical Information Fax: +44 (0)1293 613211

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Summary of Product Characteristics last updated on the eMC: 13/01/2012
SPC Levemir Cartridge 100 U/ml - Penfill, Levemir Pre-filled Pen 100 U/ml - FlexPen and InnoLet

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC. For each version, we show the dates it was published on the eMC and the reasons for change.

Updated on 13/01/2012 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 5.1 - Pharmacodynamic Properties
Date of revision of text on the SPC:   19-Dec-2011
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company


4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

There is no clinical experience with Levemir during pregnancy.Treatment with Levemir can be considered during pregnancy, but any potential benefit must be weighed against a possibly increased risk of an adverse foetalpregnancy 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 reproduction studies havedata do not indicate reproductive toxicity (see section 5.3)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 value

 

5.1     Pharmacodynamic properties

 

Text inserted: 

 

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 HbA1c at gestational week (GW) 36, and the reduction in mean HbA1c through pregnancy was similar, see table 4.

 

Table 4. Maternal glycaemic control

 

Levemir

NPH

Difference/ Odds Ratio/

Rate Ratio 95% CI

Mean HbA1c (%) at GW 36

6.27

6.33

Difference:

-0.06 [-0.21; 0.08]

Mean FPG at GW 36 (mmol/l)

4.76

5.41

Difference:

-0.65 [-1.19; -0.12]

Proportions of patients achieving HbA1c ≤6% targets at both GW 24 and GW 36 (%)

41%

32%

Odds Ratio:

1.36 [0.78; 2.37]

Overall number of major hypoglycemia episodes during pregnancy (per patient year)

1.1

1.2

Rate Ratio:

0.82 [0.39; 1.75]

 

 

 
Updated on 04/11/2011 and displayed until 13/01/2012
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   01-Oct-2011
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company


4.1     Therapeutic indications

 

Treatment of diabetes mellitus in adults, adolescents and children aged 6–172 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 insulin human insulin is expressed in international units (IU). 1 unit (U) insulin detemir corresponds to 1 international unit (IU) of insulin 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:

 

Average pre-breakfast SMPG*

Levemir dose adjustment

     > 10.0 mmol/l (180 mg/dl)

+ 8 U

     9.1-10.0 mmol/l (163-180 mg/dl)

+ 6 U

     8.1-9.0 mmol/l (145-162 mg/dl)

+ 4 U

     7.1-8.0 mmol/l (127-144 mg/dl)

+ 2 U

     6.1-7.0 mmol/l (109-126 mg/dl)

+ 2 U

If one SMPG measurement

 

     3.1-4.0 mmol/l (56-72 mg/dl)

- 2 U

      < 3.1 mmol/l (< 56 mg/dl)

- 4 U

* 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 insulin detemir 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 insulin detemir Levemir dose adjusted on an individual basis.

 

Paediatric population

 

The efficacy and safety of Levemir were demonstrated in children and adolescents and children aged 26 to 17 years and above in studies up to 126 months (see section 5.1).

 

As with all insulin medicinal products, in children and adolescents, glucose monitoring should be intensified and the insulin detemir Levemir dose adjusted on an individual basis.

 

The efficacy and safety of Levemir hasve not been studied in children below the age of 26 years. Levemir should only be used in this age group under careful medical supervision.

 

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.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

 

There is no clinical experience with Levemirinsulin detemir during pregnancy.

 

Animal reproduction studies have not revealed any differences between insulin detemir and human insulin human 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 Levemirinsulin detemir 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.

 

4.8     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 productshuman. 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).

 

Immune system disorders

Uncommon – Allergic reactions, potentially allergic reactions, urticaria, rash, eruptions*

 

Very rare – Anaphylactic reactions*

Metabolism and nutrition disorders

 

Very common – Hypoglycaemia*

 

Nervous system disorders

Rare – Peripheral neuropathy

 

Eye disorders

 

 

Uncommon – Refraction disorders

 

Uncommon – Diabetic retinopathy

 

Skin and subcutaneous tissue disorders

Uncommon – Lipodystrophy*

General disorders and administration site conditions

 

Common – Injection site reactions

 

Uncommon – Oedema

 

* 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.

 

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting: ATC code: A10AE05.

 

Mechanism of action

 

LevemirInsulin detemir is a soluble, long-acting insulin analogue with a prolonged duration of effect used as a basal insulin.

