annex i summary of product characteristicsec.europa.eu/health/documents/community-register/... ·...

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Protaphane 40 IU/mlSuspension for injection in a vial

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae).

1 ml contains 40 IU of insulin human1 vial contains 10 ml equivalent to 400 IU

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

Protaphane is a suspension of isophane (NPH) insulin.

For excipients, see 6.1 List of excipients.

3. PHARMACEUTICAL FORM

Suspension for injection in a vial.

Protaphane is a cloudy, white, aqueous suspension.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of diabetes mellitus.

4.2 Posology and method of administration

Protaphane is a long-acting insulin.

DosageDosage is individual and determined by the physician in accordance with the needs of the patient.The average range of total daily insulin requirement for maintenance therapy in type 1 diabeticpatients lies between 0.5 and 1.0 IU/kg. In pre-pubertal children it usually varies from 0.7 to1.0 IU/kg. .During the period of partial remission,, the insulin requirements can be much lower,whereas in insulin resistant states, e.g. during puberty or due to obesity, the daily insulin requirementmay be substantially higher.

Initial dosages for type 2 diabetic patients are often lower, e.g. 0.3 to 0.6 IU/kg/day.

The physician determines whether one or several daily injections are necessary. Protaphane may beused alone or mixed with fast-acting insulin. In intensive insulin therapy the suspension may be usedas basal insulin (evening and/or morning injection) with fast-acting insulin given at meals.

In patients with diabetes mellitus optimised glycaemic control delays the onset and slows theprogression of late diabetic complications. Blood glucose monitoring is therefore recommended.

Dosage adjustmentConcomitant illness, especially infections and feverish conditions, usually increases the patient'sinsulin requirement.

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Renal or hepatic impairment may reduce insulin requirement.

Adjustment of dosage may also be necessary if patients change physical activity or their usual diet.Dosage adjustment may be necessary when transferring patients from one insulin preparation toanother (see section 4.4 Special warnings and special precautions for use).

AdministrationFor subcutaneous use.

Protaphane is usually administered subcutaneously in the thigh. If convenient, the abdominal wall, thegluteal region or the deltoid region may also be used.

Subcutaneous injection into the thigh results in a slower and less variable absorption compared to theother injection sites.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.Keep the needle under the skin for at least 6 seconds to make sure the entire dose is injected.Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.

Insulin suspensions are never to be administered intravenously.

Protaphane is accompanied by a package leaflet with detailed instruction for use to be followed.

The vials are for use with insulin syringes with a corresponding unit scale. When two types of insulinare mixed, draw the amount of fast-acting insulin first, followed by the amount of long-acting insulin.

4.3 Contraindications

HypoglycaemiaHypersensitivity to human insulin or to any of the excipients (see section 6.1 List of excipients).

4.4 Special warnings and special precautions for use

Inadequate dosage or discontinuation of treatment, especially in type 1 diabetes, may lead tohyperglycaemia and diabetic ketoacidosis.Usually the first symptoms of hyperglycaemia set in gradually, over a period of hours or days. Theyinclude thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, drymouth, loss of appetite as well as acetone odour of breath (see section 4.8 Undesirable effects).In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which ispotentially lethal.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versusanimal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.A few patients who have experienced hypoglycaemic reactions after transfer from animal source

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insulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.

Before travelling between different time zones, the patient should be advised to consult the doctor,since this may mean that the patient has to take insulin and meals at different times.

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

Protaphane contains metacresol, which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

A number of medicinal products are known to interact with the glucose metabolism. The physicianmust therefore take possible interactions into account and should always ask their patients about anymedicinal products they take.

The following substances may reduce insulin requirement:Oral hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates and alcohol.

The following substances may increase insulin requirement:Thiazides, glucocorticoids, thyroid hormones and beta-sympathomimetics, growth hormoneanddanazol.

Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery fromhypoglycaemia.

Octreotide/lanreotide may both decrease and increase insulin requirement.

Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

4.6 Pregnancy and lactation

There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does notpass the placental barrier.

Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetestherapy, increase the risk of malformations and death in utero. Intensified control in the treatment ofpregnant women with diabetes is therefore recommended throughout pregnancy and whencontemplating pregnancy.Insulin requirements usually fall in the first trimester and increase subsequently during the second andthird trimesters.After delivery, insulin requirements return rapidly to pre-pregnancy values.

Insulin treatment of the nursing mother presents no risk to the baby. However, the Protaphane dosagemay need to be adjusted.

4.7 Effects on ability to drive and use machines

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

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4.8 Undesirable effects

The most often seen undesirable effect in insulin-treated patients is a change in blood glucose levels.From clinical investigations it is known that major hypoglycaemia, defined as need for assistancein treatment, occurs in approximately 20% of well-controlled patients. Based on post-marketingexperience adverse drug reactions including hypoglycaemia have been reported rarely (>1/10,000<1/1,000). The listings below are all based on post-marketing experience and is subject tounderreporting and should be interpreted in that light.

Metabolism and nutrition disorders

Rare(>1/10,000 <1/1,000)Change in bloodglucose

Hypoglycaemia:Symptoms of hypoglycaemia usually occur suddenly. They may includecold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness,unusual tiredness or weakness, confusion, difficulty in concentration,drowsiness, excessive hunger, vision changes, headache, nausea andpalpitation. Severe hypoglycaemia may lead to unconsciousness and/orconvulsions and may result in temporary or permanent impairment ofbrain function or even death.

Hyperglycaemia:Usually the first symptoms of hyperglycaemia set in gradually, over aperiod of hours or days. They include thirst, increased frequency ofurination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, lossof appetite as well as acetone odour of breath.In type 1 diabetes, untreated hyperglycaemic events eventually lead todiabetic ketoacidosis which is potentially lethal.For precautions see section 4.4 Special warnings and special precautionsfor use.

Eye disorders

Very rare(<1/10,000)

Refraction anomalies may occur upon initiation of insulin therapy. Thesesymptoms are usually of transitory nature.

General disorders and administration site conditions


Local hypersensitivity reactions (redness, swelling and itching at theinjection site) may occur during treatment with insulin. These reactionsare usually transitory and normally they disappear during continuedtreatment.


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


Symptoms of generalised hypersensitivity may include generalised skinrash, itching, sweating, gastrointestinal upset, angioneurotic oedema,difficulties in breathing, palpitation and reduction in blood pressure.Generalised hypersensitivity reactions are potentially life threatening.

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Oedema may occur upon initiation of insulin therapy. These symptoms areusually of transitory nature.

4.9 Overdose

A specific overdose of insulin cannot be defined. However, hypoglycaemia may develop oversequential stages:� Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary

products. It is therefore recommended that the diabetic patient constantly carries some sugarlumps, sweets, biscuits or sugary fruit juice

� Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated byglucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a person who has receivedappropriate instruction, or by glucose given intravenously by a medical professional. Glucosemust also be given intravenously, if the patient does not respond to glucagon within 10 to 15minutes.Upon regaining consciousness, administration of oral carbohydrate is recommended for thepatient in order to prevent relapse.After an injection of glucagon, the patient should be monitored in a hospital in order to find thereason for this severe hypoglycaemia and prevent other similar episodes.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antidiabetic agent. ATC code: A10A C01.

The blood glucose lowering effect of insulin is due to the facilitated uptake of glucose followingbinding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucoseoutput from the liver.

Protaphane is a long-acting insulin.Onset of action is within 1½ hours, reaches a maximum effect within 4-12 hours and the entire time ofduration is approximately 24 hours.

5.2 Pharmacokinetic properties

Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of aninsulin preparation is determined solely by its absorption characteristics.

