Insuman Comb 25 SoloStar 100 IU/ml suspension for injection in a pre-filled pen.

Each ml contains 100 IU insulin human (equivalent to 3.5 mg).

Each pen contains 3 ml of suspension for injection, equivalent to 300 IU insulin. One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.

Insuman Comb 25 is a biphasic isophane insulin suspension consisting of 25% dissolved insulin and 75% crystalline protamine insulin.

Human insulin is produced by recombinant DNA technology in Escherichia coli.

For the full list of excipients, see section 6.1.

Suspension for injection in a pre-filled pen.

After resuspension, milky-white suspension.

Diabetes mellitus where treatment with insulin is required.

Posology

The desired blood glucose levels, the insulin preparations to be used and the insulin dose regimen (doses and timings) must be determined individually and adjusted to suit the patient's diet, physical activity and life-style.

Daily doses and timing of administration

There are no fixed rules for insulin dose regimen. However, the average insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. The basal metabolic requirement is 40% to 60% of the total daily requirement. Insuman Comb 25 is injected subcutaneously 30 to 45 minutes before a meal.

SoloStar delivers insulin in doses from 1 to 80 units in steps of 1 unit. Each pen contains multiple doses.

Secondary dose adjustment

Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, for example, if

- the patient's weight changes,

- the patient's life-style changes,

- other circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia (see section 4.4).

Special populations

Elderly population (≧65 years old)

In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.

Renal impairment

In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism.

Hepatic impairment

In patients with severe hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

Method of administration

Insuman Comb 25 is administered subcutaneously. Insuman Comb 25 must never be injected intravenously.

Insulin absorption and hence the blood-glucose-lowering effect of a dose may vary from one injection area to another (e.g. the abdominal wall compared with the thigh). Injection sites within an injection area must be rotated from one injection to the next.

Before using SoloStar, the Instructions for Use included in the Package Leaflet must be read carefully.

For further details on handling, see section 6.6.

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

Patients hypersensitive to Insuman Comb 25 for whom no better tolerated preparation is available must only continue treatment under close medical supervision and – where necessary – in conjunction with anti-allergic treatment.

In patients with an allergy to animal insulin intradermal skin testing is recommended prior to a transfer to Insuman Comb 25, since they may experience immunological cross-reactions.

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered.

Transfer to Insuman Comb 25

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may result in the need for a change in dosage.

The need to adjust (e.g. reduce) the dose may become evident immediately after transfer. Alternatively, it may emerge gradually over a period of several weeks.

Following transfer from an animal insulin to human insulin, dose regimen reduction may be required in particular in patients who

- were previously already controlled on rather low blood glucose levels,

- have a tendency to hypoglycaemia,

- previously required high insulin doses due to the presence of insulin antibodies.

Close metabolic monitoring is recommended during the transition and in the initial weeks thereafter. In patients who require high insulin doses because of the presence of insulin antibodies, transfer under medical supervision in a hospital or similar setting must be considered.

Hypoglycaemia

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.

Particular caution should be exercised, and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:

- in whom glycaemic control is markedly improved,

- in whom hypoglycaemia develops gradually,

- who are elderly,

- after transfer from animal insulin to human insulin,

- in whom an autonomic neuropathy is present,

- with a long history of diabetes,

- suffering from a psychiatric illness,

- receiving concurrent treatment with certain other medicinal products (see section 4.5).

Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia.

If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.

Adherence of the patient to the dose regimen and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These include:

- change in the injection area,

- improved insulin sensitivity (e.g. by removal of stress factors),

- unaccustomed, increased or prolonged physical activity,

- intercurrent illness (e.g. vomiting, diarrhoea),

- inadequate food intake,

- missed meals,

- alcohol consumption,

- certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency),

- concomitant treatment with certain other medicinal products.

Intercurrent illness

Intercurrent illness requires intensified metabolic monitoring. In many cases, urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc. and they must never omit insulin entirely.

Handling of the pen

Before using SoloStar, the Instructions for Use included in the Package Leaflet must be read carefully. SoloStar has to be used as recommended in these Instructions for Use (see section 6.6).

Medication errors

Medication errors have been reported in which other Insuman formulations or other insulins have been accidentally administered. Insulin label must always be checked before each injection to avoid medication errors between insulin human and other insulins.

