NovoRapid Penfill 100 units/ml solution for injection in cartridge

United Kingdom updated to United Kingdom (Northern Ireland)

Date of revision updated to 10/2022

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 NovoRapid^®’). 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 (NovoRapid InnoLet, FlexTouch, PumpCart). These presentations are added to the local SmPC only, i.e. no change to marketing status. 

PDF of SPC uploaded to replace Word document

6.4     Special precautions for storage

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

Before opening: Store in a refrigerator (2°C - 8°C). Do not freeze.

NovoRapid vial/NovoRapid Penfill

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

Keep the vial/cartridge in the outer carton in order to protect from light.

NovoRapid FlexPen

During use or when carried as a spare: Store below 30°C. Do not refrigerate. Can be stored in a refrigerator (2°C - 8°C). Do not freeze. 
Keep the pen cap on the pen in order to protect from light.

10.       DATE OF REVISION OF THE TEXT

10/2016 06/2017

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

Track changes below. (...indicates omitted text that is unchanged)

1.         NAME OF THE MEDICINAL PRODUCT

 NovoRapid 100 units/ml solution for injection in vial

NovoRapid Penfill 100 units/ml solution for injection in cartridge

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

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

NovoRapid vial

1 ml solution contains 100 units insulin aspart* (equivalent to 3.5 mg).

1 vial contains 10 ml equivalent to 1,000 units.

NovoRapid Penfill

1 ml solution contains 100 units insulin aspart* (equivalent to 3.5 mg). 1 cartridge contains 3 ml equivalent to 300 units.

NovoRapid FlexPen

1 ml solution contains 100 units insulin aspart* (equivalent to 3.5 mg). 1 pre-filled pen contains 3 ml equivalent to 300 units.

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

For the full list of excipients, see section 6.1.

 …

4.2       Posology and method of administration

Posology

 The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.

 NovoRapid dosing is individual and determined in accordance with the needs of the patient. It should normally be used in combination with intermediate-acting or long-acting insulin.

Moreover NovoRapid can be used for continuous subcutaneous insulin infusion (CSII) in pump systems.

It can alsoor be administered intravenously by physicians or other healthcare staffprofessionals if applicable.

Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

The individual insulin requirement in adults and children is usually between 0.5 and 1.0 unit/kg/day. In a basal-bolus treatment regimen 50-70% of this requirement may be provided by NovoRapid and the remainder by intermediate-acting or long-acting insulin.

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

…

Paediatric population

NovoRapid can be used in adolescents and children and adolescents aged 2 years and above in preference to soluble human insulin when a rapid onset of action might be beneficial (see sections 5.1 and 5.2). For example, in the timing of the injections in relation to meals.

 The safety and efficacy of NovoRapid in children below 2 years of age have not been established.

No data are available.

…

Method of administration

 NovoRapid is a rapid-acting insulin analogue.

NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. Subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. Compared to soluble human insulin the faster onset of action of NovoRapid is maintained regardless of the injection site. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Due to the faster onset of action, NovoRapid should generally be given immediately before a meal. When necessary NovoRapid can be given soon after a meal.

Continuous Subcutaneous Insulin Infusion (CSII)

NovoRapid may be used for CSII in pump systems suitable for insulin infusion. CSII should be administered in the abdominal wall. Infusion sites should be rotated.
When used with an insulin infusion pump, NovoRapid should not be mixed with any other insulin medicinal products.

Patients using CSII should be comprehensively instructed in the use of the pump system and use the correct reservoir and tubing for the pump (see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

Patients administering NovoRapid by CSII must have an alternative insulin delivery method available in case of pump system failure.

Intravenous use

If necessary, NovoRapid can be administered intravenously which should be carried out by physicians or other healthcare staff if applicable.

For intravenous use, infusion systems with NovoRapid 100 units/ml at concentrations from 0.05 unit/ml to 1.0 unit/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 10% dextrose including 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 be initially adsorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during insulin infusion.

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

NovoRapid vial:

Administration with a syringe

NovoRapid vials are for use with insulin syringes with the corresponding unit scale. See also section 6.2.

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

NovoRapid Penfill:

Administration with an insulin delivery system

NovoRapid Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles.

NovoRapid Penfill is accompanied by a package leaflet with detailed instructions for use to be fol-lowed.

