Section 4.4:

Text added:

“Avoidance of accidental mix-ups/medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Actrapid and other insulin products."

Section 4.8:

UK reporting details removed - not applicable to IE SPC.

Section 10:

revision date updated to 07/2019

PDF of SPC uploaded to replace Word document

 1 pre-filled pen contains 3 ml equivalent to 300 international units. 1 ml suspension contains 100 international units isophane (NPH) insulin human* (equivalent to 3.5 mg).

4.2 Posology and method of administration
Method of administration
Insulatard is a human insulin with gradual onset and long duration of action.

 Insulatard is administered subcutaneously by injection in the thigh, the abdominal wall, the gluteal region or the deltoid region. Insulin suspensions are never to be administered intravenously.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Insulin suspensions are not to be used in insulin infusion pumps.

 For detailed user instructions, please refer to the package leaflet.  

Insulatard vial (100 international units/ml)

 Administration with a syringe

 Insulatard vials are for use with insulin syringes with a corresponding unit scale.

 Insulatard vial is accompanied by a package leaflet with detailed instructions for use to be followed. Insulatard Penfill

 Administration with an insulin delivery system

 Insulatard Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles.

 Insulatard Penfill is accompanied by a package leaflet with detailed instructions for use to be followed. Insulatard InnoLet

 Administration with InnoLet

 Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. InnoLet delivers 1-50 units in increments of 1 unit.
InnoLet delivers 1-50 units in increments of 1 unit.
Insulatard InnoLet is accompanied by a package leaflet with detailed instructions for use to be followed.

Section 4.8 includes minor editorial changes.

Sections 6.3, 6.4 and 6.5;
'(100 international units/ml)' now follows the subtitle 'Insulatard vial' i.e.  'Insulatard vial (100 international units/ml):'

Section 6.6: Text has been reworded:
Needles and syringes must not be shared.
Nedles and Insulatard Penfill must not be shared. The cartridge must not be refilled.
Needles and Insulatard InnoLet must not be shared. The cartridge must not be refilled.

 After removing Insulatard vial

,  Insulatard Penfill and Insulatard InnoLet cartridge or pre-filled pen from the refrigerator, it is recommended to allow the Insulatard vial, Insulatard Penfill and Insulatard InnoLet cartridge or pre-filled pen to reach room temperature before resuspending the insulin as instructed for first time use.

Do not use this medicinal product if you notice that the resuspended liquid is not uniformly white and cloudy.

 Insulatard which has been frozen must not be used.

The patient should be advised to discard the needle and syringe after each injection.

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

 Needels, syringes, cartridges and pre-filled- pens must not be shared.

 The cartridge must not be refilled.

 Section 8: Minor formatting changes.

Section 10: Date of revision updated to 03/2017

 1 pre-filled pen contains 3 ml equivalent to 300 international units. 1 ml suspension contains 100 international units isophane (NPH) insulin human* (equivalent to 3.5 mg).

4.2 Posology and method of administration
Method of administration
Insulatard is a human insulin with gradual onset and long duration of action.

 Insulatard is administered subcutaneously by injection in the thigh, the abdominal wall, the gluteal region or the deltoid region. Insulin suspensions are never to be administered intravenously.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the other injection sites. The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Insulin suspensions are not to be used in insulin infusion pumps.

 For detailed user instructions, please refer to the package leaflet.  

Insulatard vial (100 international units/ml)

 Administration with a syringe

 Insulatard vials are for use with insulin syringes with a corresponding unit scale.

 Insulatard vial is accompanied by a package leaflet with detailed instructions for use to be followed. Insulatard Penfill

 Administration with an insulin delivery system

 Insulatard Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles.

 Insulatard Penfill is accompanied by a package leaflet with detailed instructions for use to be followed. Insulatard InnoLet

 Administration with InnoLet

 Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. InnoLet delivers 1-50 units in increments of 1 unit.
InnoLet delivers 1-50 units in increments of 1 unit.
Insulatard InnoLet is accompanied by a package leaflet with detailed instructions for use to be followed.

Section 4.8 includes minor editorial changes.