This process is influenced by several factors (e.g. insulin dosage, injection route and site, thickness ofsubcutaneous fat, type of diabetes). The pharmacokinetics of insulins is therefore affected bysignificant intra- and inter-individual variation.

AbsorptionThe maximum plasma concentration of the insulin is reached within 2-18 hours after subcutaneousadministration.

DistributionNo profound binding to plasma proteins, except circulating insulin antibodies (if present) has beenobserved.

MetabolismHuman insulin is reported to be degraded by insulin protease or insulin-degrading enzymes andpossibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the human insulinmolecule have been proposed; none of the metabolites formed following the cleavage are active.

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EliminationThe terminal half-life is determined by the rate of absorption from the subcutaneous tissue. Theterminal half-life (t½) is therefore a measure of the absorption rather than of the elimination per se ofinsulin from plasma (insulin in the blood stream has a t½ of a few minutes). Trials have indicated a t½of about 5-10 hours.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Zinc chlorideGlycerolMetacresolPhenolDisodium phosphate dihydrateSodium hydroxide or/and hydrochloric acid (for pH adjustment)Protamine sulphateWater for injections

6.2 Incompatibilities

Insulin suspensions should not be added to infusion fluids.Medicinal products added to the insulin suspension may cause degradation of the insulin, e.g. if themedicinal products contain thiols or sulphites.

6.3 Shelf life

30 months.

After first opening: 4 weeks.

6.4 Special precautions for storage

Store at 2°C - 8°C (in a refrigerator) not near a freezing compartment.Do not freeze.Keep the container in the outer carton in order to protect from light.

During use: do not refrigerate. Do not store above 25°C.

Protect from excessive heat and sunlight.

6.5 Nature and contents of container

Glass vial (type 1) closed with a bromobutyl/polyisoprene rubber stopper and a protective tamperproofplastic cap.Pack sizes: 1 and 5 vials x 10 ml.Not all pack sizes may be marketed.

6.6 Instructions for use and handling

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Insulin preparations, which have been frozen, must not be used.Insulin suspensions should not be used if they do not appear uniformly white and cloudy after re-suspension.

7. MARKETING AUTHORISATION HOLDER

Novo Nordisk A/S Novo AlléDK-2880 BagsværdDenmark

8. MARKETING AUTHORISATION NUMBERS

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

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Protaphane 100 IU/mlSuspension for injection in a vial



1 ml contains 100 IU of insulin human1 vial contains 10 ml equivalent to 1000 IU





Suspension for injection in a vial.












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The vials are for use with insulin syringes with a corresponding unit scale. When two types of insulinare mixed, draw the amount of fast-acting insulin first, followed by the amount of long-acting insulin.





Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versusanimal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.A few patients who have experienced hypoglycaemic reactions after transfer from animal source

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insulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.
















The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. .This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

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Eye disorders










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4.9 Overdose















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6.3 Shelf life

30 months.







Glass vial (type 1) closed with a bromobutyl/polyisoprene rubber stopper and a protective tamperproofplastic cap.Pack sizes: 1 and 5 vials x 10 ml.Not all pack sizes may be marketed.


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Protaphane Penfill 100 IU/mlSuspension for injection in a cartridge



1 ml contains 100 IU of insulin human1 cartridge contains 3 ml equivalent to 300 IU





Suspension for injection in cartridge.












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The cartridges are designed to be used with Novo Nordisk delivery systems (durable devices forrepeated use) and NovoFine needles. Detailed instruction accompanying the delivery system must befollowed.





Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versusanimal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.

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A few patients who have experienced hypoglycaemic reactions after transfer from animal sourceinsulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.

















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Eye disorders










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4.9 Overdose














MetabolismHuman insulin is reported to be degraded by insulin protease or insulin-degrading enzymes and

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possibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the human insulinmolecule have been proposed; none of the metabolites formed following the cleavage are active.









6.3 Shelf life

30 months.






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Glass cartridge (type 1) with a bromobutyl rubber plunger and a bromobutyl/polyisoprene rubberstopper. The cartridge contains a glass ball to facilitate the re-suspension.Pack sizes: 1, 5 and 10 cartridges x 3 ml.Not all pack sizes may be marketed.


Cartridges should only be used in combination with products that are compatible with them and allowthe cartridge to function safely and effectively.

Protaphane Penfill is for single person use only. The container must not be refilled.







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Protaphane NovoLet 100 IU/mlSuspension for injection in a pre-filled pen



1 ml contains 100 IU of insulin human1 pre-filled pen contains 3 ml equivalent to 300 IU





Suspension for injection in a pre-filled pen.












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Protaphane NovoLet is designed to be used with NovoFine needles.NovoLet delivers 2-78 units in increments of 2 units.

The pens should be primed before injection so that the dose selector returns to zero and a drop ofinsulin appears at the needle top.The dose is set by turning the selector, which returns to zero during the injection.





Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versus

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animal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.A few patients who have experienced hypoglycaemic reactions after transfer from animal sourceinsulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.
















The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is

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particularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.







Eye disorders









Symptoms of generalised hypersensitivity may include generalised skinrash, itching, sweating, gastrointestinal upset, angioneurotic oedema,

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difficulties in breathing, palpitation and reduction in blood pressure.Generalised hypersensitivity reactions are potentially life threatening.



4.9 Overdose














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6.3 Shelf life

30 months.



Store at 2°C - 8°C (in a refrigerator) not near a freezing compartment.Do not freeze.

During use: do not refrigerate. Do not store above 30°C.Keep the pen cap on in order to protect the insulin from light.



Pre-filled pen (multidose disposable pen) comprising a pen injector with a cartridge (3 ml). Thecartridge is made of glass (type 1), containing a bromobutyl rubber plunger and a

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bromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension. The pen injector is made of plastic.Pack sizes: 5 and 10 pre-filled pens x 3 ml.Not all pack sizes may be marketed.


Pens should only be used in combination with products that are compatible with them and allow thepens to function safely and effectively.

Protaphane NovoLet is for single person use only. The container must not be refilled.







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Protaphane InnoLet 100 IU/mlSuspension for injection in a pre-filled pen




















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Protaphane InnoLet is designed to be used with NovoFine short cap needles of 8 mm or shorter inlength. The needle box is marked with an S.InnoLet delivers 1-50 units in increments of 1 unit.The pens should be primed before injection so that the dose selector returns to zero and a drop ofinsulin appears at the needle top.The dose is set by turning the selector, which returns to zero during the injection.





Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versus

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animal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.A few patients who have experienced hypoglycaemic reactions after transfer from animal sourceinsulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.
















The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car oroperating machinery).Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is

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particularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.







Eye disorders









Symptoms of generalised hypersensitivity may include generalised skinrash, itching, sweating, gastrointestinal upset, angioneurotic oedema,

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difficulties in breathing, palpitation and reduction in blood pressure.Generalised hypersensitivity reactions are potentially life threatening.



4.9 Overdose














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6.3 Shelf life

30 months.







Pre-filled pen (multidose disposable pen) comprising a pen injector with a cartridge (3 ml). Thecartridge is made of glass (type 1), containing a bromobutyl rubber plunger and a

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bromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension. The pen injector is made of plastic.Pack sizes: 1, 5 and 10 pre-filled pens x 3 ml.Not all pack sizes may be marketed.



Protaphane InnoLet is for single person use only. The container must not be refilled.







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Protaphane FlexPen 100 IU/mlSuspension for injection in a pre-filled pen




















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Protaphane FlexPen is designed to be used with NovoFine short cap needles of 8 mm or shorter inlength. The needle box is marked with an S.FlexPen delivers 1-60 units in increments of 1 unit.