 

The blood glucose lowering effect of Levemirinsulin detemir 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 Levemirinsulin detemir 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 Levemirinsulin detemir and NPH insulin

Pharmacodynamic Endpoint

LevemirInsulin detemir

CV (%)

NPH insulin

CV (%)

AUCGIR,0-24h*

27

68

GIRmax**

23

46

*Area under the curve         ** Glucose Infusion Rate p-value < 0.001 for all comparisons with Levemirinsulin detemir

 

The prolonged action of Levemirinsulin detemir 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, please see Table 2 below. In the study versus insulin glargine, Levemir insulin detemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the Levemirinsulin detemir- treated subjects completed the 52 weeks of treatment on the twice daily regimen.

 

Table 2. Change in body weight after insulin treatment

Study duration

LevemirInsulin detemir once daily

LevemirInsulin detemir twice daily

NPH insulin

Insulin glargine

20 week

+0.7 kg

 

+1.6 kg

 

26 weeks

 

+1.2 kg

+2.8 kg

 

52 weeks

+2.3 kg

+3.7 kg

 

+4.0 kg

 

In trials with investigating the use of oral antidiabetic medicinal products, combination therapy with Levemir treatment 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

 

 

Study week

Randomised Levemir + liraglutide + metformin

N = 160

Randomised Liraglutide + metformin

N = 149

P-value

Mean change in HbA1c from baseline (%)

0-26 weeks

-0.51

+0.02

<0.0001

0-52 weeks

-0.50

0.01

<0.0001

Proportions of patients achieving HbA1c <7% targets (%)

0-26 weeks

43.1

16.8

<0.0001

0-52 weeks

51.9

21.5

<0.0001

Change in body weight from baseline (kg)

0-26 weeks

-0.16

-0.95

0.0283

0-52 weeks

-0.05

-1.02

0.0416

Minor hypoglycaemic episodes (per patient year)

0-26 weeks

0.224

0.019

0.0075

0-52 weeks

0.228

0.034

0.0011

 

In long-term treatment trials in patients with type 1 diabetes receiving a basal-bolus insulin therapy, fasting plasma glucose was improved with Levemir compared with NPH insulin when given as basal/bolus therapy including in children and adolescents aged 6 to 17 years. Glycaemic control (HbA1c) with Levemir wasis 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. Furthermore, the overall risk of nocturnal hypoglycaemia in children and adolescents aged 6 to 17 years with type 1 diabetes was significantly lower with Levemir compared to NPH insulin.

 

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 Levemirinsulin detemir (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 insulin 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 Levemirinsulin detemir between elderly and young subjects.

 

Renal and hepatic impairment

There was no clinically relevant difference in pharmacokinetics of Levemirinsulin detemir between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of Levemirinsulin detemir 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 Levemirinsulin detemir.

 

Paediatric population

 

The pharmacokinetic properties of Levemirinsulin detemir 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 human.

 

 

 

 

 

 

 

 

 

 

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

10/2011
Updated on 19/05/2011 and displayed until 04/11/2011
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   01-Apr-2011
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company


Levemir SmPC

4.2 Posology and method of administration

Method of administration

Levemir InnoLet

 

is a are pre-filled pens 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.

 
Updated on 02/03/2011 and displayed until 19/05/2011
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   01-Feb-2011
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company
In section 4.4 Special warnings and precautions for use, the following paragraph has been added:-

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.



Date of revision

02/2011
Updated on 15/10/2010 and displayed until 02/03/2011
Reasons for adding or updating:
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.7 - Effects on Ability to Drive and Use Machines
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6. 6 - Instructions for use, handling and disposal
  • Change to section 10 date of revision of the text
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   01-Sep-2010
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company


SmPC changes for Levemir®

 

Extension NN729 – EMEA/H/C/528/X/44

 

 

PREVIOUS WORDING

NEW WORDING

4.1  Therapeutic indications

 

Treatment of diabetes mellitus in adults and adolescents and children aged 6  - 17 years.

 

4.1  Therapeutic indications

 

Treatment of diabetes mellitus in adults, adolescents and children aged 6–17 years.

 

4.2  Posology and method of administration

 

Levemir is a long-acting insulin analogue used as a basal insulin.

 

Posology

 

 

 

 

 

 

 

In combination with oral antidiabetic medicines it is recommended to use Levemir once daily, initially at a dose of 10 U or 0.1-0.2 U/kg. The injection can be given at any time during the day, but at the same time each day. The dose of Levemir should be titrated based on individual patients’ needs.

