Actrapid 100 international units/ml, Solution for injection in a vial

Update from 'United Kingdom' to 'United Kingdom (Northern Ireland)'.

Change to date of revision.

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). 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 less than 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 from ‘Uncommon (may affect up to 1 in 100 people)’:

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 may help to reduce 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 given injection area may help to reduce or prevent these reactions (see section 4.4).

Addition of joint SmPC covering all presentations

Additional presentations added as per the authorised EMA-approved SmPC (Actrapid 40 IU/ml vial, 100 IU/ml Penfill, 100 IU/ml InnoLet, 100 IU/ml FlexPen). These presentations are added to the local SmPC but are not marketed. ​​​​​​​

Section 4.4:

Text added: "

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Actrapid and other insulin products."

Section 4.8:

UK reporting details removed - not applicable to IE SPC.

Section 10: revision date updated to 07/2019

Key: Addition of text = in red     Deletion of text = crossed out

4.8  Undesirable effects

Reporting of suspected adverse reactions

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

6.6 Special precautions for disposal and other handling

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

Actrapid which has been frozen must not be used.

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

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

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

The cartridge must not be refilled.

In case of emergency in current Actrapid users (hospitalisation or insulin pen malfunction), Actrapid can be withdrawn with an U100 insulin syringe from a cartridge or pre-filled pen.

10. DATE OF REVISION OF THE TEXT

03/2018

1.         NAME OF THE MEDICINAL PRODUCT

Actrapid 100 international units/ml solution for injection.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial contains 10 ml equivalent to 1,000 international units. 1 ml solution contains 100 iuinternational units insulin human* (equivalent to 3.5 mg). 1 vial contains 10 ml equivalent to 1,000iu.

*Human insulin is produced in Saccharomyces cerevisiae by recombinant DNA technology.

Excipient with known effect:

100 iu of Actrapid contains approximately 5 mcmol sodium, i.e. Actrapid contains less than 1 mmol sodium (23 mg) per dose, i.e.  Actrapidand is therefore considered essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

…

4.         Clinical particulars

4.1       Therapeutic indications

Actrapid is indicated for Ttreatment of diabetes mellitus.

4.2       Posology and method of administration

Posology

The potency of human insulin is expressed in international units (iu).

Actrapid dosing is individual and determined in accordance with the needs of the patient. It can be used alone or in combination with intermediate-acting or long-acting insulin before a meal or a snack.

The individual insulin requirement is usually between 0.3 and 1.0 international unit/kg/day. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production.

In patients with diabetes mellitus optimised glycaemic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended. 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)

Actrapid can be used in elderly patients.

As with all insulin medicinal products, iIn elderly patients, glucose monitoring should be intensified and the insulin 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, iIn patients with renal or hepatic impairment, glucose monitoring should be intensified and the human insulin dose adjusted on an individual basis.

Paediatric population

Actrapid can be used in children and adolescents.

Transfer from other insulin medicinal products

When transferring from other insulin medicinal products, adjustment of the Actrapid dose and the dose of the basal insulin may be necessary.

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

Method of administration

Actrapid is a fast-acting human insulin and may be used in combination with intermediate or long-acting insulin medicinal products.

Actrapid is administered subcutaneously by injection in the abdominal wall, the thigh, the gluteal region or the deltoid region. Injection into a lifted skin fold minimises the risk of unintended intramuscular injection. The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. As with all insulin medicinal products, sSubcutaneous injection into the abdominal wall ensures a faster absorption than other injection sites. As with all insulin medicinal products, tThe duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

An injection should be followed within 30 minutes by a meal or snack containing carbohydrates.

Due to the risk of precipitation in pump catheters, Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.

Administration with a syringe

Actrapid vials are for use with insulin syringes with a corresponding unit scale. When two types of insulin are mixed always mix the insulin medicinal products in the same sequence.

Actrapid vial is accompanied by a package leaflet with detailed instructions for use to be followed.

Intravenous use

If necessary, Actrapid can be administered intravenously. whichThis should be carried out by healthcare professionals.

For intravenous use, infusion systems with Actrapid at concentrations from 0.05 international unit/ml to 1.0 international unit/ml human insulin in the infusion fluids 0.9% sodium chloride, 5% dextrose and 10% dextrose inclusive 40 mmol/l potassium chloride using polypropylene infusion bags, are stable at room temperature for 24 hours. Although stable over time, a certain amount of insulin will initially be adsorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during the insulin infusion.

…

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. In case of hypoglycaemia or if hypoglycaemia is suspected, Actrapid must not be injected. After stabilisation of 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, 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 requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the 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 insulin, human insulin or human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dose. Patients transferred to Actrapid from another type of insulin may require an increased number of daily injections or 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 reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Actrapid.

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4.8       Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see section cDescription of selected adverse reactions below.

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) 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

The Aadverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

* see section cDescription of selected adverse reactions

c. Description of selected adverse reactions

Anaphylactic reactions:

The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulty 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 concentratingon, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

In clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens and level of glycaemic control.