The pens should be primed before injection so that the dose selector returns to zero and a drop ofinsulin appears at the needle top.The dose is set by turning the selector, which returns to zero during the injection.





Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be able totake action immediately, patients should carry glucose with them at all times.Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, mayexperience a change in their usual warning symptoms of hypoglycaemia and should be advisedaccordingly (see section 4.8 Undesirable effects).Usual warning symptoms may disappear in patients with longstanding diabetes.Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.),

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species (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versusanimal source insulin) may result in a change in dosage.If an adjustment is needed when switching the patients to Protaphane, it may occur with the first doseor during the first several weeks or months.A few patients who have experienced hypoglycaemic reactions after transfer from animal sourceinsulin have reported that early warning symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previous insulin.















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Eye disorders






41







4.9 Overdose












Absorption

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The maximum plasma concentration of the insulin is reached within 2-18 hours after subcutaneousadministration.











6.3 Shelf life

30 months.





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Pre-filled pen (multidose disposable pen) comprising a pen injector with a cartridge (3 ml). Thecartridge is made of glass (type 1), containing a bromobutyl rubber plunger and abromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension. The pen injector is made of plastic.Pack sizes: 1, 5 and 10 pre-filled pens x 3 ml.Not all pack sizes may be marketed.



Protaphane FlexPen is for single person use only. The container must not be refilled.







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ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVESUBSTANCE AND MANUFACTURING AUTHORISATIONHOLDERS RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

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A MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCHRELEASE

Name and address of the manufacturer of the biological active substance Novo Nordisk A/S Novo Allé DK-2880 Bagsvaerd Denmark Name and address of the manufacturers responsible for batch release Protaphane, Protaphane NovoLet, Protaphane InnoLet, Protaphane FlexPenNovo Nordisk A/SNovo AlléDK-2880 BagsvaerdDenmark

Protaphane PenfillNovo Nordisk A/SNovo AlléDK-2880 BagsvaerdDenmarkNovo Nordisk Pharmaceutique S.A.45 Avenue d’OrléansF-28002 ChartresFrance The printed package leaflet of the medicinal product must state the name and address of themanufacturer responsible for the release of the concerned batch B CONDITIONS OF THE MARKETING AUTHORISATION

� CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ONTHE MARKETING AUTHORISATION HOLDER

Medicinal product subject to medical prescription � OTHER CONDITIONS

The holder of this marketing authorisation must inform the European Commission about the marketingplans for the medicinal product authorised by this decision.

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NOOUTER PACKAGING, ON THE IMMEDIATE PACKAGING

OUTER CARTON


Protaphane 40 IU/mlSuspension for injection in a vialInsulin human, rDNA

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml suspension contains 40 IU (1.4 mg) of insulin human, rDNA

3. LIST OF EXCIPIENTS

zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate, sodium hydroxide,hydrochloric acid, protamine sulphate and water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

1 vial of 10 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous useResuspend according to instructionsRead package leaflet before use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUTOF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

ExpiryDuring use: use within 4 weeks

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9. SPECIAL STORAGE CONDITIONS

Store at 2�C - 8�C (in a refrigerator)Do not freezeKeep the container in the outer cartonDuring use: do not refrigerate or store above 25�C

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTSOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IFAPPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Novo Nordisk A/SDK-2880 BagsværdDenmark


EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch:

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

50


OUTER CARTON








5 vials of 10 ml






8. EXPIRY DATE


51







EU/0/00/000/000


Batch:




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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Protaphane 40 IU/mlSuspension for injectionInsulin human, rDNA

2. METHOD OF ADMINISTRATION

SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 ml

53


OUTER CARTON








1 vial of 10 ml






8. EXPIRY DATE


54







EU/0/00/000/000


Batch:




55


OUTER CARTON








5 vials of 10 ml






8. EXPIRY DATE


56







EU/0/00/000/000


Batch:




57


LABEL


Protaphane 100 IU/mlSuspension for injectionInsulin human, rDNA


SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:


10 ml

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OUTER CARTON


Protaphane Penfill 100 IU/mlSuspension for injection in a cartridgeInsulin human, rDNA






1 cartridge of 3 ml


Subcutaneous usePenfill cartridges for use with Novo Nordisk insulin devicesResuspend according to instructionsRead package leaflet before useProtaphane Penfill is for use by one person only




8. EXPIRY DATE


59







EU/0/00/000/000


Batch:




60


OUTER CARTON








5 cartridges of 3 ml






8. EXPIRY DATE


61







EU/0/00/000/000


Batch:




62


OUTER CARTON








10 cartridges of 3 ml






8. EXPIRY DATE


63







EU/0/00/000/000


Batch:




64


LABEL


Protaphane Penfill 100 IU/mlSuspension for injectionInsulin human, rDNA


SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:


3 ml

65


OUTER CARTON


Protaphane NovoLet 100 IU/mlSuspension for injection in a pre-filled penInsulin human, rDNA






5 pre-filled pens of 3 ml


Subcutaneous useProtaphane NovoLet is designed to be used with NovoFine needlesResuspend according to instructionsRead package leaflet before useProtaphane NovoLet is for use by one person only




8. EXPIRY DATE


66


Store at 2�C - 8�C (in a refrigerator)Do not freezeProtect from lightDuring use: do not refrigerate or store above 30�C





EU/0/00/000/000


Batch:




67


OUTER CARTON


Protaphane NovoLet 100 IU/mlSuspension for injection in a pre-filled penInsulin human, rDNA








Subcutaneous useProtaphane NovoLet is designed to be used with NovoFine needlesResuspend according to instructionsRead package leaflet before useProtaphane NovoLet is for use by one person only




8. EXPIRY DATE


68







EU/0/00/000/000


Batch:




69


LABEL


Protaphane NovoLet 100 IU/mlSuspension for injectionInsulin human, rDNA


SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:


3 ml

70


OUTER CARTON


Protaphane InnoLet 100 IU/mlSuspension for injection in a pre-filled penInsulin human, rDNA






1 pre-filled pen of 3 ml


Subcutaneous useProtaphane InnoLet is designed to be used with NovoFine S needlesResuspend according to instructionsRead package leaflet before useProtaphane InnoLet is for use by one person only




8. EXPIRY DATE


71







EU/0/00/000/000


Batch:




72


OUTER CARTON














8. EXPIRY DATE


73







EU/0/00/000/000


Batch:




74


OUTER CARTON














8. EXPIRY DATE


75







EU/0/00/000/000


Batch:




76


LABEL


Protaphane InnoLet 100 IU/mlSuspension for injectionInsulin human, rDNA


SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:


3 ml

77


OUTER CARTON


Protaphane FlexPen 100 IU/mlSuspension for injection in a pre-filled penInsulin human, rDNA






1 pre-filled pen of 3 ml


Subcutaneous useProtaphane FlexPen is designed to be used with NovoFine S needlesResuspend according to instructionsRead package leaflet before useProtaphane FlexPen is for use by one person only




8. EXPIRY DATE


78







EU/0/00/000/000


Batch:




79


OUTER CARTON














8. EXPIRY DATE


80







EU/0/00/000/000


Batch:




81


OUTER CARTON














8. EXPIRY DATE


82







EU/0/00/000/000


Batch:




83


LABEL


Protaphane FlexPen 100 IU/mlSuspension for injectionInsulin human, rDNA


SC use

3. EXPIRY DATE

Expiry

4. BATCH NUMBER

Batch:


3 ml

84

B. PACKAGE LEAFLET

85

Protaphane

Read all of this leaflet carefully before you start using your insulin. Keep this leaflet. You mayneed to read it again.If you have further questions, please ask your doctor, diabetes nurse or pharmacist. This medicine isprescribed for you personally and you should not pass it on to others. It may harm them, even if theirsymptoms are the same as yours.

