- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.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. For patients with type 2 diabetes, the recommended starting dose of NovoMix 30 is 6 units at breakfast and 6 units at dinner (evening meal). NovoMix 30 can also be initiated once daily with 12 units 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 dosing).The following titration guideline is recommended for dose adjustments:
|Pre-meal blood glucose level||NovoMix 30 dose adjustment|
|< 4.4 mmol/l||< 80 mg/dl||- 2 units|
|4.4 6.1 mmol/l||80 110 mg/dl||0|
|6.2 7.8 mmol/l||111 140 mg/dl||+ 2 units|
|7.9 10 mmol/l||141 180 mg/dl||+ 4 units|
|> 10 mmol/l||> 180 mg/dl||+ 6 units|
Older people (≥ 65 years old)NovoMix 30 can be used in older 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.In older patients, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.
Renal and hepatic impairmentRenal or hepatic impairment may reduce the patient's insulin requirements.In patients with renal or hepatic impairment, glucose monitoring should be intensified and the insulin aspart dose adjusted on an individual basis.
Paediatric populationNovoMix 30 can be used in adolescents and children aged 10 years and above when premixed insulin is preferred. There is limited clinical experience with NovoMix 30 in children aged 69 years (see section 5.1). No data are available for NovoMix 30 in children below 6 years of age.
Transfer from other insulin medicinal productsWhen 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).Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).
Method of administrationNovoMix 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 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 has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal. When necessary, NovoMix 30 can be given soon after a meal.
Administration with an insulin delivery systemNovoMix 30 Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. NovoMix 30 Penfill is accompanied by a package leaflet with detailed instructions for use to be followed.
Administration with FlexPenNovoMix 30 FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist needles. FlexPen delivers 1-60 units in increments of 1 unit. NovoMix 30 FlexPen is colour-coded and accompanied by a package leaflet with detailed instructions for use to be followed.
HyperglycaemiaInadequate 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.
HypoglycaemiaOmission 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.Tighter control of glucose levels can increase the potential for hypoglycaemic episodes and therefore require special attention during dose intensification as outlined in section 4.2.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 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.When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.
Transfer from other insulin medicinal productsTransferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin or 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 reactionsAs 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 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.
Combination of NovoMix with pioglitazoneCases 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. 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.
PregnancyThere is limited clinical experience with NovoMix 30 in pregnancy.Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding embryotoxicity or teratogenicity.In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy levels.
Breast-feedingThere 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.
FertilityAnimal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding fertility.
a. Summary of the safety profileAdverse reactions observed in patients using NovoMix are mainly 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 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 reactionsThe 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).
|Immune system disorders||Uncommon Urticaria, rash, eruptions|
|Very rare Anaphylactic reactions*|
|Metabolism and nutrition disorders||Very common Hypoglycaemia*|
|Nervous system disorders||Rare Peripheral neuropathy (painful neuropathy)|
|Eye disorders||Uncommon Refraction disorders|
|Uncommon Diabetic retinopathy|
|Skin and subcutaneous tissue disorders||Uncommon Lipodystrophy*|
|General disorders and administration site conditions||Uncommon Oedema|
|Uncommon Injection site reactions|
c. Description of selected adverse reactionsAnaphylactic 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 concentrating, 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.Lipodystrophy:Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular area reduces the risk of developing these reactions.
d. Paediatric populationBased 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 populationsBased on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in older 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 reactionsReporting 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:
IrelandHPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: firstname.lastname@example.org
MaltaADR ReportingThe Medicines Authority Post-Licensing Directorate203 Level 3, Rue D'ArgensGŻR-1368 GżiraWebsite: www.medicinesauthority.gov.mte-mail: email@example.com
United KingdomYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
Mechanism of action and pharmacodynamic effectsThe 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 similar to that of human NPH insulin.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). Figure 1: Activity profile of NovoMix 30 (___) and biphasic human insulin 30 (---) in healthy subjects.
Clinical efficacy and safetyIn 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).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 one study, 341 patients with type 2 diabetes were randomised to treatment with NovoMix 30 either alone or in combination with metformin, or to metformin together with sulfonylurea. The primary efficacy variable - HbA1c after 16 weeks of treatment - did not differ between patients with NovoMix 30 combined with metformin and patients with metformin plus sulfonylurea. In this trial, 57% of the patients had baseline HbA1c above 9%; in these patients, treatment with NovoMix 30 in combination with metformin resulted in significantly lower HbA1c than metformin in combination with sulfonylurea.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 HbA1c was 2.8% with NovoMix 30 (mean at baseline = 9.7%). With NovoMix 30, 66% and 42% of the patients reached HbA1c levels below 7% and 6.5%, respectively, and mean FPG was reduced by about 7 mmol/l (from 14.0 mmol/l at baseline to 7.1 mmol/l).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.
Paediatric populationA 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 patients 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 patients) 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 were significantly lower with NovoMix 30 compared to biphasic human insulin 30. Final HbA1c was significantly lower in the biphasic human insulin 30 treated group compared with NovoMix 30.
Absorption, distribution and eliminationIn 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. The insulin aspart in the soluble phase of NovoMix 30 comprises 30% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as protamine-crystallised insulin aspart; this has a prolonged absorption profile similar to human NPH insulin.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 unit/kg body weight. The mean half life (t½) 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 populationsThe pharmacokinetics of NovoMix 30 have not been investigated in older patients or in patients with renal or hepatic impairment.
Paediatric populationThe pharmacokinetics of NovoMix 30 have not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children (612 years) and adolescents (1317 years) with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of insulin aspart.
NovoMix 30 Penfill:3 ml suspension in cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure (bromobutyl/polyisoprene). 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 closure (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 1 (with or without needles), 5 (without needles) and 10 (without needles) pre-filled pens. Not all pack sizes may be marketed.
Novo Nordisk Limited
3 City Place, Beehive Ring Road, Gatwick, West Sussex, RH6 0PA
+44 (0)1293 613535
+44 (0)1293 613555
+44 (0)845 600 5055
+44 (0)845 600 5055