Levemir FlexPen (Insulin detemir) 100 units/ml solution for injection in pre-filled pen

Addition of Northern Ireland to reporting of side effects section. Update of revision date.

Section 4.6

Pregnancy section updated:

The use of Levemir in pregnant women with diabetes has been investigated in a clinical trial and in a prospective non-interventional post-authorisation safety study (see section 5.1). Post-marketing data in pregnant women using Levemir, with more than 4,500 pregnancy outcomes do not indicate any increased risk of malformative or feto/neonatal toxicity. Treatment with Levemir can be considered during pregnancy, if clinically needed but any potential benefit must be weighed against a possibly increased risk of an adverse pregnancy outcome

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

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

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

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

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

Section 5.1

Pregnancy section updated:

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

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

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

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

Table 4. Maternal glycaemic control

Section 10 Date of revision of the text

Updated to: 04/2021

Section 2 – what you need to know - warnings and precautions

New text:

Skin changes at the injection site

The injection site should be rotated to help prevent changes to the fatty tissue under the skin, such as skin thickening, skin shrinking or lumps under the skin. The insulin may not work very well if you inject into a lumpy, shrunken or thickened area (see section 3 ‘How to use Levemir^®’). Tell your doctor if you notice any skin changes at the injection site. Tell your doctor if you are currently injecting into these affected areas before you start injecting in a different area. Your doctor may tell you to check your blood sugar more closely, and to adjust your insulin or your other antidiabetic medications dose.

Section 4 – possible side effects

New text:

Skin changes at the injection site: If you inject insulin at the same place, the fatty tissue may shrink (lipoatrophy) or thicken (lipohypertrophy) (may affect up to 1 in 100 people). Lumps under the skin may also be caused by build-up of a protein called amyloid (cutaneous amyloidosis; how often this occurs is not known). The insulin may not work very well if you inject into a lumpy, shrunken or thickened area. Change the injection site with each injection to help prevent these skin changes.

Deleted text:

Uncommon side effects

Changes at the injection site (lipodystrophy): The fatty tissue under the skin at the injection site may shrink (lipoatrophy) or thicken (lipohypertrophy). Changing the site with each injection reduces the risk of developing such skin changes. If you notice your skin pitting or thickening at the injection site, tell your doctor or nurse. These reactions can become more severe, or they may change the absorption of your insulin, if you inject in such a site.

Section 4 – how to report a side effect

HPRA contact details updated to short version

Section 4.2 - method of administration

Updated text:

Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8).

Section 4.4

New text:

Skin and subcutaneous tissue disorders

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 an unaffected area, and dose adjustment of antidiabetic medications may be considered.

Traceability

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

Section 4.8

Addition to adverse reaction list, skin and subcutaneous tissue disorders:

Not known – cutaneous amyloidosis†

† ADR from postmarketing sources.

Skin and subcutaneous tissue disorders

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

Addition of joint SmPC covering all presentations

Additional presentations added as per the authorised EMA-approved SmPC (Levemir FlexTouch 100 IU/ml). This presentation is added to the local SmPC but are not marketed. 

PDF of SPC uploaded to replace Word document

Following updates were made:

section 4.2 - table "Adult type 2 diabetes titration guideline" was updated to add!If one SMPG measurement"

sub-section "Method of Administration": addition of information that product is suitable only for subcutaneous injection. If administration by syringe is necessary, a vial should be used.