HUMALOG MIX 25

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PATIENT LEAFLET IN ACCORDANCE WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

This medicine is dispensed by a physician’s prescription only

Humalog Mix 50

Suspension

Active ingredient and its concentration:

Each cartridge contains:

Insulin Lispro 100 U/ml

50% Insulin Lispro (free fast-acting) and 50% Insulin Lispro Protamine in suspension (long-

acting)

For the list of inactive ingredients, please see section 6.

Read this patient leaflet carefully in its entirety before you start using this medicine. This

leaflet contains concise information about this medicine. If you have any further questions,

please contact your doctor or pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to others. It may harm

them, even if it seems to you that their illness is similar.

1. WHAT IS THIS MEDICINE INTENDED FOR?

For the treatment of diabetes in patients who require insulin to maintain balanced blood sugar

levels.

Therapeutic group:

Insulins and insulin analogs.

Insulin is a hormone secreted by the pancreas, a gland located near the stomach. This

hormone is essential to the body in utilizing glucose obtained from the food. Diabetes occurs

when the pancreas does not provide the sufficient amount of insulin to meet the body’s needs.

To balance the diabetes, the doctor has prescribed insulin injections for you.

Humalog Mix 50 is a faster acting insulin than the regular insulin mixture, therefore it can be

injected close to mealtime, before or shortly after.

2. BEFORE USING THIS MEDICINE:

Do not use the preparation if:

You are sensitive (allergic) to one of the medicine’s ingredients.

Do not use in a state of hypoglycemia (low blood sugar).

Special warnings regarding the use of this medicine:

Do not inject Humalog Mix 50 directly into the vein!

Before starting treatment with Humalog Mix 50 tell your doctor if:

You suffer from fever and vomiting or an emotional disturbance.

You suffer or have suffered in the past from impaired function of: the liver, kidney/urinary

system, thyroid gland.

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A change in the type of insulin usually requires a dosage adjustment; therefore, every change

should be made under the supervision of the attending doctor. In certain cases, the usual dose

may cause hypoglycemia, which is a result of administering a dose of insulin that is too high,

skipping a meal, more than usual physical activity or following an illness (vomiting, diarrhea,

fever). Initial symptoms of hypoglycemia can manifest as cold sweat, tachycardia, headache,

vomiting, fever, nervousness, tremor, confusion or apathy. These symptoms can pass with the

consumption of sugar or food that contains sugar (it is therefore desirable to always carry

around with you sugar cubes or sucking candies).

Your relatives and colleagues must know that you are diabetic and how they can help you in a

state of hypoglycemia. They must know that an unconscious person should not be given food or

drink for fear of choking. They should roll the patient over on his side and call for immediate

medical help. Unconsciousness can be treated with an injection of glucagon, performed by a

person who has been trained in dealing with these situations. Upon regaining consciousness,

the patient should be instructed to take sugar orally. Consult your doctor if you have experienced

repetitive reactions to insulin or another event that was accompanied by unconsciousness, since

in these cases changing the dose of insulin is necessary. If a significant drop in blood sugar

level is left untreated, it could cause loss of consciousness, temporary or permanent brain

damage and even death.

Diabetic ketosis, ketoacidosis or loss of consciousness can result from very high sugar levels in

the blood - hyperglycemia. This condition can occur if there is an increased demand for insulin

during an illness, infection, mental stress, failure to maintain a proper diet or injecting a smaller

amount of insulin than what has been prescribed by the attending physician. Ketoacidosis

symptoms can be diagnosed through a urine test that shows high levels of sugar and acetone.

The following symptoms can gradually develop within hours or days: thirst, excessive urine

volumes, loss of appetite, fatigue, dry skin, rapid and deep breathing, flushing, acetone odor

from the breath. If you feel any of these symptoms and/or breathe heavily and have a rapid

pulse, consult your doctor immediately. If these symptoms are left untreated, they can cause

diabetic coma and death.

You should tell your doctor, pharmacist or diabetes nurse whether you plan to go abroad. Due to

the time difference between countries, you may have to change the times of your meals and

injections.

Please tell your doctor or pharmacist

if you are taking or have recently taken any

other medicines, including non-prescription medications and nutritional

supplements.

