HUMALOG 200U / ml injection for pre-filled pen medication leaflet

Humalog 200 units/ml KwikPen solution for injection in a pre-filled pen

Each ml contains 200 units insulin lispro*(equivalent to 6.9 mg).

Each pre-filled pen contains 600 units of insulin lispro in 3 ml solution.

Each KwikPen delivers 1-60 units in steps of 1 unit.

* produced in E.coli by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless, aqueous solution.

For the treatment of adults with diabetes mellitus who require insulin for the maintenance of normalglucose homeostasis. Humalog 200 units/ml KwikPen is also indicated for the initial stabilisation ofdiabetes mellitus.

The dosage should be determined by the physician, according to the requirement of the patient.

Humalog may be given shortly before meals. When necessary Humalog can be given soon after meals.

Humalog takes effect rapidly and has a shorter duration of activity (2 to 5 hours) given subcutaneouslyas compared with soluble insulin. This rapid onset of activity allows a Humalog injection to be givenvery close to mealtime. The time course of action of any insulin may vary considerably in differentindividuals or at different times in the same individual. The faster onset of action compared to solublehuman insulin is maintained regardless of injection site. The duration of action of Humalog isdependent on dose, site of injection, blood supply, temperature, and physical activity.

Humalog can be used in conjunction with a longer-acting insulin or oral sulphonylurea medicinalproducts, on the advice of a physician.

Humalog KwikPens

Humalog KwikPen is available in two strengths.The Humalog 200 units/ml KwikPen (and Humalog100 units/ml KwikPen, see separate SmPC) delivers 1 - 60 units in steps of 1 unit in a single injection.

The number of insulin units is shown in the dose window of the pen regardless of strength and nodose conversion should be done when transferring a patient to a new strength or to a pen with adifferent dose step.

Humalog 200 units/ml KwikPen should be reserved for the treatment of patients with diabetesrequiring daily doses of more than 20 units of rapid-acting insulin. The insulin lispro solutioncontaining 200 units/ml should not be withdrawn from the pre-filled pen (the KwikPen) or mixed withany other insulin (see section 4.4 and section 6.2).

Insulin requirements may be reduced in the presence of renal impairment.

Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity forgluconeogenesis and reduced insulin breakdown; however, in patients with chronic hepaticimpairment, an increase in insulin resistance may lead to increased insulin requirements.

Humalog solution for injection should be given subcutaneously.

Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen. Use ofinjection sites should be rotated so that the same site is not used more than approximately once amonth, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and4.8).

When administered subcutaneously care should be taken when injecting Humalog to ensure that ablood vessel has not been entered. After injection, the site of injection should not be massaged.

Patients must be educated to use the proper injection techniques.

Humalog 200 units/ml KwikPen solution for injection should not be used in an insulin infusion pump.

Humalog 200 units/ml KwikPen solution for injection should not be used intravenously.

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Transferring a patient to another type or brand of insulin

Transferring a patient to another type or brand of insulin should be done under strict medicalsupervision. Changes in strength, brand (manufacturer), type (regular/soluble, NPH/isophane, etc.),species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNAversus animal-source insulin) may result in the need for a change in dosage. For fast-acting insulins,any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control acrossthe whole day, particularly nocturnal/fasting glucose control.

Hypoglycaemia and hyperglycaemia

Conditions which may make the early warning symptoms of hypoglycaemia different or lesspronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease ormedicinal products such as beta-blockers.

A few patients who have experienced hypoglycaemic reactions after transfer from animal-sourceinsulin to human insulin have reported that the early warning symptoms of hypoglycaemia were lesspronounced or different from those experienced with their previous insulin. Uncorrectedhypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma, or death.

The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which arepotentially lethal.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia.

Blood glucose monitoring is recommended after the change in the injection site, and dose adjustmentof antidiabetic medications may be considered.

Insulin requirements and dosage adjustment

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of dosage may also be necessary if patients undertake increased physical activity orchange their usual diet. Exercise taken immediately after a meal may increase the risk ofhypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that ifhypoglycaemia occurs, it may occur earlier after an injection when compared with soluble humaninsulin.

Combination of Humalog with pioglitazone

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin,especially in patients with risk factors for development of cardiac heart failure. This should be kept inmind, if treatment with the combination of pioglitazone and Humalog is considered. If thecombination is used, patients should be observed for signs and symptoms of heart failure, weight gainand oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.

