HUMALOG* Mix25 100U/ml suspension for injection in vial.

HUMALOG Mix25 100U/ml suspension for injection in cartridge.

HUMALOG Mix25 100U/ml KwikPen, suspension for injection.

HUMALOG Mix50 100U/ml suspension for injection in cartridge.

HUMALOG Mix50 100U/ml KwikPen, suspension for injection.

2.1 General description

HUMALOG Mix25 and HUMALOG Mix50 are white, sterile, suspensions.

2.2 Qualitative and quantitative composition

One ml contains 100U (equivalent to 3.5mg) insulin lispro (recombinant DNA origin produced in E. coli).

Vials

Each container includes 10ml equivalent to 1000U insulin lispro.

Cartridges and KwikPens

Each container includes 3ml equivalent to 300U insulin lispro.

HUMALOG Mix25 consists of 25% insulin lispro solution and 75% insulin lispro protamine suspension.

HUMALOG Mix50 consists of 50% insulin lispro solution and 50% insulin lispro protamine suspension.

For a full list of excipients, see section 6.1.

Suspension for injection.

HUMALOG Mix25 or HUMALOG Mix50 is indicated for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis.

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

HUMALOG Mix25 or HUMALOG Mix50 may be given shortly before meals. When necessary, HUMALOG Mix25 or HUMALOG Mix50 can be given soon after meals. HUMALOG Mix25 or HUMALOG Mix50 should only be given by subcutaneous injection. Under no circumstances should HUMALOG Mix25 or HUMALOG Mix50 be given intravenously.

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 Mix25 or 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.

The rapid onset and early peak of activity of HUMALOG itself is observed following the subcutaneous administration of HUMALOG Mix25 or HUMALOG Mix50. This allows HUMALOG Mix25 or HUMALOG Mix50 to be given very close to mealtime. The duration of action of the insulin lispro protamine suspension (BASAL) component of HUMALOG Mix25 or HUMALOG Mix50 is similar to that of a basal insulin (NPH [isophane]).

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 Mix25 or HUMALOG Mix50 is dependent on dose, site of injection, blood supply, temperature and physical activity.

Hypoglycaemia.

Under no circumstances should HUMALOG Mix25 or HUMALOG Mix50 be given intravenously.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, NPH, lente, 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.

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 may be reduced in the presence of renal 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.

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.

Administration of insulin lispro to children below 12 years of age should be considered only in case of an expected benefit when compared to soluble insulin.

Combination of HUMALOG Mix25 or 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 Mix25 or 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.

Insulin requirements may be increased by substances with hyperglycaemic activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta₂ 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 Mix25 or HUMALOG Mix50 with other insulins has not been studied.

The physician should be consulted when using other medications in addition to HUMALOG Mix25 or HUMALOG Mix50 (see section 4.4).

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.

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

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).

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.

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.

Local allergy in patients is common (1/100 to <1/10). 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, which is rare (1/10,000 to <1/1,000) 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 at the injection site is uncommon (1/1,000 to <1/100).

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

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.

Pharmacotherapeutic group: HUMALOG Mix25 and HUMALOG Mix50 are premixed suspensions consisting of insulin lispro (fast-acting human insulin analogue) and insulin lispro protamine suspension (intermediate-acting human insulin analogue). 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 Mix25 or 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.

Clinical trials in patients with Type 1 and Type 2 diabetes have demonstrated reduced postprandial hyperglycaemia with HUMALOG Mix25 compared to human insulin mixture 30/70. In one clinical study there was a small (0.38mmol/l) increase in blood glucose levels at night (3 a.m.).

In the figures below the pharmacodynamics of HUMALOG Mix25, HUMALOG Mix50 and BASAL are illustrated.

The above representations reflect 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.

In two 8-month open-label crossover studies, Type 2 diabetes patients who were either new to insulin therapy or already using one or two injections of insulin received 4 months of treatment with HUMALOG Mix25 (used twice daily with metformin) and insulin glargine (used once daily with metformin) in a randomised sequence. Detailed information can be found in the following table.

¹From baseline to end of HUMALOG Mix25 treatment.

²In patients randomised to HUMALOG Mix25 during the first crossover period.

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 Mix25 or HUMALOG Mix50 are representative of the individual pharmacokinetic properties of the two components. When considering the clinical relevance of these kinetics, it is more appropriate to examine the glucose utilisation curves (as discussed in section 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.

In 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.

HUMALOG Mix25: Protamine sulphate, m-cresol (1.76mg/ml), phenol (0.80mg/ml), glycerol, dibasic sodium phosphate.7H₂O, zinc oxide, water for injections. Hydrochloric acid and sodium hydroxide may be used to adjust pH to 7.0-7.8.

