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8-9603-00-002-1.qxd Front 1 8 1 100 IU/ml RA Labelling & Graphics Insert: 520x200-006 Current 2.0 Suspension - Standard File HI-CP opsætning Colour: PMS 280C + PMS 285C

Code: 100% Direction 26/08/2005 Length: Max. 29 mm (100%) 10:28 Page 1 Code end

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Mixtard® 30 InnoLet®

Suspension for injection in a pre-filled pen Qualitative and quantitative composition Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae). 1 ml contains 100 IU of insulin human. 1 pre-filled pen contains 3 ml equivalent to 300 IU. One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin. Mixtard® is a mixture of dissolved insulin and isophane (NPH) insulin. Mixtard 30 consists of 30% dissolved insulin and 70% isophane insulin. Pharmaceutical form Suspension for injection. Mixtard is a cloudy, white, aqueous suspension. Clinical particulars Therapeutic indications Treatment of diabetes mellitus. Posology and method of administration Mixtard is a dual-acting insulin containing both fast-acting and longacting insulin. An injection should be followed by a meal or snack containing carbohydrates within 30 minutes. Dual-acting (premixed) insulin products are usually given once or twice daily when a rapid initial effect together with a more prolonged effect is desired. 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 in the young or due to obesity) and lower in patients with residual, endogenous insulin production. In patients with diabetes mellitus optimised glycaemic control delays the

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onset of late diabetic complications. Optimised metabolic control, including close blood glucose monitoring, is therefore recommended. Dosage adjustment Renal or hepatic impairment may reduce insulin requirement. Administration For subcutaneous use. Mixtard is usually administered subcutaneously in the thigh or abdominal wall. If convenient, 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. Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy. Intramuscular administrations are possible under guidance by a physician. Insulin suspensions are never to be administered intravenously. Contraindications Hypoglycaemia. Hypersensitivity to human insulin or to any of the excipients. Special warnings and special precautions for use Inadequate dosage or discontinuation of treatment may, especially in type 1 diabetes (insulin-dependent diabetes mellitus), lead to hyperglycaemia. 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 as acetone breath. In type 1 diabetes, untreated hyperglycaemic events lead to ketoacidosis, which is potentially lethal. 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. Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirement. 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. Transferring a patient to another type or brand of insulin should be done under medical supervision. Changes in strength, brand, type, species (animal, human, insulin human analogue) and/or method of manufacture may result in a need for a change in dosage. If an adjustment is needed, it may be done with the first dose or during the first few weeks or months. Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia. Before travelling between different time zones, the patient should be advised to consult the doctor, 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. Mixtard contains metacresol, which may cause allergic reactions. Interaction with other medicinal products and other forms of interaction A number of medicinal products are known to interact with the glucose metabolism. The following substances may reduce the patient's 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 the patient's insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, beta-sympathomimetics 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. Pregnancy and lactation There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does not pass the

placental barrier. If untreated during pregnancy, diabetes mellitus constitutes a risk in intrauterine development. Diabetes therapy must therefore be continued during pregnancy. Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero. 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 return rapidly to pre-pregnancy values. There are no restrictions on treatment of diabetes with Mixtard during lactation. Insulin treatment of the nursing mother presents no risk to the baby. However, the Mixtard dosage, diet or both may need to be adjusted. Effects on ability to drive and use machines 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 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. Undesirable effects Adverse drug reactions observed in patients using Mixtard are mainly dosedependent and due to the pharmacologic effect of insulin. As for other insulin products, hypoglycaemia, in general, is the most frequent 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. During clinical trials, the overall rates of hypoglycaemia did not differ between patients treated with human insulin compared to insulin aspart. Frequencies of adverse drug reactions from clinical trials, which by an overall judgment are considered related to Mixtard are listed below. The frequencies are defined as: Uncommon (>1/1,000, <1/100). Isolated spontaneous cases are presented as very rare defined as: <1/10,000. Immune system disorder Uncommon ­ Urticaria, rash Very rare - Anaphylactic reactions Symptoms of generalized hypersensitivity may include generalized 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. 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 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 treatment. These symptoms are usually of transitory nature. Overdose A specific overdose of insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirements are administered: · 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-containing products. · 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 glucose given intravenously by a medical professional. Glucose must 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. Pharmacological properties Pharmacodynamic properties Pharmacotherapeutic group: insulins and analogues, intermediate-acting combined with fast-acting, insulin (human). ATC code: A10A D01. The blood glucose lowering effect of insulin occurs when the molecules facilitate the uptake of glucose by binding to insulin receptors on muscle and fat cells ­ and simultaneously inhibit the output of glucose from the liver. Mixtard is a dual-acting insulin. Onset of action is within ½ hour, reaches a maximum effect within 2 - 8 hours and the entire time of duration is up to 24 hours. Pharmacokinetic properties Insulin in the blood stream has a halflife 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 insulins is therefore affected by significant intraand inter-individual variation. Absorption The absorption profile is due to the product being a mixture of insulins with fast and protracted absorption respectively. The maximum plasma concentration of Mixtard 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 insulindegrading 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 halflife (t½) 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 t½ of a few minutes). Trials have indicated a t½ of about 5 - 10 hours. Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. Pharmaceutical particulars List of excipients Zinc chloride Glycerol Metacresol Phenol Disodium phosphate dihydrate Sodium hydroxide or/and hydrochloric acid (for pH adjustment) Protamine sulphate Water for injections