The insulin requirement of the body may change upon concomitant administration with

medicines such as:

Contraceptive pills

Steroids

Thyroid hormones

Oral antidiabetic medicines

Salicylates (for example: acetylsalicylic acid - aspirin)

Sulfa antibiotics

Octreotide (for the treatment of pulmonary hypertension)

Beta-2 agonists (for example: salbutamol, terbutaline)

Beta-blockers (for blood pressure or the heart)

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Certain antidepressant drugs (MAOIs or SSRIs)

Danazol

Certain ACE inhibitors (given for blood pressure and the heart), for example: captopril

and enalapril

Angiotensin II receptor blockers

Cases of heart failure were reported in type 2 diabetes patients who also suffer from a heart

disease or have experienced a stroke in the past, who have been treated with insulin in

combination with preparations containing pioglitazone (an oral medicine for the treatment of

diabetes). Therefore, inform your doctor as soon as possible if you experience symptoms such

as: unusual shortness of breath, rapid weight gain or localized swelling (oedema).

Use of this medicine and food:

Consult the doctor.

Use of this medicine and alcohol consumption:

Insulin requirement may decrease during concomitant use of alcohol. Dosage adjustment may

be required.

Pregnancy and breastfeeding

:

Consult a doctor or pharmacist before using this medicine.

Data on a large number of women who have used insulin lispro during pregnancy did not

indicate any adverse effect of insulin lispro on the pregnancy, health of the fetus or newborn.

Nevertheless, during pregnancy it is particularly important to maintain balanced blood sugar

levels.

Insulin requirements usually decrease during the first trimester of pregnancy and increase during

the second and third trimesters.

If you are breastfeeding, there may be a need to change your insulin dosage or diet. Consult

your doctor.

Driving and using machines:

The ability to concentrate and react may be impaired as a result of hypoglycemia or

hyperglycemia, which can be dangerous when driving a car or operating heavy machinery. If you

suffer from frequent episodes of hypoglycemia or unclear symptoms preceding an episode of

hypoglycemia, consult your doctor about whether you should drive.

3. HOW TO USE THIS MEDICINE?

Always use according to your doctor's instructions.

The dosage and manner of treatment will be determined only by the doctor.

Humalog Mix 50 is intended for subcutaneous injection. Under no circumstances should you

inject intravenously.

Do not mix Humalog Mix 50 with any other type of insulin.

Below are general instructions for injection. For detailed instructions, please see the user

manual enclosed in the package of the pen.

Before using Humalog Mix 50, it is very important to read the detailed instructions carefully and

follow them strictly. Failure to follow the instructions may result in an inaccurate insulin dose.

The amount of insulin for injection is measured in units. It is important to recognize the unit

marks on the injector pen, because the volume of insulin that is injected is calculated based on

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the number of units per ml. Use only an appropriate injector pen. Using an inappropriate injector

pen may result in an inaccurate insulin dose.

Humalog Mix 50 is presented as a white or milky suspension. The cartridge contains a small

bead to assist mixing the suspension. Examine the insulin in use frequently. Do not use if there

are clumps or solid particles stuck to the walls or bottom of the cartridge, giving the suspension

a frothy appearance.

Discarding of disposable needles after use must be strictly maintained according to the

instructions from the medical staff, in order to prevent infections. The pen and needle must be

used exclusively by you, even if you have changed the needle, in order to prevent the possibility

of transmission of diseases.

Do not store the pen in use with the needle attached.

Preparing an insulin dose when using a cartridge:

Wash your hands thoroughly. Disinfect the rubber stopper of the cartridge.

Check the appearance of insulin in the cartridge. Do not use the insulin cartridge if you

notice a change in appearance.

Humalog Mix 50 cartridges are to be used with Eli Lilly company pens only. Make sure

that Humalog Mix or Lilly cartridges are mentioned in the leaflet enclosed in the injector

pen package. Insert the cartridge into the injector pen.

Follow the instructions that appear in the leaflet enclosed in the injector pen package.

Prime the injector pen before each use. Set the injector pen to a dose of 1 or 2 units.

Hold the injector pen with the needle pointed up and tap on it so that air bubbles will rise

to the top. While the injector pen is still pointing up, press the injection button until a drop

of Humalog Mix 50 comes out of the needle. A few small air bubbles may remain in the

injector pen. That is harmless, but if the air bubble is too big, the injected insulin dose

may be less accurate.

Do not mix insulins of different types in the Humalog Mix 50 cartridge. Do not reuse the

empty cartridge. After the injection, leave the cartridge inside the injector pen.

You can see how much Humalog Mix 50 remains in the cartridge by looking at the

gauge marked on it. The distance between each mark on the gauge is about 20 units. In

case there is not enough Humalog Mix 50 for one dose, replace the cartridge.