Lipodystrophy:

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

d. Paediatric population

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the paediatric population do not indicate any differences to the broader experience in the general population.

e. Other special populations

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

f. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Appendix V

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

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6.2       Incompatibilities

Insulin medicinal products should only be added to compounds with which it is known to be compatible. Medicinal products added to the insulin solution may cause degradation of the insulin, e.g. if the medicinal products contain thiols or sulfphites.

6.3       Shelf life

Before opening: 30 months.

During use or when carried as a spare: The product canmust be stored for a maximum of 6 weeks. Store below 25°C.

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8.         MARKETING AUTHORISATION NUMBERS

EU/1/02/230/003

EU/1/02/230/004

EU/1/02/230/017

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10.       DATE OF REVISION OF THE TEXT

11/201206/2014

Lipodystrophy: The purpose is to update the wording on lipodystrophy to make the information more legible for healthcare professionals. The following sections have been updated: SmPC section 4.2 (Method of administration), SmPC section 4.8 (Undesirable effects).

Section 4.2

Injection sites should always be rotated within an anatomic the same region in order to avoid reduce the risk of lipodystrophy.

Section 4.8

Skin and subcutaneous tissue disorders

Uncommon - Lipodystrophy

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

Lipodystrophy:

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

Concomitant illness: New information has been added about ‘concomitant illness’ in SmPC section 4.4 (Special warnings and precautions for use).

Section 4.4

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

Hypoglycaemia: Hypoglycaemia has been removed from section 4.3 (Contraindications) to section 4.4 (Special warnings and precautions for use) as it is considered inadvisable to state hypoglycaemia as a contraindication due to the risk of patients believing that they should not administer insulin if they at some point have experienced an event of hypoglycaemia.

Section 4.4

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. In case of hypoglycaemia or if hypoglycaemia is suspected <Insulatard/Actrapid> must not be injected. After stabilisation of patient’s blood glucose adjustment of the dose should be considered (see sections 4.8 and 4.9).

Alcohol: ‘alcohol’ is removed from section 4.5.

Section 4.5

The following substances may reduce the patient’s insulin requirement:

Oral antidiabetic medicinal products, hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blockersing agents, angiotensin converting enzyme (ACE) inhibitors, salicylates,  alcohol, anabolic steroids and sulphonamides.

Elderly and children: Sections 4.2, 4.6 and 4.8 have been updated to reflect legislation on the elderly and children, and the EU SmPC guideline.

The remainder of the changes to the other changes are due to readability and harmonisation with the current QRD (SmPC) template.

In section 4.4 Special warnings and precautions for use - addition of the following paragraph:-

Combination of Actrapid 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 Actrapid 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.

Revision of text date
02/2011

4.4 Special warnings and precautions for use

 Inclusion of standard text concerning injection site reactions has been added:

 “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, injection site reactions may require discontinuation of Actrapid”.

4.5  Interaction with other medicinal products and other forms of interaction

 Anabolic steroids and sulphonamides have been added to the list of substances which my reduce insulin requirements. Oral contraceptives have been added to the list of substances which may increase insulin requirements. These changes are to ensure consistency with the corresponding section in the SPCs for analogue insulins.

4.8 Undesirable effects

The following information has been inserted

… “including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness”.

5.2  Pharmacokinetic properties

Addition of heading:

Children and adolescents:

 6.1 List of excipients

“for pH adjustment” has been added for sodium hydroxide

 6.2 Incompatibilities

Addition of standard statement that insulin should only be added to compounds with which it is known to be compatible

This information has been added: “Insulin products should only be added to compounds with which it is known to be compatible”.

This information has been deleted “Upon mixing Actrapid with infusion fluids an unpredictable amount of insulin will be adsorbed to the infusion material. Monitoring of the patient's blood glucose during infusion is therefore recommended”.

6.3 Shelf life

“when stored between 2˚C-8˚C” has been added to the shelf life of 30 months.

“when used or stored at room temperature (below 25˚C)” has been added to the shelf life of 6 weeks.

“After first opening” has been deleted.

 “when used or stored at room temperature (below 25˚C)” has been added to the shelf life of 6 weeks.

6.4 Special precautions for storage

There have been a number of editorial changes to these sections, generally to standardise the statements. There have been no changes to the actual shelf life or storage conditions.

“Before use” has been added in front of: “Store in a refrigerator (2°C - 8°C)”.

This sentence has been added “Do not store them in or too near the freezer section or cooling element”.

6.5 Nature and contents of container

Size of container has been specified as “10ml”.

6.6 Special precautions for disposal and other handling

These sentences have been added:

“For intravenous use, infusion systems with Actrapid at concentrations 0.05 IU/ml – 1.0 IU/ml insulin human in he following infusion fluids: 0.9% sodium chloride, 5% dextrose and 10% dextrose inclusive 40 mmol/l potassium chloride, using polypropylene infusion bags, are stable at room temperature for 24 hours. Although stable over time, a certain amount of insulin will initially be absorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during the infusion”.

“Any unused product or waste material should be disposed of in accordance with local requirements”.

9.    Date of first authorisation/renewal of the authorisation

Date of last renewal: 18 October 2007