Protaphane 40 IU/ml Suspension for injection in a vialInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).The active substance is insulin human made by recombinant biotechnology.1 ml contains 40 IU of insulin human. 1 vial contains 10 ml equivalent to 400 IU.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 1 or 5 vials of10 ml (not all packs may be marketed).The marketing authorisation holder and manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880Bagsværd, Denmark.

1 What Protaphane is

Protaphane is human insulin to treat diabetes. It comes in a 10 ml vial that you use to fill a syringe.Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.

2 Before you use Protaphane

Do not use Protaphane► If you feel a hypo coming on (a hypo is short for a hypoglycaemic reaction and is symptoms of

low blood sugar). See 4 What to do in an emergency for more about hypos► If you have ever had an allergic reaction to this insulin product, metacresol or any of the other

ingredients (see box, below left). Look out for the signs of allergy in 5 Possible side effects.

Take special care with Protaphane► If you have trouble with your kidneys or liver, or with your adrenal, pituitary or thyroid glands► If you are drinking alcohol: watch for signs of a hypo► If you are exercising more than usual or if you want to change your usual diet► If you are ill: carry on taking your insulin► If you are going abroad: travelling over time zones may affect your insulin needs► If you are pregnant, or planning a pregnancy: you must be especially careful to control your

blood sugar; too much or too little could harm your health and the baby’s► If you are breastfeeding: there’s no risk to the baby, but you may need to adjust your insulin and

your diet► If you drive or use tools or machines: watch out for signs of a hypo. Your ability to concentrate

or to react will be less during a hypo. Never drive or use machinery if you feel a hypo comingon. Discuss with your doctor whether you should drive or use machines at all, if you have a lotof hypos or if you find it hard to recognise hypos.

Other medicines and ProtaphaneMany medicines affect the way glucose works in your body and they may influence your insulin dose.Listed below are the most important medicines which may affect your insulin treatment. Talk to yourdoctor if you take or change any other medicines, even those not prescribed.

86

Your need for insulin may change if you also take: oral hypoglycaemic agents; monoamine oxidaseinhibitors (MAOI); certain beta-blockers; ACE-inhibitors; acetylsalicylic acid; thiazides;glucocorticoids; thyroid hormone therapy; beta-sympathomimetics; growth hormone; danazol;octreotide and lanreotide.

3 Using Protaphane

Talk about your insulin needs with your doctor and diabetes nurse. Follow their advice carefully. Thisleaflet is a general guide.If your doctor has switched you from one type or brand of insulin to another, your dose may have tobe adjusted by your doctor.

Before using Protaphane► Make sure it is the right type of insulin► Disinfect the rubber membrane with surgical spirit.

Do not use Protaphane► If the protective cap is loose or missing. Each vial has a protective, tamperproof plastic cap. If it

isn’t in perfect condition when you get the vial, return the vial to your supplier► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane)► If it’s not uniformly white and cloudy when it’s mixed.

How to use this insulinProtaphane is for injection under the skin (subcutaneously). Never inject your insulin directly into avein or muscle. Always vary the sites you inject, to avoid lumps (see 5 Possible side effects). The bestplace to give yourself an injection is the front of your thighs. If convenient, the front of your waist(abdomen), your buttocks or the front of your upper arms may be used.You should always measure your blood glucose regularly.Protaphane vials are for use with insulin syringes with the corresponding unit scale.

To inject Protaphane on its own� Just before injecting this insulin, roll the vial between your hands until the liquid is uniformly

white and cloudy� Draw air into the syringe, in the same amount as the dose of insulin you need� Inject the air into the vial: push the needle through the rubber stopper and press the plunger� Turn the vial and syringe upside down� Draw the right dose of insulin into the syringe� Pull the needle out of the vial� Make sure there is no air left in the syringe: point the needle upwards and push the air out� Check you have the right dose� Inject straight away.

To mix Protaphane with fast-acting insulin� Roll the vial of Protaphane between your hands. Do this until the liquid is uniformly white and

cloudy� Draw as much air into the syringe as the dose of Protaphane you need. Inject the air into the

Protaphane vial, then pull out the needle� Draw as much air into the syringe as the dose of fast-acting insulin you need. Inject the air into

the fast-acting insulin vial. Then turn the vial and syringe upside down� Draw the right dose of fast-acting insulin into the syringe. Pull the needle out of the vial.

Make sure there is no air left in the syringe: point the needle upwards and push the air out.Check the dose

� Now push the needle into the vial of Protaphane. Then turn the vial and syringe upside down� Draw the right dose of Protaphane into the syringe. Pull the needle out of the vial.

Make sure there is no air left in the syringe, and check the dose

87

� Inject the mixture straight away.

Always mix fast-acting and long-acting insulin in this order.

Inject the insulin� Inject the insulin under the skin. Use the injection technique advised by your doctor or diabetes

nurse� Keep the needle under your skin for at least 6 seconds to make sure the full dose has been

delivered.

4 What to do in an emergency

If you get a hypoA hypo means your blood sugar level is too low.The warning signs of a hypo may come on suddenly and can include: cold sweat; cool pale skin;headache; rapid heart beat; feeling sick; feeling very hungry; temporary changes in vision; drowsiness;unusual tiredness and weakness; nervousness or tremor; feeling anxious; feeling confused; difficulty inconcentrating.If you get any of these signs: eat glucose tablets or a high sugar snack (sweets, biscuits, fruit juice),then rest.Don’t take any insulin if you feel a hypo coming on.Carry glucose tablets, sweets, biscuits or fruit juice with you, just in case.Tell people that if you pass out (become unconscious), they should: turn you on your side and getmedical help straight away. They should not give you any food or drink. It could choke you.► If severe hypoglycaemia is not treated, it can cause brain damage (temporary or permanent) and

even death► If you have a hypo that makes you pass out, or a lot of hypos, talk to your doctor. The amount

or timing of insulin, food or exercise may need to be adjusted.

Using glucagonYou may recover more quickly from unconsciousness with an injection of the hormone glucagon bysomeone who knows how to use it. If you are given glucagon you will need glucose or a sugary snackas soon as you are conscious. If you do not respond to glucagon treatment, you will have to be treatedin a hospital. Contact your doctor or an emergency ward after an injection of glucagon: you need tofind the reason for your hypo to avoid getting more.

Causes of a hypoYou get a hypo if your blood sugar gets too low. This might happen:� If you take too much insulin� If you eat too little or miss a meal� If you exercise more than usual.

If your blood sugar gets too highYour blood sugar may get too high (this is called hyperglycaemia).The warning signs appear gradually. They include: increased urination; feeling thirsty; losing yourappetite; feeling sick (nausea or vomiting); feeling drowsy or tired; flushed, dry skin; dry mouth and afruity smell of the breath.If you get any of these signs: test your blood sugar level; test your urine for ketones if you can; thenseek medical advice straight away.These may be signs of a very serious condition called diabetic ketoacidosis. If you don’t treat it, thiscould lead to diabetic coma and death.

Causes of a hyperglycaemia� Having forgotten to take your insulin� Repeatedly taking less insulin than you need

88

� An infection or a fever� Eating more than usual� Less exercise than usual.

5 Possible side effects

Like all medicines, Protaphane can have side effects. The most common side effects are low or highblood sugar (hypo or hyperglycaemia). During clinical trials every one in five patients experienced ahypo requiring help from others. See the advice in 4 What to do in an emergency.

In daily life not all side effects may be reported. Therefore the side effects listed below may occurmore frequently than stated.