General instructions for injection:

Use a new needle for each injection in order to prevent infections.

Wash your hands thoroughly.

Before injecting, roll the injector pen in your hands about 10 times and invert it 180°

about 10 times until the insulin is evenly mixed. This action may be repeated. Do not

shake vigorously as this may cause frothing which may interfere with the correct

measurement of the dose.

Set the injector pen to the desired dose according to the injector pen instructions for use.

Clean the injection site with an alcohol-soaked swab.

"Pinch" a wide area of skin and lift it.

Insert the injector pen needle under the skin.

Inject the insulin by pushing the injection button all the way down and wait 5 seconds

before retracting the needle from the skin.

Pull the injector pen needle out at a straight angle. Do not rub the injection site.

Put the external cover of the needle back on and discard the disposable items in

accordance with the instructions provided to you by the medical staff.

10. Immediately after injecting, remove the needle from the injector pen in order to ensure

sterility, prevent leakage of insulin from the injector pen, entry of air and needle clogging.

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Do not reuse the needle. Destroy the needle according to the instructions received from

the medical staff. Return the pen cover to its place.

11. Change the injection site each time.

Consult your doctor or nurse about desirable injection sites.

Do not mix different insulin types in the Humalog Mix 50 cartridge. Do not reuse the

cartridge if it is empty.

Do not exceed the recommended dose.

Tests and follow up:

During the course of treatment with this medicine, blood and urine tests should be carried out.

If you have accidentally taken a higher dose,

you may experience low blood sugar

levels. Check your blood sugar level.

If you are experiencing mild hypoglycemia, eat sugar or drink a sweet beverage. Afterwards, eat

a fruit, a biscuit or a sandwich, in accordance with the doctor’s instructions. You should rest after

a mild hypoglycemic event.

If you have taken an overdose or if a child has accidentally swallowed the medicine, proceed

immediately to a doctor or hospital emergency room and bring the package of the medicine with

you.

If your condition worsens, breathing becomes shallow and skin turns pale, inform your doctor

immediately. In cases of severe hypoglycemia, a glucagon injection can be used. After the

injection, you should eat sugar or glucose.

If you do not respond to the glucagon injection, you should be admitted to the hospital.

If you have forgotten to inject Humalog Mix 50,

you may experience high blood sugar

levels.

If hypoglycemia or hyperglycemia are left untreated, you may experience: headaches, nausea,

vomiting, dehydration, loss of consciousness and even death.

If you are ill, you may need to adjust your insulin dosage. Even if you are not eating as usual,

you still require insulin! Test your blood and urine and inform the doctor accordingly.

Even if there is an improvement in your health condition, do not stop treatment with this

medicine without consulting your doctor.

Do not take medicines in the dark! Check the label and dose each time you take your medicine.

Wear glasses if you need them.

If you have further questions regarding the use of this medicine, consult a doctor or pharmacist.

4. SIDE EFFECTS:

As with any medicine, using Humalog Mix 50 may cause side effects in some users. Do not be

alarmed while reading the list of side effects, you may not experience any of them.

Hypoglycemia is the most common side effect that patients treated with insulin may experience.

Severe hypoglycemia may lead to loss of consciousness and in extreme cases, even death.

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Hypoglycemia may occur as a result of a combination of insulin dosage and other factors such

as the patient's nutrition and physical activity.

The first symptoms of low blood sugar levels appear quickly and include: tiredness, nervousness

or tremor, headache, rapid heartbeat, nausea and cold sweat.

Oedema - swelling of the arms, ankles, fluid retention, particularly at the beginning of treatment

with insulin or during a change in treatment.

Side effects and drug interactions in children and infants:

Parents should report to the doctor about any side effect or additional medicine given to the

child!

Common side effects:

Local allergy: redness, swelling, itching at the injection site. This side effect usually clears up

within several days or weeks, following the period of adaptation to the medicine.

Uncommon side effects:

Lipodystrophy (thickening of the skin around the injection area) – continue your treatment and

refer to a doctor immediately!

Rare side effects:

Systemic allergy: rash over the whole body, shortness of breath, wheezing, drop in blood

pressure, fast heartbeat or sweating. Severe cases of a generalised allergy can be life-

threatening. Notify the doctor immediately!

If any of these side effects gets worse, or if you suffer from a side effect not mentioned in this

leaflet, consult the doctor.