 

Based on study results, the following titration guideline is recommended:

 

Upper case L has been replaced with lower case l in the table. e.g. ‘> 10.0 mmol/L (180 mg/dL)’ now ‘> 10.0 mmol/l (180 mg/dl)’

 

When Levemir is used as part of a basal-bolus insulin regimen Levemir should be administered once or twice daily depending on patients’ needs. Dosage of Levemir should be adjusted individually.

 

Adjustment of dosage may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

 

Special populations

 

As with all insulin products, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin detemir dosage adjusted on an individual basis.

 

 

 

 

 

 

 

 

 

Paediatric use

 

The efficacy and safety of Levemir were demonstrated in children and adolescents aged 6 to 17 years in studies up to 6 months (see section 5.1).

 

 

 

 

 

 

The efficacy and safety of Levemir have not been studied in children below the age of 6 years. Levemir should only be used in this age group under careful medical supervision.

 

Transfer from other insulin products

 

Transfer to Levemir from other intermediate or long-acting insulin products may require adjustment of dose and timing of administration (see section 4.4).

 

 

As with all insulin products, close glucose monitoring is recommended during the transfer and in the initial weeks thereafter.

 

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

 

Method of administration

 

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 therefore always be rotated within the same region. As with all insulin products the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

 

 

 

 

 

 

 

Levemir Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. Levemir Penfill is accompanied by a package leaflet with detailed instruction for use to be followed.

 

 

 

Levemir FlexPen are pre-filled pens designed to be used with NovoFine or NovoTwist needles. FlexPen delivers 1-60 units in increments of 1 unit. Levemir FlexPen is colour coded and accompanied by a package leaflet with detailed instruction for use to be followed.

 

 

 

 

 

Levemir InnoLet are pre-filled pens designed to be used with NovoFine needles. InnoLet delivers 1-50 units in increments of 1 unit. Levemir InnoLet is accompanied by a package leaflet with detailed instruction for use to be followed.

 

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 insulin human is expressed in international units (IU). 1 unit (U) insulin detemir corresponds to 1 international unit (IU) of insulin human.

 

In combination with oral antidiabetic medicinal products 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:

 

Upper case L has been replaced with lower case l in the table. e.g. ‘> 10.0 mmol/L (180 mg/dL)’ now ‘> 10.0 mmol/l (180 mg/dl)’

 

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 insulin detemir 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 insulin detemir dose adjusted on an individual basis.

 

Paediatric population

 

The efficacy and safety of Levemir were demonstrated in children and adolescents aged 6 to 17 years in studies up to 6 months (see section 5.1).

 

As with all insulin medicinal products, in children and adolescents, glucose monitoring should be intensified and the insulin detemir dose adjusted on an individual basis.

 

The efficacy and safety of Levemir have not been studied in children below the age of 6 years. Levemir should only be used in this age group under careful medical supervision.

 

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 are pre-filled pens designed to be used with NovoFine 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.

 

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

 

 

 

 

 

 

 

 

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.

 

 

 

 

 

 

 

 

 

 

Transfer from other insulin 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 dosage. Patients transferred to Levemir from another type of insulin may require a change in dosage from that used with their usual insulins. 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.

 

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.

 

4.5  Interaction with other medicinal products and other forms of interaction

 

Beta-blocking agents may mask the symptoms of hypoglycaemia.

 

Octreotide/lanreotide may both increase or decrease insulin requirement.

4.5  Interaction with other medicinal products and other forms of interaction

 

Beta-blockers may mask the symptoms of hypoglycaemia.

 

Octreotide/lanreotide may either increase or decrease the insulin requirement.

 

4.6  Pregnancy and lactation

 

Pregnancy

There is no clinical experience with insulin detemir 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 insulin detemir during breast-feeding. Caution should be exercised when prescribing to breast-feeding women. Breast-feeding women may require adjustments in insulin dose and diet.

 

 

4.6  Fertility, pregnancy and lactation

 

Pregnancy

 

There is no clinical experience with insulin detemir during pregnancy.

 

Animal reproduction studies have not revealed any differences between insulin detemir and insulin human 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 insulin detemir 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 a car or operating machinery).

 

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).

