sanofi-aventis

Insuman Comb 25 100 IU/ml suspension for injection in a vial

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

Each vial contains 5 ml of suspension for injection, equivalent to 500 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 a full list of excipients, see section 6.1.

Suspension for injection in a vial.

After resuspension, milky-white suspension.

Diabetes mellitus where treatment with insulin is required.

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.

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).

Use in specific patient groups

In patients with hepatic or renal impairment as well as in the elderly, insulin requirements may be diminished (see section 4.4).

Administration

Insuman Comb 25 contains 100 IU of insulin per ml suspension. Only injection syringes designed for this strength of insulin (100 IU per ml) are to be used. The injection syringes must not contain any other medicinal product or residue (e.g. traces of heparin).

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.

For further details on handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Insuman Comb 25 must not be administered intravenously and must not be used in infusion pumps or external or implanted insulin pumps.

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 patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism. In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.

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

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.

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 agents, 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 agents (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.

Lactation

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

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 operating 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 operate machines in these circumstances.

Hypoglycaemia, in general the most frequent undesirable effect of insulin therapy, 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 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.

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, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Uncommon: shock

Not known: immediate type allergic reactions (hypotension, angioneurotic oedema, bronchospasm, generalised skin reactions), anti-insulin antibodies

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

Common: oedema

Not known: sodium retention

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

Eyes disorders

Not known: proliferative retinopathy, diabetic retinopathy, visual impairment

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

Not known: lipodystrophy

As with any insulin therapy, 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

Common: injection site reactions

Uncommon: injection site urticaria

Not known: injection site inflammation, injection site swelling, injection site pain, injection site pruritus, injection site erythema.

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: Insulins and analogues for injection, intermediate-acting combined with fast-acting, ATC Code: A10AD01.

Mode 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 characteristics

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.

Concerning mixing or incompatibility with other insulins see section 6.6. 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 vial:

The product may be stored for a maximum of 4 weeks not above 25°C and away from direct heat or direct light.

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

It is recommended that the date of the first use be noted on the label.

Unopened vials:

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

Opened vials:

For storage precautions, see section 6.3.

5 ml solution in a vial (type 1 colourless glass) with a flanged cap (aluminium), a stopper (chlorobutyl rubber (type 1)) and a tear-off cap (polypropylene).

Packs of 1 and 5 vials are available.

Not all pack sizes may be marketed.

Before withdrawing insulin from the vial for the first time, remove the plastic protective cap.

Immediately before withdrawal from the vial into the injection syringe, the insulin must be resuspended. This is best done by rolling the vial at an oblique angle between the palms of the hands. Do not shake the vial vigorously as this may lead to changes in the suspension (giving the vial a frosted appearance; see below) and cause frothing. Froth may interfere with the correct measurement of the dose.

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 vial. These changes sometimes give the vial a frosted appearance. In such cases, a new vial yielding a uniform suspension must be used. It is also necessary to change to a new vial if the insulin requirement changes substantially.

As with all insulin preparations, Insuman Comb 25 must not be mixed with solutions containing reducing agents such as thioles and sulphites. It must also 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).

Mixing of insulins

Insuman Comb 25 may be mixed with all Sanofi-Aventis human insulins, but NOT with those designed specifically for use in insulin pumps. Insuman Comb 25 must also NOT be mixed with insulins of animal origin or with insulin analogues.

If two different insulins have to be drawn into one single injection syringe, it is recommended that the shorter-acting insulin be drawn first to prevent contamination of the vial by the longer-acting preparation. It is advisable to inject immediately after mixing. Insulins of different concentration (e.g. 100 IU per ml and 40 IU per ml) must not be mixed.

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

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

EU/1/97/030/043

Date of first authorisation: 21 February 1997

Date of latest renewal: 21 February 2007

February 2011