Side effects reported rarely (less than 1 in a 1.000)Low or high blood sugar. Taking too much or too little Protaphane may cause respectively hypo orhyperglycaemia.

Side effects reported very rarely (less than 1 in 10.000)Vision problems. When you first start your insulin treatment, it may disturb your vision, but thereaction usually disappears.

Changes at the injection site. If you inject yourself too often in the same site, lumps may developunderneath. Prevent this by choosing different injection sites each time within the same area.

Signs of allergy. Reactions (redness, swelling, itching) at the injection site may occur (local allergicreactions). These usually go away after a few weeks of taking your insulin. If they do not go away, seeyour doctor.Seek medical advice straight away:► If signs of allergy spread to other parts of your body, or► If you suddenly feel unwell, and you: start sweating; start being sick (vomiting); have difficulty

in breathing; have a rapid heart beat; feel dizzy.You may have a very rare serious allergic reaction to Protaphane or one of its ingredients (called asystemic allergic reaction). See also the warning in 2 Before you use Protaphane.

Swollen joints. When you start taking insulin, water retention may cause swelling around your anklesand other joints. This soon goes away.

If you notice any side effects, also those not mentioned in this leaflet, please inform your doctor orpharmacist.

6 How to store Protaphane

Keep out of the reach and sight of children.Protaphane vials that are not being used are to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane vials that are being used or about to be used are not to be kept in the fridge. You can carrythem with you and keep them at room temperature (below 25�C) for up to 4 weeks.

Always keep the vial in the outer carton when you’re not using it in order to protect it from light.Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.

Leaflet last approved on

89

Protaphane


Protaphane 100 IU/ml Suspension for injection in a vialInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).The active substance is insulin human made by recombinant biotechnology.1 ml contains 100 IU of insulin human. 1 vial contains 10 ml equivalent to 1000 IU.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 1 or 5 vials of10 ml (not all packs may be marketed).The marketing authorisation holder and manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880Bagsværd, Denmark.


Protaphane is human insulin to treat diabetes. It comes in a 10 ml vial that you use to fill a syringe.Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.









Other medicines and ProtaphaneMany medicines affect the way glucose works in your body and they may influence your insulin dose.Listed below are the most important medicines which may affect your insulin treatment. Talk to yourdoctor if you take or change any other medicines, even those not prescribed.

90

Your need for insulin may change if you also take: oral hypoglycaemic agents; monoamine oxidaseinhibitors (MAOI); certain beta-blockers; ACE-inhibitors; acetylsalicylic acid; thiazides;glucocorticoids; thyroid hormone therapy; beta-sympathomimetics; growth hormone; danazol;octreotide and lanreotide.

3 Using Protaphane


Before using Protaphane► Make sure it is the right type of insulin► Disinfect the rubber membrane with surgical spirit.

Do not use Protaphane► If the protective cap is loose or missing. Each vial has a protective, tamperproof plastic cap. If it

isn’t in perfect condition when you get the vial, return the vial to your supplier► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane)► If it’s not uniformly white and cloudy when it’s mixed.

How to use this insulinProtaphane is for injection under the skin (subcutaneously). Never inject your insulin directly into avein or muscle. Always vary the sites you inject, to avoid lumps (see 5 Possible side effects). The bestplace to give yourself an injection is the front of your thighs. If convenient, the front of your waist(abdomen), your buttocks or the front of your upper arms may be used.You should always measure your blood glucose regularly.Protaphane vials are for use with insulin syringes with the corresponding unit scale.

To inject Protaphane on its own� Just before injecting this insulin, roll the vial between your hands until the liquid is uniformly

white and cloudy� Draw air into the syringe, in the same amount as the dose of insulin you need� Inject the air into the vial: push the needle through the rubber stopper and press the plunger� Turn the vial and syringe upside down� Draw the right dose of insulin into the syringe� Pull the needle out of the vial� Make sure there is no air left in the syringe: point the needle upwards and push the air out� Check you have the right dose� Inject straight away.

To mix Protaphane with fast-acting insulin� Roll the vial of Protaphane between your hands. Do this until the liquid is uniformly white and

cloudy� Draw as much air into the syringe as the dose of Protaphane you need. Inject the air into the

Protaphane vial, then pull out the needle� Draw as much air into the syringe as the dose of fast-acting insulin you need. Inject the air into

the fast-acting insulin vial. Then turn the vial and syringe upside down� Draw the right dose of fast-acting insulin into the syringe. Pull the needle out of the vial.

Make sure there is no air left in the syringe: point the needle upwards and push the air out.Check the dose

� Now push the needle into the vial of Protaphane. Then turn the vial and syringe upside down� Draw the right dose of Protaphane into the syringe. Pull the needle out of the vial.

Make sure there is no air left in the syringe, and check the dose

91

� Inject the mixture straight away.

Always mix fast-acting and long-acting insulin in this order.

Inject the insulin� Inject the insulin under the skin. Use the injection technique advised by your doctor or diabetes

nurse� Keep the needle under your skin for at least 6 seconds to make sure the full dose has been

delivered.








Causes of a hyperglycaemia� Having forgotten to take your insulin� Repeatedly taking less insulin than you need

92

� An infection or a fever� Eating more than usual� Less exercise than usual.












Keep out of the reach and sight of children.Protaphane vials that are not being used are to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane vials that are being used or about to be used are not to be kept in the fridge. You can carrythem with you and keep them at room temperature (below 25�C) for up to 6 weeks.

Always keep the vial in the outer carton when you’re not using it in order to protect it from light.Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.


94

Protaphane Penfill


Protaphane Penfill 100 IU/ml Suspension for injection in a cartridgeInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).The active substance is insulin human made by recombinant biotechnology.1 ml contains 100 IU of insulin human. 1 cartridge contains 3 ml equivalent to 300 IU.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 1, 5 or 10cartridges of 3 ml (not all packs may be marketed).The marketing authorisation holder is Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark.The manufacturers are: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark and NovoNordisk Pharmaceutique S.A., 45 Avenue d’Orléansd’Orléans, F-28002 Chartres, France.


Protaphane is human insulin to treat diabetes. It comes in a 3 ml cartridge, called Penfill, which fitsinto an insulin delivery system.Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.









95

Other medicines and ProtaphaneMany medicines affect the way glucose works in your body and they may influence your insulin dose.Listed below are the most important medicines which may affect your insulin treatment. Talk to yourdoctor if you take or change any other medicines, even those not prescribed.Your need for insulin may change if you also take: oral hypoglycaemic agents; monoamine oxidaseinhibitors (MAOI); certain beta-blockers; ACE-inhibitors; acetylsalicylic acid; thiazides;glucocorticoids; thyroid hormone therapy; beta-sympathomimetics; growth hormone; danazol;octreotide and lanreotide.

3 Using Protaphane


Before using Protaphane► Make sure it is the right type of insulin► Always check the Penfill cartridge, including the rubber plunger (stopper). Don’t use it if any

damage is seen or if the part of the rubber plunger that you can see exceeds the white band.Take it back to your supplier

► Disinfect the rubber membrane with surgical spirit.

Do not use Protaphane► If Penfill or the device containing Penfill is dropped or crushed, there is a risk of damage and

leakage of insulin► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane)► If it’s not uniformly white and cloudy when it’s mixed.

Do not refill Protaphane Penfill.Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems and NovoFineneedles.If you are treated with Protaphane Penfill and another insulin Penfill cartridge, you should use twoinsulin delivery systems, one for each type of insulin.