NovoRapid FlexPen:

Administration with FlexPen

NovoRapid FlexPen is aare pre-filled pen (colour-coded) 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.

NovoRapid FlexPen is colour-coded and accompanied by a package leaflet with detailed instructions for use to be followed.

NovoRapid vial, Penfill and FlexPen

Continuous Subcutaneous Insulin Infusion (CSII)

NovoRapid may be used for CSII in pump systems suitable for insulin infusion. CSII should be administered in the abdominal wall. Infusion sites should be rotated.

When used with an insulin infusion pump, NovoRapid should not be mixed with any other insulin medicinal products.

Patients using CSII should be comprehensively instructed in the use of the pump system and use the correct reservoir and tubing for the pump (see section 6.6). The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

Patients administering NovoRapid by CSII must have an alternative insulin delivery method available in case of pump system failure.

Intravenous use

If necessary, NovoRapid can be administered intravenously which should be carried out by healthcare professionals.

For intravenous use, infusion systems with NovoRapid 100 units/ml at concentrations from 0.05 unit/ml to 1.0 unit/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 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 be initially adsorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during insulin infusion.

 …

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 physicians or other healthcare staffprofessional. 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.         PHARMACOLOGICAL PROPERTIES

 5.1       Pharmacodynamic properties

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 Clinical efficacy

Clinical trials in patients with type 1 diabetes have demonstrated a lower postprandial blood glucose with NovoRapid compared to soluble human insulin (Fig. I). In two long-term open label trials in patients with type 1 diabetes comprising 1070 and 884 patients, respectively, NovoRapid reduced glycatedglycosylated haemoglobin by 0.12 [95% C.I. 0.03; 0.22] percentage points and by 0.15 [95% C.I. 0.05; 0.26] percentage points compared to human insulin; a difference of doubtfullimited clinical significance.

Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycaemia with insulin aspart compared with soluble human insulin. The risk of daytime hypoglycaemia was not significantly increased.

Insulin aspart is equipotent to soluble human insulin on a molar basis.

Special populations

Elderly (≥ 65 years old)

A randomised, double-blind cross-over PK/PD trial comparing insulin aspart with soluble human insulin was performed in elderly patients with type 2 diabetes (19 patients aged 65-83 years, mean age 70 years). The relative differences in the pharmacodynamic properties (GIR_max,AUC_{GIR, 0-120 min}) between insulin aspart and human insulin in the elderly were similar to those seen in healthy subjects and in younger subjectspatients with diabetes.

Paediatric population

A clinical trial comparing preprandial soluble human insulin with postprandial insulin aspart was performed in small children (20 patients aged 2 to less than 6 years, studied for 12 weeks, among those four were younger than 4 years old) and a single dose PK/PD trial was performed in children (6-12 years) and adolescents (13-17 years). The pharmacodynamic profile of insulin aspart in children was similar to that seen in adults.

Pregnancy

A clinical trial comparing safety and efficacy of insulin aspart vs. human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies (insulin aspart: 157; human insulin: 165)) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn.

In addition the data from a clinical trial including 27 women with gestational diabetes randomised to treatment with insulin aspart vs. human insulin (insulin aspart: 14; human insulin: 13) showed similar safety profiles between treatments.

Insulin aspart is equipotent to soluble human insulin on a molar basis.

5.2       Pharmacokinetic properties

…

 Special populations

Elderly (≥ 65 years old)

The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly patientssubjects (65-83 years, mean age 70 years) with type 2 diabetes were similar to those observed in healthy subjects and in younger subjects patients with diabetes. A decreased absorption rate was observed in elderly patients, resulting in a later t_max (82 (interquartile range: 60-120) minutes), whereas C_max was similar to that observed in younger subjects patients with type 2 diabetes and slightly lower than in subjects patients with type 1 diabetes.

Hepatic impairment

A single dose pharmacokinetic study of insulin aspart was performed in 24 subjects with hepatic function ranging from normal to severely impaired. In patientssubjects with hepatic impairment, absorption rate was decreased and more variable, resulting in delayed t_max from about 50 min in subjects with normal hepatic function to about 85 min in patientssubjects with moderate and severe hepatic impairment. AUC, C_max and CL/F were similar in patientssubjects with reduced hepatic function compared with subjects with normal hepatic function.