Sections 6.3, 6.4 and 6.5;
'(100 international units/ml)' now follows the subtitle 'Insulatard vial' i.e.  'Insulatard vial (100 international units/ml):'

Section 6.6: Text has been reworded:
Needles and syringes must not be shared.
Nedles and Insulatard Penfill must not be shared. The cartridge must not be refilled.
Needles and Insulatard InnoLet must not be shared. The cartridge must not be refilled.

 After removing Insulatard vial

,  Insulatard Penfill and Insulatard InnoLet cartridge or pre-filled pen from the refrigerator, it is recommended to allow the Insulatard vial, Insulatard Penfill and Insulatard InnoLet cartridge or pre-filled pen to reach room temperature before resuspending the insulin as instructed for first time use.

Do not use this medicinal product if you notice that the resuspended liquid is not uniformly white and cloudy.

 Insulatard which has been frozen must not be used.

The patient should be advised to discard the needle and syringe after each injection.

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

 Needels, syringes, cartridges and pre-filled- pens must not be shared.

 The cartridge must not be refilled.

 Section 8: Minor formatting changes.

Section 10: Date of revision updated to 03/2017

The following are the only changes made to the SmPC:

4.2          Posology and method of administration

The following are the only changes made to the SmPC:

4.2          Posology and method of administration

1.            NAME OF THE MEDICINAL PRODUCT

Insulatard 100 international units/ml suspension for injection.

Insulatard Penfill 100 international units/ml suspension for injection in cartridge.

Insulatard InnoLet 100 international units/ml suspension for injection in pre-filled pen.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml suspension contains 100 international units isophane (NPH) insulin human* (equivalent to 3.5 mg).

1 vial contains 10 ml equivalent to 1,000 international units.

1 cartridge contains 3 ml equivalent to 300 international units.

1 pre-filled pen contains 3 ml equivalent to 300 international units.

*Human insulin is produced in Saccharomyces cerevisiae by recombinant DNA technology.

Excipient with known effect:

100 iu of Insulatard contains approximately 30 mcmol sodium, i.e. Insulatard contains less than 1 mmol sodium (23 mg) per dose, i.e. Insulatard and is therefore considered essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

…

4.         CLINICAL PARTICULARS

4.1       Therapeutic indications

Insulatard is indicated for tTreatment of diabetes mellitus.

4.2       Posology and method of administration

Posology

The potency of human insulin is expressed in international units (iu).

Insulatard dosing is individual and determined in accordance with the needs of the patient. The physician determines whether one or several daily injections are necessary. Insulatard may be used alone or mixed with fast-acting insulin. In intensive insulin therapy the suspension may be used as basal insulin (evening and/or morning injection) with fast-acting insulin given at meals. Blood glucose monitoring is recommended to achieve optimal glycaemic control.

The individual insulin requirement is usually between 0.3 and 1.0 international unit/kg/day. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production.

In patients with diabetes mellitus optimised glycaemic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended. Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Special populations

Elderly (≥ 65 years old)

Insulatard can be used in elderly patients.

As with all insulin medicinal products, iIn elderly patients, glucose monitoring should be intensified and the insulin dose adjusted on an individual basis.

Renal and hepatic impairment

Renal or hepatic impairment may reduce the patient’s insulin requirements.

As with all insulin medicinal products, iIn patients with renal or hepatic impairment, glucose monitoring should be intensified and the human insulin dose adjusted on an individual basis.

Paediatric population

Insulatard can be used in children and adolescents.

Transfer from other insulin medicinal products

When transferring from other intermediate or long-acting insulin medicinal products, adjustment of the Insulatard dose and timing of administration may be necessary.

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).

Method of administration

Insulatard is a long-acting human insulin.

Insulatard is administered subcutaneously by injection in the thigh, the abdominal wall, the gluteal region or the deltoid region. Insulin suspensions are never to be administered intravenously.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the other injection sites. As with all insulin medicinal products, tThe duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Insulin suspensions are not to be used in insulin infusion pumps.

Administration with a syringe

Insulatard vials are for use with insulin syringes with a corresponding unit scale.

