ACTRAPHANE 40 PENFILL 100UI / ml injection suspension in cartridge medication leaflet

Actraphane 50 Penfill 100 international units/ml suspension for injection in cartridge.

1 cartridge contains 3 ml equivalent to 300 international units. 1 ml suspension contains100 international units soluble insulin human*/isophane (NPH) insulin human* in the ratio 50/50(equivalent to 3.5 mg).

*Human insulin is produced in Saccharomyces cerevisiae by recombinant DNA technology.

Actraphane 50 contains less than 1 mmol sodium (23 mg) per dose, i.e. Actraphane 50 is essentially‘sodium-free’.

For the full list of excipients, see section 6.1.

Suspension for injection.

The suspension is cloudy, white and aqueous.

Actraphane is indicated for treatment of diabetes mellitus.

The potency of human insulin is expressed in international units.

Actraphane dosing is individual and determined in accordance with the needs of the patient.

Premixed insulin medicinal products are usually given once or twice daily when a rapid initial effecttogether with a more prolonged effect is desired. Blood glucose monitoring is recommended toachieve optimal glycaemic control.

The individual insulin requirement is usually between 0.3 and 1.0 international unit/kg/day.

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

Elderly (≥ 65 years old)

Actraphane can be used in elderly patients.

In elderly patients, glucose monitoring should be intensified and the insulin dose adjusted on anindividual basis.

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

In patients with renal or hepatic impairment, glucose monitoring should be intensified and the humaninsulin dose adjusted on an individual basis.

Actraphane can be used in children and adolescents.

Transfer from other insulin medicinal products

When transferring from other intermediate or long-acting insulin medicinal products, adjustment ofthe Actraphane dose and timing of administration may be necessary.

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (seesection 4.4).

Actraphane is a dual-acting human insulin. It is a biphasic formulation containing both fast-acting andlong-acting insulin.

Actraphane is administered subcutaneously by injection in the thigh, the abdominal wall, the glutealregion or the deltoid region. Injection sites should always be rotated within the same region in order toreduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8). Insulinsuspensions are never to be administered intravenously. Injection into a lifted skin fold minimises therisk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected.

Subcutaneous injection into the abdominal wall ensures a faster absorption compared to the otherinjection sites. The duration of action will vary according to the dose, injection site, blood flow,temperature and level of physical activity.

An injection should be followed within 30 minutes by a meal or snack containing carbohydrates.

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

Administration with an insulin delivery system

Actraphane Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFineor NovoTwist needles. Actraphane Penfill is only suitable for subcutaneous injections from a reusablepen. If administration by syringe is necessary, a vial should be used.

Actraphane Penfill is accompanied by a package leaflet with detailed instructions for use to befollowed.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Before travelling between different time zones, the patient should seek the doctor’s advice since thismay mean that the patient has to take the insulin and meals at different times.

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead tohyperglycaemia and diabetic ketoacidosis. Usually, the first symptoms of hyperglycaemia developgradually 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 ispotentially lethal.

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 caseof hypoglycaemia or if hypoglycaemia is suspected, Actraphane must not be injected. Afterstabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections4.8 and 4.9).

Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

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

When patients are transferred between different types of insulin medicinal products, the early warningsymptoms of hypoglycaemia may change or become less pronounced than those experienced withtheir previous insulin.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin orinsulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) mayresult in a need for a change in dose. Patients transferred to Actraphane from another type of insulinmay require an increased number of daily injections or a change in dose from that used with theirusual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or duringthe first few weeks or months.

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 givenarea reduces the risk of developing these reactions. Reactions usually resolve in a few days to a fewweeks. On rare occasions, injection site reactions may require discontinuation of Actraphane.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden 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 anunaffected area, and dose adjustment of antidiabetic medications may be considered.

Combination of Actraphane 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 inmind if treatment with the combination of pioglitazone and Actraphane is considered. If thecombination is used, patients should be observed for signs and symptoms of heart failure, weight gainand oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between Actraphane and other insulin products.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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

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

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

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

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growthhormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

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

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does notpass the placental barrier.

Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetestherapy, increase the risk of malformations and death in utero. Intensified blood glucose control andmonitoring of pregnant women with diabetes are recommended throughout pregnancy and whencontemplating pregnancy. Insulin requirements usually fall in the first trimester and increasesubsequently during the second and third trimesters. After delivery, insulin requirements normallyreturn rapidly to pre-pregnancy values.

There is no restriction on treatment with Actraphane during breast-feeding. Insulin treatment of thenursing mother presents no risk to the baby. However, the Actraphane dose may need to be adjusted.

Animal reproduction studies with human insulin have not revealed any adverse effects on fertility.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies ofhypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see

Description of selected adverse reactions 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 a transitory nature. Fast improvement in blood glucose control may beassociated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapywith abrupt improvement in glycaemic control may be associated with temporary worsening ofdiabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression ofdiabetic retinopathy.