Renal impairment

A single dose pharmacokinetic study of insulin aspart in 18 subjects with renal function ranging from normal to severely impaired was performed. No apparent effect of creatinine clearance values on AUC, C_max, CL/F and t_max of insulin aspart was found. Data were limited in subjects patients with moderate and severe renal impairment. Subjects Patients with renal failure necessitating dialysis treatment were not investigated.

…

6.2       Incompatibilities

Substances added to NovoRapid may cause degradation of insulin aspart., e.g. if the medicinal product contains thiols or sulphites.

This medicinal product must not be diluted or mixed with other medicinal products, except with NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.

6.3       Shelf life

Before opening: 30 months.

NovoRapid vial/NovoRapid Penfill/NovoRapid FlexPen

During use or when carried as a spare: The product must be stored for a maximum of 4 weeks. Store below 30°C.

6.4       Special precautions for storage

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

Before opening: Store in a refrigerator (2°C - 8°C). Do not freeze.

NovoRapid vial/NovoRapid Penfill

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

NovoRapid vial:

Keep the vial/cartridge in the outer carton in order to protect from light.

NovoRapid FlexPen

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

Keep the cartridge in the outer carton in order to protect from light.

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

NovoRapid FlexPen:

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

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

6.5          Nature and contents of container

NovoRapid vial:

10 ml solution in vial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and a protective tamper-proof plastic cap.

 Pack sizes of 1 or 5 vials of 10 ml or a multipack containingof 5 packs of 1 x 10 ml vials. Not all pack sizes may be marketed.

NovoRapid Penfill:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure

(bromobutyl/polyisoprene).

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

NovoRapid FlexPen:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure

(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens. Not all pack sizes may be marketed.

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.

 NovoRapid which has been frozen must not be used.

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

NovoRapid may be used in an infusion pump system (CSII) as described in section 4.2. Tubings in which the inner surface materials are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.

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

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

The cartridge must not be refilled.

Needles and syringes must not be shared.

Needles and NovoRapid Penfill must not be shared. The cartridge must not be refilled.

Needles and NovoRapid FlexPen must not be shared. The cartridge must not be refilled.

Needles and NovoRapid FlexTouch must not be shared. The cartridge must not be refilled.

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

NovoRapid which has been frozen must not be used.

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

NovoRapid may be used in an infusion pump system (CSII) as described in section 4.2. Tubings in which the inner surface materials are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.

NovoRapid Penfill:

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

NovoRapid FlexPen:

In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from a FlexPen.

NovoRapid FlexTouch:

In case of emergency in current NovoRapid users (hospitalisation or insulin pen malfunction), NovoRapid can be withdrawn with an U100 insulin syringe from a FlexTouch Pen.

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

...

8.         MARKETING AUTHORISATION NUMBERS

NovoRapid vial

EU/1/99/119/001

EU/1/99/119/008

EU/1/99/119/015

NovoRapid Penfill

EU/1/99/119/003

EU/1/99/119/006

NovoRapid FlexPenEU/1/99/119/008

EU/1/99/119/009

EU/1/99/119/010

EU/1/99/119/011

EU/1/99/119/015

EU/1/99/119/017

EU/1/99/119/018

…

10.          DATE OF REVISION OF THE TEXT

HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie

the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
email: imbpharmacovigilance@imb.ie

....


10. DATE OF REVISION OF THE TEXT

 Changes are shown below.
"..." indicates unchanged omitted text.

1.      NAME OF THE MEDICINAL PRODUCT

NovoRapid 100 unitsU/ml solution for injection.

NovoRapid Penfill 100 unitsU/ml solution for injection in cartridge.

NovoRapid FlexPen 100 unitsU/ml solution for injection in pre-filled pen.

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 100 unitsU insulin aspart* (equivalent to 3.5 mg).

1 vial contains 10 ml equivalent to 1,000 unitsU.

1 cartridge contains 3 ml equivalent to 300 unitsU.

1 pre-filled pen contains 3 ml equivalent to 300 unitsU.

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

Excipient with known effect:

100 U NovoRapid contains approximately 30 mcmol sodium, i.e. NovoRapid contains less than 1 mmol sodium (23 mg) per dose and is therefore considered essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Solution for injection.