Combination of Insuman 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 Insuman 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 substances affect glucose metabolism and may require dose adjustment of human insulin.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens (e.g. in oral contraceptives), phenothiazine derivatives, somatropin, sympathomimetic medicinal products (e.g. epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, protease inhibitors and atypical antipsychotic medicinal products (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia which may sometimes be followed by hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

Pregnancy

For insulin human, no clinical data on exposed pregnancies are available. Insulin does not cross the placental barrier. Caution should be exercised when prescribing to pregnant women.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

Breast-feeding

No effects on the suckling child are anticipated. Insuman Comb 25 can be used during breast-feeding. Breast-feeding women may require adjustments in insulin dose and diet.

Fertility

No clinical or animal data with insulin human on male or female fertility are available.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machines).

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 symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

Summary of the safety profile

Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement. In clinical studies and during marketed use, the frequency varies with patient population and dose regimens. Therefore, no specific frequency can be presented.

Tabulated list of adverse reactions

The following related adverse reactions from clinical investigations are listed below by system organ class and in order of decreasing incidence: 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 the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Immune system disorders

Immediate type allergic reactions to insulin or to the excipients may be life-threatening.

Insulin administration may cause anti-insulin antibodies to form. In rare cases, the presence of such anti-insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

Metabolism and nutrition disorders

Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage.

Prolonged or severe hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.

Insulin may cause sodium retention and oedema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Eyes disorders

A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.

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

Lipodystrophy may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions.

General disorders and administration site conditions

Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks.

Symptoms

Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.

Management

Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in dose regimen of the medicinal product, meal patterns, or physical activity may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, intermediate-acting combined with fast-acting, ATC Code: A10AD01.

Mechanism of action

Insulin

- lowers blood glucose and promotes anabolic effects as well as decreasing catabolic effects,

- increases the transport of glucose into cells as well as the formation of glycogen in the muscles and the liver, and improves pyruvate utilisation. It inhibits glycogenolysis and gluconeogenesis,

- increases lipogenesis in the liver and adipose tissue and inhibits lipolysis,

- promotes the uptake of amino acids into cells and promotes protein synthesis,

- enhances the uptake of potassium into cells.

Pharmacodynamic effects

Insuman Comb 25 (a biphasic isophane insulin suspension with 25% dissolved insulin) is an insulin with gradual onset and long duration of action. Following subcutaneous injection, onset of action is within 30 to 60 minutes, the phase of maximum action is between 2 and 4 hours after injection and the duration of action is 12 to 19 hours.

In healthy subjects, the serum half-life of insulin is approximately 4 to 6 minutes. It is longer in patients with severe renal insufficiency. However, it must be noted that the pharmacokinetics of insulin do not reflect its metabolic action.

The acute toxicity was studied following subcutaneous administration in rats. No evidence of toxic effects was found. Studies of pharmacodynamic effects following subcutaneous administration in rabbits and dogs revealed the expected hypoglycaemic reactions.

Protamine sulphate,

metacresol,

phenol,

zinc chloride,

sodium dihydrogen phosphate dihydrate,

glycerol,

sodium hydroxide,

hydrochloric acid (for pH adjustment),

water for injections.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Insuman Comb 25 must not be mixed with solutions containing reducing substances such as thioles and sulphites.

Mixing of insulins

Insuman Comb 25 must not be mixed with any other insulin or with insulin analogues.

Care must be taken to ensure that no alcohol or other disinfectants enter the insulin suspension.

2 years.

Shelf life after first use of the pen

The pen in-use or carried as a spare may be stored for a maximum of 4 weeks not above 25°C and away from direct heat or direct light.

Pens in-use must not be stored in the refrigerator.

The pen cap must be put back on the pen after each injection in order to protect from light.

Not in-use pens

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Do not put Insuman Comb 25 next to the freezer compartment or a freezer pack.

Keep the pre-filled pen in the outer carton in order to protect from light.

In-use pens

For storage conditions after first opening of the medicinal product, see section 6.3.

3 mlsuspension in a cartridge (type 1 colourless glass) with a plunger (bromobutyl rubber (type 1)) and a flanged cap (aluminium) with a stopper (bromobutyl or laminate of polyisoprene and bromobutyl rubber (type 1)).

Each cartridge contains 3 balls (stainless steel).

The cartridges are sealed in a disposable pen injector.

Injection needles are not included in the pack.

Packs of 3, 4, 5, 6, 9 or 10 pens are available.

Not all pack sizes may be marketed.

Before first use, Insuman Comb 25 must be kept at room temperature for 1 to 2 hours and then resuspended to check the contents. This is best done by gently tilting the pen back and forth (at least ten times). Each cartridge contains three small metal balls to facilitate quick and thorough mixing of the contents. Later on, the insulin must be resuspended again prior to each injection.

