insulin lispro: prescribing information – dosing, contraindications, interactions, side effects

For the treatment of adults and children with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Humalog is also indicated for the initial stabilisation of diabetes mellitus.

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

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

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

Posology

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

Junior KwikPen

Humalog 100 units/ml Junior KwikPen is suitable for patients who may benefit from finer insulin dose adjustments.

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 subcutaneously as compared with soluble insulin. This rapid onset of activity allows a Humalog injection (or, in the case of administration by continuous subcutaneous infusion, a Humalog bolus) to be given very close to mealtime. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. As with all insulin preparations, the duration of action of Humalog is dependent 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 agents, on the advice of a physician.

Special populations

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
Humalog can be used in adolescents and children (see section 5.1).

Method of administration

Subcutaneous use

Humalog preparations should be given by subcutaneous injection.

The KwikPen and Junior KwikPen are only suitable for subcutaneous injections. Humalog in cartridges is only suitable for subcutaneous injections from a Lilly reusable pen or compatible pump systems for continuous subcutaneous insulin infusion (CSII).

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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
When administered subcutaneously care should be taken when injecting Humalog 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.

Humalog KwikPens
Humalog KwikPen is available in two strengths. The Humalog 100 units/ml KwikPen (and Humalog 200 units/ml KwikPen, see separate SmPC) delivers 1 – 60 units in steps of 1 unit in a single injection.
The Humalog 100 units/ml Junior KwikPen delivers 0.5 – 30 units in steps of 0.5 units in a single injection. The number of insulin units is shown in the dose window of the pen regardless of strength and no dose conversion should be done when transferring a patient to a new strength or to a pen with a different dose step.

Use of Humalog in an insulin infusion pump
For subcutaneous injection of Humalog using a continuous infusion pump, you may fill the pump reservoir from a Humalog 100 units/ml vial. Some pumps are compatible with cartridges that can be inserted intact into the pump.

Only certain CE-marked insulin infusion pumps may be used to infuse insulin lispro. Before infusing insulin lispro, the pump manufacturer’s instructions should be studied to ascertain the suitability for the particular pump. Use the correct reservoir and catheter for the pump. When filling the pump reservoir avoid damaging it by using the correct needle length on the filling system. The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set. In the event of a hypoglycaemic episode, the infusion should be stopped until the episode is resolved. If repeated or severe low blood glucose levels occur consider the need to reduce or stop an insulin infusion. A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If an interruption to insulin flow is suspected, follow the instructions in the pump product literature. When used with an insulin infusion pump, Humalog should not be mixed with any other insulin.

Intravenous administration of insulin

If necessary, Humalog may also be administered intravenously, for example: for the control of blood glucose levels during ketoacidosis, acute illnesses or during intra and post operative periods.

Humalog 100 units/ml is available in vials if administration of intravenous injection is necessary.

Intravenous injection of insulin lispro should be carried out following normal clinical practise for intravenous injections, for example by an intravenous bolus or by an infusion system. Frequent monitoring of the blood glucose levels is required.

Infusion systems at concentrations from 0.1 units/ml to 1.0 units/ml insulin lispro in 0.9% sodium chloride or 5% dextrose are stable at room temperature for 48 hours. It is recommended that the system is primed before starting the infusion to the patient.

Posology

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

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

The rapid onset and early peak of activity of Humalog itself is observed following the subcutaneous administration of Humalog Mix25. This allows Humalog Mix25 to be given very close to mealtime.

The duration of action of the insulin lispro protamine suspension component of Humalog Mix25 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 Mix25 is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Special populations

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 Mix25 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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Humalog Mix25 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.

KwikPen

The KwikPen delivers 1 – 60 units in steps of 1 unit in a single injection. The needed dose is dialled in units. The number of units is shown in the dose window of the pen.

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

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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

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.

KwikPen

The KwikPen delivers 1 – 60 units in steps of 1 unit in a single injection. The needed dose is dialled in units. The number of units is shown in the dose window of the pen.

Posology

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 subcutaneously as compared with soluble insulin. This rapid onset of activity allows a Humalog injection to be given very close to mealtime. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. The duration of action of Humalog is dependent 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 medicinal products, on the advice of a physician.

Humalog KwikPens

Humalog KwikPen is available in two strengths.The Humalog 200 units/ml KwikPen (and Humalog 100 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 no

dose conversion should be done when transferring a patient to a new strength or to a pen with a different dose step.

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

Special populations

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.

Method of administration

Humalog solution for injection should be given subcutaneously.

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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Humalog 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.

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.

Hypoglycaemia.

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) ;
not known (cannot be estimated form the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders

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

Oedema

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

Reporting of suspected adverse reactions

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

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) ;
not known (cannot be estimated form the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders

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

Oedema

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

Reporting of suspected adverse reactions

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

Summary of safety profile

Hypoglycaemia is the most frequent adverse reaction of insulin lispro 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) ;
not known (cannot be estimated form the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders

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

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

Reporting of suspected adverse reactions

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal 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 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. For fast-acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control.

Vial

When mixing Humalog with a longer acting insulin, the shorter-acting Humalog should be drawn into the syringe first, to prevent contamination of the vial by the longer-acting insulin. Mixing of the insulins ahead of time or just before the injection should be on advice of the physician. However, a consistent routine must be followed.

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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

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 in mind, if treatment with the combination of pioglitazone and Humalog 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 KwikPen as well as other insulin products.

Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who

are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

Excipients

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

Traceability

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

Under no circumstances should Humalog Mix25 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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

Combination of Humalog Mix25 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 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 KwikPen as well as other insulin products.
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

Excipients

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

Traceability

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

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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

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

Excipients

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of 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 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. For fast-acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control.

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 medicinal products 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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

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 in mind, if treatment with the combination of pioglitazone and Humalog 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 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 dose correctly. Overdose can result causing severe hypoglycemia. The insulin lispro solution for injection containing 200 units/ml must not be transferred from the KwikPen to any other insulin delivery device, including insulin infusion pumps.
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.

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

Excipients

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 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 medicinal products 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.

The physician should be consulted when using other medications in addition to Humalog (see section 4.4).

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), sulphate 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 with other insulins has not been studied.

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

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 Mix50 with other insulins has not been studied.

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

Insulin requirements may be increased by medicinal products 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 medicinal products with hypoglycaemic activity, such as oral hypoglycemics, 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.

The physician should be consulted when using other medicinal products in addition to Humalog 200 units/ml KwikPen (see section 4.4).

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).

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.

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 using machines).

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.

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

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 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). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

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

As with all insulin preparations, the time course of insulin lispro action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection,

blood supply, temperature and physical activity. The typical activity profile following subcutaneous injection is illustrated below.

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.

Clinical trials have been performed in children (61 patients aged 2 to 11) and children and adolescents (481 patients aged 9 to 19 years), comparing insulin lispro to human soluble insulin. The pharmacodynamic profile of insulin lispro in children is similar to that seen in adults.

When used in subcutaneous infusion pumps, treatment with insulin lispro has been shown to result in lower glycosylated haemoglobin levels compared to soluble insulin. In a double-blind, crossover study, the reduction in glycosylated haemoglobin levels after 12 weeks dosing was 0.37 percentage points with insulin lispro, compared to 0.03 percentage points for soluble insulin (p = 0.004).

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

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

Pharmacotherapeutic 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 Mix25. 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 (0.38 mmol/l) increase in blood glucose levels at night (3a.m.).

In the figure below the pharmacodynamics of Humalog Mix25 and BASAL are illustrated.

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.

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.

Insulin-Naive Patients n = 78
Not Insulin-Naive Patients n = 97
Mean total daily insulin dose at endpoint

Pharmacotherapeutic 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.

Hypoglycaemic activity

Time, hours

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.

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 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). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated reduced postprandial hyperglycaemia 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 the same individual and is dependent on dose, site of injection, blood supply, temperature and physical activity. 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 to maintain the subject's whole blood glucose concentrations near fasting levels and is an indicator of the effect 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 to those for insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects as shown in the graph below (figure 2).

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

Time (hr)
Glucose
Infusion
Rate
(mg/min)
Insulin lispro 200 units/ml
Insulin lispro 100 units/ml

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

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

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

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical

relevance of these kinetics, it is 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.

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 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 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.

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 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 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.

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is 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.

Insulin lispro 200 units/ml solution for injection was bioequivalent to insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects.
Time to maximum concentration was also similar between formulations.

For the treatment of adults and children with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Liprolog is also indicated for the initial stabilisation of diabetes mellitus.

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

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

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

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

Junior KwikPen
Liprolog 100 units/ml Junior KwikPen is suitable for patients who may benefit from finer insulin dose adjustments.

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

Liprolog takes effect rapidly and has a shorter duration of activity (2 to 5 hours) given subcutaneously as compared with soluble insulin. This rapid onset of activity allows a Liprolog injection (or, in the case of administration by continuous subcutaneous infusion, a Liprolog bolus) to be given very close to mealtime. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. As with all insulin preparations, the duration of action of Liprolog is dependent on dose, site of injection, blood supply, temperature, and physical activity.

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

Liprolog KwikPens
Liprolog KwikPen is available in two strengths. The Liprolog 100 units/ml KwikPen (and Liprolog 200 units/ml KwikPen, see separate SmPC) delivers 1 – 60 units in steps of 1 unit in a single injection.
The Liprolog 100 units/ml Junior KwikPen delivers 0.5 – 30 units in steps of 0.5 units in a single injection. The number of insulin units is shown in the dose window of the pen regardless of strength and no dose conversion should be done when transferring a patient to a new strength or to a pen with a different dose step.

Special populations

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
Liprolog can be used in adolescents and children (see section 5.1).

Method of administration

Liprolog preparations should be given by subcutaneous injection.
The KwikPen and Junior KwikPen are only suitable for subcutaneous injections. Liprolog in cartridges is only suitable for subcutaneous injections from a Lilly reusable insulin pen, BerliPen® areo 3 or compatible pump systems for continuous subcutaneous insulin infusion (CSII).

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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Liprolog 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.

Use of Liprolog in an insulin infusion pump
For subcutaneous injection of Liprolog using a continuous infusion pump, you may fill the pump reservoir from a Liprolog 100 units/ml vial. Some pumps are compatible with cartridges that can be inserted intact into the pump.

Only certain CE-marked insulin infusion pumps may be used to infuse insulin lispro. Before infusing insulin lispro, the pump manufacturer’s instructions should be studied to ascertain the suitability for the particular pump. Use the correct reservoir and catheter for the pump. When filling the pump reservoir avoid damaging it by using the correct needle length on the filling system. The infusion set

(tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set. In the event of a hypoglycaemic episode, the infusion should be stopped until the episode is resolved. If repeated or severe low blood glucose levels occur, consider the need to reduce or stop an insulin infusion. A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If an interruption to insulin flow is suspected, follow the instructions in the pump product literature. When used with an insulin infusion pump, Liprolog should not be mixed with any other insulin.