Side effects may be reported to the Ministry of Health by using the on-line form in the following

link:

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic%40

moh.health.gov.il

5. HOW TO STORE THIS MEDICINE?

Before opening, store refrigerated at a temperature of 2

C. Do not freeze.

During use, do not store in a refrigerator, but in a place as cool as possible (below 30

Do not expose to direct sunlight or excessive heat. The insulin can be used for up to 28

days from first opening.

Do not use the medicine after the expiry date (exp. date) stated on the package. The

expiry date refers to the last day of that month.

In case of any doubt, consult the pharmacist who dispensed this medicine to you.

Avoid poisoning! This medicine, and all other medicines, must be stored in a closed

place out of the reach and sight of children and/or infants, to avoid poisoning. Do not

induce vomiting unless explicitly instructed to do so by the doctor.

Do not store different medications in the same package.

Do not throw the medication into the sewer or household waste bin. Ask your pharmacist

how to dispose of medications which you no longer need – this will help protect the

environment.

6. ADDITIONAL INFORMATION

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In addition to the active ingredients, Humalog Mix 50 also contains:

Dibasic Sodium Phosphate, Glycerol, Liquefied Phenol, Metacresol, Protamine Sulphate, Zinc

Oxide, Hydrochloric Acid Solution 10%, Sodium Hydroxide Solution 10%, water for injection.

What the medicine looks like and contents of the package:

Humalog Mix 50 is a white sterile suspension. Each cartridge contains 300 units (3 ml). Every

package contains 5 cartridges.

Registration holder:

Eli Lilly Israel Ltd., P.O.B. 2160, Herzliya Pituach 46120

Manufacturer

: Eli Lilly & Company Ltd., Indianapolis, Indiana, USA

Manufacturing site:

Eli Lilly Italia S.p.A, Sesto Fiorentino, Italy

Lilly France S.A.S., Fegersheim, France

Drug registration number at the national medicines registry of the Ministry of

Health:

Humalog Mix 50: 115-35-29723

This leaflet was reviewed and approved by the Ministry of Health in April 2017.

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HUMALOG MIX 50

1.

NAME OF THE MEDICINAL PRODUCT

Humalog Mix50 100 units/ml suspension for injection in

cartridge

2.

Qualitative and quantitative composition

Each ml contains 100 units insulin lispro* (equivalent to 3.5mg).

Humalog Mix50 consists of 50% insulin lispro solution and 50% insulin lispro protamine

suspension.

Each cartridge contains 300 units of insulin lispro in 3 ml suspension

*produced in

E.coli

by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Suspension for injection.

White suspension.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Humalog Mix50 is indicated for the treatment of patients with diabetes mellitus who require insulin for

the maintenance of normal glucose homeostasis.

4.2

Posology and method of administration

Posology

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

Humalog Mix50 may be given shortly before meals. When necessary, Humalog Mix50 can be

given soon after meals. Humalog Mix50 should only be given by subcutaneous injection. Under no

circumstances should Humalog Mix50 be given intravenously.

The rapid onset and early peak of activity of Humalog itself is observed following the

subcutaneous administration of Humalog Mix50. This allows Humalog Mix50 to be given

very close to mealtime.

The duration of action of the insulin lispro protamine suspension component of Humalog Mix50 is

similar to that of a basal insulin (NPH).

The time course of action of any insulin may vary considerably in different individuals or at different

times in the same individual. As with all insulin preparations, the duration of action of Humalog Mix50

is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Special populations

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Renal impairment

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

Hepatic impairment

Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for

gluconeogenesis and reduced insulin breakdown; however, in patients with chronic hepatic impairment,

an increase in insulin resistance may lead to increased insulin requirements.

Paediatric population

Administration of Humalog Mix50 to children below 12 years of age should be considered only in case of

an expected benefit when compared to soluble insulin.

Method of administration

Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen. Use of injection

sites should be rotated so that the same site is not used more than approximately once a month.

When administered subcutaneously care should be taken when injecting Humalog Mix50 to ensure that a

blood 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.

4.3

Contraindications

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

Hypoglycaemia.

4.4 Special warnings and precautions for use

Under no circumstances should Humalog Mix50 be given intravenously.

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 medical

supervision. Changes in strength, brand (manufacturer), type (regular/soluble, NPH/isophane, , etc.),

species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA

versus animal-source insulin) may result in the need for a change in dosage.

Hypoglycaemia and hyperglycaemia

Conditions which may make the early warning symptoms of hypoglycaemia different or less

pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease or

medications such as beta-blockers.