Mixing the insulinBefore you put the Penfill cartridge into the insulin delivery system, move it slowly up and downbetween positions A and B and back (see the picture) so that the glass ball moves from one end of thecartridge to the other. Repeat this movement before first use at least 20 times and for every injection atleast 10 times. The movement should always be repeated until the liquid appears uniformly white andcloudy. Complete the other stages of injection without delay.

If the cartridge is already inside the insulin delivery system, move the delivery system slowly up anddown between A and B and back with the cartridge inside it at least 10 times. Do this again beforeevery injection.Check there are at least 12 units of insulin left in the cartridge to allow even mixing. If there areless than 12 units left, use a new one.

96

How to use this insulinProtaphane is for injection under the skin (subcutaneously). Never inject your insulin directly into avein or muscle. Always vary the sites you inject, to avoid lumps (see 5 Possible side effects). The bestplace to give yourself an injection is the front of your thighs. If convenient, the front of your waist(abdomen), your buttocks or the front of your upper arms may be used.You should always measure your blood glucose regularly.

How to inject this insulin� Inject the insulin under the skin. Use the injection technique advised by your doctor or

diabetes nurse and described in your delivery system manual� Keep the needle under your skin for at least 6 seconds to make sure that the full dose has

been delivered� After each injection be sure to remove the needle. Otherwise, the liquid may leak out when

the temperature changes and the strength of the insulin may change.







If your blood sugar gets too highYour blood sugar may get too high (this is called hyperglycaemia).The warning signs appear gradually. They include: increased urination; feeling thirsty; losing yourappetite; feeling sick (nausea or vomiting); feeling drowsy or tired; flushed, dry skin; dry mouth and afruity smell of the breath.If you get any of these signs: test your blood sugar level;; test your urine for ketones if you can; thenseek medical advice straight away.These may be signs of a very serious condition called diabetic ketoacidosis. If you don’t treat it, this

97

could lead to diabetic coma and death.

Causes of a hyperglycaemia� Having forgotten to take your insulin� Repeatedly taking less insulin than you need� An infection or a fever� Eating more than usual� Less exercise than usual.












Keep out of the reach and sight of children.Protaphane Penfill that is not being used is to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane Penfill that is being used or about to be used is not to be kept in the fridge. You can carryit with you and keep it at room temperature (below 30�C) for up to 6 weeks.Always keep your cartridge in the outer carton when you’re not using it in order to protect it fromlight.

98

Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.


99

Protaphane NovoLet


� This side of the leaflet:1 What Protaphane is2 Before you use Protaphane3 Using Protaphane4 In an emergency5 Possible side effects6 How to store Protaphane

Overleaf: Using your NovoLet

Protaphane NovoLet 100 IU/ml suspension for injection in a pre-filled penInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).The active substance is insulin human made by recombinant biotechnology. 1 ml contains 100 IU ofinsulin human. 1 pre-filled pen contains 3 ml equivalent to 300 IU.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 5 or 10 pre-filled pens of 3 ml (not all packs may be marketed).The marketing authorisation holder and manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880Bagsværd, Denmark.


Protaphane is human insulin to treat diabetes. It comes in a 3 ml pre-filled pen (called NovoLet –see overleaf for detailed instructions).Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.






blood sugar; too much or too little could harm your health and the baby’s

100

► If you are breastfeeding: there’s no risk to the baby, but you may need to adjust your insulin andyour diet

► If you drive or use tools or machines: watch out for signs of a hypo. Your ability to concentrateor to react will be less during a hypo. Never drive or use machinery if you feel a hypo comingon. Discuss with your doctor whether you should drive or use machines at all, if you have a lotof hypos or if you find it hard to recognise hypos.


3 Using Protaphane


Injecting insulin� See overleaf for detailed instructions.

Before using Protaphane► Make sure it is the right type of insulin.

Do not use Protaphane► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane))► If it’s not uniformly white and cloudy when it’s mixed.

Protaphane is for injection under the skin (subcutaneously). Never inject your insulin directly into avein or muscle. Always vary the sites you inject, to avoid lumps (see 5 Possible side effects). The bestplace to give yourself an injection is the front of your thighs. If convenient, the front of your waist(abdomen), your buttocks or the front of your upper arms may be used.You should always measure your blood glucose regularly.



even death

101

► If you have a hypo that makes you pass out, or a lot of hypos, talk to your doctor. The amountor timing of insulin, food or exercise may need to be adjusted.




Causes of a hyperglycaemia� Having forgotten to take your insulin� Repeatedly taking less insulin than you need� An infection or a fever� Eating more than usual� Less exercise than usual


Like all medicines, Protaphane can have side effects.

Common side effects (up to 10%)

Low or high blood sugar (hypo or hyperglycaemia). Taking too much or too little Protaphane maycause respectively hypo or hyperglycaemia. See the advice in 4 What to do in an emergency.

Rare side effects (up to 0.1%)

Vision problems. When you first start your insulin treatment, it may disturb your vision, but thereaction usually disappears.

Changes at the injection site. Reactions (redness, swelling, itching) at the injection site may occurand will normally disappear during use. If you inject yourself too often in the same site, lumps maydevelop underneath. Prevent this by choosing different injection sites each time within the same area.

Signs of allergy. Very rarely, people get redness, swelling or itching around the area of the insulininjection (local allergic reactions). These usually go away after a few weeks of taking your insulin. Ifthey do not go away, see your doctor.Seek medical advice straight away:

102

► If signs of allergy spread to other parts of your body, or► If you suddenly feel unwell, and you: start sweating; start being sick (vomiting); have difficulty





Keep out of the reach and sight of children.Protaphane NovoLet that is not being used is to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane NovoLet that is being used, about to be used or carried as a spare is not to be kept in thefridge. You can carry it with you and keep it at room temperature (below 30�C) for up to 6 weeks.Always keep the pen cap on your NovoLet when you’re not using it in order to protect it from light.Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.

Now turn over for information on using your NovoLet.


103

Information on how to inject Protaphane NovoLet

Please read the following instructions carefully before using your Protaphane NovoLet.

IntroductionProtaphane NovoLet is a simple, compact pre-filled pen. You can dial doses from 2 to 78 units inincrements of 2 units. Protaphane NovoLet is designed to be used with NovoFine needles.

104

1 Getting started

Check the label to be sure that your Protaphane NovoLet contains the correct type of insulin. Take offthe pen cap.

Before every injection:� Check there are at least 12 units of insulin left in the cartridge to allow even mixing. If there

are less than 12 units left, use a new Protaphane NovoLet� Move the pen slowly up and down between positions a and b and back (picture A) so that

the glass ball moves from one end of the cartridge to the other. Repeat this movement before thefirst use at least 20 times and for every injection at least 10 times. The movement should alwaysbe repeated, until the liquid appears uniformly white and cloudy

� After mixing complete all the following stages of injection without delay� Disinfect the rubber membrane with surgical spirit� Remove the protective tab from a NovoFine needle� Screw the needle straight and tightly onto Protaphane NovoLet (picture B)� Pull off the big outer needle cap and the inner needle cap. Do not discard the big outer

needle cap.

2 Priming to get rid of air prior to each injection

Small amounts of air may collect in the needle and cartridge during normal use.To avoid injection of air and ensure proper dosing:� Hold Protaphane NovoLet with the needle pointing upwards� Tap the cartridge gently with your finger a few times. Any air bubbles will collect at the top

of the cartridge� Keeping the needle upwards, turn the cartridge for one click in the direction of the arrow

(picture C)� Still with the needle upwards, press the push-button fully down (picture D)� A drop of insulin should appear at the needle tip. If not, repeat the procedure no more than 6

times.

If a drop of insulin still does not appear, the device is defective and must not be used.