Intravenous administration of insulin
If necessary, Liprolog may also be administered intravenously, for example: for the control of blood glucose levels during ketoacidosis, acute illnesses or during intra and post operative periods.
Liprolog 100 units/ml is available in vials if administration of intravenous injection is necessary.

Intravenous injection of insulin lispro should be carried out following normal clinical practise for intravenous injections, for example by an intravenous bolus or by an infusion system. Frequent monitoring of the blood glucose levels is required.
Infusion systems at concentrations from 0.1 units/ml to 1.0 units/ml insulin lispro in 0.9% sodium chloride or 5% dextrose are stable at room temperature for 48 hours. It is recommended that the system is primed before starting the infusion to the patient.

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

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

The rapid onset and early peak of activity of Liprolog itself is observed following the subcutaneous administration of Liprolog Mix25. This allows Liprolog Mix25 to be given very close to mealtime. The duration of action of the insulin lispro protamine suspension component of Liprolog Mix25 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 Liprolog Mix25 is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Special populations

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 Liprolog Mix25 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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Liprolog Mix25 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.

KwikPen
The KwikPen delivers 1 – 60 units in steps of 1 unit in a single injection. The needed dose is dialled in units. The number of units is shown in the dose window of the pen.

Posology

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

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

The rapid onset and early peak of activity of Liprolog itself is observed following the subcutaneous administration of Liprolog Mix50. This allows Liprolog Mix50 to be given very close to mealtime. The duration of action of the insulin lispro protamine suspension component of Liprolog 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 Liprolog Mix50 is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Special populations

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 Liprolog 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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Liprolog 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.

KwikPen
The KwikPen delivers 1 – 60 units in steps of 1 unit in a single injection. The needed dose is dialled in units. The number of units is shown in the dose window of the pen.

Posology

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

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

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

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

Liprolog KwikPens
Liprolog KwikPen is available in two strengths. The Liprolog 200 units/ml KwikPen (and Liprolog 100 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 no dose conversion should be done when transferring a patient to a new strength or to a pen with a different dose step.

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

Special populations

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.

Method of administration

Liprolog solution for injection should be given subcutaneously.

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, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).

When administered subcutaneously care should be taken when injecting Liprolog 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.

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

Liprolog 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.

Hypoglycaemia.

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);
not known (cannot be estimated form the available data)

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

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

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

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) ;
not known (cannot be estimated form the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

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

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

Summary of safety profile

Hypoglycaemia is the most frequent adverse reaction of insulin lispro 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) ;
not known (cannot be estimated form the available data).

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

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Immune system disorders

Local allergy

X

Systemic allergy

X

Skin and subcutaneous tissue disorders

Lipodystrophy

X

Cutaneous amyloidosis

X

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.

Skin and subcutaneous tissue disorders
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

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

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

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of 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 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. For fast-acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control.

Vial
The shorter-acting Liprolog should be drawn into the syringe first, to prevent contamination of the vial by the longer-acting insulin. Mixing of the insulins ahead of time or just before the injection should be on advice of the physician. However, a consistent routine must be followed.

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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

Combination of Liprolog 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 Liprolog 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 Liprolog KwikPen as well as other insulin products.
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

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

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

Under no circumstances should Liprolog Mix25 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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of antidiabetic medications may be considered.

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 dose adjustments
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.

Combination of Liprolog Mix25 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 Liprolog Mix25 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 Liprolog KwikPen as well as other insulin products.
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

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

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

Under no circumstances should Liprolog 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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.

Combination of Liprolog 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 Liprolog 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 Liprolog KwikPen as well as other insulin products.
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

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

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of 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 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. For fast-acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control.

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 medicinal products 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.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of 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 or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.

Combination of Liprolog 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 Liprolog 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 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 dose correctly. Overdose can result causing severe hypoglycemia. The insulin lispro solution for injection containing 200 units/ml must not be transferred from the KwikPen to any other insulin delivery device, including insulin infusion pumps.

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

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

Excipients
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 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 medicinal products 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.

The physician should be consulted when using other medications in addition to Liprolog (see section 4.4).

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 Liprolog Mix25 with other insulins has not been studied.

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

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 Liprolog Mix50 with other insulins has not been studied.

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

Insulin requirements may be increased by medicinal products 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 medicinal products with hypoglycaemic activity, such as oral hypoglycemics, 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.

The physician should be consulted when using other medicinal products in addition to Liprolog 200 units/ml KwikPen (see section 4.4).

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).

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.

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 using machines).

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.

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

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 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). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

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

As with all insulin preparations, the time course of insulin lispro action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature and physical activity. The typical activity profile following subcutaneous injection is illustrated below.

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.

Clinical trials have been performed in children (61 patients aged 2 to 11) and children and adolescents (481 patients aged 9 to 19 years), comparing insulin lispro to human soluble insulin. The pharmacodynamic profile of insulin lispro in children is similar to that seen in adults.

When used in subcutaneous infusion pumps, treatment with insulin lispro has been shown to result in lower glycosylated haemoglobin levels compared to soluble insulin. In a double-blind, crossover study, the reduction in glycosylated haemoglobin levels after 12 weeks dosing was 0.37 percentage points with insulin lispro, compared to 0.03 percentage points for soluble insulin (p = 0.004).