Insulatard vial is accompanied by a package leaflet with detailed instructions for use to be followed.

Administration with an insulin delivery system

Insulatard Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles.

Insulatard Penfill is accompanied by a package leaflet with detailed instructions for use to be followed.

Administration with InnoLet

Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm.

InnoLet delivers 1-50 units in increments of 1 unit.

Insulatard InnoLet is accompanied by a package leaflet with detailed instructions for use to be followed.

…

4.4       Special warnings and precautions for use

Before travelling between different time zones, the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected, Insulatard must not be injected. After stabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.8 and 4.9).

Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin or human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dose. Patients transferred to Insulatard from another type of insulin may require an increased number of daily injections or a change in dose from that used with their usual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Injection site reactions

As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within a given area may help to reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Insulatard.

Combination of Insulatard 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 Insulatard 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 medicinal products are known to interact with glucose metabolism.

The following substances may reduce the patient’s insulin requirement:

Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphfonamides.

The following substances may increase the patient’s insulin requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

…

4.8       Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see Description of selected adverse reactionssection c below.

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur. These reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

b. Tabulated list of adverse reactions

The aAdverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: 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).

* see Description of selected adverse reactionssection c

c. Description of selected adverse reactions

Anaphylactic reactions:

The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulty in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.

Hypoglycaemia:

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentratingon, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

In clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens and level of glycaemic control.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduces the risk of developing these reactions.

d. Paediatric population

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the paediatric population do not indicate any differences to the broader experience in the general population.

e. Other special populations

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

…

6.1       List of excipients

Zinc chloride

Glycerol

Metacresol

Phenol

Disodium phosphate dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Protamine sulfphate

Water for injections

…

6.3       Shelf life

Before opening: 30 months.

Insulatard vial:

During use or when carried as a spare: The product canmust be stored for a maximum of 6 weeks. Store below 25°C.

Insulatard Penfill and Insulatard InnoLet:

During use or when carried as a spare: The product can must be stored for a maximum of 6 weeks. Store below 30°C.

…

6.5       Nature and contents of container

Insulatard vial:

10 ml suspension in vVial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and a protective tamper-proof plastic cap containing 10 ml of suspension.

Pack sizes of 1 and 5 vials of 10 ml or a multipack of 5 packs of 1 x 10 ml vial.

Not all pack sizes may be marketed.

Insulatard Penfill:

3 ml suspension in cCartridge (type 1 glass) with a plunger (bromobutyl) and a rubber stopperclosure (bromobutyl/polyisoprene) containing 3 ml of suspension. The cartridge contains a glass ball to facilitate resuspension.

Pack sizes of 1, 5 and 10 cartridges.

Not all pack sizes may be marketed.

Insulatard InnoLet:

3 ml suspension in cCartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper (bromobutyl/polyisoprene) containing 3 ml of suspensioned in a pre-filled multidose disposable pen made of polypropylene. The cartridge contains a glass ball to facilitate resuspension.

Pack sizes of 1, 5 and 10 pre-filled pens.

Not all pack sizes may be marketed.

…

8.         MARKETING AUTHORISATION NUMBERS

Insulatard 100 international unitsIU/ml                  EU/1/02/233/003; EU/1/02/233/004; EU/1/02/233/017

Insulatard Penfill 100 IUinternational units/ml       EU/1/02/233/006; EU/1/02/233/005; EU/1/02/233/007

Insulatard InnoLet 100 international unitsIU/ml   EU/1/02/233/011; EU/1/02/233/010; EU/1/02/233/012

…

10.       DATE OF REVISION OF THE TEXT

11/201206/2014

1.            NAME OF THE MEDICINAL PRODUCT

Insulatard 100 international units/ml suspension for injection.

Insulatard Penfill 100 international units/ml suspension for injection in cartridge.

Insulatard InnoLet 100 international units/ml suspension for injection in pre-filled pen.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml suspension contains 100 international units isophane (NPH) insulin human* (equivalent to 3.5 mg).

1 vial contains 10 ml equivalent to 1,000 international units.

