ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Insulin Human Winthrop Rapid 100 IU/ml solution for injection in a vial
2.
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. 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 a full list of excipients, see section 6.1.
3.
Solution for injection in a vial.
Clear, colourless solution of water-like consistency.
4.
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.
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 life-style changes,
2
-
the patient's weight 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
Insulin Human Winthrop Rapid contains 100 IU of insulin per ml solution. 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 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.
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.
Hypersensitivity to the active substance or to any of the excipients.
Insulin Human Winthrop Rapid must not be used in external or implanted insulin pumps or in
peristaltic pumps with silicone tubing.
Patients hypersensitive 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 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.
3
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,
-
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.
4
-
have a tendency to hypoglycaemia,
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,
-
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.
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.
5
-
intercurrent illness (e.g. vomiting, diarrhoea),
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. Insulin Human Winthrop Rapid 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.
6
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.
7
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Insulins and analogues for injection, fast-acting, ATC Code: A10AB01.
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,
Pharmacodynamic characteristics
Insulin Human Winthrop Rapid is an insulin with rapid onset and short duration of action. Following
subcutaneous injection, onset of action is within 30 minutes, the phase of maximum action is between
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.
6.1 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.
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 solution.
6.3 Shelf life
2 years.
8
-
enhances the uptake of potassium into cells.
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 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.
6.5 Nature and contents of container
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.
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
.
As with all insulin preparations, Insulin Human Winthrop Rapid
must not be mixed with solutions
containing reducing agents such as thioles and sulphites. It must also 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 Sanofi-Aventis human insulins, but NOT with
those 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.
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.
9
7.
Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany
8.
EU/1/06/368/011
EU/1/06/368/012
9.
Date of first authorisation: 17 January 2007
10
1.
Insulin Human Winthrop Rapid 40 IU/ml solution for injection in a vial
2.
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. 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 a full list of excipients, see section 6.1.
3.
Solution for injection in a vial.
Clear, colourless solution of water-like consistency.
4.
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.
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 life-style changes,
11
-
the patient's weight 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
Insulin Human Winthrop Rapid contains 40 IU of insulin per ml solution. Only injection syringes
designed for this strength of insulin (40 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 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.
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.
Hypersensitivity to the active substance or to any of the excipients.
Insulin Human Winthrop Rapid must not be used in external or implanted insulin pumps or in
peristaltic pumps with silicone tubing.
Patients hypersensitive 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 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.
12
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,
-
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.
13
-
have a tendency to hypoglycaemia,
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,
-
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.
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.
14
-
intercurrent illness (e.g. vomiting, diarrhoea),
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. Insulin Human Winthrop Rapid 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.
15
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.
16
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Insulins and analogues for injection, fast-acting, ATC Code: A10AB01.
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,
Pharmacodynamic characteristics
Insulin Human Winthrop Rapid is an insulin with rapid onset and short duration of action. Following
subcutaneous injection, onset of action is within 30 minutes, the phase of maximum action is between
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.
6.1 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.
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 solution.
6.3 Shelf life
2 years.
17
-
enhances the uptake of potassium into cells.
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 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.
6.5 Nature and contents of container
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
.
As with all insulin preparations, Insulin Human Winthrop Rapid
must not be mixed with solutions
containing reducing agents such as thioles and sulphites. It must also 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 Sanofi-Aventis human insulins, but NOT with
those 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.
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.
18
7.
Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany
8.
EU/1/06/368/001
EU/1/06/368/002
9.
Date of first authorisation: 17 January 2007
19
1.
Insulin Human Winthrop Rapid 100 IU/ml solution for injection in a cartridge
2.
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. 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 a full list of excipients, see section 6.1.
3.
Solution for injection in a cartridge.
Clear, colourless solution of water-like consistency.
4.
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.
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 life-style changes,
20
-
the patient's weight 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
Insulin Human Winthrop Rapid is administered subcutaneously.
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.
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.
Hypersensitivity to the active substance or to any of the excipients.