Avoidance of medication errors when using insulin lispro (200 units/ml) in pre-filled pen:

The insulin lispro solution for injection containing 200 units/ml must not be transferred from the pre-filled pen, the KwikPen, to a syringe. The markings on the insulin syringe will not measure the dosecorrectly. Overdose can result causing severe hypoglycemia. The insulin lispro solution for injectioncontaining 200 units/ml must not be transferred from the KwikPen to any other insulin deliverydevice, including insulin infusion pumps.

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between the two different strengths of Humalog as well as other insulin products.

Patients must visually verify the dialled units on the dose counter of the pen. Therefore, therequirement for patients to self-inject is that they can read the dose counter on the pen. Patients whoare blind or have poor vision must be instructed to always get help/assistance from another person whohas good vision and is trained in using the insulin device.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially“sodium-free”.

Insulin requirements may be increased by medicinal products with hyperglycaemic activity, such asoral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta2 stimulants (such asritodrine, salbutamol, terbutaline).

Insulin requirements may be reduced in the presence of medicinal products with hypoglycaemicactivity, such as oral hypoglycemics, salicylates (for example, acetylsalicylic acid), sulpha antibiotics,certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), certainangiotensin converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor blockers, beta-blockers, octreotide or alcohol.

The physician should be consulted when using other medicinal products in addition to Humalog200 units/ml KwikPen (see section 4.4).

Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro onpregnancy or on the health of the foetus/newborn.

It is essential to maintain good control of the insulin-treated (insulin-dependent or gestationaldiabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester andincrease during the second and third trimesters. Patients with diabetes should be advised to informtheir doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucosecontrol, as well as general health, is essential in pregnant patients with diabetes.

Patients with diabetes who are breast-feeding may require adjustments in insulin dose, diet or both.

Insulin lispro did not induce fertility impairment in animal studies (see section 5.3).

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 or usingmachines).

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.

Hypoglycaemia is the most frequent adverse reaction of insulin lispro therapy that a patient withdiabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases,death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of boththe insulin dose and other factors e.g. a patient`s level of diet and exercise.

The following related adverse reactions from clinical trials are listed below as MedDRA preferredterm by system organ class and in order of decreasing incidence (very common: ≥1/10; common:≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000) ;not known (cannot be estimated form the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system Very Common Uncommon Rare Very Notorgan classes common rare known

Local allergy X

Systemic allergy X

Lipodystrophy X

Cutaneous

Xamyloidosis

Local allergy

Local allergy in patients is common). Redness, swelling, and itching can occur at the site of insulininjection. This condition usually resolves in a few days to a few weeks. In some instances, thiscondition may be related to factors other than insulin, such as irritants in the skin cleansing agent orpoor injection technique.

Systemic allergy

Systemic allergy, which is rare but potentially more serious, is a generalised allergy to insulin. It maycause a rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fastpulse, or sweating. Severe cases of generalised allergy may be life-threatening.

Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulinabsorption. Continuous rotation of the injection site within the given injection area may help to reduceor prevent these reactions (see section 4.4).

Oedema

Cases of oedema have been reported with insulin therapy, particularly if previous poor metaboliccontrol is improved by intensified insulin therapy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Insulins have no specific overdose definitions because serum glucose concentrations are a result ofcomplex interactions between insulin levels, glucose availability and other metabolic processes.

Hypoglycaemia may occur as a result of an excess of insulin activity relative to food intake and energyexpenditure.

Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating andvomiting.

Mild hypoglycaemic episodes will respond to oral administration of glucose or other sugar orsaccharated products.

Correction of moderately severe hypoglycaemia can be accomplished by intramuscular orsubcutaneous administration of glucagon, followed by oral carbohydrate when the patient recoverssufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.

If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously.

However, glucose solution must be given intravenously if glucagon is not available or if the patientfails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.

Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recurafter apparent clinical recovery.

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

ATC code: A10AB04

The primary activity of insulin lispro is the regulation of glucose metabolism.

In addition, insulins have several anabolic and anti-catabolic actions on a variety of different tissues.

Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and protein synthesis andamino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, proteincatabolism and amino acid output.

Insulin lispro has a rapid onset of action (approximately 15 minutes), thus allowing it to be givencloser to a meal (within zero to 15 minutes of the meal) when compared to soluble insulin(30 to 45 minutes before). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to5 hours) when compared to soluble insulin.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated reduced postprandialhyperglycaemia with insulin lispro compared to soluble human insulin.

The time course of insulin lispro action may vary in different individuals or at different times in thesame individual and is dependent on dose, site of injection, blood supply, temperature and physicalactivity. The typical activity profile following subcutaneous injection is illustrated below.