A few patients who have experienced hypoglycaemic reactions after transfer from animal-source

insulin to human insulin have reported that the early warning symptoms of hypoglycaemia were less

pronounced or different from those experienced with their previous insulin. Uncorrected

hypoglycaemic 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 are

potentially lethal.

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 or

change their usual diet. Exercise taken immediately after a meal may increase the risk of

hypoglycaemia.

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Combination of Humalog Mix50 with pioglitazone:

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin,

especially in patients with risk factors for development of cardiac heart failure. This should be kept in

mind, if treatment with the combination of pioglitazone and Humalog Mix50 is considered. If the

combination is used, patients should be observed for signs and symptoms of heart failure, weight gain

and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.

Avoidance of medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental

mix-ups between the two different strengths of Humalog as well as other insulin products.

Excipients

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

“sodium-free”.

4.5

Interaction with other medicinal products and other forms of interaction

Insulin requirements may be increased by substances with hyperglycaemic activity, such as oral

contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta

stimulants (such as

ritodrine, salbutamol, terbutaline).

Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such

as oral hypoglycaemics, salicylates (for example, acetylsalicylic acid), sulpha antibiotics, certain

antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), certain

angiotensin converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor blockers, beta-

blockers, octreotide or alcohol.

Mixing Humalog Mix50 with other insulins has not been studied.

The physician should be consulted when using other medications in addition to Humalog Mix (see

section 4.4).

4.6

Fertility, pregnancy and lactation

Pregnancy

Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin

lispro on pregnancy or on the health of the foetus/newborn.

It is essential to maintain good control of the insulin-treated (insulin-dependent or gestational diabetes)

patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase

during the second and third trimesters. Patients with diabetes should be advised to inform their doctor if

they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as

general health, is essential in pregnant patients with diabetes.

Breast-feeding

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

Fertility

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

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

may constitute a risk in situations where these abilities are of special importance (e.g. driving a car

or operating machinery).

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Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is

particularly important in those who have reduced or absent awareness of the warning signs of

hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be

considered in these circumstances.

4.8

Undesirable effects

Summary of safety profile

Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes

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 both the

insulin dose and other factors e.g. a patient`s level of diet and exercise.

Tabulated list of adverse reactions

The following related adverse reactions from clinical trials are listed below as MedDRA preferred term

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).

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

MedDRA system

organ classes

Very

common

Common

Uncommon

Rare

Very

rare

Immune system disorders

Local allergy

Systemic allergy

Skin and subcutaneous tissue disorders

Lipodystrophy

Description of selected adverse reactions

Local allergy

Local allergy in patients is common. Redness, swelling, and itching can occur at the site of insulin

injection. This condition usually resolves in a few days to a few weeks. In some instances, this

condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or

poor injection technique.

Systemic allergy

Systemic allergy, which is rare but potentially more serious, is a generalised allergy to insulin. It may

cause a rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast

pulse, or sweating. Severe cases of generalised allergy may be life- threatening.

Lipodystrophy

Lipodystrophy at the injection site is uncommon.

Oedema

Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic

control is improved by intensified insulin therapy.

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://sideeffects.health.gov.il/

4.9

Overdose

Insulins have no specific overdose definitions because serum glucose concentrations are a result of

complex 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

energy expenditure.

Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and

vomiting.

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

saccharated products.

Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous

administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently.

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 patient

fails 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

recur after apparent clinical recovery.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmaco-therapeutic group:

Drugs used in diabetes, insulins and analogues for injection, intermediate

or long acting combined with fast acting.

ATC Code: A10A D04.

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 and

amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein

catabolism and amino acid output.

Insulin lispro has a rapid onset of action (approximately 15 minutes), thus allowing it to be given

closer to a meal (within zero to 15 minutes of the meal) when compared to soluble insulin (30 to 45

minutes before). The rapid onset and early peak of activity of insulin lispro is observed following the

subcutaneous administration of Humalog Mix50. Humalog basal has an activity profile that is very

similar to that of a basal insulin (NPH) over a period of approximately 15 hours.

In the figure below the pharmacodynamics of Humalog MIX50 and BASAL are illustrated.

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The above representation reflects the relative amount of glucose over time required to maintain the

subject's whole blood glucose concentrations near fasting levels and is an indicator of the effect of

these insulins on glucose metabolism over time.

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 a

glucose 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 more

rapid and of a shorter duration.

