NovoMix 30 Penfill

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 ‘How to use NovoMix^® 30’). 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).

Correction to version number in document footer

Sectoin 4.2: addition of thefollowing:

In patients with type 2 diabetes, a dose reduction of 20% is recommended for patients with an HbA1c less than 8% when a GLP-1 receptor agonist is added to NovoMix 30, to minimise the risk of hypoglycaemia. For patients with an HbA1c higher than 8% a dose reduction should be considered. Subsequently, dosage should be adjusted individually.

Section 4.5: addition of the following:

GLP-1 receptor agonists

NovoMix 30 Penfill

Administration with an insulin delivery system

NovoMix 30 Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. NovoMix 30 Penfill is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used.

NovoMix 30 FlexPen

Administration with FlexPen

NovoMix 30 FlexPen is a pre-filled pen (colour-coded) designed to be used with NovoFine or NovoTwist needles. FlexPen delivers 1–60 units in increments of 1 unit. NovoMix 30 FlexPen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used.

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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 may help to reduces or prevent 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 NovoMix 30.

 ...

 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.

4.5          Interaction with other medicinal products and other forms of interaction

A number of medicinal products are known to interact with the glucose metabolism.

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

Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfphonamides.

...

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).

Patients should be advised to take precautions to avoid hypoglycaemia while driving or operating a machine. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving or operating a machine should be considered in these circumstances.

4.8          Undesirable effects

 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:

Ireland

HPRA Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 67625177836

Website: www.hpraimb.ie

e-mail: imbpharmacovigilance@imb.iemedsafety@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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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5.            PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, intermediate- or long-acting combined with fast-acting. ATC code: A10AD05.

NovoMix 30 is a biphasic suspension of 30% soluble insulin aspart (rapid-acting human insulin analogue) and 70% protamine-crystallised insulin aspart (intermediate-acting human insulin analogue).

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10.          DATE OF REVISION OF THE TEXT

11/201307/2014

Changes are highlighted below.
"..." indicates unchanged text which has been ommited.

1.         NAME OF THE MEDICINAL PRODUCT

... unitsU/ml

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

... unitsU 

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

For thea full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Suspension for injection in cartridge. Penfill.

The suspension is cloudy, Wwhite and aqueoussuspension.

4.         CLINICAL PARTICULARS

4.1      Therapeutic indications

NovoMix 30 is indicated for Ttreatment of diabetes mellitus in adults, adolescents and children aged 10 to 17 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).

...

In patients with type 2 diabetes, NovoMix 30 can be given as monotherapy. NovoMix 30 can also be given in combination with oral antidiabetic medicinal products if the patient's blood glucose is inadequately controlled with oral antidiabetic medicinal products alone. For patients with type 2 diabetes, the recommended starting dose of NovoMix 30 is 6 unitsU at breakfast and 6 unitsU at dinner (evening meal). NovoMix 30 can also be initiated once daily with 12 unitsU at dinner (evening meal). When using NovoMix 30 once daily, it is generally recommended to move to twice -daily when reaching 30 units by splitting the dose into equal breakfast and dinner doses. If twice daily dosing with NovoMix 30 results in recurrent daytime hypoglycaemic episodes, the morning dose can be split into morning and lunchtime doses (thrice daily dosingdose).

The following titration guideline is recommended for dose adjustments:

The lowest of the three previous days’ pre-meal blood glucose levels should be used. The dose should not be increased if hypoglycaemia occurred within these days. Dose adjustments can be made once a week until target HbA_1c is reached. Pre-meal blood glucose levels should be used to evaluate the adequacy of the preceding dose.

The combination of NovoMix 30 with pioglitazone should only be considered following clinical evaluation of the patient’s risk of developing signs or symptoms of fluid-related adverse reactions. The initiation of NovoMix 30 should be undertaken cautiously titrating to the lowest dose required to achieve glycaemic control (see section 4.4).

In patients with type 1 diabetes, the individual insulin requirement is usually between 0.5 and 1.0 unitU/kg/day. NovoMix 30 may fully or partially meet this requirement. The daily insulin requirement may be higher in patients with insulin resistance (e.g. due to obesity), and lower in patients with residual endogenous insulin production.

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

In patients with diabetes mellitus optimised metabolic control effectively delays the onset and slows the progression of diabetic late complications. Optimised metabolic control, including glucose monitoring, is therefore recommended.

Special populations

ElderlyOlder peopleatients (≥ 65 years old)

NovoMix 30 can be used in older patientselderly patients; however there is limited experience with the use of NovoMix 30 in combination with oral antidiabetic medicinal products in patients older than 75 years.