Insulin Human Winthrop Rapid must not be used in external or implanted insulin pumps or in
peristaltic pumps with silicone tubing.
Patients hypersensitive 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 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 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.
21
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,
-
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,
-
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
22
-
have a tendency to hypoglycaemia,
-
intercurrent illness (e.g. vomiting, diarrhoea),
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.
Pens to be used with Insulin Human Winthrop Rapid cartridges
The Insulin Human Winthrop Rapid cartridges should only be used with the following pens: OptiPen,
ClikSTAR, Tactipen and Autopen 24 and should not be used with any other reusable pen as the dosing
accuracy has only been established with the listed pens.
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.
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.
23
Lactation
No effects on the suckling child are anticipated. Insulin Human Winthrop Rapid 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.
24
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Insulins and analogues for injection, fast-acting, ATC Code: A10AB01.
25
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,
Pharmacodynamic characteristics
Insulin Human Winthrop Rapid is an insulin with rapid onset and short duration of action. Following
subcutaneous injection, onset of action is within 30 minutes, the phase of maximum action is between
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.
6.1 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.
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 solution.
6.3 Shelf life
2 years.
Shelf life after first use of the cartridge
:
The cartridge in-use (in the insulin pen) 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.
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.
26
-
enhances the uptake of potassium into cells.
6.4 Special precautions for storage
Unopened cartridges
:
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Do not put Insulin Human Winthrop 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 precautions, see section 6.3.
6.5 Nature and contents of container
3 ml solution 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)).
Packs of 3, 4, 5, 6, 9 or 10 cartridges are available.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Insulin pen
The Insulin Human Winthrop Rapid cartridges are to be used only in conjunction with OptiPen,
ClikSTAR, Autopen 24 or Tactipen (see section 4.4). Not all of these pens may be marketed 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 be
discarded, and a new insulin pen has to be used.
If the pen malfunctions (see instructions for using the pen), the solution may be drawn from the
cartridge into an injection syringe (suitable for an insulin with 100 IU/ml) and injected.
Cartridges
Before insertion into the pen, Insulin Human Winthrop Rapid
must be kept at room temperature for 1
to 2 hours.
Inspect the cartridge before use. 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
.
Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).
Empty cartridges must not be refilled.
As with all insulin preparations, Insulin Human Winthrop Rapid
must not be mixed with solutions
containing reducing agents such as thioles and sulphites. It must also 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).
27
Mixing of insulins
Insulin Human Winthrop Rapid may be mixed with all Sanofi-Aventis human insulins, but NOT with
those 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.
Insulin Human Winthrop Rapid cartridges are not designed to allow any other insulin to be mixed in
the cartridge.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany
8.
EU/1/06/368/088
EU/1/06/368/013
EU/1/06/368/014
EU/1/06/368/093
EU/1/06/368/098
EU/1/06/368/015
9.
Date of first authorisation: 17 January 2007
28
1.
FURTHER INFORMATION
What Insulin Human Winthrop Infusat contains
-
The active substance is insulin human. One ml of Insulin Human Winthrop Infusat contains
100 IU (International Units) of the active substance insulin human.
-
The other ingredients are: phenol, zinc chloride, trometamol, poloxamer 171, glycerol,
hydrochloric acid (for pH adjustment) and water for injections.
What Insulin Human Winthrop Infusat looks like and contents of the pack
Insulin Human Winthrop Infusat is a clear, colourless solution for injection, with no solid particles
visible, and of water-like consistency.
Insulin Human Winthrop Infusat is supplied in cartridges containing 3.15 ml solution (315 IU). Pack
of 5 cartridges of 3.15 ml is available.
925
Marketing Authorisation Holder and Manufacturer
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00
Luxembourg/Luxemburg
sanofi-aventis Belgium
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
България
sanofi-aventis Bulgaria EOOD
Тел.: +359 (0)2 970 53 00
Magyarország
sanofi-aventis zrt., Magyarország
Tel.: +36 1 505 0050
Česká republika
sanofi-aventis, s.r.o.