 

4.8  Undesirable effects

 

 

 

Adverse reactions observed in patients using Levemir are mainly dose-dependent and due to the pharmacologic effect of insulin. The overall percentage of treated patients expected to experience adverse drug reactions is estimated to be 12%.

 

Hypoglycaemia is a common undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement. 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. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

 

Injection site reactions are seen more frequently during treatment with Levemir than with human insulin. 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.

 

 

 

 

 

 

 

 

 

 

 

 

Adverse reactions listed below are classified according to 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).

 

Nervous system disorders

 

 

Rare - Peripheral neuropathy

Fast improvement in blood glucose control may be associated with the condition “acute painful neuropathy”, which is usually reversible

Eye disorders

 

 

Uncommon - Refraction disorders

Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Uncommon - Diabetic retinopathy

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy.

Metabolism and nutrition disorders

 

 

Common – Hypoglycaemia

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. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

General disorders and administration site conditions

 

 

 

Common - Injection site reactions

Injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching) at the injection site may occur during treatment with insulin. These reactions are usually transitory and normally they disappear during continued treatment.

Uncommon - Lipodystrophy

Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

Uncommon - Oedema

Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Immune system disorders*

 

 

Common

In three clinical studies with subjects treated in combination with oral antidiabetic agents a frequency of 2.2% of allergic reactions and potentially allergic reactions have been observed.

Uncommon

Allergic reactions, potentially allergic reactions, urticaria, rash and eruptions:

Such symptoms may be due to generalised hypersensitivity. Other signs of generalised hypersensitivity may be itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life threatening (anaphylactic reactions).

* Frequencies are uncommon in basal-bolus regimen, but common in three clinical trials in combination with oral antidiabetic medicine.

 

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 insulin human. 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).

 

Immune system disorders

Uncommon – Allergic reactions, potentially allergic reactions, urticaria, rash, eruptions*

 

Very rare – Anaphylactic reactions*

Metabolism and nutrition disorders

 

Very common – Hypoglycaemia*

 

Nervous system disorders

Rare – Peripheral neuropathy

 

Eye disorders

 

 

Uncommon – Refraction disorders

 

Uncommon – Diabetic retinopathy

 

Skin and subcutaneous tissue disorders

Uncommon – Lipodystrophy*

General disorders and administration site conditions

 

Common – Injection site reactions

 

Uncommon – Oedema

 

* 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 by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or by glucose given intravenously by a health care professional. Glucose must also 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.

 

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.

 

5.1  Pharmacodynamic properties

 

Pharmacotherapeutic group: Insulins and analogues for injection, long-acting: ATC code: A10AE05.

 

Mechanism of action

 

…….

 

Table 1. Within-Subject Variability of the time action profile of insulin detemir and NPH insulin

…….

 

Studies in patients with type 2 diabetes treated with basal insulin in combination with oral antidiabetic medicines demonstrated that glycaemic control (HbA1c) with Levemir is comparable to NPH insulin and insulin glargine and associated with less weight gain, please see Table 2 below. In the study versus insulin glargine, insulin detemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the insulin detemir-treated subjects completed the 52 weeks of treatment on the twice daily regimen.

…….

In trials with the use of OAD-insulin combination therapy Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.

 

…….

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. Furthermore, the overall risk of nocturnal hypoglycaemia in children and adolescents aged 6 to 17 years with type 1 diabetes was significantly lower with Levemir compared to NPH insulin.

 

5.1  Pharmacodynamic properties

 

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting: ATC code: A10AE05.

 

Mechanism of action

 

…….

 

Table 1. Within-subject variability of the time action profile of insulin detemir and NPH insulin

…….

 

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, please see Table 2 below. In the study versus insulin glargine, insulin detemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the insulin detemir-treated subjects completed the 52 weeks of treatment on the twice daily regimen.

…….

In trials with the use of oral antidiabetic medicinal products combination therapy Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.

…….

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. Furthermore, the overall risk of nocturnal hypoglycaemia in children and adolescents aged 6 to 17 years with type 1 diabetes was significantly lower with Levemir compared to NPH insulin.

 

5.2      Pharmacokinetic properties

 

Metabolism

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

…….

 

Special populations

Paediatric patients: The pharmacokinetic properties of insulin detemir 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.

 

Elderly: There was no clinically relevant difference in pharmacokinetics of insulin detemir between elderly and young subjects.

 

Renal and hepatic impairment: There was no clinically relevant difference in pharmacokinetics of insulin detemir between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of insulin detemir 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 insulin detemir.