As with all insulin medicinal products, iIn older patientselderly 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

NovoMix 30 can be used in children and adolescents and children aged 10 years and above when premixed insulin is preferred. For children from 6 to 9 years old limited clinical data exists There is limited clinical experience with NovoMix 30 in children aged 6–9 years (see section 5.1).

No data are available forof NovoMix 30 in children below 6 years of age.No clinical studies with NovoMix 30 have been carried out in children under the age of 6 years.

NovoMix 30 should only be used in this age group under careful medical supervision.

Transfer from other insulin medicinal products

When transferring a patient from biphasic human insulin to NovoMix 30, start with the same dose and regimen. Then titrate according to individual needs (see the titration guideline in the table above).

As with all insulin medicinal products, cClose glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).

Method of administration

NovoMix 30 is a biphasic suspension of the insulin analogue, insulin aspart. The suspension contains rapid-acting and intermediate-acting insulin aspart in the ratio 30/70.

NovoMix 30 is for subcutaneous administration only. NovoMix 30 must not be administrated intravenously, as it may result in severe hypoglycaemia. Intramuscular administration should be avoided. NovoMix 30 is not to be used in insulin infusion pumps.

NovoMix 30 is administered subcutaneously by injection in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. The influence of different injection sites on the absorption of NovoMix 30 has not been investigated. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

...

NovoMix 30 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.

...

NovoMix 30 is administered subcutaneously by injection in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used. Injection sites should always be rotated within the same region. The influence of different injection sites on the absorption of NovoMix 30 has not been investigated. 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.

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

NovoMix 30 must not be administered intravenously, as it may result in severe hypoglycaemia. Intramuscular administration should be avoided. NovoMix 30 is not to be used in insulin infusion pumps.

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.

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.

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, NovoMix must not be injected. After stabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.2, 4.8 and 4.9).

Compared with biphasic human insulin, NovoMix 30 may have a more pronounced glucose lowering effect up to 6 hours after injection. This may have to be compensated for in the individual patient, through adjustment of insulin dose and/or food intake.

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 the insulin dose.

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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, human insulin or 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 NovoMix 30 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 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 NovoMix 30.

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4.5      Interaction with other medicinal products and other forms of interaction

...

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

...

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 operatingusing machinesry).

...

4.8      Undesirable effects

a. Summary of the safety profile

Adverse reactions observed in patients using NovoMix are mainly dose-dependent and due to the pharmacological effect of insulin aspart.

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 below.

At the beginning of the insulin treatment, refraction anomalies, oedema and local injection sitehypersensitivity reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur.; tThese 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 c.

c. Description of selected adverse reactions

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 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. During clinical trials, the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.

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.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy)is reported as uncommon. It may occur at the injection site. Continuous rotation of the injection site within the particular area reduces the risk of developing these reactions; therefore it is recommended 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 older patientsthe 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:

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 67625177836

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

...

5.         PHARMACOLOGICAL PROPERTIES

5.1      Pharmacodynamic properties

...

Mechanism of action and pharmacodynamic effects

The blood glucose lowering effect of insulin aspart 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.

NovoMix 30 is a biphasic insulin, which contains 30% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal (within zero to 10 minutes of the meal) when compared to soluble human insulin. The crystalline phase (70%) consists of protamine-crystallised insulin aspart, which has an activity profile that is similar to that of human NPH insulin (Figure 1).

When NovoMix 30 is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 4 hours after injection. The duration of action is up to 24 hours (Figure 1).

...

Clinical efficacy and safety

In a 3 month trial in patients with type 1 and type 2 diabetes, NovoMix 30 showed equal control of glycosylated haemoglobin compared to treatment with biphasic human insulin 30. Insulin aspart is equipotent to human insulin on a molar basis. Compared to biphasic human insulin 30, administration of NovoMix 30 before breakfast and dinner resulted in lower postprandial blood glucose after both meals (breakfast and dinner).

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In one study, patients with type 2 diabetes, insufficiently controlled on oral hypoglycaemic agents alone, were randomised to treatment with twice daily NovoMix 30 (117 patients) or once daily insulin glargine (116 patients). After 28 weeks of treatment following the dosing guideline outlined in section 4.2, the mean reduction in HbA_1c was 2.8% with NovoMix 30 (mean at baseline = 9.7%). With NovoMix 30, 66% and 42% of the patients reached HbA_1c levels below 7% and 6.5%, respectively, and mean FPG was reduced by about 7 mmol/lL (from 14.0 mmol/lL at baseline to 7.1 mmol/lL).

...

