Novo Nordisk Limited

Actrapid 100 IU/ml solution for injection in a vial

Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae).

1 ml contains 100 IU of insulin human

1 vial contains 10 ml equivalent to 1000 IU

One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.

For a full list of excipients, see section 6.1.

Solution for injection in a vial.

Clear, colourless, aqueous solution.

Treatment of diabetes mellitus.

Actrapid is a fast-acting insulin and may be used in combination with long-acting insulin products.

Dosage

Dosage is individual and determined in accordance with the needs of the patient. The individual insulin requirement is usually between 0.3 and 1.0 IU/kg/day. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production.

In patients with diabetes mellitus optimised glycaemic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended.

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

Dosage adjustment

Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirement.

Renal or hepatic impairment may reduce insulin requirement.

Adjustment of dosage may also be necessary if patients change physical activity or their usual diet.

Dosage adjustment may be necessary when transferring patients from one insulin preparation to another (see section 4.4).

Administration

For subcutaneous or intravenous use. Actrapid may also be administered intravenously, which should only be carried out by health care professionals.

Actrapid is administered subcutaneously in the abdominal wall. The thigh, the gluteal region or the deltoid region may also be used.

Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites.

Injection into a lifted skin fold minimises the risk 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.

Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.

The vials are for use with insulin syringes with a corresponding unit scale. When two types of insulin are mixed, draw the amount of fast-acting insulin first, followed by the amount of long-acting insulin.

Actrapid is accompanied by a package leaflet with detailed instruction for use to be followed.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Hypoglycaemia

Inadequate dosage or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia.

Usually the first symptoms of hyperglycaemia set in 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.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see sections 4.8 and 4.9).

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

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 long-standing diabetes.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.), origin (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dosage. If an adjustment is needed when switching the patients to Actrapid, it may occur with the first dose or during the first several weeks or months.

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 Actrapid.

A few patients who have experienced hypoglycaemic reactions after transfer from animal source insulin have reported that early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin.

Before travelling between different time zones, the patient should be advised to consult the physician, since this may mean that the patient has to take insulin and meals at different times.

Due to the risk of precipitation in pump catheters, Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.

Actrapid contains metacresol, which may cause allergic reactions.

Combination of Actrapid 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 in mind if treatment with the combination of pioglitazone and Actrapid 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.

A number of medicinal products are known to interact with glucose metabolism. The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.

The following substances may reduce insulin requirement:

Oral hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids and sulphonamides.

The following substances may increase insulin requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones and beta-sympathomimetics, growth hormone and danazol.

Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.

Octreotide/lanreotide may both decrease and increase insulin requirement.

Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier.

Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero. Intensified control in the treatment of pregnant women with diabetes is therefore recommended throughout pregnancy and when contemplating pregnancy.

Insulin requirements usually fall in the first trimester and subsequently increase during the second and third trimesters.

After delivery, insulin requirements return rapidly to pre-pregnancy values.

Insulin treatment of the nursing mother presents no risk to the baby. However, the Actrapid dosage may need to be adjusted.

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 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.

As for other insulin products, in general, hypoglycaemia is the most frequently occurring undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement. In clinical trials and during marketed use the frequency varies with patient population and dose regimens. Therefore, no specific frequency can be presented. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Frequencies of adverse drug reactions from clinical trials that are considered related to Actrapid, are listed below. The frequencies are defined as: uncommon (1/1000, < 1/100). Isolated spontaneous cases are presented as very rare defined as < 1/10,000, including isolated reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders

Uncommon – Peripheral neuropathy

Fast improvement in blood glucose control may be associated with a condition termed "acute painful neuropathy", which is usually reversible.

Eye disorders

Uncommon – Refraction disorders

Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Very rare – Diabetic retinopathy

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening 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 sites within an area.

General disorders and administration site conditions

Uncommon – Injection site reactions

Injection site reactions (redness, swelling, itching, pain and haematoma at the injection site) may occur during treatment with insulin. Most reactions are transitory and disappear during continued treatment.

Uncommon – Oedema

Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Immune system disorders

Uncommon – Urticaria, rash

Very rare – Anaphylactic reactions

Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation, reduction in blood pressure and fainting/loss of consciousness. Generalised hypersensitivity reactions are potentially life threatening.

A specific overdose of insulin cannot be defined. However, hypoglycaemia may develop over sequential stages:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patients carry some sugar lumps, sweets, biscuits or sugary fruit juice.

• 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 person who has received appropriate instruction, or by 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.

Pharmacotherapeutic group: insulins and analogues for injection, fast-acting, insulin (human). ATC code: A10A B01.

The blood glucose lowering effect of insulin 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.

A clinical trial in a single intensive care unit treating hyperglycaemia (blood glucose above 10 mmol/L) in 204 diabetic and 1344 non-diabetic patients undergoing major surgery showed that normoglycaemia (blood glucose 4.4 – 6.1 mmol/L) induced by intravenous Actrapid reduced mortality by 42% (8% versus 4.6%).

Actrapid is a fast-acting insulin.

Onset of action is within ½ hour, reaches a maximum effect within 1.5-3.5 hours and the entire time of duration is approximately 7-8 hours.

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

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

Absorption

The maximum plasma concentration is reached within 1.5-2.5 hours after subcutaneous administration.

Distribution

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

Metabolism

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

Elimination

The terminal half-life is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life (t_½) is therefore a measure of the absorption rather than of the elimination per se of insulin from plasma (insulin in the blood stream has a t_½ of a few minutes). Trials have indicated a t_½ of about 2-5 hours.

Children and adolescents

The pharmacokinetic profile of Actrapid has been studied in a small number (n=18) of diabetic children (aged 6-12 years) and adolescents (aged 13-17 years). The data are limited but suggest that the pharmacokinetic profile in children and adolescents may be similar to that in adults. However, there were differences between age groups in C_max, stressing the importance of individual titration of human insulin.

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

Zinc chloride

Glycerol

Metacresol

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

Insulin products should only be added to compounds with which it is known to be compatible. Medicinal products added to the insulin solution may cause degradation of the insulin, e.g. if the medicinal products contain thiols or sulphites.

30 months when stored between 2˚C-8˚C.

6 weeks when used or stored at room temperature (below 25˚C).

Before use: Store in a refrigerator (2°C - 8°C).

Do not store them in or too near the freezer section or cooling element.

Do not freeze.

During use: do not refrigerate. Do not store above 25°C.

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

Protect from excessive heat and sunlight.

10 ml glass vial (type 1) closed with a bromobutyl/polyisoprene rubber stopper and a protective tamper-proof plastic cap.

Pack size: 1 x 10 ml.

For intravenous use, infusion systems with Actrapid at concentrations 0.05 IU/ml – 1.0 IU/ml insulin human in he following infusion fluids: 0.9% sodium chloride, 5% dextrose and 10% dextrose inclusive 40 mmol/l potassium chloride, using polypropylene infusion bags, are stable at room temperature for 24 hours. Although stable over time, a certain amount of insulin will initially be absorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during the infusion.

Insulin preparations, which have been frozen must not be used.

Insulin solutions should not be used if they do not appear water clear and colourless.

Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.

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

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Date of first authorisation; 07 October 2002

Date of last renewal: 18 October 2007

02/2011