humulin public assessment report pls 00006 0665-073 · humulin s 100 iu/ml solution for injection...

Humulin S 100 IU/ml solution for injection in vial UK/H/030/062-071

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Public Assessment Report

Decentralised Procedure

Humulin S vial 100 IU/ml

solution for injection in vial Humulin I vial 100 IU/ml suspension for injection

Humulin M3 vial 100 IU/ml suspension for injection

Humulin S cartridges 100 IU/ml solution for injection

Humulin I cartridges 100 IU/ml suspension for injection

Humulin M3 cartridges 100 IU/ml suspension for injection

Humulin S Kwikpen 100 IU/ml solution for injection

Humulin I Kwikpen 100 IU/ml suspension for injection

Humulin M3 Kwikpen 100 IU/ml suspension for injection

Procedure Nos: UK/H/030/062–071

UK Licence Nos: PL 00006/0665–0673

Applicant: Eli Lilly & Company Limited


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LAY SUMMARY This is a summary of the public assessment report (PAR) for Humulin S 100 IU/ml solution for injection in vial and associated formulations (PLs 00006/0665-0673) regarding a line extension to replace the Master Cell Bank (MCB) for human insulin drug substance. The final Humulin insulin preparations are unaffected by this change in MCB. This application only concerns changes to the quality data, cross reference to the original complete application is made for pre-clinical and clinical data.

This report is not intended to provide practical advice on how to use Humulin S 100 IU/ml solution for injection in vial. For practical advice on how to use Humulin S 100 IU/ml solution for injection in vial, patients should read the package leaflet or contact their doctor or pharmacist. This report covers nine Humulin insulin preparations but for the purpose of this summary, only Humulin S 100 IU/ml solution for injection will be referred to. Full product information for all preparations is provided later in this report. What is Humulin S 100 IU/ml solution for injection and what is it used for? All the humulin preparations in this application have been prescribed for the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis. The different humulin preparations included in this application are described below. How does Humulin S 100 IU/ml solution for injection work? Humulin S contains the active substance human insulin, which is used to treat diabetes. You get diabetes if your pancreas does not make enough insulin to control the level of glucose in your blood (blood sugar). Humulin S is used to control glucose in the long term. Humulin is a rapidly acting insulin preparation. Your doctor may tell you to use Humulin S as well as a longer-acting insulin. Each kind of insulin comes with its own patient information leaflet to tell you about it. Do not change your insulin unless your doctor tells you to. Be very careful if you do change insulin. Each type of insulin has a different colour and symbol on the pack and the vial so that you can easily tell the difference. How is Humulin S 100 IU/ml solution for injection used? Humulin S Humulin S is a sterile, clear, colourless, aqueous solution of human insulin and is available in the following preparations: a solution for injection in a vial (PL 00006/0665), a solution for injection in a cartridge (PL 00006/0669), and a solution for injection in a pre-filled pen (PL 00006/0671). Humulin S should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. It may also be administered intravenously.


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Humulin I (Isophane) may be administered in combination with Humulin S (Soluble) (See Instructions for use and handling - for Mixing of Insulins). Humulin I Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer and is available in the following preparations: a suspension for injection in a vial (PL 00006/0666), a suspension for injection in a cartridge (PL 0006/0668), and a suspension for injection in a pre-filled pen (PL 00006/0672). Humulin I should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Humulin I (Isophane) may be administered in combination with Humulin S (Soluble). (See Instructions for use and handling for Mixing of Insulins). Humulin M3 Humulin M3 is a sterile suspension of human insulin in the proportion of 30% soluble insulin to 70% isophane insulin and is available in the following preparations: a suspension for injection in a cartridge (PL 00006/0670), a suspension for injection in a pre-filled pen (PL 00006/0673), and a suspension for injection in a vial (PL 00006/0667). Humulin M3 should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Humulin Mixture formulation is a ready-made defined mixture of soluble and isophane insulin designed to avoid the need for the patient to mix insulin preparations. A patient's treatment regimen should be based on their individual metabolic requirements. For all Humulin insulin preparations, 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. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. What benefits of Humulin S 100 IU/ml solution for injection have been shown in studies? The company provided its own data on efficacy studies. These studies have shown that Humulin S 100 IU/ml is effective in the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis. What are the possible side effects from Humulin S 100 IU/ml solution for injection? Human insulin may cause hypoglycaemia (low blood sugar). Possible side effects are listed below:- Systemic allergy is very rare (affects less than 1 person in 10,000).