Paediatric population

A 16-week clinical trial comparing postprandial glycaemic control of meal-related NovoMix 30 with meal-related human insulin/biphasic human insulin 30 and bedtime NPH insulin was performed in 167 patientssubjects aged 10 to 18 years. Mean HbA_1c remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycaemia rate with NovoMix 30 or biphasic human insulin 30.

In a smaller (54 patientssubjects) and younger (age range 6 to 12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment), the rate of hypoglycaemic episodes and the postprandial glucose increase werewas significantly lower with NovoMix 30 compared to biphasic human insulin 30. Final HbA_1c was significantly lower in the biphasic human insulin 30 treated group compared with NovoMix 30.

5.2      Pharmacokinetic properties

Absorption, distribution and elimination

...

The maximum serum insulin concentration is, on average, 50% higher with NovoMix 30 than with biphasic human insulin 30. The time to maximum concentration is, on average, half of that for biphasic human insulin 30. In healthy volunteers, a mean maximum serum concentration of 140  32 pmol/l was reached about 60 minutes after a subcutaneous dose of 0.20 unitU/kg body weight. The mean half life (t_½) of NovoMix 30, reflecting the absorption rate of the protamine bound fraction, was about 8-9 hours. Serum insulin levels returned to baseline 15-18 hours after a subcutaneous dose. In type 2 diabetic patients, the maximum concentration was reached about 95 minutes after dosing, and concentrations well above zero for not less than 14 hours post-dosing were measured.

Special populations

The pharmacokinetics of NovoMix 30 has have not been investigated in older patientselderly patients, or in patients with renal or hepatic impairment.

Paediatric population

The pharmacokinetics of NovoMix 30 has have not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children (6–12 years) and adolescents (13–17 years) with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar t_max as in adults. However, C_max differed between the age groups, stressing the importance of the individual titration of insulin aspart.

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6.         PHARMACEUTICAL PARTICULARS

6.1      List of excipients

Glycerol

Phenol

Metacresol

Zinc chloride

Disodium phosphate dihydrate

Sodium chloride

Protamine sulphfate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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6.3      Shelf life

Before opening: 2 years.

During use or when carried as a spareAfter first opening: The product can be stored for Aa maximum of 4 weeks. when sStored below 30°C.

6.4      Special precautions for storage

Before opening: Store in a refrigerator (2°C – 8°C). Keep away from the cooling element. Do not freeze.

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

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

NovoMix 30 Penfill: Keep the cartridge in the outer carton in order to protect it from light.

NovoMix 30 FlexPen: Keep the cap on FlexPen in order to protect it from light.

For storage conditions of the medicinal product, see section 6.3.NovoMix 30 must be protected from excessive heat and light.

6.5      Nature and contents of container

NovoMix 30 Penfill:

3 ml suspension in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper (bromobutyl/polyisoprene) in a carton. The cartridge contains a glass ball to facilitate resuspension.

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

NovoMix 30 FlexPen:

3 ml suspension in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene. The cartridge contains a glass ball to facilitate resuspension.

...

6.6      Special precautions for disposal and other handling

...

Do not use this medicinal product if you notice thatNovoMix 30 must not be used if the resuspended liquid isdoes not appear uniformly white, and cloudy and aqueous.

The necessity of resuspending the NovoMix 30 suspension immediately before use is to be stressed to the patient.

...

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

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8.         MARKETING AUTHORISATION NUMBER(S)

EU/1/00/142/004

EU/1/00/142/005

EU/1/00/142/009

EU/1/00/142/010

EU/1/00/142/023

EU/1/00/142/024

EU/1/00/142/025

...

10.      DATE OF REVISION OF THE TEXT

11/2013

Combination of NovoMix 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 NovoMix 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.

SmPC changes for NovoMix 30 Penfill and NovoMix 30 FlexPen

Renewal – EMEA/H/C/308/R/60

blue and deleted text is striked through  :

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.

medicinal products drugs (OAD), octreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking agents, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids and sulphonamides.

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

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

growth hormone and danazol.

or reduce the hypoglycaemic effect of insulin.

10/2009

 Inclusion of text concerning transferring patients from biphasic human insulin to NovoMix 30 has been added under the dose recommendation:

 Dose recommendation

“When transferring a patient from biphasic human insulin to NovoMix 30, start with the same dose and regimen. Then titrate according to individual needs (See titration guidelines in table above)”.

 5.1    Pharmacodynamic properties

A meta-analysis including nine trials in patients with type 1 and type 2 diabetes showed that fasting blood glucose was higher in patients treated with NovoMix 30, than in patients treated with biphasic human insulin 30.