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

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

Pharmacotherapeutic 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 Liprolog Mix25. Liprolog 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 Liprolog Mix25 compared to human insulin mixture 30/70. In one clinical study there was a small (0.38 mmol/l) increase in blood glucose levels at night (3a.m.).

In the figure below the pharmacodynamics of Liprolog Mix25 and Liprolog Basal are illustrated.

Liprolog Mix25
Liprolog Basal

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.

Time, hours
Hypoglycaemic activity

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 Liprolog 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.

Insulin-Naive Patients n = 78
Not Insulin-Naive Patients n = 97
Mean total daily insulin dose at endpoint

Pharmacotherapeutic 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 Liprolog Mix50. Liprolog 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 Liprolog Mix50 and Liprolog Basal are illustrated.

Hypoglycaemic activity

Time, hours

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.

Liprolog Basal
Liprolog Mix50

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.

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 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). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated reduced postprandial hyperglycaemia 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 the same individual and is dependent on dose, site of injection, blood supply, temperature and physical activity. 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 to maintain the subject's whole blood glucose concentrations near fasting levels and is an indicator of the effect 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 to those for insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects as shown in the graph below (figure 2).

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

Time (hr)
Glucose
Infusion Rate
(mg/min)
Insulin lispro 200 units/ml
Insulin lispro 100 units/ml

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

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

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

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is 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.

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 Liprolog Mix25 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 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.

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 Liprolog 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 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.

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is 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.

Insulin lispro 200 units/ml solution for injection was bioequivalent to insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects.
Time to maximum concentration was also similar between formulations.

Treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above.

Treatment of diabetes mellitus in adults.

Posology

Lyumjev is a mealtime insulin for subcutaneous injection and should be administered zero to two minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal (see section 5.1).

Lyumjev 100 units/mL is suitable for continuous subcutaneous insulin infusion (CSII) and is used for both the bolus and basal insulin requirement.

The initial dose should take into account the type of diabetes, weight of the patient and their blood glucose levels.

The early onset of action must be considered when prescribing Lyumjev (see section 5.1). Continued adjustment of the dose of Lyumjev should be based on the patient’s metabolic needs, blood glucose monitoring results, and glycaemic control goal. Dose adjustments may be needed, when switching from another insulin, with changes in physical activity, changes in concomitant medicinal products, changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycaemia or hyperglycaemia (see sections 4.4 and 4.5).

Switching from another mealtime insulin medicinal product

If converting from another mealtime insulin to Lyumjev, the change can be done on a unit-to-unit basis. The potency of insulin analogues, including Lyumjev, is expressed in units. One (1) unit of Lyumjev corresponds to 1 international unit (IU) of human insulin or 1 unit of other fast-acting insulin analogues.

Missed doses

Patients who forget a mealtime dose should monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

Special populations

Elderly
The safety and efficacy of Lyumjev has been established in elderly patients aged 65 to 75 years. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see sections 4.8, 5.1 and 5.2). The therapeutic experience in patients ≥ 75 years of age is limited.

Renal impairment
Insulin requirements may be reduced in the presence of renal impairment. In patients with renal impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Hepatic impairment
Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown. In patients with hepatic impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Paediatric population

Lyumjev can be used in adolescents and children from the age of 1 year (see section 5.1). There is no clinical experience with the use of Lyumjev in children below the age of 3 years. Similar to adults, dosage should be adjusted individually. Lyumjev is recommended to be administered zero to two minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal when needed.

Method of administration

Patients should be trained on proper use and injection technique before initiating Lyumjev. Patients should be told to:
- Always check insulin labels before administration.
- Inspect Lyumjev visually before use and discard for particulate matter or discolouration.

• Injection or infusion sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
• Carry a spare or alternative administration method in case their delivery system breaks.

Subcutaneous injection

Lyumjev should be injected subcutaneously into the abdomen, upper arm, thigh or buttocks (see section 5.2).

Lyumjev should generally be used in combination with an intermediate or long-acting insulin. A different injection site should be used if injecting at the same time as another insulin.

When injecting a blood vessel should not be entered.

Devices should be discarded if any part looks broken or damaged.

The needle should be discarded after each injection.

Lyumjev vials
If subcutaneous administration by syringe is necessary, a vial should be used.

The syringe must have 100 units/mL markings.

Patients using vials must never share needles or syringes.

Lyumjev cartridges
Lyumjev in cartridges is only suitable for subcutaneous injections from a Lilly reusable pen.

Lyumjev cartridges 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.

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.

Lyumjev KwikPens
The KwikPen and Junior KwikPen are only suitable for subcutaneous injections.

Lyumjev KwikPens are available in two concentrations: Lyumjev 100 units/mL KwikPen and Lyumjev 200 units/mL KwikPen. See the separate SmPC for Lyumjev 200 units/mL KwikPen.
The KwikPen delivers 1 - 60 units in steps of 1 unit in a single injection.
The Lyumjev 100 units/mL Junior KwikPen delivers 0.5 - 30 units in steps of 0.5 units in a single injection.

The number of insulin units is shown in the dose window of the pen regardless of concentration and no dose conversion should be done when transferring a patient to a new concentration or to a pen with a different dose step.

Lyumjev 100 units/mL Junior KwikPen is suitable for patients who may benefit from finer insulin dose adjustments.

For detailed user instructions, please refer to the instructions for use provided with the package leaflet.

