Novomix 30 100 U/ml Suspension for Injection

NovoMix u00ae 30 is indicated for the treatment of insulin requiring patients with diabetes mellitus.

Posology
NovoMix 30 should not be administered intravenously (see contraindications). The dosage of NovoMix u00ae 30 for each patient is individualised. NovoMix u00ae 30 has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal. When necessary NovoMix u00ae 30 can be given soon after a meal.
Type 1 diabetes
In patients with type 1 diabetes the individual insulin requirement is usually between 0,5 and 1,0 Units/kg/day. NovoMix u00ae 30 may fully or partially meet this requirement.
Type 2 diabetes
In patients with type 2 diabetes, NovoMix u00ae 30 can be given as monotherapy if oral antidiabetic medicines cannot be tolerated or are contraindicated or in combination with oral antidiabetic medicines, when the blood glucose is inadequately controlled with oral antidiabetic medicines alone. For patients with type 2 diabetes, the recommended starting dose of NovoMix u00ae 30 is 6 U at breakfast and 6 U at dinner (evening meal). 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 u00ae 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. When using NovoMix u00ae 30 once daily, it is generally recommended to move to twice-daily subcutaneous injections when reaching 30 units by splitting the dose into equal breakfast and dinner doses. Dose titration should continue as needed. A NovoMix u00ae 30 thrice-daily regimen can be safely initiated from a twice-daily regimen by splitting the morning dose into equal morning and lunch doses. Further adjustments to a thrice-daily regimen should be made based on the recommended titration guideline below. The following titration guideline is recommended for dose adjustments: The lowest of three previous daysu2019 pre-meal 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 HbA1c is reached. Pre-meal blood glucose levels should be used to evaluate the adequacy of the preceding dose as illustrated in the following table:
Pre-meal blood glucose level (mmol/l) NovoMix u00ae 30 dose adjustment (U)
< 4,4 - 2
4,4 u2013 6,1 0
6,2 u2013 7,8 + 2
7,9 u2013 10 + 4
> 10 + 6
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. In patients with diabetes mellitus optimised metabolic control delays the onset and slows the progression of diabetic late complications. Optimised metabolic control, including HbA1c and glucose monitoring, is therefore recommended. 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.
Special populations
Renal and hepatic impairment
Renal or hepatic impairment may reduce the patientu2019s insulin requirements. Paediatric population
Novomix u00ae 30 can be used in adolescents and children aged 10 years and above when premixed insulin is preferred. Limited clinical data exists for children aged 6 to 9 years.
Method of administration
Avoidance of accidental mix-ups/medicine errors
Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between NovoMix u00ae 30 and other insulin products. NovoMix u00ae 30 should be administered in immediate relation to a meal. The fast onset of action should therefore be considered in patients with concomitant diseases or medication where a delayed absorption of food might be expected. NovoMix u00ae 30 is administered subcutaneously in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used. Injection sites should be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8). The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. Subcutaneous injection in the abdominal wall results in a faster absorption than from other injection sites. However, the faster onset of action of NovoMix u00ae 30 is maintained regardless of injection site. The necessity of resuspending the NovoMix u00ae 30 suspension immediately before use is to be stressed to the patient. The resuspended liquid must appear uniformly white and cloudy. FlexPen u00ae : Instructions for use and handling are reflected in the patient information leaflet (Use of FlexPen u00ae). To avoid possible transmission of disease, FlexPen u00ae is for single person use only. Penfill u00ae : Instructions for use and handling are reflected in the patient information leaflet (Use of Penfill u00ae). NovoMix u00ae 30 Penfill u00ae cartridges are designed to be used with the Novo Nordisk insulin delivery system and NovoFine u00ae or NovoTwist u00ae needles. Always ensure that the injection device is assembled according to the manufactureru2019s directions. Please refer to the instructions included with the relevant device. Before use, check that the Penfill u00ae cartridge is intact (i.e. no fissures). Do not use Penfill u00ae if any damage is seen. Always expel air, with the needle pointing upwards, before injection. The needle should be removed immediately after each injection and discarded.