HUMALOG Mix50: Protamine sulphate, m-cresol (2.20mg/ml), phenol (1.00mg/ml), glycerol, dibasic sodium phosphate.7H₂O, zinc oxide, water for injections. Hydrochloric acid and sodium hydroxide may be used to adjust pH to 7.0-7.8.

Mixing HUMALOG Mix25 or 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.

Unopened vials

3 years

Unused cartridges & pre-filled pens

After cartridge insertion, or after first use (vial and pre-filled pen)

28 days

Unused cartridge and unused pre-filled pens

After cartridge insertion or first use (pre-filled pen)

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

Vials

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

Unopened vials

Store in a refrigerator (2°C - 8°C).

After first use (vials only)

Store in a refrigerator (2°C - 8°C) or below 30°C.

HUMALOG Mix25 100U/ml suspension for injection in vial

The suspension is contained in Type I flint glass vials, sealed with butyl or halobutyl stoppers, and secured with aluminium seals. Dimeticone or silicone emulsion may have been used to treat the vial stoppers.

1 x 10ml HUMALOG Mix25 vial.

HUMALOG Mix25 or HUMALOG Mix50 100U/ml suspension for injection in 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 3ml HUMALOG Mix25 cartridges for a 3ml pen.

2 x (5 x 3ml) HUMALOG Mix25 cartridges for a 3ml pen.

5 x 3ml HUMALOG Mix50 cartridges for a 3ml pen.

2 x (5 x 3ml) HUMALOG Mix50 cartridges for a 3ml pen.

HUMALOG Mix25 or HUMALOG Mix50 100U/ml KwikPen, suspension for injection

The suspension is contained in Type I flint glass cartridges, sealed with 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. The 3ml cartridges are sealed in a disposable pen injector, called the 'KwikPen'. Needles are not included.

5 x 3ml HUMALOG Mix25 100U/ml KwikPens.

2 x (5 x 3ml) HUMALOG Mix25 100U/ml KwikPens.

5 x 3ml HUMALOG Mix50 100U/ml KwikPens.

2 x (5 x 3ml) HUMALOG Mix50 100U/ml KwikPens.

Not all packs may be marketed.

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

HUMALOG Mix25 100U/ml suspension for injection in vial

Instructions for Use and Handling

The vial is to be used in conjunction with an appropriate syringe (100 U markings).

a) Vial - Preparing a dose

Vials containing HUMALOG Mix25 should be rotated in the palms of the hands before use to resuspend the insulin until it appears uniformly cloudy or milky. Do not shake vigorously as this may cause frothing which may interfere with the correct measurement of the dose. The vials 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 vial, giving it a frosted appearance.

1. Wash your hands.

2. If using a new vial, flip off the plastic protective cap, but do not remove the stopper.

3. Draw air into the syringe equal to the prescribed HUMALOG Mix25 dose. Wipe the top of the vial with an alcohol swab. Put the needle through rubber top of the HUMALOG Mix25 vial and inject the air into the vial.

4. Turn the vial and syringe upside down. Hold the vial and syringe firmly in one hand.

5. Making sure the tip of the needle is in the HUMALOG Mix25, withdraw the correct dose into the syringe.

6. Before removing the needle from the vial, check the syringe for air bubbles that reduce the amount of HUMALOG Mix25 in it. If bubbles are present, hold the syringe straight up and tap its side until the bubbles float to the top. Push them out with the plunger and withdraw the correct dose.

7. Remove the needle from the vial and lay the syringe down so that the needle does not touch anything.

b) Vial - Injecting a dose

1. Choose a site for injection.

2. Clean the skin as instructed.

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

4. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.

5. Dispose of the syringe and needle safely.

6. Use of the injection sites should be rotated so that the same is not used more than approximately once a month.

HUMALOG Mix25 or HUMALOG Mix50 100U/ml suspension for injection in cartridges

Instructions for Use and Handling

HUMALOG Mix25 or HUMALOG Mix50 cartridges are to be used with a CE marked pen as recommended in the information provided by the device manufacturer.

a) Cartridge - Preparing a dose

Cartridges containing HUMALOG Mix25 or HUMALOG Mix50 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 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.

The cartridges 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 cartridge, giving a frosted appearance.

HUMALOG Mix25 or HUMALOG Mix50 cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled.

The following is a general description. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection.

b) Cartridge - Injecting a dose

1. Wash your hands.

2. Choose a site for injection.

3. Clean the skin as instructed.

4. Remove outer needle cap.

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

6. Press the knob.

7. Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.

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

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

HUMALOG Mix25 or HUMALOG Mix50 100U/ml KwikPen, suspension for injection

a) Instructions for use and handling

The KwikPen 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 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.

The cartridges 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 cartridge, giving a frosted appearance.

b) 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.

Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA Houten, The Netherlands.

13 April 2012

POM

*HUMALOG, HUMALOG MIX25, HUMALOG MIX50 (insulin lispro) and KWIKPEN are trademarks of Eli Lilly and Company.

HLG42M