5.2

Pharmacokinetic properties

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak

blood levels 30 to 70 minutes following subcutaneous injection. The pharmacokinetics of insulin lispro

protamine suspension are consistent with those of an intermediate acting insulin such as NPH. The

pharmacokinetics of Humalog Mix50 are representatives of the individual pharmacokinetic properties

components.

When

considering the

clinical

relevance

these

kinetics, it

more

appropriate to examine the glucose utilisation curves (as discussed in 5.1).

Insulin lispro maintains more rapid absorption when compared to soluble human insulin in patients with

renal impairment. In patients with type 2 diabetes over a wide range of renal function the

pharmacokinetic differences between insulin lispro and soluble human insulin were generally

maintained and shown to be independent of renal function. Insulin lispro maintains more rapid

absorption and elimination when compared to soluble human insulin in patients with hepatic

impairment.

5.3

Preclinical safety data

in vitro

tests, including binding to insulin receptor sites and effects on growing cells, insulin lispro

behaved in a manner that closely resembled human insulin. Studies also demonstrate that the

dissociation 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.

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6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Protamine sulphate, metaCresol, liquefied phenol, glycerol, dibasic sodium phosphate, zinc oxide,

water for injection. hydrochloric acid solution 10% and sodium hydroxide solution 10% may be used

to adjust pH.

6.2

Incompatibilities

Mixing Humalog Mix50 with other insulins has not been studied. In the absence of compatibility

studies, this medicinal product must not be mixed with other medicinal products.

6.3

Shelf life

Before use

The expiry date of the product is indicated on the packaging materials.

After cartridge insertion

28 days.

6.4

Special precautions for storage

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

Before use

Store in a refrigerator (2°C - 8°C).

After cartridge insertion

Store below 30°C. Do not refrigerate. The pen with the inserted cartridge should not be stored with

the needle attached.

6.5

Nature and contents of container

Cartridge

The suspension is contained in type I flint glass cartridges, sealed with butyl or halobutyl disc seals and

plunger heads and secured with aluminium seals. Dimeticone or silicone emulsion may have been used

to treat the cartridge plunger, and/or the glass cartridge.

5 x 3 ml Humalog Mix50 Cartridges for a 3ml pen.

6.6

Special precautions for disposal and other handling

Instructions for use and handling

To prevent the possible transmission of disease, each cartridge must be used by one patient only, even

if the needle on the delivery device is changed.

The patient should discard the needle after every

injection.

The Humalog Mix50 should be examined frequently and should not be used if clumps of material are

present or if solid white particles stick to the bottom or wall of the container, giving it a frosted

appearance.

Preparing a dose

Cartridges containing Humalog Mix 50 should be rotated in the palms of the hands ten times and

inverted 180° ten times immediately before use to resuspend the insulin until it appears uniformly

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cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small

glass bead to assist mixing.

Do not shake vigorously as this may cause frothing which may interfere with the correct measurement

of the dose.

Humalog Mix50 cartridges are to be used with a Lilly reusable insulin pen and should not be used with

any other reusable pen as the dosing accuracy has not been established with other pens.

The instructions with each individual pen must be followed for loading the cartridge, attaching the needle

and administering the insulin injection.

Injecting a dose

If using a pre-filled or reusable pen refer to the detailed instructions for preparing the pen and injecting

the dose, the following is a general description.

1. Wash your hands.

2. Choose a site for injection.

3. Clean the skin as instructed.

4. Stabilise the skin by spreading it or pinching up a large area. Insert the needle and inject as instructed.

5. Pull the needle out and apply gentle pressure over the injection site for several

seconds. Do not rub the area.

6. Using the outer needle cap, unscrew the needle and dispose of it safely.

7. Use of injection sites should be rotated so that the same site is not used

more than approximately once a month.

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

7.

MANUFACTURER

Eli Lilly & Company Ltd., USA

Lilly Technology Center, Indianapolis, Indiana 46285, USA

8.

MANUFACTURING SITE

Eli Lilly Italia S.P.A, Italy

Via A. Gramsci, 731-733, 50019, Sesto Fiorentino, Italy

Lilly France S.A.S., 2 Rue du Colonel Lilly 67640, Fegersheim, France

9.

LICENSE HOLDER

Eli Lilly Israel Ltd P.O.Box 2160, Herzliya Pituach 46120

The content of this leaflet was reviewed and approved by the Ministry of Health in April 2017, and was

updated in accordance with the Ministry of Health’s guidelines in February 2020.

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