1 cartridge contains 3 ml equivalent to 300 international units.

1 pre-filled pen contains 3 ml equivalent to 300 international units.

*Human insulin is produced in Saccharomyces cerevisiae by recombinant DNA technology.

Excipient with known effect:

100 iu of Insulatard contains approximately 30 mcmol sodium, i.e. Insulatard contains less than 1 mmol sodium (23 mg) per dose, i.e. Insulatard and is therefore considered essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

…

4.         CLINICAL PARTICULARS

4.1       Therapeutic indications

Insulatard is indicated for tTreatment of diabetes mellitus.

4.2       Posology and method of administration

Posology

The potency of human insulin is expressed in international units (iu).

Insulatard dosing is individual and determined in accordance with the needs of the patient. The physician determines whether one or several daily injections are necessary. Insulatard may be used alone or mixed with fast-acting insulin. In intensive insulin therapy the suspension may be used as basal insulin (evening and/or morning injection) with fast-acting insulin given at meals. Blood glucose monitoring is recommended to achieve optimal glycaemic control.

The individual insulin requirement is usually between 0.3 and 1.0 international unit/kg/day. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production.

In patients with diabetes mellitus optimised glycaemic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended. Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Special populations

Elderly (≥ 65 years old)

Insulatard can be used in elderly patients.

As with all insulin medicinal products, iIn elderly patients, glucose monitoring should be intensified and the insulin dose adjusted on an individual basis.

Renal and hepatic impairment

Renal or hepatic impairment may reduce the patient’s insulin requirements.

As with all insulin medicinal products, iIn patients with renal or hepatic impairment, glucose monitoring should be intensified and the human insulin dose adjusted on an individual basis.

Paediatric population

Insulatard can be used in children and adolescents.

Transfer from other insulin medicinal products

When transferring from other intermediate or long-acting insulin medicinal products, adjustment of the Insulatard dose and timing of administration may be necessary.

Close glucose monitoring is recommended during the transfer and in the initial weeks thereafter (see section 4.4).

Method of administration

Insulatard is a long-acting human insulin.

Insulatard is administered subcutaneously by injection in the thigh, the abdominal wall, the gluteal region or the deltoid region. Insulin suspensions are never to be administered intravenously.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy. Subcutaneous injection into the thigh results in a slower and less variable absorption compared to the other injection sites. As with all insulin medicinal products, tThe duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Insulin suspensions are not to be used in insulin infusion pumps.

Administration with a syringe

Insulatard vials are for use with insulin syringes with a corresponding unit scale.

Insulatard vial is accompanied by a package leaflet with detailed instructions for use to be followed.

Administration with an insulin delivery system

Insulatard Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles.

Insulatard Penfill is accompanied by a package leaflet with detailed instructions for use to be followed.

Administration with InnoLet

Insulatard InnoLet is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm.

InnoLet delivers 1-50 units in increments of 1 unit.

Insulatard InnoLet is accompanied by a package leaflet with detailed instructions for use to be followed.

…

4.4       Special warnings and precautions for use

Before travelling between different time zones, the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times.

Hyperglycaemia

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected, Insulatard must not be injected. After stabilisation of the patient’s blood glucose, adjustment of the dose should be considered (see sections 4.8 and 4.9).

Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.

Transfer from other insulin medicinal products

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal insulin, human insulin or human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dose. Patients transferred to Insulatard from another type of insulin may require an increased number of daily injections or a change in dose from that used with their usual insulin medicinal products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Injection site reactions

As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. Continuous rotation of the injection site within a given area may help to reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Insulatard.

Combination of Insulatard 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 Insulatard 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 medicinal products are known to interact with glucose metabolism.

The following substances may reduce the patient’s insulin requirement:

Oral antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphfonamides.

The following substances may increase the patient’s insulin requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

…

4.8       Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, please see Description of selected adverse reactionssection c below.

At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur. These reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

b. Tabulated list of adverse reactions

The aAdverse reactions listed below are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: 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).

* see Description of selected adverse reactionssection c

c. Description of selected adverse reactions

Anaphylactic reactions:

The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulty in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.