Incompatibilities In general terms, insulin should only be added to compounds with which it is known to be compatible. Insulin suspensions should not be added to infusion fluids. Shelf life and special precautions for storage 30 months. Mixtard 30 InnoLet® in use should not be kept in a refrigerator. Mixtard 30 InnoLet may be kept at room temperature (not above 30°C) for up to 6 weeks after first opening. Store Mixtard 30 InnoLet, which is not in use in a refrigerator (2°C - 8°C) not in or near the cooling compartment. Do not freeze. Keep the pen cap on in order to protect the insulin from light. Protect from excessive heat and sunlight. Nature and contents of container 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. Produced by Novo Nordisk A/S Novo Allé DK-2880 Bagsværd, Denmark

Mixtard®, InnoLet®, NovoFine® and S are trademarks owned by Novo Nordisk A/S, Denmark © 2000/2005

Novo Nordisk A/S

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Instructions to be given to the patient on how to use Mixtard® 30 InnoLet®

Mixtard 30 InnoLet is a simple, compact pre-filled pen able to deliver 1 to 50 units in increments of 1 unit. Mixtard 30 InnoLet is designed to be used with NovoFine® S needles of 8 mm or shorter in length. Look for an S on the needle box. The S stands for short cap. Mixtard InnoLet is for single person use only. Do not use if it has not been stored correctly. As a precautionary measure, the patient should always carry a spare insulin delivery device in case InnoLet is lost or damaged.

Preparing for injection Check the label to make sure that Mixtard 30 InnoLet contains the correct type of insulin. Take off the pen cap (as shown by the arrow). Mixing is easier when the insulin has reached room temperature. Suspending the insulin Before every injection: · Check there are at least 12 units of insulin left in the cartridge to allow even mixing. If there are less than 12 units left, use a new Mixtard 30 InnoLet · Move the pen slowly up and down between positions A and B and back so that the glass ball moves from one end of the cartridge to the other (picture 1A) at least 20 times. Repeat this movement at least 10 times before each injection. The movement must always be repeated until the liquid appears uniformly white and cloudy · After mixing complete all the following stages of injection without delay. Attaching the needle · Disinfect the rubber membrane with a medicinal swab · Remove the protective tab from a NovoFine S needle · Screw the needle straight and tightly onto Mixtard 30 InnoLet (picture 1B) · Pull off the big outer needle cap and the inner needle cap. The big outer needle cap may be stored in the compartment.

1A

Push-button

Dose selector dial Residual scale Dose scale Insulin cartridge

Priming to expel air Small amounts of air may collect in the needle and cartridge during normal use. To avoid injection of air and ensure proper dosing: · Dial 2 units by turning the dose selector clockwise · Hold Mixtard 30 InnoLet with the needle upwards and tap the cartridge gently with a finger a few times to make any air bubbles collect at the top of the cartridge (picture 1C) · Keeping the needle upwards, press the push-button and the dose selector returns to zero · A drop of insulin must appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times. If a drop of insulin still does not appear, the device is defective and must not be used.

1C

Injecting the insulin · Insert the needle into the skin · Deliver the dose by pressing the push-button fully down (picture 3). Clicks will be heard as the dose selector returns to zero · After the injection, the needle must remain under the skin for at least 6 seconds to ensure that the full dose has been delivered · Make sure not to block the dose selector while injecting, as the dose selector must be allowed to return to zero when the push-button is pressed · Remove the needle after each injection.

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Removing the needle · Replace the big outer needle cap and unscrew the needle (picture 4). Dispose of it carefully. Use a new needle for each injection. Remove the needle after each injection. Otherwise, the liquid may leak out when the temperature changes, and the strength of the insulin may change. Health care professionals, relatives and other carers must follow general precautionary measures for removal and disposal of needles to eliminate the risk of unintended needle penetration. Dispose of the used Mixtard 30 InnoLet carefully without the needle attached.

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Compartment for needles

Rubber membrane Needle

1B

Pen cap

Protective tab

Inner needle cap

Big outer needle cap

Setting the dose · Always check that the push-button is fully depressed and the dose selector is set to zero · Dial the number of units required by turning the dose selector clockwise (picture 2). Do not use the residual scale to measure the dose of insulin · A click will be heard for every single unit dialled. The dose can be corrected by turning the dial either way. A dose larger than the number of units remaining in the cartridge cannot be set.

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Maintenance Mixtard 30 InnoLet is designed to work accurately and safely. It must be handled with care. If it is dropped, damaged or crushed, there is a risk of leakage of insulin. Do not refill Mixtard 30 InnoLet. Clean Mixtard 30 InnoLet by wiping it with a medicinal swab. Do not soak it, wash or lubricate it. This may damage the mechanism.

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