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3 Setting the dose

� Put the cap back on the pen, with 0 next to the dosage indicator (picture E)� Check that the push-button is fully down. If it isn’t, turn the cap until the push-button is fully

depressed� Hold your Protaphane NovoLet horizontally. Now you’re ready to set the dose you need� Turn the cap in the direction of the arrow (picture F) to set the right dose. You’ll feel the

cap clicking, and the push-button will rise up� Don’t put your hand over the push-button when you set the dose. If the push-button cannot

rise freely, some of your insulin will be pushed out of the needle� The scale on the cap shows 0, 2, 4, 6, 8, 10, 12, 14, 16 and 18 units. For every click you feel

when you turn the cap, you set 2 units more. The push-button also rises as you turn the cap� The scale under the push-button shows 20, 40 and 60 units. Every time you fully turn the

cap, you set 20 units.

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Dosage examples

� To set 8 units:Turn the cap until 8 is opposite the dosage indicator; four clicks

� To select 26 units:Turn the cap round 1 full turn, so 0 is opposite the dosage indicator again. You’ve now set 20units.Keep turning the cap until 6 is opposite the dosage indicator. On the push-button scale you’llsee a 20-line.Add the 6 from the dosage indicator to the 20 on the push-button scale. There, you’ve set 26units (picture G).

To check a dose you set� Note the figure on the cap next to the dosage indicator� Note the highest figure you can see on the push-button scale� Add the two together to show the dose you set� If you have set a wrong dose, simply turn the cap forwards or backwards until you set the right

number of units.

The maximum dose is 78 units� Don’t try to set a dose higher than 78 units. Otherwise, insulin will leak out of the needle and

the dose will be incorrect� If you have, by mistake, tried to set a dose over 78 units, follow these steps:

Turn the cap back as far as you can. Turn it till the push-button is fully down and you can feelresistance.Then take the cap off and put it back on again, lining up the 0 next to the dosage indicator. Nowset the dose again.Remember that 78 units is the maximum dose.

� After the dose is set, remove the cap to inject the insulin. Go straight on to 4 Making theinjection.

4 Making the injection

� Insert the needle into your skin. Use the injection technique advised by your doctor� Deliver the dose by pressing the push-button fully down. Be careful only to push the push-

button when injecting

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� Keep the push-button fully depressed after the injection until the needle has beenwithdrawn from the skin. The needle should remain under the skin for at least 6 seconds. Thiswill ensure that the full dose has been delivered.

Subsequent injections� Always check that the push-button is completely down. If not, turn the cap until the push-

button is fully depressed, then proceed as described in 1 Getting started� You may hear a clicking sound when you press the push-button. Don’t use this to set or

check your dose; it may not be accurate� You can’t set a dose higher than the number of units left in the cartridge� You can use the insulin level indicator to estimate how much is left. But you can’t use it to

set or select your dose.

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5 Removing the needle � Replace the big outer needle cap and unscrew the needle. Dispose of it carefully.

Use a new needle for each injection.Be sure to remove the needle after each injection. Otherwise, the liquid may leak out when thetemperature changes and the strength of the insulin may change. Health care professionals, relatives and other carers should follow general precautionary measures forremoval and disposal of needles to eliminate the risk of unintended needle penetration.Close your Protaphane NovoLet fully with 0 next to the dosage indicator.Dispose of your used Protaphane NovoLet carefully without the needle attached.

6 Maintenance

Your Protaphane NovoLet is designed to work accurately and safely. It should be handled with care. Ifit is dropped or crushed, there is a risk of damage and leakage of insulin.As a precautionary measure, always carry a spare insulin delivery device in case your NovoLet is lostor damaged.Do not refill Protaphane NovoLet.You can clean the exterior of your Protaphane NovoLet by wiping it with cotton wool moistened withsurgical spirit. Do not soak it in surgical spirit or wash or lubricate it. This may damage themechanism.

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Protaphane InnoLet



Overleaf: Using your InnoLet

Protaphane InnoLet 100 IU/ml Suspension for injection in a pre-filled penInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).The active substance is insulin human made by recombinant biotechnology.1 ml contains 100 IU of insulin human. 1 pre-filled pen contains 3 ml equivalent to 300 IU.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 1, 5 or 10 pre-filled pens of 3 ml (not all packs may be marketed).The marketing authorisation holder and manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880Bagsværd, Denmark.


Protaphane is human insulin to treat diabetes. It comes in a 3 ml pre-filled pen (called InnoLet –see overleaf for detailed instructions).Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.







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Other medicines and ProtaphaneMany medicines affect the way glucose works in your body and they may influence your insulin dose.Listed below are the most important medicines which may affect your insulin treatment. Talk to yourdoctor if you take or change any other medicines, even those not prescribed.Your need for insulin may change if you also take: oral hypoglycaemics; monoamine oxidaseinhibitors (MAOI); certain beta-blockers; ACE-inhibitors; acetylsalicylic acid; thiazides;glucocorticoids; thyroid hormone therapy; beta-sympathomimetics; growth hormone; danazol;octreotide and lanreotide.

3 Using Protaphane




Do not use Protaphane► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane)► If it’s not uniformly white and cloudy when it’s mixed.



If you get a hypoA hypo means your blood sugar level is too low.The warning signs of a hypo may come on suddenly and can include: cold sweat; cool pale skin;headache; rapid heart beat; feeling sick; feeling very hungry; temporary changes in vision; drowsiness;unusual tiredness and weakness; nervousness or tremor; feeling anxious; feeling confused; difficulty inconcentrating.If you get any of these signs: eat glucose tablets or a high sugar snack (sweets, biscuits, fruit juice),then rest.Don’t take any insulin if you feel a hypo coming on.Carry glucose tablets, sweets, biscuits or fruit juice with you, just in case.Tell people that if you pass out (become unconscious), they should: turn you on your side and getmedical help straight away.. They should not give you any food or drink. It could choke you.► If severe hypoglycaemia is not treated, it can cause brain damage (temporary or permanent) and

even death

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Keep out of the reach and sight of children.Protaphane InnoLet that is not being used is to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane InnoLet that is being used, about to be used or carried as a spare is not to be kept in thefridge. You can carry it with you and keep it at room temperature (below 30�C) for up to 6 weeks.Always keep the pen cap on your InnoLet when you’re not using it in order to protect it from light.Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.

Now turn over for information on using your InnoLet.


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Information on how to inject Protaphane InnoLet

Please read the following instructions carefully before using your Protaphane InnoLet.

IntroductionProtaphane InnoLet is a simple, compact pre-filled pen able to deliver 1 to 50 units in increments of 1unit.Protaphane InnoLet is designed to be used with NovoFine S needles of 8 mm or shorter in length.Look for an S on the needle box. The S stands for short cap.

1 Preparing for injection

Check the label to be sure that your Protaphane InnoLet contains the correct type of insulin. Take offthe pen cap (as shown by the arrow).

1A Suspending the insulin


are less than 12 units left, use a new Protaphane InnoLet� Move the pen slowly up and down between positions A and B and back so that the glass ball

moves from one end of the cartridge to the other. Repeat this movement before the first use atleast 20 times and for every injection at least 10 times. The movement should always berepeated, until the liquid appears uniformly white and cloudy

� After mixing complete all the following stages of injection without delay.

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1B Attaching the needle

� Disinfect the rubber membrane with surgical spirit� Remove the protective tab from a NovoFine S short cap needle� Screw the needle straight and tightly onto Protaphane InnoLet� Pull off the big outer needle cap and the inner needle cap. You may want to store the big

outer needle cap in the compartment.