 

5.2      Pharmacokinetic properties

 

Biotransformation

 

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

 

Special populations

 

 

 

 

 

 

Elderly (≥ 65 years old)

There was no clinically relevant difference in pharmacokinetics of insulin detemir between elderly and young subjects.

 

Renal and hepatic impairment

There was no clinically relevant difference in pharmacokinetics of insulin detemir between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of insulin detemir 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 insulin detemir.

 

Paediatric population

 

The pharmacokinetic properties of insulin detemir 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. Receptor affinity data and in vitro mitogenicity tests revealed no evidence of an increased mitogenic potential compared to human insulin.

 

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 insulin human.

 

 

6.6  Special precautions for disposal and other handling

 

Levemir Penfill, Levemir FlexPen and Levemir InnoLet are for use by one person only.

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.

 

 

 

10.  DATE OF REVISION OF THE TEXT

 

08/2010

10.    DATE OF REVISION OF THE TEXT

 

09/2010

 

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

 

 
Updated on 24/09/2010 and displayed until 15/10/2010
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
Date of revision of text on the SPC:   01-Aug-2010
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company
In section 4.2, the sentence relating to the types of Novo Nordisk needles which can be used with the Penfill has been updated to include NovoTwist needles, as well as NovoFine needles.
Updated on 21/05/2009 and displayed until 24/09/2010
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 6. 3 - Shelf Life
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   14-Apr-2009
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company
4.1    Therapeutic indications

Treatment of diabetes mellitus sentence added “in adults and adolescents and children aged 6  - 17 years.”
4.2     Posology and method of administration

Posology

In combination with oral antidiabetic medicines – Sentence added “it is recommended to use Levemir once daily”, initially at a dose of 10 U or 0.1-0.2 U/kg. Sentence added “The injection can be given at any time during the day, but at the same time each day.”

 

Transfer from other insulin products

For patients who require twice daily dosing to optimise blood glucose control, the evening dose can be administered in the evening or at bedtime. Sentence added “Adjustment of dosage may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.”

 

Paediatric use

 

The efficacy and safety of Levemir have not been studied in children below the age of 6 years. Sentence added Levemir should only be used in this age group under careful medical supervision.

5.2     Pharmacokinetic properties

Paragraphs added:

Renal and hepatic impairment: There was no clinically relevant difference in pharmacokinetics of insulin detemir between subjects with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of insulin detemir 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 insulin detemir.

6.3     Shelf life

Changed from 2 years to 30 months.

10.     DATE OF REVISION OF THE TEXT

Deleted: 06/2007

Inserted:

Date of first authorisation: 01 June 2004

Date of last renewal: 16 April 2009

 

04/2009
Updated on 24/08/2007 and displayed until 21/05/2009
Reasons for adding or updating:
  • Change to section 6.1 - List of Excipients
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   06/2007
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company
6.1 List of Excipients
Mannitol replaced with glycerol.
Updated on 19/07/2007 and displayed until 24/08/2007
Reasons for adding or updating:
  • Removal of Black Triangle
Date of revision of text on the SPC:   02/2007
Legal Category:   POM
Black Triangle (CHM):   NO

Free-text change information supplied by the pharmaceutical company
Removal of the black triangle.
 
Updated on 14/03/2007 and displayed until 19/07/2007
Reasons for adding or updating:
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
  • Change to section 10 date of revision of the text
Date of revision of text on the SPC:   02/2007
Legal Category:   POM
Black Triangle (CHM):   YES

Free-text change information supplied by the pharmaceutical company

The SPC update is to include Levemir and OAD combination therapy and the introduction of a new pre-filled pen, InnoLet. The principal changes to the SPC text may be summarised as follows:

 


3. Pharmaceutical Form
Addition of:
"Solution of injection in a pre-filled pen.  InnoLet." 

 

4.2 Posology and method of administration

 

To accommodate use of Levemir with both bolus insulin and OADs the opening sentence has been generalised to state that 'Levemir is a long-acting insulin analogue used as a basal insulin.'

 

The description of dosage has been divided into combination with OADs and use in basal-bolus regimens. A new text for Levemir + OAD combination therapy has been inserted with a recommended starting dose and titration guideline. 

Under "Administration" Levemir InnoLet has been included.

 

 

4.8 Undesirable effects

 

A new statement has been included under 'Immune system disorders' concerning the reporting at a higher frequency of allergic reactions or potentially allergic reactions in three clinical studies in which subjects were treated with Levemir + OAD combination therapy.

 

There has been a clarification concerning injection site reactions. Previously it was stated that: 'Most minor reactions to insulins at the injection site are usually of a transitory nature…' This has now been changed to:  'Most of the injection site reactions are minor and are usually of a transitory nature…'

 

5.1 Pharmacodynamic properties

 

New information has been included in this section describing results of studies in which Levemir was used in combination with OADs. This states that glycaemic control as measured by HbA1c is comparable to NPH insulin and insulin glargine but with less weight gain (a table of changes in body weight is included) and that there is a lower risk of nocturnal hypoglycaemia compared to NPH insulin. It is also noted that in the study versus once-daily insulin glargine, insulin detemir was allowed to be administered once or twice daily and 55% of the insulin detemir-treated subjects completed the 52 weeks of treatment on a twice daily regimen.

 

The statement 'The blood glucose lowering effect of Levemir has been demonstrated in clinical trials outside a basal bolus regimen. However, outside a basal bolus regimen non inferiority of HbA1c has not been demonstrated' has been deleted.

 

The general statement 'Unlike other insulins, intensive therapy with Levemir is not associated with undesirable weight gain' has been deleted. However, there is a new statement on weight gain with OAD combination therapy (see above) and the statement on weight gain in type 1 diabetics in comparison with NPH insulin has been retained.

 

A new statement has been included concerning antibody development: 'Antibody development has been observed with the use of Levemir. However, this does not appear to have any impact on glycaemic control.'

6.4 Special precautions for storage
Levemir InnoLet has been included.

6.5 Nature and contents of container
Levemir InnoLet has been included.

8. Marketing Authorisation (Number(s)
Levemir InnoLet has been included.

10. Date of revision of the text
02/2007

 
Updated on 22/08/2006 and displayed until 14/03/2007
Reasons for adding or updating:
  • Change to section 2 - qualitative and quantitative composition
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.3 - Contra-indications
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6.1 - List of Excipients
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 6 - Instruction for Use/Handling
  • Change to section 9 - Date of Renewal of Authorisation
  • Change to section 10 (date of (partial) revision of the text
Date of revision of text on the SPC:   07/2006
Legal Category:   POM
Black Triangle (CHM):   YES

Free-text change information supplied by the pharmaceutical company

The changes are mainly concerned with an update to the information on injections site reactions. There are additionally a few editorial changes. The changes are as follows:

 

Section 2. Qualitative and quantitative composition

Editorial change (reference to full list of excipients).

 

Section 3 Pharmaceutical form

Editorial changes.

 

Section 4.2 Posology and method of administration

Addition of cross-reference to section 5.1 (Pharmacodynamic properties) to statement on use in children and adolescents.

 

Section 4.4 Special warnings and precautions for use

Amendment of section title according to revised template for SPCs.

Addition of new paragraph concerning injection site reactions:

"As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, swelling and inflammation. 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, injections site reactions may require discontinuation of Levemir."

 

Section 4.8 Undesirable effects

The second paragraph which describes injection site reactions with Levemir has been amended:

"Injection site reactions are commonly seen more frequently during treatment with Levemir than with human insulin. , namely in 2% of patients. These reactions include redness, inflammation, bruising, swelling and itching at the injection site. Most minor reactions to insulins at the injection site and are usually of a transitory nature, i.e. they normally disappear during continued treatment in a few days to a few weeks."

In the sub-section 'Immune system disorders' generalised hypersensitivity reactions have been clarified as anaphylactic reactions.

 

Section 5.3 Preclinical safety data

Editorial change.

 

Section 6.4 Special precautions for storage

Editorial change.

 

Section 6.6 Special precautions for disposal

Amendment of section title according to revised template for SPCs.

10. Date of revision of the text
07/2006

 

 
Updated on 14/09/2005 and displayed until 22/08/2006
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 10 (date of (partial) revision of the text
Updated on 13/04/2005 and displayed until 14/09/2005
Reasons for adding or updating:
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 10 (date of (partial) revision of the text
Updated on 29/06/2004 and displayed until 13/04/2005
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic Properties
Updated on 22/06/2004 and displayed until 29/06/2004
Reasons for adding or updating:
  • New SPC for new product
  • Pending awaiting re-submission

Active Ingredients/Generics

 
  insulin detemir