To prevent the possible transmission of disease, each pen must be used by one patient only, even if the needle is changed.

CSII (insulin pump)
Use a pump suitable for insulin infusion. Fill the pump reservoir from a Lyumjev 100 units/mL vial.

Patients using a pump should follow the instructions provided with the pump and infusion set.
Use the correct reservoir and catheter for the pump.

When filling the pump reservoir avoid damaging it by using the correct needle length on the filling system. The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.

A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels (see section 4.4).

Intravenous use

Lyumjev 100 units/mL is available in vials if administration of intravenous injection is necessary. This medicinal product must not be mixed with any other insulin or any other medicinal product except those mentioned in section 6.6.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Intravenous administration of Lyumjev 100 units/mL must be performed under medical supervision.

Posology

Lyumjev is a mealtime insulin for subcutaneous injection and should be administered zero to two minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal (see section 5.1).

The initial dose should take into account the type of diabetes, weight of the patient and their blood glucose levels.

The early onset of action must be considered when prescribing Lyumjev (see section 5.1). Continued adjustment of the dose of Lyumjev should be based on the patient’s metabolic needs, blood glucose monitoring results, and glycaemic control goal. Dose adjustments may be needed, when switching from another insulin, with changes in physical activity, changes in concomitant medicinal products, changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycaemia or hyperglycaemia (see sections 4.4 and 4.5).

Switching from another mealtime insulin medicinal product

If converting from another mealtime insulin to Lyumjev, the change can be done on a unit-to-unit basis. The potency of insulin analogues, including Lyumjev, is expressed in units. One (1) unit of Lyumjev corresponds to 1 international unit (IU) of human insulin or 1 unit of other fast-acting insulin analogues.

Missed doses

Patients who forget a mealtime dose should monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

Special populations

Elderly
The safety and efficacy of Lyumjev has been established in elderly patients aged 65 to 75 years. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see sections 4.8, 5.1 and 5.2). The therapeutic experience in patients ≥ 75 years of age is limited.

Renal impairment
Insulin requirements may be reduced in the presence of renal impairment. In patients with renal impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Hepatic impairment
Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown. In patients with hepatic impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Paediatric population

The safety and efficacy of Lyumjev 200 units/mL in children and adolescents below 18 years of age have not been established.

Method of administration

Patients should be trained on proper use and injection technique before initiating Lyumjev. Patients should be told to:
- Always check insulin labels before administration.
- Inspect Lyumjev visually before use and discard for particulate matter or discolouration.
- Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
- Ensure when injecting that a blood vessel has not been entered.
- Discard the needle after each injection.
- Discard devices if any part looks broken or damaged.
- Carry a spare or alternative administration method in case their delivery system breaks.

Lyumjev should be injected subcutaneously into the abdomen, upper arm, thigh or buttocks (see section 5.2).

Lyumjev should generally be used in combination with an intermediate or long-acting insulin. A different injection site should be used if injecting at the same time as another insulin.

The Lyumjev 200 units/mL KwikPen is only suitable for subcutaneous injections.

Lyumjev 200 units/mL should not be administered using a continuous subcutaneous insulin infusion (CSII) pump.

Lyumjev 200 units/mL should not be administered intravenously.

Lyumjev is available in two concentrations: Lyumjev 200 units/mL KwikPen and Lyumjev 100 units/mL KwikPen. See the separate SmPC for Lyumjev 100 units/mL KwikPen. The KwikPen 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 concentration and no dose conversion should be done when transferring a patient to a new concentration or to a pen with a different dose step.

For detailed user instructions, please refer to the instructions for use provided with the package leaflet.

To prevent the possible transmission of disease, each pen must be used by one patient only, even if the needle is changed.

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

Summary of safety profile

The most frequently reported adverse reactions during treatment are hypoglycaemia (very common) and infusion site reactions in patients using CSII system (very common) (see sections 4.2, 4.4 and 4.9).

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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

MedDRA system organ class
Very common
Common
Uncommon
Not known
Metabolism and nutrition disorders
Hypoglycaemia

General disorders and administration site conditions
Infusion site reactionsa
Allergic reactions b
Oedema

Injection site reactions c

Skin and subcutaneous tissue disorders

Lipodystrophy
Cutaneous amyloidosis
Rash
Pruritus aReported in PRONTO-Pump-2 bSee section 4.8 Description of selected adverse reactions cReported in PRONTO-T1D, PRONTO-T2D and PRONTO-Peds

Description of selected adverse reactions

Hypoglycaemia

Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin. The incidence of severe hypoglycaemia in the 26 week phase 3 adult clinical studies was 5.5% in patients with type 1 diabetes mellitus and 0.9% in patients with type 2 diabetes (see tables 2 and 3). In study PRONTO-Peds, severe hypoglycaemia was reported in 0.7% of paediatric patients treated with Lyumjev.

The symptoms of hypoglycaemia usually occur suddenly. They may include listlessness, confusion, palpitations, sweating, vomiting, and headache.

There were no clinically significant differences in the frequency of hypoglycaemia with administration of Lyumjev or the comparator (another medicinal product containing insulin lispro) across all studies.
In studies where Lyumjev and the comparator were administered at different times relative to meals, there were no clinically relevant differences in the frequency of hypoglycaemia.

Hypoglycaemia may occur earlier after an injection/infusion of Lyumjev compared to other mealtime insulins due to the earlier onset of action.

Allergic reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Lyumjev.