Solution for injection in cartridge. Penfill.

Solution for injection in pre-filled pen. FlexPen.

The solution is clear, colourless and aqueous.

4.      CLINICAL PARTICULARS

4.1    Therapeutic indications

NovoRapid is indicated for Ttreatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

4.2    Posology and method of administration

Posology

The potency of insulin analogues, including insulin aspart, is expressed in units (U), whereas the potency of human insulin is expressed in international units (IU).

...

The individual insulin requirement in adults and children is usually between 0.5 and 1.0 unitU/kg/day. In a basal-bolus treatment regimen 50-70% of this requirement may be provided by NovoRapid and the remainder by intermediate-acting or long-acting insulin.

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)

NovoRapid can be used in elderly patients.

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

Paediatric population

NovoRapid can be used in children and adolescents aged 2 years and above in preference to soluble human insulin when a rapid onset of action might be beneficial (see sections 5.1 and 5.2). For example, in the timing of the injections in relation to meals.

The safety and efficacy of NovoRapid in children below 2 years of age have not been established.

No data are available.

No clinical studies with NovoRapid have been carried out in children under the age of 2 years. NovoRapid should only be used in this age group under careful medical supervision.

...

Method of administration

NovoRapid is a rapid-acting insulin analogue.

NovoRapid is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. As with all insulin medicinal products, sSubcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites. Compared to soluble human insulin the faster onset of action of NovoRapid is maintained regardless of the injection site. 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.

...

For intravenous use, infusion systems with NovoRapid 100 unitsU/ml at concentrations from 0.05 unitU/ml to 1.0 unitU/ml insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 10% dextrose inclusive 40 mmol/l potassium chloride using polypropylene infusion bags, are stable at room temperature for 24 hours.

...

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

... 

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 reduces may help to reduce 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 NovoRapid.

...

Insulin antibodies

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

...

4.8      Undesirable effects

a. Summary of the safety profile

Adverse reactions observed in patients using NovoRapid are mainly due to the pharmacologic effect of insulin.

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 c below4.8, Description of selected adverse reactions).

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

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

* see section 4.8, Description of selected adverse reactions.c

c. Description of selected adverse reactions

...

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 reducereduces the risk of developing these reactions.

d. Paediatric population

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

e. Other special populations

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

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 the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

email: imbpharmacovigilance@imb.ie

... 

5.2    Pharmacokinetic properties

Absorption, distribution and elimination

In NovoRapid substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin. NovoRapid is therefore more rapidly absorbed from the subcutaneous layer compared to soluble human insulin.

The time to maximum concentration is, on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492±256 pmol/l was reached 40 (interquartile range: 30–40) minutes after a subcutaneous dose of 0.15 unitU/kg bodyweight in type 1 diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a lower C_max (352±240 pmol/l) and later t_max (60 (interquartile range: 50–90) minutes). The intra-individual variability in time to maximum concentration is significantly less for NovoRapid than for soluble human insulin, whereas the intra-individual variability in C_max for NovoRapid is larger.

Special populations

Elderly (≥ 65 years old)

The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly subjects (65-83 years, mean age 70 years) with type 2 diabetes were similar to those observed in healthy subjects and in younger subjects with diabetes. A decreased absorption rate was observed in elderly subjectspatients, resulting in a later t_max (82 (interquartile range: 60-120) minutes), whereas C_max was similar to that observed in younger subjects with type 2 diabetes and slightly lower than in subjects with type 1 diabetes.

...

6.3    Shelf life

Before opening: 30 months.

During use or when carried as a spare: The product must be stored for a maximum of 4 weeks. Stored below 30°C.

6.5      Nature and contents of container

NovoRapid vial:

10 ml solution in vial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and a protective tamper-proof plastic cap.

Pack sizes of 1 or 5 vials of 10 ml or  a multipack of 5 packs of 1 x 10 ml vials. Not all pack sizes may be marketed.

NovoRapid Penfill:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper

(bromobu-tyl/polyisoprene).

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

NovoRapid FlexPen:

3 ml solution in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper

(bromobu-tyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens. Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

... 

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

...