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Local allergy is common (affects less than 1 person in 10). Lipodystrophy (thickening or pitting of the skin) is uncommon (affects less than 1 person in 100). For the full list of all side effects reported with Humulin S 100 IU/ml solution for injection, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why is Humulin S 100 IU/ml solution for injection approved? The MHRA decided that Humulin S 100 IU/ml solution for injection’s benefits are greater than its risk and recommended that it be approved for use. Other information about Humulin S 100 IU/ml solution for injection Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Portugal, Spain, Sweden, The Netherlands and the UK agreed to grant Marketing Authorisations for Humulin S 100 IU/ml solution for injection in vial and its associated humulin preparations on 17th July 2014. Marketing Authorisations were granted in the UK on 13th August 2014. This summary was last updated 10th October 2014.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 6

Module 2: Summary of Product Characteristics Page 7

Module 3: Patient Information Leaflet Page 73

Module 4: Labelling Page 103

Module 5: Scientific Discussion Page 114

I. Introduction

II. About the Product

III. Scientific Overview and Discussion

IV. Quality aspects

V. Non-clinical aspects

VI. Clinical aspects

VII. Overall conclusion and Benefit-Risk Assessment

Module 6: Steps taken after initial procedure Page 116


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Module 1

Information about initial procedure

Product name Humulin S 100 IU/ml solution for injection in vial

Humulin I 100 IU/ml suspension for injection in vial

Humulin M3 100 IU/ml suspension for injection in vial

Humulin S 100 IU/ml solution for injection in cartridge

Humulin I 100 IU/ml suspension for injection in cartridge

Humulin M3 100 IU/ml suspension for injection in cartridge

Humulin S Kwikpen 100 IU/ml solution for injection

Humulin I Kwikpen 100 IU/ml suspension for injection

Humulin M3 Kwikpen 100 IU/ml suspension for injection

Type of

application

Article 8.3, line extension application

Active substance Human insulin

Form Solution for injection

Suspension for injection

Strength 100 IU/ml

MA holder Eli Lilly & Company Limited

RMS United Kingdom

CMSs Austria, Belgium, Denmark, Finland, France, Germany,

Greece, Ireland, Italy, Luxembourg, Portugal, Spain,

Sweden, The Netherlands

Procedure

number

UK/H/030/062-071

Timetable Day 210: 17th July 2014


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Module 2

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Humulin S (Soluble) 100 IU/ml solution for injection in vial

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml contains 100 IU human insulin (produced in E.coli by recombinant DNA technology). One vial contains 10 ml equivalent to 1000 IU of soluble insulin. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

A solution for injection in a vial. Humulin S is a sterile, clear, colourless, aqueous solution of human insulin.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.

4.2 Posology and method of administration The dosage should be determined by the physician, according to the requirement of the patient. Humulin S should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. It may also be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.


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Humulin I (Isophane) may be administered in combination with Humulin S (Soluble) (See Instructions for use and handling - for Mixing of Insulins). Each pack contains a patient information leaflet with instructions on how to inject insulin.

4.3 Contraindications

Hypoglycaemia. Hypersensitivity to Humulin or to the formulation excipients, unless used as part of a desensitisation programme. Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.

4.4 Special warnings and precautions for use

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin with pioglitazone


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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 human insulin 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.

4.5 Interaction with other medicinal products and other forms of interaction

A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take. Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides. Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.

Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.

4.6 Fertility, pregnancy and lactation 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 doctors if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.

4.7 Effects on ability to drive and use machines

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery). 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.


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4.8 Undesirable effects Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise. Local allergy in patients is common (1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause 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. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required. Lipodystrophy at the injection site is uncommon (1/1,000 to < 1/100). Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

4.9 Overdose

Insulin has 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 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 sugar 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 occur after apparent clinical recovery.


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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Humulin S: ATC code A10A B01. Humulin S is a rapidly acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism. In addition insulin has 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. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin S

Time (hours)

5.2 Pharmacokinetic properties

The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.

5.3 Preclinical safety data

Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

m-cresol glycerol


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water for injections. The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.

6.2 Incompatibilities

Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.