 In patients with type 2 diabetes a meta-analysis showed a reduced risk of overall nocturnal hypoglycaemic episodes and major hypoglycaemia with NovoMix 30 compared to biphasic human insulin 30. The risk of overall daytime hypoglycaemic episodes was increased in patients treated with NovoMix 30”.

 10. DATE OF REVISION OF THE TEXT

 Date amended from 06/2008 to: 07/2008

 Dose recommendation

 In the second paragraph the statement:

‘When using NovoMix 30 once daily, it is generally recommended to split the dose into two when reaching 30 units and continue titrating the dose.’

has been changed to:

‘When using NovoMix 30 once daily, it is generally recommended to move to twice daily when reaching 30 units by splitting the dose into equal breakfast and dinner doses. If twice daily dosing with NovoMix 30 results in recurrent daytime hypoglycaemic episodes, the morning dose can be split into morning and lunchtime doses (thrice daily dosing).’

 The paragraphs concerning combination of NovoMix 30 with pioglitazone, and insulin requirements in patients with insulin resistance or residual endogenous insulin production are unchanged, but have been moved to follow the titration guideline table. The statements concerning use of pre-breakfast and pre-dinner blood glucose to evaluate adequacy of dosing has also been moved to follow the titration guideline table and has been amended to a more general statement describing use of pre-meal blood glucose levels.

 Section 4.6 Pregnancy and lactation

 The first sentence:

‘There is limited clinical experience with insulin aspart in pregnancy.’

has been changed to:

‘There is limited clinical experience with NovoMix 30 in pregnancy.’

4.2     Posology and method of administration

 The following information has been inserted

 “NovoMix 30 can be used in children and adolescents aged 10 years and above when premixed insulin is preferred. For children 6-9 years limited clinical data exists (see section 5.1)”

 In the last paragraph, the words “with NovoMix 30” has been deleted  in front of the words “in children” and the words “and adolescents” have been deleted. In front of the words” under the age of  the number “18” has been deleted and the number “6” has been inserted in front of “years”.

 4.4     Special warnings and precautions for use

 In the sentence starting with “Compared with biphasic human insulin, NovoMix 30 may have a” the words “more pronounced glucose lowering” have been inserted and the words “stronger hypoglycaemic” have been deleted.

 In the sentence starting with “As with any” the word “insulin” has been inserted.

In the last line of the sentence starting with “Combination of NovoMix 30 with pioglitazone:” the words “in the dose” have been inserted in front of “reduction”

 4.5     Interaction with other medicinal products and other forms of interaction

 The words “antidiabetic drugs (OAD)” have been inserted in front of Oral. The words “hypoglycaemic agents (OHAs”) have been deleted.

 4.8     Undesirable effects

 After the word “NovoMix” the number “30” had been deleted and the word “products” has been inserted.

 5.1     Pharmacodynamic properties

In the first paragraph, the words “for injection” have been inserted in front of the word “analogues”.

The following sentences has been inserted:

“Children and adolescents: A 16 week clinical trial comparing postprandial glycaemic control of meal-related NovoMix 30 with meal-related human insulin/biphasic human insulin 30 and bedtime NPH insulin was performed in 167 subjects aged 10 to 18 years. Mean HbA₁c remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycaemia rate with NovoMix 30 or biphasic human insulin 30.

In a smaller (54 subjects) and younger (age range 6 to 12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment) the rate of hypoglycaemic episodes and the postprandial glucose increase was significantly lower with NovoMix 30 compared to biphasic human insulin 30. Final HbA_1c was significantly lower in the biphasic human insulin 30 treated group compared with NovoMix 30.”

5.2     Pharmacokinetic properties

The following sentence has been inserted:

“Children and adolescents: The pharmacokinetics of NovoMix 30 has not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children (6-12 years) and adolescents (13-17 years) with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar t_max as in adults. However C_max differed between the age groups, stressing the importance of the individual titration of insulin aspart.”

In the last sentence, the word “children” has been deleted.

6.1     List of excipients

 “(for pH adjustment)” has been added for “Sodium hydroxide”

 “(for pH adjustment)” has been added for “Hydrochloric acid”

6.6     In the heading “Special precautions for disposal and other handling” has been inserted and the words “Instructions for use and handling” have been deleted.

In the second paragraph, the words “NovoMix 30 FlexPen” has been inserted and the words “the delivery system” have been deleted.

In the third paragraph the words “and NovoMix 30 FlexPen” have been inserted.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 1 August 2005

10.     DATE OF REVISION OF THE TEXT