Injection/Infusion site reactions

As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising or itching at the site of Lyumjev injection or infusion.

In studies PRONTO-T1D and PRONTO-T2D (multiple-dose injection [MDI] administration), injection site reactions occurred in 2.7% of adult patients treated with Lyumjev. These reactions were usually mild and normally disappeared during continued treatment. Of the 1 116 patients who received Lyumjev, 1 discontinued treatment due to injection site reactions (< 0.1%).

In study PRONTO-Peds, injection site reactions occurred in 6.2% of paediatric patients treated with Lyumjev. These events were mild or moderate. Of the 418 patients treated with Lyumjev, 2 discontinued treatment due to injection site reactions (< 0.5%).

In study PRONTO-Pump-2, infusion site reactions were reported in 38% of patients treated with Lyumjev. The majority of these events were mild. Of the 215 patients treated with Lyumjev, 7 discontinued treatment due to infusion site reactions (3.3%).

Immunogenicity

Administration of insulin can cause formation of insulin antibodies. The presence of anti-drug antibodies did not have a clinically meaningful effect on the pharmacokinetics, efficacy, or safety of Lyumjev.

Skin and subcutaneous tissue disorders

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

Oedema

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

Paediatric population

Safety and efficacy have been investigated in a therapeutic confirmatory trial in children with type 1 diabetes aged 3 to < 18 years. In the trial, 418 patients were treated with Lyumjev. The frequency, type and severity of adverse reactions observed in the paediatric population is consistent with the safety profile in adult patients.

Other special populations

Based on results from clinical trials with insulin lispro in general, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population. The safety information in very elderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited (see section 5.1).

Reporting of suspected adverse reactions

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

Summary of safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia (very common) (see sections 4.2, 4.4 and 4.9).

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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

MedDRA system organ class
Very common
Common
Uncommon
Not known
Metabolism and nutrition disorders
Hypoglycaemia

General disorders and administration site conditions

Allergic reactions*
Oedema

Injection site reactions

Skin and subcutaneous tissue disorders

Lipodystrophy
Cutaneous amyloidosis
Rash
Pruritus
*See section 4.8 Description of selected adverse events

Description of selected adverse reactions

Hypoglycaemia

Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin. The incidence of severe hypoglycaemia in the 26 week phase 3 clinical studies was 5.5% in patients with type 1 diabetes mellitus and 0.9% in patients with type 2 diabetes (see tables 2 and 3).
The symptoms of hypoglycaemia usually occur suddenly. They may include listlessness, confusion, palpitations, sweating, vomiting, and headache.

There were no clinically significant differences in the frequency of hypoglycaemia with administration of Lyumjev or the comparator (another medicinal product containing insulin lispro) across all studies.
In studies where Lyumjev and the comparator were administered at different times relative to meals, there were no clinically relevant differences in the frequency of hypoglycaemia.

Hypoglycaemia may occur earlier after an injection of Lyumjev compared to other mealtime insulins due to the earlier onset of action.

Allergic reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Lyumjev.

Injection site reactions

As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising or itching at the site of Lyumjev injection. These reactions are usually mild and usually disappear during continued treatment.

Immunogenicity

Administration of insulin can cause formation of insulin antibodies. The presence of anti-drug antibodies did not have a clinically meaningful effect on the pharmacokinetics, efficacy, or safety of Lyumjev.

Skin and subcutaneous tissue disorders

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

Oedema

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

Special populations

Based on results from clinical trials with insulin lispro in general, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population. The safety information in very elderly patients (≥ 75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited (see section 5.1).

Reporting of suspected adverse reactions

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

Traceability

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

Hypoglycaemia

Hypoglycaemia is the most common adverse reaction of insulin therapy (see section 4.8). The timing of hypoglycaemia usually reflects the time-action profile of the administered insulin formulations.
Hypoglycaemia may occur earlier after an injection/infusion when compared to other mealtime insulins due to the earlier onset of action of Lyumjev (see section 5.1).

Hypoglycaemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Severe hypoglycaemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Symptomatic awareness of hypoglycaemia may be less pronounced in patients with longstanding diabetes.

Hyperglycaemia

The use of inadequate doses or discontinuation of treatment may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Patients should be educated to recognize the signs and symptoms of ketoacidosis and to get immediate help when ketoacidosis is suspected.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of antidiabetic medications may be considered.

Insulin requirements and dose adjustments

Changes in insulin, insulin concentration, manufacturer, type, or method of administration may affect glycaemic control and predispose to hypoglycaemia or hyperglycaemia. These changes should be made cautiously under close medical supervision and the frequency of glucose monitoring should be increased. For patients with type 2 diabetes, dose adjustments in concomitant anti-diabetic treatment may be needed (see sections 4.2 and 4.5).

In patients with renal or hepatic impairment, glucose monitoring should be intensified and dose adjusted on an individual basis (see section 4.2).

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of dose 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.

Hyperglycaemia and ketoacidosis due to insulin pump device malfunction

Malfunction of the insulin pump or insulin infusion set can rapidly lead to hyperglycaemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis is necessary. Interim subcutaneous injections with Lyumjev may be required.

Thiazolidinediones (TZDs) used in combination with insulin

TZDs can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin and a TZD should be observed for signs and symptoms of heart failure. If heart failure develops, consider discontinuation of the TZD.

Hypersensitivity and allergic reactions

Severe, life-threatening, generalised allergy, including anaphylaxis, can occur with insulin medicinal products, including Lyumjev (see section 4.8). If hypersensitivity reactions occur, discontinue Lyumjev.