Figure 1:

The above representation (figure 1) reflects the relative amount of glucose over time required tomaintain the subject's whole blood glucose concentrations near fasting levels and is an indicator of theeffect of these insulins (100 units/ml) on glucose metabolism over time.

The pharmacodynamic responses of insulin lispro 200 units/ml solution for injection were similar tothose for insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single20 unit dose in healthy subjects as shown in the graph below (figure 2).

Insulin lispro 200 units/ml

Glucose 600 Insulin lispro 100 units/ml

Infusion

Rate(mg/min) 4000 1 2 3 4 5 6 7 8

Time (hr)

Figure 2: Arithmetic mean glucose infusion rate versus time profiles following subcutaneousadministration of 20 units of insulin lispro 200 units/ml or insulin lispro 100 units/ml

In patients with type 2 diabetes on maximum doses of sulphonyl urea agents, studies have shown thatthe addition of insulin lispro significantly reduces HbA1c compared to sulphonyl urea alone. Thereduction of HbA1c would also be expected with other insulin products e.g. soluble or isophaneinsulins.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated a reduced number ofepisodes of nocturnal hypoglycaemia with insulin lispro compared to soluble human insulin. In somestudies, reduction of nocturnal hypoglycaemia was associated with increased episodes of daytimehypoglycaemia.

The glucodynamic response to insulin lispro is not affected by renal or hepatic function impairment.

Glucodynamic differences between insulin lispro and soluble human insulin, as measured during aglucose clamp procedure, were maintained over a wide range of renal function.

Insulin lispro has been shown to be equipotent to human insulin on a molar basis but its effect is morerapid and of a shorter duration.

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peakblood levels 30 to 70 minutes following subcutaneous injection. When considering the clinicalrelevance of these kinetics, it is more appropriate to examine the glucose utilisation curves (asdiscussed in 5.1).

Insulin lispro maintains more rapid absorption when compared to soluble human insulin in patientswith renal impairment. In patients with type 2 diabetes over a wide range of renal function thepharmacokinetic differences between insulin lispro and soluble human insulin were generallymaintained and shown to be independent of renal function. Insulin lispro maintains more rapidabsorption and elimination when compared to soluble human insulin in patients with hepaticimpairment.

Insulin lispro 200 units/ml solution for injection was bioequivalent to insulin lispro 100 units/mlsolution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects.

Time to maximum concentration was also similar between formulations.

In in vitro tests, including binding to insulin receptor sites and effects on growing cells, insulin lisprobehaved in a manner that closely resembled human insulin. Studies also demonstrate that thedissociation of binding to the insulin receptor of insulin lispro is equivalent to human insulin. Acute,one month and twelve month toxicology studies produced no significant toxicity findings.

Insulin lispro did not induce fertility impairment, embryotoxicity or teratogenicity in animal studies.

m-Cresol

Glycerol

Trometamol

Zinc oxide

Water for injections

Hydrochloric acid and sodium hydroxide may be used to adjust pH.

This medicinal product should not be mixed with any other insulin or any other medicinal product.

The solution for injection should not be diluted.

Before use3 years.

After first use28 days.

Do not freeze. Do not expose to excessive heat or direct sunlight.

Store in a refrigerator (2°C - 8°C).

After first use

Store below 30°C. Do not refrigerate. The pre-filled pen should not be stored with the needle attached.

Type I glass cartridges, sealed with halobutyl disc seals and plunger heads and secured withaluminium seals. Dimeticone or silicone emulsion may be used to treat the cartridge plunger, and/orthe glass cartridge. The 3 ml cartridges which contain 600 units insulin lispro (200 units/ml), aresealed in a disposable pen injector, called the “KwikPen”. Needles are not included.

1 pre-filled pen of 3 ml2 pre-filled pens of 3 ml5 pre-filled pens of 3 ml

Multipacks containing 10 (2 packs of 5) pre-filled pens of 3 ml

Not all packs may be marketed.

Instructions for use and handling

To prevent the possible transmission of disease, each pen must be used by one patient only, even if theneedle is changed. The patient should discard the needle after every injection.

The Humalog solution should be clear and colourless. Humalog should not be used if it appearscloudy, thickened, or slightly coloured or if solid particles are visible.

Handling of the pre-filled pen

Before using the KwikPen the user manual included in the package leaflet must be read carefully. The

KwikPen has to be used as recommended in the user manual.

Pens should not be used if any part looks broken or damaged.

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

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

EU/1/96/007/039

EU/1/96/007/040

EU/1/96/007/041

EU/1/96/007/042

Date of first authorisation: 30th April 1996

Date of last renewal: 30th April 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu