Novo Nordisk Limited

Insulatard 100 IU/ml suspension for injection in a vial.

Insulatard Penfill 100 IU/ml suspension for injection in a cartridge.

Insulatard InnoLet 100 IU/ml suspension for injection in a pre-filled pen.

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.

1 cartridge contains 3 ml equivalent to 300 IU.

1 pre-filled pen contains 3 ml equivalent to 300 IU.

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

Insulatard is a suspension of isophane (NPH) insulin.

For a full list of excipients, see section 6.1.

Suspension for injection in a vial.

Suspension for injection in cartridge.

Suspension for injection in a pre-filled pen.

Cloudy, white, aqueous suspension.

Treatment of diabetes mellitus.

Insulatard is a long-acting insulin.

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.

The physician determines whether one or several daily injections are necessary. Insulatard may be used alone or mixed with fast-acting insulin. In intensive insulin therapy the suspension may be used as basal insulin (evening and/or morning injection) with fast-acting insulin given at meals.

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

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 use. Insulin suspensions are never to be administered intravenously.

Insulatard is administered subcutaneously in the thigh. If convenient, the abdominal wall, the gluteal region or the deltoid region may also be used.

Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the 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.

The cartridges are designed to be used with Novo Nordisk delivery systems (durable devices for repeated use) and NovoFine or NovoTwist needles. Detailed instruction accompanying the delivery system must be followed.

Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm.

InnoLet delivers 1-50 units in increments of 1 unit. The patient should be advised not to use any counterfeit needles.

The pens should be primed before injection so that the dose selector returns to zero and a drop of insulin appears at the needle top.

The dose is set by turning the selector, which returns to zero during the injection.

Insulatard 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 longstanding 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 Insulatard, 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 Insulatard.

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.

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

Insulatard contains metacresol, which may cause allergic reactions.

Combination of Insulatard 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 Insulatard 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 Insulatard 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 Insulatard are listed below. The frequencies are defined as: uncommon (1/1,000 to <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

Very rare - Peripheral neuropathy

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

Eye disorders

Very rare - Refraction disorders

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

Uncommon - 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, intermediate-acting, insulin (human). ATC code: A10A C01.

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.

Insulatard is a long-acting insulin.

Onset of action is within 1½ hours, reaches a maximum effect within 4-12 hours and the entire duration of action is approximately 24 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 of the insulin is reached within 2-18 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_½of about 5-10 hours.

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

Phenol

Disodium phosphate dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Protamine sulphate

Water for injections

Insulin products should only be added to compounds with which it is known to be compatible. Insulin suspensions should not be added to infusion fluids.

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

Insulatard vial:

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

Insulatard Penfill and Insulatard InnoLet:

6 weeks when used or carried as a spare (below 30°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.

Insulatard vial:

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.

Insulatard Penfill:

During use: do not refrigerate. Do not store above 30°C.

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

Protect from excessive heat and sunlight.

Insulatard InnoLet:

During use: do not refrigerate. Do not store above 30°C.

Keep the pen cap on in order to protect from light.

Protect from excessive heat and sunlight.

Insulatard vial:

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

Pack sizes: 1 and 5 vials x 10 ml and a multipack with 5 x (1 x 10 ml) vials.

Not all pack sizes may be marketed.

Insulatard Penfill:

3 ml glass cartridge (type 1) with a bromobutyl rubber plunger and a bromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension.

Pack sizes: 1, 5 and 10 cartridges x 3 ml.

Not all pack sizes may be marketed.

Insulatard InnoLet:

Pre-filled pen (multidose disposable pen) comprising a pen injector with a cartridge (3 ml). The cartridge is made of glass (type 1), containing a bromobutyl rubber plunger and a bromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension. The pen injector is made of plastic.

Pack sizes: 1, 5 and 10 pre-filled pens x 3 ml.

Not all pack sizes may be marketed.

Cartridges and Pens should only be used in combination with products that are compatible with them and allow the cartridge to function safely and effectively.

Insulin preparations which have been frozen must not be used.

After removing Insulatard vial, Insulatard Penfill and Insulatard InnoLet from the refrigerator it is recommended to allow the vial, Penfill and InnoLet to reach room temperature (not above 25°C) before resuspending the insulin as instructed for first time use.

Insulin suspensions should not be used if they do not appear uniformly white and cloudy after resuspension.

Insulatard Penfill and Insulatard InnoLet are for single person use only. The container must not be refilled.

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 latest renewal: 18 September 2007

04/2011