6.3 Shelf life

Unopened vials 3 years. After first use 28 days.

6.4 Special precautions for storage

Do not freeze. Do not expose to excessive heat or direct sunlight. Unopened vials Store in a refrigerator (2 C – 8 C). After first use Store below 30°C.

6.5 Nature and contents of container

10 ml of solution in a vial (type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic). Pack size 1.

6.6 Special precautions for disposal

Do not reuse needles. Dispose of the needle in a responsible manner. Needles must not be shared. Vials can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A solution for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings). a) Preparing a dose Vials containing Humulin S formulation do not require resuspension and should only be used if it is clear, colourless, with no solid particles visible and if it is of water-like appearance.


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Mixing of insulins: The shorter acting insulin should be drawn into the syringe first, to prevent contamination of the vial by the longer acting preparation. It is advisable to inject directly after mixing. However, if a delay is necessary, a consistent routine must be followed. Alternatively a separate syringe or, separate cartridges of Humulin S and I can be used for administration of the correct amount of each formulation. Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse. Use an insulin syringe marked for the strength of insulin being administered. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.

7 MARKETING AUTHORISATION HOLDER Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Trading style: Lilly Industries Limited

8 MARKETING AUTHORISATION NUMBER(S)

PL 00006/0665

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/08/2014

10 DATE OF REVISION OF THE TEXT

13/08/2014


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Humulin I (Isophane) 100 IU/ml suspension for injection in vial


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One vial contains 10 ml equivalent to 1000 IU of isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a vial. Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.




4.2 Posology and method of administration

The dosage should be determined by the physician, according to the requirement of the patient. Humulin I should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. Humulin I (Isophane) may be administered in combination with Humulin S (Soluble). (See Instructions for use and handling for Mixing of Insulins).


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Each pack contains a patient information leaflet with instructions on how to inject insulin. 4.3 Contraindications



Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin 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 human insulin


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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.




4.6 Fertility, pregnancy and lactation

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 doctors if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.



4.8 Undesirable effects

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.


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Local allergy in patients is common (1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause 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. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required. Lipodystrophy at the injection site is uncommon (1/1,000 to < 1/100). Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

4.9 Overdose



5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Humulin I: ATC code A10A C01. Humulin I is an intermediate acting insulin preparation.


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The prime activity of insulin is the regulation of glucose metabolism. In addition insulin has 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. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin I







m-cresol glycerol phenol protamine sulphate dibasic sodium phosphate 7H2O zinc oxide water for injections. The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.

Time (hours)


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6.2 Incompatibilities Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.

6.3 Shelf life Unopened vials 3 years. After first use 28 days.


Do not freeze. Do not expose to excessive heat or direct sunlight. Unopened vials Store in a refrigerator (2 C – 8 C). After first use Store below 30°C.


10 ml of suspension in a vial (type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic). Pack size 1.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles must not be shared. Vials can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings). a) Preparing a dose Vials containing Humulin I formulation should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The vials should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the vial, giving a frosted appearance. Mixing of insulins: The shorter acting insulin should be drawn into the syringe first, to prevent contamination of the vial by the longer acting preparation. It is advisable to inject directly after mixing. However, if a delay is necessary, a consistent routine must be followed.


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Alternatively a separate syringe or, separate cartridges of Humulin S and I, can be used for administration of the correct amount of each formulation. Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse. Use an insulin syringe marked for the strength of insulin being administered. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.

7 MARKETING AUTHORISATION HOLDER

Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Trading style: Lilly Industries Limited


PL 00006/0666

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 13/08/2014


13/08/2014


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Humulin I (Isophane) 100 IU/ml suspension for injection in cartridge


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One cartridge contains 3 ml equivalent to 300 IU of isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a cartridge. Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.





The dosage should be determined by the physician, according to the requirement of the patient. Humulin I should be given by subcutaneous injection but may although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. Each pack contains a patient information leaflet with instructions on how to inject insulin.


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4.3 Contraindications Hypoglycaemia. Hypersensitivity to Humulin or to the formulation excipients, unless used as part of a desensitisation programme. Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.


Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin 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 human insulin is considered. If the combination is used, patients should be observed for signs and symptoms


23

of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.











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4.9 Overdose




Pharmaco-therapeutic group: Humulin I: ATC code A10A C01. Humulin I is an intermediate acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism.