Hypoglycaemia:

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentratingon, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

In clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens and level of glycaemic control.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduces the risk of developing these reactions.

d. Paediatric population

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in the paediatric population do not indicate any differences to the broader experience in the general population.

e. Other special populations

Based on post-marketing sources and clinical trials, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

…

6.1       List of excipients

Zinc chloride

Glycerol

Metacresol

Phenol

Disodium phosphate dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Protamine sulfphate

Water for injections

…

6.3       Shelf life

Before opening: 30 months.

Insulatard vial:

During use or when carried as a spare: The product canmust be stored for a maximum of 6 weeks. Store below 25°C.

Insulatard Penfill and Insulatard InnoLet:

During use or when carried as a spare: The product can must be stored for a maximum of 6 weeks. Store below 30°C.

…

6.5       Nature and contents of container

Insulatard vial:

10 ml suspension in vVial (type 1 glass) closed with a disc (bromobutyl/polyisoprene rubber) and a protective tamper-proof plastic cap containing 10 ml of suspension.

Pack sizes of 1 and 5 vials of 10 ml or a multipack of 5 packs of 1 x 10 ml vial.

Not all pack sizes may be marketed.

Insulatard Penfill:

3 ml suspension in cCartridge (type 1 glass) with a plunger (bromobutyl) and a rubber stopperclosure (bromobutyl/polyisoprene) containing 3 ml of suspension. The cartridge contains a glass ball to facilitate resuspension.

Pack sizes of 1, 5 and 10 cartridges.

Not all pack sizes may be marketed.

Insulatard InnoLet:

3 ml suspension in cCartridge (type 1 glass) with a plunger (bromobutyl) and a rubber closurestopper (bromobutyl/polyisoprene) containing 3 ml of suspensioned in a pre-filled multidose disposable pen made of polypropylene. The cartridge contains a glass ball to facilitate resuspension.

Pack sizes of 1, 5 and 10 pre-filled pens.

Not all pack sizes may be marketed.

…

8.         MARKETING AUTHORISATION NUMBERS

Insulatard 100 international unitsIU/ml                  EU/1/02/233/003; EU/1/02/233/004; EU/1/02/233/017

Insulatard Penfill 100 IUinternational units/ml       EU/1/02/233/006; EU/1/02/233/005; EU/1/02/233/007

Insulatard InnoLet 100 international unitsIU/ml   EU/1/02/233/011; EU/1/02/233/010; EU/1/02/233/012

…

10.       DATE OF REVISION OF THE TEXT

11/201206/2014

Lipodystrophy: The purpose is to update the wording on lipodystrophy to make the information more legible for healthcare professionals. The following sections have been updated: SmPC section 4.2 (Method of administration), SmPC section 4.8 (Undesirable effects).

Section 4.2

Injection sites should always be rotated within an anatomic the same region in order to avoid reduce the risk of lipodystrophy.

Section 4.8

Skin and subcutaneous tissue disorders

Uncommon - Lipodystrophy

Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduce the risk of developing these reactions.

Concomitant illness: New information has been added about ‘concomitant illness’ in SmPC section 4.4 (Special warnings and precautions for use).

Section 4.4

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

Hypoglycaemia: Hypoglycaemia has been removed from section 4.3 (Contraindications) to section 4.4 (Special warnings and precautions for use) as it is considered inadvisable to state hypoglycaemia as a contraindication due to the risk of patients believing that they should not administer insulin if they at some point have experienced an event of hypoglycaemia.

Section 4.4

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected <Insulatard/Actrapid> must not be injected. After stabilisation of patient’s blood glucose adjustment of the dose should be considered (see sections 4.8 and 4.9).

Alcohol: ‘alcohol’ is removed from section 4.5.

Section 4.5

The following substances may reduce the patient’s insulin requirement:

Oral antidiabetic medicinal products, hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blockersing agents, angiotensin converting enzyme (ACE) inhibitors, salicylates,  alcohol, anabolic steroids and sulphonamides.