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

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

7.      MARKETING AUTHORISATION HOLDER

Novo Nordisk A/S,

 Novo Allé,

 DK-2880 Bagsværd,

 Denmark

8.      MARKETING AUTHORISATION NUMBERS

EU/1/99/119/001

EU/1/99/119/003

EU/1/99/119/006

EU/1/99/119/008

EU/1/99/119/009

EU/1/99/119/010

EU/1/99/119/011

EU/1/99/119/015

EU/1/99/119/017

EU/1/99/119/018

 ... 

10.      DATE OF REVISION OF THE TEXT

1107/20132

...

Combination of NovoRapid 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 NovoRapid 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.

(with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens.

NovoRapid SmPC has been updated as stated in blue below:

4.1 Therapeutic indications
Treatment of diabetes mellitus sentence added "in adults and adolescents and children aged 2  - 17 years."

4.2 Posology and method of administration
Posology
Sentence added "Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control."
Sentence added "Adjustment of dosage may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness."
The following sentence has been changed "Renal or hepatic impairment may reduce the patient's insulin requirements. Careful glucose monitoring and dose adjustments of insulin aspart are recommended in these patients." to "As with all insulin products, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin aspart dosage adjusted on an individual basis."

No studies have been performed in children below the age of 2 years.Sentence added

NovoRapid should only be used in this age group under careful medical supervision.

4.3 Contraindications
''Hypoglycaemia" has been removed

4.4 Special warnings and precautions for use
Sentence added 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.

Octreotide/lanreotide may both increase or decrease insulin requirement.

6.2 Incompatibilities
Sentence added This medicinal product must not be mixed with other medicinal products. Exceptions are NPH (Neutral Protamine Hagedorn) insulin and infusion fluids as described in section 4.2.

6.3 Shelf life
Changed from The in-use shelf life is 4 weeks. to After first opening: A maximum of 4 weeks when stored below 30°C.

6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Keep the cartridge in the outer carton in order to protect from light.
Keep the cap on FlexPen in order to protect from light.
After first opening or carried as a spare: Do not refrigerate. Store below 30°C.
NovoRapid must be protected from excessive heat and light.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of last renewal: 30 April 2009

10. DATE OF REVISION OF THE TEXT
04/2009

The changes are mainly concerned with an extension of the usage to include pregnancy. There are additionally a few editorial changes. The changes are as follows:

Section 2. Qualitative and quantitative composition

The excipient metacresol is listed with concentration. Editorial change to reference full list of excipients in section 6.1.

Editorial changes: Reference to NovoRapid being given before the meal has been changed to before a meal and a cross-reference to the clinical trials described in sections 5.1 and 5.2 has been inserted in the paragraph concerning use in children.

Section 4.3. Contraindications

Editorial change: reference to active substance rather than insulin aspart (hypersensitivity).

Section 4.4. Special warnings and precautions for use

Amendment of section title according to revised template for SPCs.

Section 4.6. Pregnancy and lactation

Revised text based on clinical studies now states that NovoRapid can be used to treat pregnant women with diabetes (type 1, type 2 and gestational):

"There is limited clinical experience with NovoRapid in pregnancy.

Animal reproductions studies have not revealed any differences between NovoRapid and human insulin regarding embryotoxicity or teratogenicity.

NovoRapid (insulin aspart) can be used in pregnancy. Data from two randomised controlled clinical trials (157 and 14 insulin aspart-exposed pregnancies respectively) do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn when compared to insulin human (see section 5.1).

Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes, type 2 diabetes or gestational diabetes) is are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy levels."

The statements on use of NovoRapid during lactation are unchanged. 

Section 4.8. Undesirable effects

Editorial changes plus clarification that within each frequency grouping undesirable effects are presented in order of decreasing seriousness.

Section 5.1. Pharmacodynamic properties

Editorial changes (Type 1/2 to type 1/2).

Inclusion of a description of the two clinical trials supporting use of NovoRapid in pregnancy.

Section 5.2. Pharmacokinetic properties

Editorial changes (Type 1/2 to type 1/2).

Section 5.3. Preclinical safety studies

Mention of animal reproduction studies deleted from section 4.6 (Pregnancy) now included in this section.

Section 6.1. List of excipients

Editorial changes.

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.

Editorial change.

Section 9. Date of first authorisation/renewal of the authorisation