INSUMAN RAPID 100UI / ml SOLOSTAR injection for pre-filled pen medication leaflet

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

Insuman Rapid SoloStar 100 IU/ml solution for injection in a pre-filled pen

Insuman Rapid 100 IU/ml in a cartridge

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

Each cartridge contains 3 ml of solution for injection, equivalent to 300 IU insulin.

Insuman Rapid 100 IU/ml in a pre-filled pen

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

Each pen contains 3 ml of solution for injection, equivalent to 300 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.

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.

Insuman Rapid 100 IU/ml in a pre-filled pen

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

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 100 IU/ml in a cartridge

Insuman Rapid 100 IU/ml in cartridges is only suitable for subcutaneous injections from a reusablepen. If administration by syringe or intravenous injection is necessary, a vial should be used (seesection 4.4).

Insuman Rapid SoloStar 100 IU/ml in a pre-filled pen

Insuman Rapid SoloStar 100 IU/ml in pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe or intravenous injection is necessary, a vial should be used (see section 4.4).

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.

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 thepatient'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.

Insuman Rapid 100 IU/ml in a cartridge

Pens to be used with Insuman Rapid 100 IU/ml in cartridges

Insuman Rapid 100 IU/ml in cartridges is only suitable for subcutaneous injections from a reusablepen. If administration by syringe or intravenous injection is necessary, a vial should be used.

The Insuman Rapid cartridges should only be used with the following pens:

- JuniorSTAR which delivers Insuman Rapid in 0.5 unit dose increments

- ClikSTAR, Tactipen, Autopen 24, AllStar and AllStar PRO which all deliver Insuman Rapid in 1unit dose increments.

These cartridges should not be used with any other reusable pen as the dosing accuracy has only beenestablished with the listed pens (see section 4.2 and 6.6).

Not all of these pens may be marketed in your country.

Insuman Rapid SoloStar 100 IU/ml in a pre-filled pen

Handling of the pen

Insuman Rapid SoloStar 100 IU/ml in pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe or intravenous injection is necessary, a vial should be used (seesection 4.2).Before using SoloStar, the Instructions for Use included in the Package Leaflet must beread carefully. SoloStar has to be used as recommended in these Instructions for Use (see section 6.6).

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 organclass 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.

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 intramuscular administrationin rabbits gave no remarkable findings. Studies of pharmacodynamic effects following subcutaneousadministration in rabbits and dogs revealed the expected hypoglycaemic reactions.

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 100 IU/ml in a cartridge or Insuman rapid SoloStar 100 IU/ml in a pre-filled pen mustnot 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 solution.

2 years.

Insuman Rapid 100 IU/ml in a cartridge

The cartridge in-use (in the insulin pen) or carried as a spare may be stored for a maximum of 4 weeksnot above 25°C and away from direct heat or direct light.

The pen containing a cartridge 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.

Insuman rapid SoloStar 100 IU/ml in a pre-filled pen

The pen in-use or carried as a spare may be stored for a maximum of 4 weeks not above 25°C andaway 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.

Insuman Rapid 100 IU/ml in a cartridge

Unopened cartridges

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

In-use cartridges

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

Insuman rapid SoloStar 100 IU/ml in a pre-filled pen

Not in-use pens

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 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.

Insuman Rapid 100 IU/ml in a cartridge3 ml solution in a cartridge (type 1 colourless glass) with a plunger (bromobutyl rubber (type 1)) and aflanged cap (aluminium) with a stopper (bromobutyl or laminate of polyisoprene and bromobutylrubber (type 1)).

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

Not all pack sizes may be marketed.

Insuman rapid SoloStar 100 IU/ml in a pre-filled pen3 ml solution in a cartridge (type 1 colourless glass) with a plunger (bromobutyl rubber (type 1)) and aflanged cap (aluminium) with a stopper (bromobutyl or laminate of polyisoprene and bromobutylrubber (type 1)).

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.

Insuman Rapid 100 IU/ml in a cartridge

Insuman Rapid 100 IU/ml in cartridges is only suitable for subcutaneous injections from a reusablepen. If administration by syringe or intravenous injection is necessary, a vial should be used. The

Insuman Rapid cartridges are to be used only in conjunction with the pens: ClikSTAR, Autopen 24,

Tactipen, AllStar, AllStar PRO or JuniorSTAR (see section 4.2 and 4.4). Not all of these pens may bemarketed in your country.

The pen should be used as recommended in the information provided by the device manufacturer.

The manufacturer’s instructions for using the pen must be followed carefully for loading the cartridge,attaching the injection needle, and administering the insulin injection.

If the insulin pen is damaged or not working properly (due to mechanical defects) it has to bediscarded, and a new insulin pen has to be used.

Cartridges

Before insertion into the pen, Insuman Rapid must be kept at room temperature for 1 to 2 hours.

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

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Empty cartridges must not be refilled.

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 cartridges are not designed to allow any other insulin to be mixed in the cartridge.

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

Insuman rapid SoloStar 100 IU/ml in a pre-filled pen

Insuman Rapid SoloStar 100 IU/ml in pre-filled pen is only suitable for subcutaneous injections. Ifadministration by syringe or intravenous injection is necessary, a vial should be used (see section 4.2and 4.4).

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.

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 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).

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

Before using the SoloStar pre-filled pen, the Instructions for Use included in the package leaflet mustbe read carefully.

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

EU/1/97/030/030

EU/1/97/030/055

EU/1/97/030/056

EU/1/97/030/085

EU/1/97/030/090

EU/1/97/030/095

EU/1/97/030/140

EU/1/97/030/141

EU/1/97/030/142

EU/1/97/030/143

EU/1/97/030/144

EU/1/97/030/145

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