Elderly and children: Sections 4.2, 4.6 and 4.8 have been updated to reflect legislation on the elderly and children, and the EU SmPC guideline.

The remainder of the changes to the other changes are due to readability and harmonisation with the current QRD (SmPC) template.

Lipodystrophy: The purpose is to update the wording on lipodystrophy to make the information more legible for healthcare professionals. The following sections have been updated: SmPC section 4.2 (Method of administration), SmPC section 4.8 (Undesirable effects).

Section 4.2

Injection sites should always be rotated within an anatomic the same region in order to avoid reduce the risk of lipodystrophy.

Section 4.8

Skin and subcutaneous tissue disorders

Uncommon - Lipodystrophy

Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

Lipodystrophy:

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduce the risk of developing these reactions.

Concomitant illness: New information has been added about ‘concomitant illness’ in SmPC section 4.4 (Special warnings and precautions for use).

Section 4.4

Concomitant illness, especially infections and feverish conditions, usually increases the patient’s insulin requirement. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

Hypoglycaemia: Hypoglycaemia has been removed from section 4.3 (Contraindications) to section 4.4 (Special warnings and precautions for use) as it is considered inadvisable to state hypoglycaemia as a contraindication due to the risk of patients believing that they should not administer insulin if they at some point have experienced an event of hypoglycaemia.

Section 4.4

Hypoglycaemia

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. In case of hypoglycaemia or if hypoglycaemia is suspected <Insulatard/Actrapid> must not be injected. After stabilisation of patient’s blood glucose adjustment of the dose should be considered (see sections 4.8 and 4.9).

Alcohol: ‘alcohol’ is removed from section 4.5.

Section 4.5

The following substances may reduce the patient’s insulin requirement:

Oral antidiabetic medicinal products, hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blockersing agents, angiotensin converting enzyme (ACE) inhibitors, salicylates,  alcohol, anabolic steroids and sulphonamides.

Elderly and children: Sections 4.2, 4.6 and 4.8 have been updated to reflect legislation on the elderly and children, and the EU SmPC guideline.

The remainder of the changes to the other changes are due to readability and harmonisation with the current QRD (SmPC) template.

a pre-filled pen designed to be used with NovoFine or NovoTwist disposable short cap needles up to a length of 8 mm. or shorter in length. The needle box is marked with an S.

InnoLet delivers 1-50 units in increments of 1 unit.

The patient should be advised not to use any counterfeit needles.

a pre-filled pen designed to be used with NovoFine or NovoTwist disposable short cap needles up to a length of 8 mm. or shorter in length. The needle box is marked with an S.

InnoLet delivers 1-50 units in increments of 1 unit.

The patient should be advised not to use any counterfeit needles.

In 4.4     Special warnings and precautions for use the addtion of the following paragraph,

 

Combination of Insulatard 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 Insulatard 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.

Date of revision of text
02/2011

In 4.4     Special warnings and precautions for use the addtion of the following paragraph,

 

Combination of Insulatard 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 Insulatard 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.

Date of revision of text
02/2011

4.4 Special warnings and precautions for use

Inclusion of standard text concerning injection site reactions has been added:

"As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, swelling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Insulatard"

4.5 Interaction with other medicinal products and other forms of interaction

Anabolic steroids and sulphonamides have been added to the list of substances which may reduce insulin requirements. Oral contraceptives have been added to the list of substances which may increase insulin requirements. These changes are to ensure consistency with the corresponding section in the SPCs for analogue insulins.

4.8 Undesirable effects

The following information has been inserted
"including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness"

5.3 Pharmacokinetic properties
Preclinical has been changed to "Non-clinical"

6.1 List of excipients
"for pH adjustment"  has been added for sodium hydroxide

6.2 Incompatibilities

Addition of standard statement that insulin should only be added to compounds with which it is known to be compatible

6.3 Shelf life

"when stored between 2C-8C" has been added to the shelf life of 30 months.

¡°Insulatard:¡± heading inserted.
¡°After first opening¡± has been deleted

Additional sentence included ¡°when used or stored at room temperature (below 25¢ªC)¡± has been added to the shelf life of 6 weeks.