Medication errors

Lyumjev should not be used by patients with visual impairment without help of a trained person.

To avoid medication errors between Lyumjev and other insulins, patients need to always check the insulin label before each injection.

Patients should always use a new needle for each injection to prevent infections and a blocked needle.
In the event of a blocked needle it should be replaced with a new needle.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

Traceability

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

Hypoglycaemia

Hypoglycaemia is the most common adverse reaction of insulin therapy (see section 4.8). The timing of hypoglycaemia usually reflects the time-action profile of the administered insulin formulations.
Hypoglycaemia may occur earlier after an injection when compared to other mealtime insulins due to the earlier onset of action of Lyumjev (see section 5.1).

Hypoglycaemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Severe hypoglycaemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Symptomatic awareness of hypoglycaemia may be less pronounced in patients with longstanding diabetes.

Hyperglycaemia

The use of inadequate doses or discontinuation of treatment may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Patients should be educated to recognize the signs and symptoms of ketoacidosis and to get immediate help when ketoacidosis is suspected.

Injection technique

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden 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 adjustment of antidiabetic medications may be considered.

Insulin requirements and dose adjustments

Changes in insulin, insulin concentration, manufacturer, type, or method of administration may affect glycaemic control and predispose to hypoglycaemia or hyperglycaemia. These changes should be made cautiously under close medical supervision and the frequency of glucose monitoring should be

increased. For patients with type 2 diabetes, dose adjustments in concomitant anti-diabetic treatment may be needed (see sections 4.2 and 4.5).

In patients with renal or hepatic impairment, glucose monitoring should be intensified and dose adjusted on an individual basis (see section 4.2).

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of dose 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.

Thiazolidinediones (TZDs) used in combination with insulin

TZDs can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin and a TZD should be observed for signs and symptoms of heart failure. If heart failure develops, consider discontinuation of the TZD.

Hypersensitivity and allergic reactions

Severe, life-threatening, generalised allergy, including anaphylaxis, can occur with insulin medicinal products, including Lyumjev (see section 4.8). If hypersensitivity reactions occur, discontinue Lyumjev.

Medication errors

Lyumjev should not be used by patients with visual impairment without help of a trained person.

To avoid medication errors between Lyumjev and other insulins, patients need to always check the insulin label before each injection.

Do not transfer insulin from the Lyumjev Pen 200 units/mL to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdose and severe hypoglycaemia.

Patients should always use a new needle for each injection to prevent infections and a blocked needle.
In the event of a blocked needle it should be replaced with a new needle.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to sayessentially “sodium-free”.

The following substances may reduce insulin requirement: Antidiabetic medicinal products (oral or injectable), salicylates, sulphonamides, certain antidepressants (monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blocking agents, or somatostatin analogues.

The following substances may increase insulin requirement: oral contraceptives, corticosteroids, thyroid hormones, danazol, sympathomimetic agents, diuretics, or growth hormone.

Alcohol may increase or decrease the blood glucose lowering effect of Lyumjev. Consumption of large amounts of ethanol concomitantly with insulin use may lead to severe hypoglycaemia.

Beta-blockers may blunt the signs and symptoms of hypoglycaemia.

TZDs can cause dose-related fluid retention, particularly when used in combination with insulin, and exacerbate heart failure (see section 4.4).

Pregnancy

A large amount of data on pregnant women (more than 1 000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of insulin lispro. Lyumjev can be used during pregnancy if clinically needed.

It is essential to maintain good control of an 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. After delivery, insulin requirements normally return rapidly to pre-pregnancy values. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control is essential in pregnant patients with diabetes.

Breast-feeding

Lyumjev can be used during 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.

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 using machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those patients 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.

Overdose causes hypoglycaemia with accompanying symptoms that include listlessness, confusion, palpitations, sweating, vomiting, and headache.

Hypoglycaemia may occur as a result of an excess of insulin lispro relative to food intake, energy expenditure, or both. Mild episodes of hypoglycaemia usually can be treated with oral glucose. More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery. Adjustments in medicinal product dose, meal patterns, or exercise may be needed.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Medicinal products used in diabetes, insulins and analogues for injection, fast-acting, ATC code: A10AB04

Mechanism of action

The primary activity of Lyumjev is the regulation of glucose metabolism. Insulins, including insulin lispro, the active substance in Lyumjev, exert their specific action through binding to insulin receptors.
Receptor-bound insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

Lyumjev is a formulation of insulin lispro that contains citrate and treprostinil. Citrate increases local vascular permeability and treprostinil induces local vasodilation to achieve accelerated absorption of insulin lispro.

Pharmacodynamic effects

Early and late insulin action

A glucose clamp study was conducted in 40 type 1 diabetes patients given Lyumjev and Humalog subcutaneously as a single 15 unit dose. Results are provided in Figure 1. Lyumjev has been shown to be equipotent to Humalog on a unit for unit basis but its effect is more rapid with a shorter duration of action.

• Onset of action of Lyumjev was 20 minutes post dose, 11 minutes faster than Humalog.
• During the first 30 minutes post dose, Lyumjev had a 3-fold greater glucose lowering effect compared to Humalog.
• Maximum glucose-lowering effect of Lyumjev occurred between 1 and 3 hours after injection.
• The late insulin action, from 4 hours until the end of the glucose clamp, was 54% lower with Lyumjev than observed with Humalog.
• The duration of action of Lyumjev was 5 hours, 44 minutes shorter than Humalog.
• The total glucose infused during the clamp was comparable between Lyumjev and Humalog.

Figure 1. Mean glucose infusion rate (GIR) in patients with type 1 diabetes after subcutaneous injection of Lyumjev or Humalog (15 unit dose)

Similarly, a faster early insulin action and a reduced late insulin action was observed with Lyumjev in type 2 diabetes patients.

Total and maximum glucose lowering effect of Lyumjev increased with dose within the therapeutic dose range. The early onset and total insulin action were similar when Lyumjev was administered in the abdomen, upper arm, or thigh.

Postprandial Glucose (PPG) Lowering

Lyumjev reduced the PPG during a standardized test meal over the complete 5 hour test meal period (change from premeal area under the curve (AUC) (0 – 5 h)) compared to Humalog.
- In patients with type 1 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by 32% when given at the start of the meal and 18% when given 20 minutes after the start of the meal compared to Humalog.
- In patients with type 2 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by 26% when given at the start of the meal and 24% when given 20 minutes after the start of the meal compared to Humalog.

Pharmacotherapeutic group: Medicinal products used in diabetes, insulins and analogues for injection, fast-acting, ATC code: A10AB04

Mechanism of action

The primary activity of Lyumjev is the regulation of glucose metabolism. Insulins, including insulin lispro, the active substance in Lyumjev, exert their specific action through binding to insulin receptors.
Receptor-bound insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

Lyumjev is a formulation of insulin lispro that contains citrate and treprostinil. Citrate increases local vascular permeability and treprostinil induces local vasodilation to achieve accelerated absorption of insulin lispro.

Pharmacodynamic effects

Early and late insulin action

A glucose clamp study was conducted in 40 type 1 diabetes patients given Lyumjev and Humalog subcutaneously as a single 15 unit dose. Results are provided in Figure 1. Lyumjev has been shown to be equipotent to Humalog on a unit for unit basis but its effect is more rapid with a shorter duration of action.

• Onset of action of Lyumjev was 20 minutes post dose, 11 minutes faster than Humalog.
• During the first 30 minutes post dose, Lyumjev had a 3-fold greater glucose lowering effect compared to Humalog.
• Maximum glucose-lowering effect of Lyumjev occurred between 1 and 3 hours after injection.
• The late insulin action, from 4 hours until the end of the glucose clamp, was 54% lower with Lyumjev than observed with Humalog.
• The duration of action of Lyumjev was 5 hours, 44 minutes shorter than Humalog.
• The total glucose infused during the clamp was comparable between Lyumjev and Humalog.

Figure 1. Mean glucose infusion rate (GIR) in patients with type 1 diabetes after subcutaneous injection of Lyumjev or Humalog (15 unit dose)

Similarly, a faster early insulin action and a reduced late insulin action was observed with Lyumjev in type 2 diabetes patients.

Total and maximum glucose lowering effect of Lyumjev increased with dose within the therapeutic dose range. The early onset and total insulin action were similar when Lyumjev was administered in the abdomen, upper arm, or thigh.

Postprandial Glucose (PPG) Lowering

Lyumjev reduced the PPG during a standardized test meal over the complete 5 hour test meal period (change from premeal area under the curve (AUC) (0-5h)) compared to Humalog.

• In patients with type 1 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by 32% when given at the start of the meal and 18% when given 20 minutes after the start of the meal compared to Humalog.

- In patients with type 2 diabetes, Lyumjev reduced the PPG during the 5 hour test meal period by 26% when given at the start of the meal and 24% when given 20 minutes after the start of the meal compared to Humalog.

Absorption

Absorption of insulin lispro was accelerated and the duration of exposure was shorter in healthy subjects and patients with diabetes following injection of Lyumjev compared to Humalog. In patients with type 1 diabetes:
- Insulin lispro appeared in circulation approximately 1 minute after injection of Lyumjev, which was five minutes faster than Humalog.
- Time to 50% maximum concentration was 14 minutes shorter with Lyumjev compared to Humalog.
- Following injection of Lyumjev, there was seven times more insulin lispro in circulation during the first 15 minutes compared to Humalog and three times more insulin lispro during the first 30 minutes compared to Humalog.

• After administration of Lyumjev the time to maximum insulin lispro concentration was achieved at 57 minutes.
• Following injection of Lyumjev there was 41% less insulin lispro in circulation after 3 hours following injection compared to Humalog.
• The duration of insulin lispro exposure for Lyumjev was 60 minutes shorter compared to Humalog.
• The total insulin lispro exposure (ratio and 95% CI of 1.03 (0.973, 1.09)) and maximum concentration (ratio and 95% CI of 1.06 (0.97, 1.16)) were comparable between Lyumjev and Humalog.

In type 1 patients, the day-to-day variability (coefficient of variation [CV%]) of Lyumjev was 13% for total insulin lispro exposure (AUC, 0 - 10h) and 23% for maximum insulin lispro concentration (Cmax).The absolute bioavailability of insulin lispro after subcutaneous administration of Lyumjev in the abdomen, upper arm and thigh was approximately 65%. The accelerated absorption of insulin lispro is maintained regardless of injection site (abdomen, upper arm and thigh). No exposure data are available following injection in the buttocks.

Maximum concentration and time to maximum concentration were comparable for the abdomen and upper arm regions; time to maximum concentration was longer and maximum concentration lower for the thigh.