Tel: +420 233 086 111
Malta
sanofi-aventis Malta Ltd.
Tel: +356 21493022
Danmark
sanofi-aventis Denmark A/S
Tlf: +45 45 16 70 00
Nederland
sanofi-aventis Netherlands B.V.
Tel: +31 (0)182 557 755
Deutschland
Sanofi-Aventis Deutschland GmbH
Tel: +49 (0)180 2 222010
Norge
Aventis Pharma Norge AS
Tlf: +47 67 10 71 00
Eesti
sanofi-aventis Estonia OÜ
Tel: +372 627 34 88
Österreich
sanofi-aventis GmbH
Tel: +43 1 80 185 – 0
Ελλάδα
sanofi-aventis AEBE
Τηλ: +30 210 900 16 00
Polska
sanofi-aventis Sp. z o.o.
Tel.: +48 22 280 00 00
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
Portugal
sanofi-aventis - Produtos Farmacêuticos, Lda.
Tel: +351 21 35 89 400
France
sanofi-aventis France
Tél: 0 800 222 555
Appel depuis l’étranger : +33 1 57 63 23 23
România
sanofi-aventis România S.R.L.
Tel: +40 (0) 21 317 31 36
Ireland
sanofi-aventis Ireland Ltd.
Tel: +353 (0) 1 403 56 00
Slovenija
sanofi-aventis d.o.o.
Tel: +386 1 560 48 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
sanofi-aventis Pharma Slovakia s.r.o.
Tel: +421 2 33 100 100
926
Italia
sanofi-aventis S.p.A.
Tel: 800 13 12 12 (domande di tipo tecnico)
+39 02 393 91 (altre domande e chiamate
dall'estero)
Suomi/Finland
sanofi-aventis Oy
Puh/Tel: +358 (0) 201 200 300
Κύπρος
sanofi-aventis Cyprus Ltd.
Τηλ: +357 22 871600
Sverige
sanofi-aventis AB
Tel: +46 (0)8 634 50 00
Latvija
sanofi-aventis Latvia SIA
Tel: +371 67 33 24 51
United Kingdom
sanofi-aventis
Tel: +44 (0) 1483 505 515
Lietuva
UAB sanofi-aventis Lietuva
Tel: +370 5 2755224
This leaflet was last approved on {date}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
HYPERGLYCAEMIA AND HYPOGLYCAEMIA
Always carry some sugar (at least 20 grams) with you.
Carry some information with you to show you are diabetic.
HYPERGLYCAEMIA (high blood sugar levels)
If your blood sugar is too high (hyperglycaemia),
you may not have injected enough insulin.
Why does hyperglycaemia occur?
Examples include:
-
you have not injected your insulin or not injected enough, or if it has become less effective, for
example through incorrect storage,
-
your insulin pump does not work properly,
-
you are doing less exercise than usual, you are under stress (emotional distress, excitement), or
you have an injury, operation, infection or fever,
-
you are taking or have taken certain other medicines (see section 2, "Using other medicines").
Warning symptoms of hyperglycaemia
Thirst, increased need to urinate, tiredness, dry skin, reddening of the face, loss of appetite, low blood
pressure, fast heart beat, and glucose and ketone bodies in urine. Stomach pain, fast and deep
breathing, sleepiness or even loss of consciousness may be signs of a serious condition (ketoacidosis)
resulting from lack of insulin.
What should you do if you experience hyperglycaemia
Test your blood sugar level and your urine for ketones as soon as any of the above symptoms
occur.
Severe hyperglycaemia or ketoacidosis must always be treated by a doctor, normally in a
hospital.
927
HYPOGLYCAEMIA (low blood sugar levels)
If your blood sugar level falls too much you may become unconscious. Serious hypoglycaemia may
cause a heart attack or brain damage and may be life-threatening. You normally should be able to
recognise when your blood sugar is falling too much so that you can take the right actions.