The adverse reactions listed below are based on clinical trial data and classified according to MedDRAfrequency and System Organ Class. Frequency categories are defined according to the followingconvention: 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 theavailable data).

Immune system disorders Uncommon - Urticaria, rash

Very rare - Anaphylactic reactions*

Metabolism and nutrition Very common - Hypoglycaemia*disorders

Nervous system disorders Uncommon - Peripheral neuropathy (painful neuropathy)

Eye disorders Very rare - Refraction disorders

Uncommon - Diabetic retinopathy

Skin and subcutaneous tissue Uncommon - Lipodystrophy*disorders

Not known - Cutaneous amyloidosis*†

General disorders and Uncommon - Injection site reactionsadministration site conditions Uncommon - Oedema

* see Description of selected adverse reactions† ADR from postmarketing sources.

Anaphylactic reactions

The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching,sweating, gastrointestinal upset, angioneurotic oedema, difficulty in breathing, palpitation andreduction in blood pressure) is very rare but can potentially be life threatening.

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is toohigh in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/orconvulsions 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 paleskin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficultyin concentrating, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

In clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens andlevel of glycaemic control.

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at theinjection site and delay local insulin absorption. Continuous rotation of the injection site within thegiven injection area may help to reduce or prevent these reactions (see section 4.4).

Based on post-marketing sources and clinical trials, the frequency, type and severity of adversereactions observed in the paediatric population do not indicate any differences to the broaderexperience in the general population.

Based on post-marketing sources and clinical trials, the frequency, type and severity of adversereactions observed in elderly patients and in patients with renal or hepatic impairment do not indicateany differences to the broader experience in the general population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A specific overdose of insulin cannot be defined, however, hypoglycaemia may develop oversequential stages if too high a dose relative to the patient’s requirement is administered:

* Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugaryproducts. It is therefore recommended that the diabetic patient always carries sugar-containingproducts.

* Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated withglucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or withglucose 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 regainingconsciousness, administration of oral carbohydrates is recommended for the patient in order toprevent a relapse.

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection,intermediate- or long-acting combined with fast-acting, insulin (human). ATC code: A10AD01.

Mechanism of action and pharmacodynamic effects

The blood glucose lowering effect of insulin is due to the facilitated uptake of glucose followingbinding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucoseoutput from the liver.

Actraphane is a dual-acting insulin.

Onset of action is within ½ hour, reaches a maximum effect within 2-8 hours and the entire durationof action is up to 24 hours.

Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of aninsulin preparation is determined solely by its absorption characteristics.

This process is influenced by several factors (e.g. insulin dose, injection route and site, thickness ofsubcutaneous fat, type of diabetes). The pharmacokinetics of insulin medicinal products are thereforeaffected by significant intra- and inter-individual variation.

The absorption profile is due to the product being a mixture of insulin products with fast andprotracted absorption respectively. The maximum plasma concentration of the fast-acting insulin isreached within 1.5-2.5 hours after subcutaneous administration.

No profound binding to plasma proteins, except circulating insulin antibodies (if present) has beenobserved.

Human insulin is reported to be degraded by insulin protease or insulin-degrading enzymes andpossibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the human insulinmolecule have been proposed; none of the metabolites formed following the cleavage are active.

The terminal half-life is determined by the rate of absorption from the subcutaneous tissue. Theterminal half-life (t½) is therefore a measure of the absorption rather than of the elimination per se ofinsulin from plasma (insulin in the blood stream has a t½ of a few minutes). Trials have indicated a t½of about 5-10 hours.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Zinc chloride

Glycerol

Metacresol

Phenol

Disodium phosphate dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Protamine sulfate

Water for injections

Insulin medicinal products should only be added to compounds with which it is known to becompatible.

Insulin suspensions should not be added to infusion fluids.

Before opening: 30 months.

During use or when carried as a spare: The product can be stored for a maximum of 6 weeks. Storebelow 30°C.

Before opening: Store in a refrigerator (2°C - 8°C). Do not freeze.

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

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

Cartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closure (bromobutyl/polyisoprene)containing 3 ml of suspension. The cartridge contains a glass ball to facilitate resuspension.

Pack sizes of 1, 5 and 10 cartridges. Not all pack sizes may be marketed.

Needles and Actraphane Penfill must not be shared. The cartridge must not be refilled.

After removing Actraphane Penfill from the refrigerator, it is recommended to allow the Actraphane

Penfill to reach room temperature before resuspending the insulin as instructed for first time use.

Do not use this medicinal product if you notice that the resuspended liquid is not uniformly white andcloudy.

Actraphane which has been frozen must not be used.

The patient should be advised to discard the needle after each injection.

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

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/02/229/017

EU/1/02/229/018

EU/1/02/229/019

Date of first authorisation: 07 October 2002

Date of latest renewal: 18 September 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.