Novorapid 100 U/mL Solution for injection.

NovoRapid u00ae is indicated for treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

Posology
The dosage of NovoRapid u00ae for each patient is individualised. It should normally be used in combination with intermediate-acting or long-acting insulin given at least once a day. The individual insulin requirement is usually between 0,5 and 1,0 units/kg/day in adults and children from 1 year. In a meal-related treatment 50 u2013 70 % of this requirement may be provided by NovoRapid u00ae and the remainder provided by intermediate-acting or long-acting insulin. NovoRapid u00ae may be used for continuous subcutaneous insulin infusion (CSII) in the pump systems ( Disetronic Pump H-TRON u00ae plus V100 and MiniMed u00ae 506 Pump) suitable for insulin infusion. Patients using CSII should be comprehensively instructed in the use of the pump system. The infusion set and reservoir should be changed every 48 hours using aseptic technique. Patients administering NovoRapid u00ae by CSII must have alternative insulin available in case of pump system failure.
Paediatric population
NovoRapid u00ae can be used in children and adolescents aged 1 year and above in preference to soluble human insulin when a rapid onset of action might be beneficial, for example, in the timing of the injections in relation to meals. The safety and efficacy of NovoRapid u00ae in children below 1 year of age have not been established. No data are available.
Method of administration
NovoRapid u00ae is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region or by infusion in the abdominal wall. 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). NovoRapid u00ae may also be administered intravenously. When injected subcutaneously into the abdominal wall, the onset of action will occur within 10 u2013 20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after the injection. The duration of action is 3 to 5 hours. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. Due to the fast onset of action NovoRapid u00ae should generally be given immediately before a meal. When necessary, NovoRapid u00ae may be given immediately after the meal.

• Hypersensitivity to insulin aspart or any of the excipients of NovoRapid u00ae (see section 6.1).
• Hypoglycaemia.

Before travelling between different time zones, the patient should seek the doctoru2019s 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. Usually the first symptoms of hyperglycaemia usually develop gradually, over a period of hours or days. They include nausea, vomiting, drowsiness, flushed dry skin, dry mouth, increased frequency of urination, thirst and 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.
Hypoglycaemia
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia. Especially in children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake, physical activities and current blood glucose level in order to minimise the risk of 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/or convulsions and may result in temporary or permanent impairment of brain function or even death. Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change including a less pronounced intensity of their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Since NovoRapid u00ae should be administered in immediate relation to a meal, the rapid onset of action should therefore be considered in patients with concomitant diseases or medication where a delayed absorption of food might be expected. Concomitant illness, especially infections, usually increases the patientu2019s insulin requirements. Concomitant diseases in the kidney or liver can require changes in the insulin dose.
Transfer from other insulin medicines
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 a change in dosage. Patients transferred to NovoRapid u00ae from another type of insulin may require an increased number of daily injections or a change in dosage from that used with their previous insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
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.
Combination of pioglitazone and insulin medicines:
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 insulin medicines 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.
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 hyperglycaemia or hypoglycaemia.

A number of medicines are known to interact with the glucose metabolism. Possible interaction must therefore be taken into account by the doctor. The following substances may reduce the patientu2019s insulin requirements: Oral hypoglycaemic medicines, octreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), salicylates, alcohol, anabolic steroids and sulphonamides. The following substances may increase the patientu2019s insulin requirements: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol. Concomitant use of beta blockers may result in lowered blood-sugar levels and may mask the symptoms of hypoglycaemia. If a beta-adrenergic beta blocker or a MAOI is added to the patientu2019s treatment, adjustment of the insulin dosage may be necessary. Octreotide/lanreotide may either increase or decrease the insulin requirement. Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

Pregnancy
NovoRapid u00ae does not cross the placental barrier and can be used in pregnancy. Intensified blood glucose control and monitoring of pregnant women with diabetes (Type 1, Type 2 or gestational diabetes) are recommended throughout pregnancy and when contemplating pregnancy. Both hypoglycaemia and hyperglycaemia which can occur in inadequately controlled diabetes therapy may increase the risk of malformations and death in utero. 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.
Breastfeeding
There are no restrictions on treatment with NovoRapid u00ae during breastfeeding as NovoRapid u00ae does not cross into breast milk. However, the NovoRapid u00ae 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 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.

Summary of the safety profile
Side effects observed in patients using NovoRapid u00ae are mainly due to the pharmacologic effect of insulin. The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control. Frequencies of other adverse reactions listed below are based on clinical trial data and the frequencies are defined as: Very common ( u2265 1/10); common ( u2265 1/100 to < 1/10; uncommon ( u2265 1/1 000 to u02c2 1/100); rare ( u2265 1/10 000 to u02c2 1/1 000); very rare ( u02c2 1/10 000); not known (cannot be estimated from the available data):
System organ class Side effect and frequency
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): Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Uncommon: Refraction (blurred vision):
Eye disorders
Refraction anomalies may occur upon institution of insulin therapy and are usually of transitory nature. Uncommon: 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.
Skin and subcutaneous tissue disorders
Uncommon: Lipodystrophy*: Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection site within an area. Not known: Cutaneous amyloidosis* u2020
General disorders and administration site conditions
Uncommon: Injection site reactions: Injection site reactions (pain, redness, swelling, bruising and itching at the injection site) may occur during treatment with NovoRapid u00ae. These reactions are usually transitory and normally disappear during continued treatment. Uncommon: Oedema: Oedema may occur upon institution of NovoRapid u00ae therapy and is usually of transitory nature.

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patientu2019s requirement are administered:
u2022 Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carry some sugar lumps or sugar containing products, e.g. a few biscuits.
u2022 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.