Why does hypoglycaemia occur?
Examples include:
-
you inject too much insulin,
-
you miss meals or delay them,
-
you do not eat enough, or eat food containing less carbohydrate than normal (sugar and
substances similar to sugar are called carbohydrates; however, artificial sweeteners are NOT
carbohydrates),
-
you drink alcohol, particularly if you are not eating much,
-
you are doing more exercise than usual or a different type of physical activity,
-
you are recovering from an injury or operation or other stress,
-
you are recovering from an illness or from fever,
-
you are taking or have stopped taking certain other medicines (see section 2, "Using other
medicines").
Hypoglycaemia is also more likely to occur if:
-
you have just begun insulin treatment or changed to another insulin preparation,
-
your blood sugar levels are almost normal or are unstable,
-
you change the area of skin where you inject insulin (for example from the thigh to the upper
arm),
-
you suffer from severe kidney or liver disease, or some other disease such as hypothyroidism.
Warning symptoms of hypoglycaemia
- In your body
Examples of symptoms that tell you that your blood sugar level is falling too much or too fast:
sweating, clammy skin, anxiety, fast heart beat, high blood pressure, palpitations and irregular
heartbeat. These symptoms often develop before the symptoms of a low sugar level in the brain.
- In your brain
Examples of symptoms that indicate a low sugar level in the brain: headaches, intense hunger, nausea,
vomiting, tiredness, sleepiness, sleep disturbances, restlessness, aggressive behaviour, lapses in
concentration, impaired reactions, depression, confusion, speech disturbances (sometimes total loss of
speech), visual disorders, trembling, paralysis, tingling sensations (paraesthesia), numbness and
tingling sensations in the area of the mouth, dizziness, loss of self-control, inability to look after
yourself, convulsions, loss of consciousness.
The first symptoms which alert you to hypoglycaemia ("warning symptoms") may change, be weaker
or may be missing altogether if
-
you are elderly, if you have had diabetes for a long time or if you suffer from a certain type of
nervous disease (diabetic autonomic neuropathy),
-
you have recently suffered hypoglycaemia (for example the day before) or if it develops slowly,
-
you have recently changed from an animal insulin to a human insulin such as Insulin Human
Winthrop,
-
you are taking or have taken certain other medicines (see section 2, "Using other medicines").
928
-
you lose carbohydrates due to vomiting or diarrhoea,
-
you have almost normal or, at least, greatly improved blood sugar levels,
In such a case, you may develop severe hypoglycaemia (and even faint) before you are aware of the
problem. Be familiar with your warning symptoms. If necessary, more frequent blood sugar testing
can help to identify mild hypoglycaemic episodes that may otherwise be overlooked. If you are not
confident about recognising your warning symptoms, avoid situations (such as driving a car) in which
you or others would be put at risk by hypoglycaemia.
What should you do if you experience hypoglycaemia
1.
Stop your insulin infusion (if necessary, by withdrawing the needle) at least until you feel that
you are fully alert again. Immediately take about 10 to 20 g sugar, such as glucose, sugar cubes
or a sugar-sweetened beverage. Caution: Artificial sweeteners and foods with artificial
sweeteners (such as diet drinks) are of no help in treating hypoglycaemia.
2.
Then eat something that has a long-acting effect in raising your blood sugar (such as bread or
pasta). Your doctor or nurse should have discussed this with you previously.
3.
If the hypoglycaemia comes back again take another 10 to 20 g sugar.
4.
Speak to a doctor immediately if you are not able to control the hypoglycaemia or if it recurs.
Tell your relatives, friends and close colleagues the following:
If you are not able to swallow or if you are unconscious, you will require an injection of glucose or
glucagon (a medicine which increases blood sugar). These injections are justified even if it is not
certain that you have hypoglycaemia.
It is advisable to test your blood sugar immediately after taking glucose to check that you really have
hypoglycaemia.
929
Source: European Medicines Agency
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