¡°Insulatard Penfill and Insulatard InnoLet:¡± heading inserted
¡°6 weeks when used or carried as a spare (below 30¢ªC)¡± additional sentence

6.4 Special precautions for storage

There have been a number of editorial changes to these sections, generally to standardise the statements. There have been no changes to the actual shelf life or storage conditions.

¡°Before use¡± has been added in front of: ¡°Store in a refrigerator (2¡ÆC - 8¡ÆC)¡±.
This sentence has been added ¡°Do not store them in or too near the freezer section or cooling element¡±.

Insulatard:
Deleted: ¡°Keep the vial in the outer carton in order to protect from light.¡±

Inserted : ¡°Keep the vial in the outer carton in order to protect from light.
Protect from excessive heat and sunlight¡± has been inserted

Insulatard Penfill:
Deleted: ¡°Keep the cartridge in the outer carton in order to protect from light¡± has been deleted.
Inserted: ¡°Keep the cartridge in the outer carton in order to protect from light.
Protect from excessive heat and sunlight¡± has been inserted.

These sentences have been added:

¡°After removing Insulatard, Insulatard Penfill or Insulatard InnoLet from the refrigerator it is recommended to allow the vial, Penfill or InnoLet to reach room temperature (not above 25¢ªC) before resuspending the insulin as instructed for first time use.¡±.

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

9. Date of first authorisation/renewal of the authorisation

Date of last renewal: 18 October 2007

10. Date of revision of the text

09/2007

4.4 Special warnings and precautions for use

Inclusion of standard text concerning injection site reactions has been added:

"As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, swelling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Insulatard"

4.5 Interaction with other medicinal products and other forms of interaction

Anabolic steroids and sulphonamides have been added to the list of substances which may reduce insulin requirements. Oral contraceptives have been added to the list of substances which may increase insulin requirements. These changes are to ensure consistency with the corresponding section in the SPCs for analogue insulins.

4.8 Undesirable effects

The following information has been inserted
"including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness"

5.3 Pharmacokinetic properties
Preclinical has been changed to "Non-clinical"

6.1 List of excipients
"for pH adjustment"  has been added for sodium hydroxide

6.2 Incompatibilities

Addition of standard statement that insulin should only be added to compounds with which it is known to be compatible

6.3 Shelf life

"when stored between 2C-8C" has been added to the shelf life of 30 months.

¡°Insulatard:¡± heading inserted.
¡°After first opening¡± has been deleted

Additional sentence included ¡°when used or stored at room temperature (below 25¢ªC)¡± has been added to the shelf life of 6 weeks.

¡°Insulatard Penfill and Insulatard InnoLet:¡± heading inserted
¡°6 weeks when used or carried as a spare (below 30¢ªC)¡± additional sentence

6.4 Special precautions for storage

There have been a number of editorial changes to these sections, generally to standardise the statements. There have been no changes to the actual shelf life or storage conditions.

¡°Before use¡± has been added in front of: ¡°Store in a refrigerator (2¡ÆC - 8¡ÆC)¡±.
This sentence has been added ¡°Do not store them in or too near the freezer section or cooling element¡±.

Insulatard:
Deleted: ¡°Keep the vial in the outer carton in order to protect from light.¡±

Inserted : ¡°Keep the vial in the outer carton in order to protect from light.
Protect from excessive heat and sunlight¡± has been inserted

Insulatard Penfill:
Deleted: ¡°Keep the cartridge in the outer carton in order to protect from light¡± has been deleted.
Inserted: ¡°Keep the cartridge in the outer carton in order to protect from light.
Protect from excessive heat and sunlight¡± has been inserted.

These sentences have been added:

¡°After removing Insulatard, Insulatard Penfill or Insulatard InnoLet from the refrigerator it is recommended to allow the vial, Penfill or InnoLet to reach room temperature (not above 25¢ªC) before resuspending the insulin as instructed for first time use.¡±.

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

9. Date of first authorisation/renewal of the authorisation

Date of last renewal: 18 October 2007

10. Date of revision of the text

09/2007