After resuspension, the fluid must have a uniformly milky appearance. Insuman Comb 25 must not be used if this cannot be achieved, i.e. if the suspension remains clear, for example, or if clumps, particles or flocculation appear in the insulin or stick to the wall or bottom of the cartridge. These changes sometimes give the cartridge a frosted appearance. In such cases, a new pen yielding a uniform suspension must be used. It is also necessary to change to a new pen if the insulin requirement changes substantially.

Empty pens must never be re-used and must be properly discarded.

To prevent the possible transmission of disease, each pen must be used by one patient only.

It must be remembered that

- insulin protamine crystals dissolve in an acid pH range,

- the soluble insulin part precipitates out at a pH of approximately 4.5 to 6.5.

Insulin label must always be checked before each injection to avoid medication errors between insulin human and other insulins (see section 4.4).

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

Handling of the pen

The patient should be advised to read the instructions for use included in the package leaflet carefully before using SoloStar.

Important information for use of SoloStar:

• Before each use, a new needle must always be carefully attached and a safety test must be performed. A dose should not be selected and/or the injection button should not be pressed without a needle attached. Only use needles that are compatible for use with SoloStar.

• Special caution must be taken to avoid accidental needle injury and transmission of infection.

• SoloStar must never be used if it is damaged or if the patient is not sure if it is working properly.

• The patient must always have a spare SoloStar available in case the SoloStar is lost or damaged.

Storage instructions

Please check section 6.4 of this SPC for instructions on how to store SoloStar.

If SoloStar is in cool storage, it should be taken out 1 to 2 hours before you inject to allow it to warm up. Cold insulin is more painful to inject.

The used SoloStar must be discarded as required by your local authorities.

Maintenance

SoloStar has to be protected from dust and dirt.

The outside of the SoloStar can be cleaned by wiping it with a damp cloth.

The pen must not be soaked, washed or lubricated as this may damage it.

SoloStar is designed to work accurately and safely. It should be handled with care. The patient should avoid situations where SoloStar may be damaged. If the patient is concerned that the SoloStar may be damaged, he must use a new one.

Step 1. Check the insulin

The label on the pen should be checked to make sure it contains the correct insulin. Insuman SoloStar is white with a colour on the injection button. The injection button colour will vary based on the formulation of Insuman insulin used.

After removing the pen cap, the appearance of the insulin should also be checked:

The insulin suspensions (Insuman Basal or Insuman mixtures) should be mixed by turning SoloStar up and down at least 10 times to resuspend the insulin. The pen should be turned gently to avoid foaming in the cartridge. After mixing, the insulin suspensions must have an evenly milky-white appearance.

Step 2. Attach the needle

Only needles that are compatible for use with SoloStar should be used.

A new sterile needle will be always used for each injection. After removing the cap, the needle should be carefully attached straight onto the pen.

Step 3. Perform a safety test

Prior to each injection, a safety test has to be performed to ensure that pen and needle work properly and to remove air bubbles.

A dose of 2 units has to be selected.

The outer and inner needle caps should be removed.

While holding the pen with the needle pointing upwards, the insulin reservoir should be tapped gently with the finger so that any air bubbles rise up towards the needle.

Then the injection button should be pressed in completely.

If insulin has been expelled through the needle tip, then the pen and the needle are working properly. If no insulin appears at the needle tip, step 3 should be repeated until insulin appears at the needle tip.

Step 4. Select the dose

The dose can be set in steps of 1 unit, from a minimum of 1 unit to a maximum of 80 units. If a dose greater than 80 units is required, it should be given as two or more injections.

The dose window must show “0” following the safety test. The dose can then be selected.

Step 5. Inject the dose

The patient should be informed on the injection technique by his health care professional.

The needle should be inserted into the skin.

The injection button should be pressed in completely. Then the injection button should be held down 10 seconds before withdrawing the needle. This ensures that the full dose of insulin has been injected.

Step 6. Remove and discard the needle

The needle should always be removed after each injection and discarded. This helps prevent contamination and/or infection, entry of air into the insulin reservoir and leakage of insulin. Needles mut not be re-used.

Special caution must be taken when removing and disposing of the needle. Recommended safety measures for removal and disposal of needles must be followed (e.g. a one handed capping technique) in order to reduce the risk of accidental needle injury and transmission of infectious diseases.

The pen cap should be replaced on the pen.

Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany

EU/1/97/030/160

Date of first authorisation: 21 February 1997

Date of latest renewal: 21 February 2007

3 July 2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu