INSUMAN RAPID 100UI / ml solution for injection in vial medication leaflet

Insuman Rapid 40 IU/ml solution for injection in a vial

Insuman Rapid 100 IU/ml solution for injection in a vial

Insuman Rapid 40 IU/ml in a vial

Each ml contains 40 IU insulin human (equivalent to 1.4 mg).

Each vial contains 10 ml of solution for injection, equivalent to 400 IU insulin.

Insuman Rapid 100 IU/ml in a vial

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

Each vial contains 5 ml of solution for injection, equivalent to 500 IU insulin, or 10 ml of solution forinjection, equivalent to 1000 IU insulin.

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

Insuman Rapid is a neutral insulin solution (regular insulin).

*

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

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution.

Diabetes mellitus where treatment with insulin is required. Insuman Rapid is also suitable for thetreatment of hyperglycaemic coma and ketoacidosis, as well as for achieving pre-, intra- andpost-operative stabilisation in patients with diabetes mellitus.

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, physicalactivity and life-style.

Daily doses and timing of administration

There are no fixed rules for insulin dose regimen. However, the average insulin requirement is often0.5 to 1.0 IU per kg body weight per day. The basal metabolic requirement is 40% to 60% of the totaldaily requirement. Insuman Rapid is injected subcutaneously 15 to 20 minutes before a meal.

In the treatment of severe hyperglycaemia or ketoacidosis in particular, insulin administration is part ofa complex therapeutic regimen which includes measures to protect patients from possible severecomplications of a relatively rapid lowering of blood glucose. This regimen requires close monitoring(metabolic status, acid-base and electrolyte status, vital parameters etc.) in an intensive care unit orsimilar setting.

Secondary dose adjustment

Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulinrequirement. 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- orhyperglycaemia (see section 4.4).

Elderly population(≧65 years old)

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

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

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

Insuman Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps withsilicone tubing.

Insuman Rapid is administered subcutaneously.

Insulin absorption and hence the blood-glucose-lowering effect of a dose may vary from one injectionarea to another (e.g. the abdominal wall compared with the thigh). Injection sites within an injectionarea must be rotated from one injection to the next in order to reduce the risk of lipodystrophy andcutaneous amyloidosis (see section 4.4 and 4.8).

Insuman Rapid 40 IU/ml in a vial

Only injection syringes designed for this strength of insulin (40 IU per ml) are to be used. The injectionsyringes must not contain any other medicinal product or residue (e.g. traces of heparin).

Insuman Rapid 100 IU/ml in a vial

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

Insuman Rapid may also be administered intravenously. Intravenous insulin therapy must generallytake place in an intensive care unit or under comparable monitoring and treatment conditions (see'Daily doses and timing of administration').

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.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Patients hypersensitive to Insuman Rapid for whom no better tolerated preparation is available mustonly continue treatment under close medical supervision and - where necessary - in conjunction withanti-allergic treatment.

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

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

Transfer to Insuman Rapid

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. 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 needfor a change in dose.

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 inparticular 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. Inpatients who require high insulin doses because of the presence of insulin antibodies, transfer undermedical supervision in a hospital or similar setting must be considered.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorptionand worsened glycaemic control following insulin injections at sites with these reactions. A sudden change inthe injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucosemonitoring is recommended after the change in the injection site, and dose adjustment of antidiabeticmedications may be considered.

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 inpatients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patientswith significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk ofcardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferativeretinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis followinghypoglycaemia).

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 certainrisk 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 andawareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factorsincreasing the susceptibility to hypoglycaemia require particularly close monitoring and maynecessitate 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 oradrenocortical insufficiency),

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

Intercurrent illness requires intensified metabolic monitoring. In many cases, urine tests for ketones areindicated, and often it is necessary to adjust the insulin dose. The insulin requirement is oftenincreased. Patients with type 1 diabetes must continue to consume at least a small amount ofcarbohydrates 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 have been reported in which other Insuman formulations or other insulins have beenaccidentally administered. Insulin label must always be checked before each injection to avoidmedication 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 inmind if treatment with the combination of pioglitazone and Insuman is considered. If the combinationis 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.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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 tohypoglycaemia 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 antipsychoticmedicinal products (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken theblood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia which maysometimes 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.

For insulin human, no clinical data on exposed pregnancies are available. Insulin does not cross theplacental 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 controlthroughout pregnancy. Insulin requirements may decrease during the first trimester and generallyincrease during the second and third trimesters. Immediately after delivery, insulin requirementsdecline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

No effects on the suckling child are anticipated. Insuman Rapid can be used during breast-feeding.

Breast-feeding women may require adjustments in insulin dose and diet.

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 orhyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk insituations 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 isparticularly important in those who have reduced or absent awareness of the warning symptoms ofhypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it isadvisable to drive or use machines in these circumstances.

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

The following related adverse reactions from clinical investigations are listed below by system organ classand 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 estimatedfrom the available data).

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

MedDRA system Common Uncommon Not knownorgan classes

Immune system Shock Immediate typedisorders allergic reactions(hypotension,angioneurotic oedema,bronchospasm,generalised skinreactions);

Anti-insulin antibodies

Metabolism and Oedema Hypoglycaemia;nutrition disorders Sodium retention

Eye disorders Proliferativeretinopathy;

Diabetic retinopathy;

Visual impairment

Skin and subcutaneous Lipodystrophy;tissue disorders Cutaneous amyloidosis

General disorders and Injection site reactions Injection site urticaria Injection siteadministration site inflammation;conditions Injection site pain;

Injection site pruritus;

Injection site erythema;

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 suchanti-insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency tohyper- or hypoglycaemia.

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 adrenergiccounter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked isthe phenomenon of counter-regulation and its symptoms.

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

A marked change in glycaemic control may cause temporary visual impairment, due to temporaryalteration 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 beassociated with temporary worsening of diabetic retinopathy.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulinabsorption. Continuous rotation of the injection site within the given injection area may help toreduce or prevent these reactions (see section 4.4.).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

More severe episodes with coma, seizure, or neurologic impairment may be treated withintramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrateintake and observation may be necessary because hypoglycaemia may recur after apparent clinicalrecovery.

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting,

ATC Code: A10AB01.

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 musclesand 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.

Insuman Rapid is an insulin with rapid onset and short duration of action. Following subcutaneousinjection, onset of action is within 30 minutes, the phase of maximum action is between 1 and 4 hoursafter injection and the duration of action is 7 to 9 hours.

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

The acute toxicity was studied following subcutaneous administration in rats. No evidence of toxiceffects was found. Local tolerability studies following subcutaneous and intramuscularadministration in rabbits gave no remarkable findings. Studies of pharmacodynamic effectsfollowing subcutaneous administration in rabbits and dogs revealed the expected hypoglycaemicreactions.

Metacresol,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 insection 6.6.

Insuman Rapid must not be mixed with solutions containing reducing substances such as thioles andsulphites.

Mixing of insulins

Insuman Rapid must not be mixed with insulin human formulations designed specifically for use ininsulin pumps.

Insuman Rapid must also not be mixed with insulins of animal origin or with insulin analogues.

Insulins of different concentration (e.g. 100 IU per ml and 40 IU per ml) must not be mixed.

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

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 ordirect 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.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Do not put Insuman Rapid 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 conditions after first opening of the medicinal product, see section 6.3.

Insuman Rapid 40 IU/ml in a vial10 ml solution in a vial (type 1 colourless glass) with a flanged cap (aluminium), a stopper (chlorobutylrubber (type 1)) and a tear-off cap (polypropylene).

Packs of 1 and 5 vials are available.

Not all pack sizes may be marketed.

Insuman Rapid 100 IU/ml in a vial5 ml solution in a vial and 10 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.

Do not shake the vial vigorously as this may cause frothing. Froth may interfere with the correctmeasurement of the dose.

Insuman Rapid must only be used if the solution is clear, colourless, with no solid particles visible, andif it is of a water-like consistency.

Insuman Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps withsilicone tubing.

It must be remembered that neutral regular insulin 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 insulinhuman and other insulins (see section 4.4).

Mixing of insulins

Insuman Rapid may be mixed with all insulin human formulations, but not with those designedspecifically for use in insulin pumps. Concerning incompatibility with other insulins, see section 6.2.

If two different insulins have to be drawn into one single injection syringe, it is recommended that theshorter-acting insulin be drawn first to prevent contamination of the vial by the longer-actingpreparation. It is advisable to inject immediately after mixing

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

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

EU/1/97/030/028

EU/1/97/030/029

EU/1/97/030/031

EU/1/97/030/032

EU/1/97/030/196

EU/1/97/030/197

Date of first authorisation: 21 February 1997

Date of latest renewal: 21 February 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu