Novo Nordisk Limited

1.    NAME OF THE MEDICINAL PRODUCT

NovoMix 30 Penfill 100 U/ml, suspension for injection in a cartridge.

NovoMix 30 FlexPen 100 U/ml, suspension for injection in a pre-filled pen.

1.    NAME OF THE MEDICINAL PRODUCT

NovoMix 30 Penfill 100 U/ml suspension for injection in cartridge.

NovoMix 30 FlexPen 100 U/ml suspension for injection in pre-filled pen.

“,” and “a” removed.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Soluble insulin aspart*/protamine-crystallised insulin aspart*……… 100 U/ml in the ratio of 30/70

* produced by recombinant DNA technology in Saccharomyces cerevisiae.

One unit of insulin aspart corresponds to 6 nmol, 0.035 mg salt-free anhydrous insulin aspart.

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of the suspension contains 100 U soluble insulin aspart*/protamine-crystallised insulin aspart* in the ratio 30/70 (equivalent to 3.5 mg).

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

3.    PHARMACEUTICAL FORM

Suspension for injection in a cartridge.

Suspension for injection in a pre-filled pen.

NovoMix 30 is a white suspension.

3.    PHARMACEUTICAL FORM

Suspension for injection in cartridge. Penfill.

Suspension for injection in cartridge. FlexPen.

White suspension.

4.1  Therapeutic indications

Treatment of diabetes mellitus.

4.1  Therapeutic indications

Treatment of diabetes mellitus in adults, adolescents and children aged 10 to 17 years.

4.2  Posology and method of administration

Dose recommendation

Dosage of NovoMix 30 is individual and determined in accordance with the needs of the patient.

In patients with type 2 diabetes, NovoMix 30 can be given in monotherapy or in combination with oral antidiabetic drugs for which the combination with insulin is approved, when the blood glucose is inadequately controlled with those oral antidiabetic drugs alone.

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).

NovoMix 30 dosing is individual and determined in accordance with the needs of the patient. Blood glucose monitoring and insulin dose adjustments are recommended to achieve optimal glycaemic control.

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.

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).

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 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 events.

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.

In patients with type 1 diabetes the individual insulin requirement is usually between 0.5 and 1.0 Units/kg/day.

In patients with type 1 diabetes the individual insulin requirement is usually between 0.5 and 1.0 U/kg/day.

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).

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.

NovoMix 30 can be used in elderly patients; however there is limited experience with the use of NovoMix 30 in combination with OADs in patients older than 75 years.

Renal or hepatic impairment may reduce the patient’s insulin requirements.

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

No studies have been performed in children under the age of 6 years.

NovoMix 30 should never be administered intravenously.

Special populations

Elderly (≥ 65 years old)

NovoMix 30 can be used in elderly 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, in elderly patients, glucose monitoring should be intensified and 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, in patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin aspart dose adjusted on an individual basis.

Paediatric population

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

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 titration guideline in table above).

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

Method of administration

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 Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine needles. The patient should be advised not to use any counterfeit needles.

NovoMix 30 FlexPen are pre-filled pens designed to be used with NovoFine or NovoTwist needles.  FlexPen delivers 1-60 units in increments of 1 unit.  The patient should be advised not to use any counterfeit needles.

NovoMix 30 Penfill is accompanied by a package leaflet with detailed instructions for use to be followed.

NovoMix 30 FlexPen is colour-coded and accompanied by a package leaflet with detailed instructions for use to be followed.

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

o      Hypoglycaemia.

4.4  Special warnings and precautions for use

The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

4.4  Special warnings and precautions for use

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia (see section 4.8 and section 4.9).  Compared with biphasic human insulin, NovoMix 30 may have a more pronounced glucose lowering effect up to 6 hours after injection.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see section 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.

Usual warning symptoms may disappear in patients with longstanding diabetes.

NovoMix 30 should be administered in immediate relation to a meal. The rapid onset of action should therefore be considered in patients with concomitant diseases or treatment with other medicinal products where a delayed absorption of food might be expected.

Since NovoMix 30 should be administered in immediate relation to a meal the rapid onset of action should be considered in patients with concomitant diseases or treatment where a delayed absorption of food might be expected.

Concomitant illness, especially infections, usually increases the patient’s insulin requirements.

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

When patients are transferred between different types of insulin products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.

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.

Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dosage. Patients taking NovoMix 30 may need a change in dosage from that used with their usual insulin. If a dosage adjustment is needed, it may be done with the first dose or during the first few weeks or months.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal, human, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dose. Patients transferred to 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 insulins. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

Insulin suspensions are not to be used in insulin infusion pumps.

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 NovoMix 30.

Injection site reactions

As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, 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.

4.5    Interaction with other medicinal products and other forms of interaction

Beta-blocking agents may mask the symptoms of hypoglycaemia.

4.5    Interaction with other medicinal products and other forms of interaction

Beta-blockers may mask the symptoms of hypoglycaemia.

4.6  Pregnancy and lactation

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no restrictions on treatment with NovoMix 30 during lactation. Insulin treatment of the breast-feeding mother presents no risk to the baby. However, the NovoMix 30 dosage may need to be adjusted.

Breast-feeding

There are no restrictions on treatment with NovoMix 30 during breast-feeding. Insulin treatment of the nursing mother presents no risk to the baby. However, the NovoMix 30 dose may need to be adjusted.

Fertility

Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding fertility.

4.7  Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

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 in order to avoid hypoglycaemia whilst driving. 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 should be considered in these circumstances.

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 using machines).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. 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 should be considered in these circumstances.

4.8  Undesirable effects

Adverse drug reactions observed in patients using NovoMix products are mainly dose-dependent and due to the pharmacologic effect of insulin. As for other insulin products, hypoglycaemia, in general is the most frequently occurring undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement and therefore require special attention during dose intensification as outlined in section 4.2. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

In clinical trials and during marketed use the frequency varies with patient population and dose regimens therefore no specific frequency can be presented. During clinical trials the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.

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 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 below.

At the beginning of the insulin treatment, refraction anomalies, oedema and local hypersensitivity reactions (pain, redness, hives, inflammation, 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 c.

c. Description of selected adverse reactions

Hypoglycaemia:

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

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 is reported as uncommon. It may occur at the injection site; 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 the elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

4.9  Overdose

·                Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carry sugar-containing products

·                Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person or glucose given intravenously by a medical professional. Glucose must also be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness administration of oral carbohydrate is recommended for the patient in order to prevent relapse.

4.9    Overdose

•      Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar-containing products

•      Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously, by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.

5.1  Pharmacodynamic properties

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

5.1  Pharmacodynamic properties

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).

The blood glucose lowering effect of insulin occurs when the molecules facilitate the uptake of glucose by binding to insulin receptors on muscle and fat cells - and simultaneously inhibit the output of glucose from the liver.

Mechanism of action

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.

Children and adolescents:

Paediatric population

5.2  Pharmacokinetic properties

In insulin aspart substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers in the soluble fraction of NovoMix 30, as compared with soluble human insulin.

5.2    Pharmacokinetic properties

Absorption, distribution and elimination

In insulin aspart substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin.

Children and adolescents:

The pharmacokinetics of NovoMix 30 has not been investigated in elderly, or patients with impaired renal or liver function.

Special populations

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

Paediatric population

5.3  Preclinical safety data

Non-clinical data with insulin aspart reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.

5.3    Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

6.3  Shelf life

The in-use shelf life is 4 weeks (not above 30°C).

6.3    Shelf life

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) away from the freezing compartment. Do not freeze.

NovoMix 30 Penfill cartridges and NovoMix 30 FlexPen in use or carried as a spare: can be kept at ambient temperature (below 30°C) for up to 4 weeks, but any remainder must then be discarded. Do not refrigerate. Do not store above 30ºC. Keep the cartridges in the outer carton or keep the cap on the pen when NovoMix 30 FlexPen is not in use in order to protect from light.

After removing NovoMix 30 Penfill and NovoMix 30 FlexPen from the refrigerator it is recommended to allow them to reach room temperature before resuspending the insulin as instructed for the first time use.

6.4    Special precautions for storage

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

NovoMix 30 Penfill:

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

NovoMix 30 FlexPen:

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.

NovoMix 30 must be protected from excessive heat and light.

6.5  Nature and contents of container

NovoMix 30 Penfill:

A glass (Type 1) cartridge which is closed with a latex-free (bromobutyl) rubber piston at one end and a latex-free (bromobutyl/polyisoprene) rubber closure at the other. The cartridge contains a glass ball to facilitate resuspension. Each cartridge contains 3 ml suspension.

Cartons of 5 or 10 cartridges.

NovoMix 30 FlexPen:

A glass (Type 1) cartridge which is closed with a latex-free (bromobutyl) rubber piston at one end and a latex-free (bromobutyl/polyisoprene) rubber closure at the other in a multidose disposable pre-filled pen with a pen injector (plastic). The cartridge contains a glass ball to facilitate resuspension. Each pre-filled pen contains 3 ml suspension.

Cartons of 5 or 10 pre-filled pens.

6.5    Nature and contents of container

NovoMix 30 Penfill:

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

Pack sizes of 5 and 10 pre-filled pens.

6.6  Special precautions for disposal and other handling

The cartridges are designed to be used with Novo Nordisk delivery systems (durable devices for repeated use) and NovoFine needles. Detailed instruction accompanying the cartridge and delivery system must be followed.

NovoFine S needles are designed to be used with the pre-filled pen. Detailed instruction accompanying NovoMix 30 FlexPen must be followed.

NovoMix 30 Penfill and NovoMix 30 FlexPen are for use by one person only. The cartridge and NovoMix 30 FlexPen must not be refilled.

The resuspended liquid must appear uniformly white and cloudy.

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

6.6    Special precautions for disposal and other handling

Needles, NovoMix 30 Penfill and NovoMix 30 FlexPen must not be shared. The cartridge must not be refilled.

After removing NovoMix 30 Penfill and NovoMix 30 FlexPen from the refrigerator, it is recommended to allow NovoMix 30 Penfill and NovoMix 30 FlexPen to reach room temperature before resuspending the insulin as instructed for first time use.

NovoMix 30 must not be used if the resuspended liquid does not appear uniformly white and cloudy.

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 1 August 2005

9.      DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 2 July 2010

10.  DATE OF REVISION OF THE TEXT

10/2009

10.    DATE OF REVISION OF THE TEXT

07/2010

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

LEGAL CATEGORY

POM (Prescription Only Medicine)