Insulin Human Winthrop - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Insulin Human Winthrop Rapid 100 IU/ml solution for injection in a vial

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 for injection, equivalent to 1000 IU insulin. One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.

Insulin Human Winthrop 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.

3. PHARMACEUTICAL FORM

Solution for injection in a vial.

Clear, colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Diabetes mellitus where treatment with insulin is required. Insulin Human Winthrop Rapid is also suitable for the treatment of hyperglycaemic coma and ketoacidosis, as well as for achieving pre-, intra- and post-operative stabilisation in patients with diabetes mellitus.

4.2 Posology and method of administration

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. Insulin Human Winthrop 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 of a complex therapeutic regimen which includes measures to protect patients from possible severe complications 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 or similar setting.

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

Insulin Human Winthrop Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing.

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).

Insulin Human Winthrop Rapid is administered subcutaneously.

Insulin absorption and hence the blood-glucose-lowering eff 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.

Insulin Human Winthrop Rapid may also be administered intravenously. Intravenous insulin therapy must generally take 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for usePatients h

sitive to Insulin Human Winthrop Rapid 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 Insulin Human Winthrop Rapid, 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 Insulin Human Winthrop Rapid

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 Insulin Human Winthrop 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 Insulin Human Winthrop 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 Insulin Human Winthrop 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

For insulin human, no clinical data on exposed pregnancies from controlled clinical studies are available. Insulin does cross the placental barrier, although not in clinically significant amount. A limited amount of data on pregnant women (less than 300 pregnancy outcomes reported) exposed to marketed insulin human indicates no safety issues in use of insulin human in pregnancy. 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. Insulin Human Winthrop Rapid 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.

4.7 Effects on ability to drive and use machines

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.                        or

4.8 Undesirable effects

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).

Whin each.requency grouping, adverse reactions are peened in order of decreasing —.

MedDRA system organ classes	Common	Uncommon	Not known
Immune system disorders		Shock	Immediate type allergic reactions (hypotension, angioneurotic oedema, bronchospasm, generalised skin reactions); Anti-insulin antibodies
Metabolism and nutrition disorders	Oedema		Hypoglycaemia; Sodium retention
Eye disorders			Proliferative retinopathy; Diabetic retinopathy; Visual impairment
Skin and subcutaneous tissue disorders			Lipodystrophy
General disorders and administration site conditions	Injection site reactions	Injection site urticaria	Injection site inflammation; Injection site pain; Injection site pruritus; Injection site erythema;

MedDRA system organ classes	Common	Uncommon	Not known
			Injection site swelling

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.

vCr

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.

4.9 Overdose

Symptoms <3^

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting, ATC Code: A10AB01.

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

Insulin Human Winthrop Rapid is an insulin with rapid onset and short duration subcutaneous injection, onset of action is within 30 minutes, the phase of maxim 1 and 4 hours after injection and the duration of action is 7 to 9 hours.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

The acute toxicity was studied following subcutaneous administration in rats. No evidence of toxic effects was found. Local tolerability studies following subcutaneous and intramuscular administration in rabbits gave no remarkable findings. Studies of pharmacodynamic effects following subcutaneous administration in rabbits and dogs revealed the expected hypoglycaemic reactions.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Metacresol,

sodium dihydrogen phosphate dihydrate, glycerol,

sodium hydroxide,

hydrochloric acid (for pH adjustment), water for injections.

6.2 Incompatibilities

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

Insulin Human Winthrop Rapid must not be mixed with solutions containing reducing substances such as thioles and sulphites.

Mixing of insulins

Insulin Human Winthrop Rapid must not be mixed with insulin human formulations designed specifically for use in insulin pumps.

Insulin Human Winthrop 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.

6.3 Shelf life 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.

6.4 Special precautions for storage

Unopened vials

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Do not put Insulin Human Winthrop Rapid next to the freezer compa Keep the vial in the outer carton in order to protect from light.

Opened vials

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

6.5 Nature and contents of container 5 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.

6.6 Special precautions for disposal and other handling

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 correct measurement of the dose.

Insulin Human Winthrop 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.

Insulin Human Winthrop Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone 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 insulin human and other insulins (see section 4.4).

Mixing of insulins

Insulin Human Winthrop Rapid may be mixed with all insulin human formulations, but not with those designed specifically 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 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.

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

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/368/011

EU/1/06/368/012

EU/1/06/368/169

EU/1/06/368/170

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 January 2007

Date of latest renewal: 17 January 2012