• Hypoglycaemia
• Hypersensitivity to insulin aspart or any of the excipients
• Intravenous injection

NovoMix u00ae 30 should never be administered intravenously (see contraindications). Do not use NovoMix u00ae 30 in insulin 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 may, especially in Type 1 diabetes (insulin-dependent diabetes mellitus), lead to hyperglycaemia and diabetic ketoacidosis. The first symptoms of hyperglycaemia usually come on gradually, over a period of hours or days. They include nausea, vomiting, drowsiness, flushed dry skin, dry mouth, increased urination, thirst and loss of appetite as well an acetone breath. Untreated hyperglycaemic events are potentially lethal.
Hypoglycaemia
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia. Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Severe hypoglycaemia may lead to unconsciousness and may result in temporary or permanent impairment of brain function or even death. Compared with biphasic human insulin, NovoMix u00ae 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. Tighter control of glucose levels can increase the potential for hypoglycaemic episodes and therefore require special attention during dose intensification as outlined under the section of Dosage and directions for use. Concomitant illness, especially infections, usually increases the patientu2019s 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 products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.
Transfer from other insulin medicines
Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type species, human, insulin analogue, and/or method of manufacture may result in the need for a change in dosage. Patients taking NovoMix u00ae 30 may need a change in dosage from that used with their previous insulin. If adjustment is needed, it may be done with the first dose or during the first few weeks or months.
Injection site reactions
At the beginning of the insulin treatment injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at injection site) may occur. These reactions are usually of transitory nature.
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 medicines may be considered.
Combination of pioglitazone with NovoMix 30
Cases of congestive heart failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. This should be kept in mind if treatment with the combination of pioglitazone and NovoMix 30 is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
NovoMix 30 is not to be used in insulin infusion pumps.
Insulin antibodies
Insulin administration may cause insulin antibodies to form. In some cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycaemia or hypoglycaemia.

A number of medicines are known to interact with the glucose metabolism. The following medicines may reduce the patientu2019s insulin requirements: Oral hypoglycaemic medicines (OHAu2019s), octreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking medicines, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBu2019s), salicylates, alcohol, anabolic steroids and sulphonamides. The following medicines may increase the patientu2019s insulin requirements: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics and danazol. Beta-blocking medicines may mask the symptoms of hypoglycaemia and inhibit the bodyu2019s response to hypoglycaemia. Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

Pregnancy
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 normally return to pre-pregnancy values.
Breastfeeding
There are no restrictions on treatment with NovoMix u00ae 30 during lactation or for women breastfeeding their infants. However, the NovoMix u00ae 30 dosage may need to be adjusted.

The patientu2019s 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 while driving. This is particularly important in those patients 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.

(a) Summary of the safety profile
Hypoglycaemia is the most common occurring adverse reactions reported during treatment.
(b) Tabulated summary of adverse reactions
The adverse reactions listed below are based on clinical trial data. The frequency categories are defined according to the following convention: Very common (u2265 1/10); common (u22651/100 to < 1/10); Uncommon (u2265 1/1 000 to < 1/100); Rare (u2265 1/10 000 to < 1/1 000); Very rare (< 1/10 000).
System Organ Class Side effect and frequency
Metabolism and nutrition disorders Very common u2022 Hypoglycaemia
Immune system disorders: Uncommon u2022 Urticaria, rash, eruptions
Very rare u2022 Anaphylactic reactions
Eye disorders: Uncommon u2022 Refraction disorders u2022 Diabetic retinopathy
Skin and subcutaneous tissue disorders: Uncommon u2022 Lipodystrophy may occur at injection site u2022 Not known: Cutaneous amyloidosis u03ee
General disorders and administration site conditions: Uncommon u2022 Oedema u2022 Injection site reactions
Nervous system disorders: Rare u2022 Peripheral neuropathy (painful neuropathy) u03ee
u03ee ADR from post-marketing sources
(c) Description of selected adverse reactions
Anaphylactic reactions
The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioedema, difficulties in breathing, palpitations and reduction in blood pressure) is very rare but can potentially be life threatening.
Refraction disorders
Refraction anomalies may occur at the beginning of the insulin treatment and are usually of transitory nature.
Diabetic retinopathy
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.
Peripheral neuropathy (painful neuropathy)
Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible.
Skin and subcutaneous tissue disorders
Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.3).

Insulin has no specific overdose definitions, but hypoglycaemia may develop over sequential stages.
u2022 Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carries some sugar lumps or a source of sugar, e.g. biscuits.
u2022 Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0,5 to 1,0 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.