1C Priming to get rid of air prior to each injection

Small amounts of air may collect in the needle and cartridge during normal use.To avoid injection of air and ensure proper dosing:� Dial 2 units by turning the dose selector clockwise� Hold Protaphane InnoLet with the needle upwards and tap the cartridge gently with your

finger a few times to make any air bubbles collect at the top of the cartridge� Keeping the needle upwards, press the push-button and the dose selector returns to zero� A drop of insulin should appear at the needle tip. If not, repeat the procedure no more than 6

times.

If a drop of insulin still does not appear, the device is defective and must not be used.

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2 Setting the dose

� Always check that the push-button is fully depressed and the dose selector is set to zero� Dial the number of units required by turning the dose selector clockwise. Do not use the

residual scale to measure your dose of insulin� You will hear a click for every single unit dialled. The dose can be corrected by turning the

dial either way.

You cannot set a dose larger than the number of units remaining in the cartridge.

3 Making the injection

� Insert the needle into your skin. Use the injection technique advised by your doctor� Deliver the dose by pressing the push-button fully down. You will hear clicks as the dose

selector returns to zero� After the injection, the needle should remain under the skin for at least 6 seconds to ensure

that the full dose has been delivered� Make sure not to block the dose selector while injecting, as the dose selector must be allowed

to return to zero when you press the push-button� Remove the needle after each injection.

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4 Removing the needle

� Replace the big outer needle cap and unscrew the needle. Dispose of it carefully.

Use a new needle for each injection.

Be sure to remove the needle after each injection. Otherwise, the liquid may leak out when thetemperature changes, and the strength of the insulin may change.Health care professionals, relatives and other carers should follow general precautionary measures forremoval and disposal of needles to eliminate the risk of unintended needle penetration.Dispose of your used Protaphane InnoLet carefully without the needle attached.

5 Maintenance

Your Protaphane InnoLet is designed to work accurately and safely. It should be handled with care. Ifit is dropped or crushed, there is a risk of damage and leakage of insulin.As a precautionary measure, always carry a spare insulin delivery device in case your InnoLet is lostor damaged.Do not refill Protaphane InnoLet.You can clean your Protaphane InnoLet by wiping it with cotton wool moistened with surgical spirit.Do not soak it in surgical spirit or wash or lubricate it. This may damage the mechanism.

117

Protaphane FlexPen



Overleaf: Using your FlexPen

Protaphane FlexPen 100 IU/ml Suspension for injection in a pre-filled penInsulin human, rDNA.Protaphane is an isophane insulin suspension (NPH).1 ml contains 100 IU of insulin human. 1 pre-filled pen contains 3 ml equivalent to 300 IU.The active substance is insulin human made by recombinant biotechnology.Protaphane also contains zinc chloride, glycerol, metacresol, phenol, disodium phosphate dihydrate,sodium hydroxide, hydrochloric acid, protamine sulphate and water for injections.The suspension for injection comes as a cloudy, white, aqueous suspension in packs of 1, 5 or 10 pre-filled pens of 3 ml (not all packs may be marketed).The marketing authorisation holder and manufacturer is Novo Nordisk A/S, Novo Allé, DK-2880Bagsværd, Denmark.


Protaphane is human insulin to treat diabetes. It comes in a 3 ml pre-filled pen (called FlexPen –see overleaf for detailed instructions).Protaphane is a long-acting insulin. This means that it will start to lower your blood sugar about 1 ½hours after you take it, and the effect will last for approximately 24 hours. Protaphane is often given incombination with fast-acting insulins.







118




3 Using Protaphane




Do not use Protaphane► If it hasn’t been stored correctly or been frozen (see 6 How to store Protaphane)► If it’s not uniformly white and cloudy when it’s mixed.




even death

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Keep out of the reach and sight of children.Protaphane FlexPen that is not being used is to be stored in the fridge at 2�C - 8�C, away from thefreezer compartment. Do not freeze.Protaphane FlexPen that is being used, about to be used or carried as a spare is not to be kept in thefridge. You can carry it with you and keep it at room temperature (below 30�C) for up to 6 weeks.Always keep the pen cap on your FlexPen when you’re not using it in order to protect it from light.Protaphane should be protected from excessive heat and sunlight.Do not use Protaphane after the expiry date stated on the label and carton.

Now turn over for information on using your FlexPen.


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Information on how to inject Protaphane FlexPen

Please read the following instructions carefully before using your Protaphane FlexPen.

IntroductionProtaphane FlexPen is a unique dial-a-dose insulin pen. You can dial doses from 1 to 60 units inincrements of 1 unit. Protaphane FlexPen is designed to be used with NovoFine S needles of 8 mm orshorter in length.. Look for an S on the needle box. The S stands for short cap.

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1 Getting started

Check the label to be sure that your Protaphane FlexPen contains the correct type of insulin. Take offthe pen cap.


are less than 12 units left, use a new Protaphane FlexPen� Move the pen slowly up and down between positions 1 and 2 and back (picture A) so that

the glass ball moves from one end of the cartridge to the other. Repeat this movement beforefirst use at least 20 times and for every injection at least 10 times. The movement should alwaysbe repeated, until the liquid appears uniformly white and cloudy

� After mixing complete all the following stages of injection without delay� Disinfect the rubber membrane with surgical spirit� Remove the protective tab from a NovoFine S short cap needle� Screw the needle straight and tightly onto Protaphane FlexPen (picture B)� Pull off the big outer needle cap and the inner needle cap (picture C). Do not discard the big

outer needle cap.

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2 Priming to get rid of air prior to each injection

Small amounts of air may collect in the needle and cartridge during normal use.To avoid injection of air and ensure proper dosing:� Dial 2 units (picture D)� Hold Protaphane FlexPen with the needle pointing upwards and tap the cartridge gently

with your finger a few times to make any air bubbles collect at the top of the cartridge (picture

E)� Keeping the needle upwards, press the push-button all the way in. The dose selector returns

to zero� A drop of insulin should appear at the needle tip. If not, repeat the procedure no more than 6

times.

If a drop of insulin still does not appear, the device is defective, and must not be used.

3 Setting the dose

� Check that the dose selector is set at zero� Dial the number of units you need to inject (picture F).

The dose can be corrected either up or down by turning the dose selector in either direction. Whendialling back, be careful not to push the push-button as insulin will come out.Do not use the residual scale to measure your dose of insulin.You cannot set a dose larger than the number of units left in the cartridge.

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4 Making the injection � Insert the needle into your skin (picture G). Use the injection technique advised by your

doctor� Deliver the dose by pressing the push-button all the way in (picture H). Be careful only to

push the push-button when injecting� Keep the push-button fully depressed after the injection until the needle has been

withdrawn from the skin. The needle should remain under the skin for at least 6 seconds. Thiswill ensure that the full dose has been delivered.

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5 Removing the needle � Replace the big outer needle cap and unscrew the needle (picture I). Dispose of it carefully.

Use a new needle for each injection.

Be sure to remove the needle after each injection. Otherwise, the liquid may leak out when thetemperature changes, and the strength of the insulin may change. Health care professionals, relatives and other carers should follow general precautionary measures forremoval and disposal of needles to eliminate the risk of unintended needle penetration.Dispose of your used Protaphane FlexPen carefully without the needle attached.

6 Maintenance

Your Protaphane FlexPen is designed to work accurately and safely. It should be handled with care. Ifit is dropped or crushed, there is a risk of damage and leakage of insulin.As a precautionary measure, always carry a spare insulin delivery device in case your FlexPen is lostor damaged.Do not refill Protaphane FlexPen.You can clean the exterior of your Protaphane FlexPen by wiping it with cotton wool moistened withsurgical spirit. Do not soak it in surgical spirit or wash or lubricate it. This may damage themechanism.

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