25

In addition insulin has 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. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin I








Time (hours)


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6.3 Shelf life Unused cartridge 3 years. After cartridge insertion 28 days.


Unused cartridge Store in a refrigerator (2 C – 8 C). Do not freeze. Do not expose to excessive heat or direct sunlight. After cartridge insertion Store below 30°C. Do not refrigerate. The pen with the inserted cartridge should not be stored with the needle attached.


3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber). Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Cartridges can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A suspension for injection in a 3 ml cartridge to be used with a CE marked pen as recommended in the information provided by the device manufacturer. a) Preparing a dose Cartridges containing Humulin I formulation should be rolled in the palms of the hands ten times and inverted 1800 ten times immediately before use to resuspend the insulin until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The cartridges should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled.


27

The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0669




13/08/2014


28


Humulin S (Soluble) 100 IU/ml solution for injection in cartridge


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One cartridge contains 3 ml equivalent to 300 IU of soluble insulin. For a full list of excipients, see section 6.1.


A solution for injection in a cartridge. Humulin S is a sterile, clear, colourless, aqueous solution of human insulin.





The dosage should be determined by the physician, according to the requirement of the patient. Humulin S should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. It may also be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. Each pack contains a patient information leaflet with instructions on how to inject insulin.


Hypoglycaemia.


29

Hypersensitivity to Humulin or to the formulation excipients, unless used as part of a desensitisation programme. Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.


Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin 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 human insulin 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.


30









Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise. Local allergy in patients is common (1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few


31

weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause 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. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required. Lipodystrophy at the injection site is uncommon (1/1,000 to < 1/100). Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

4.9 Overdose




Pharmaco-therapeutic group: Humulin S: ATC code A10A B01. Humulin S is a rapidly acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism. In addition insulin has several anabolic and anti-catabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and


32

protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin S

Time (hours)







m-cresol glycerol water for injections. The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.




33

6.3 Shelf life Unused cartridge 2 years. After cartridge insertion 28 days.




3 ml solution in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber). Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Cartridges can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A solution for injection in a 3 ml cartridge to be used with a CE marked pen as recommended in the information provided by the device manufacturer. a) Preparing a dose Cartridges containing Humulin S formulation do not require resuspension and should only be used if it is clear, colourless, with no solid particles visible and if it is of water-like appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.


34

7 MARKETING AUTHORISATION HOLDER Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Trading style: Lilly Industries Limited


PL 00006/0668




13/08/2014


35


Humulin M3 (Mixture 3) 100 IU/ml suspension for injection in cartridge


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One cartridge contains 3 ml equivalent to 300 IU of biphasic isophane insulin – 30 % soluble insulin / 70 % isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a cartridge. Humulin M3 is a sterile suspension of human insulin in the proportion of 30 % soluble insulin to 70 % isophane insulin.





The dosage should be determined by the physician, according to the requirement of the patient. Humulin M3 should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.


36

Humulin Mixture formulation is a ready-made defined mixture of soluble and isophane insulin designed to avoid the need for the patient to mix insulin preparations. A patient's treatment regimen should be based on their individual metabolic requirements. Each pack contains a patient information leaflet with instructions on how to inject insulin.




Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.


37

Combination of human insulin 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 human insulin 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.









38


4.9 Overdose



39


5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Humulin M3: ATC code A10A D01. Humulin M3 is an intermediate acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism. In addition insulin has 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. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin M3

Time (hours)







m-cresol


40

glycerol phenol protamine sulphate dibasic sodium phosphate 7H2O zinc oxide water for injections. The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.



6.3 Shelf life

Unused cartridge 3 years. After cartridge insertion 28 days.




3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber). Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Cartridges can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A suspension for injection in a 3 ml cartridge to be used with a CE marked pen as recommended in the information provided by the device manufacturer. a) Preparing a dose Cartridges containing Humulin M3 formulation should be rolled in the palms of the hands ten times and inverted 1800 ten times immediately before use to resuspend the insulin until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed.


41

Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The cartridges should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled. The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0670




13/08/2014


42


Humulin I KwikPen (Isophane) 100 IU/ml suspension for injection


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One pre-filled pen contains 3 ml equivalent to 300 IU of isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a pre-filled pen. Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.





The dosage should be determined by the physician, according to the requirement of the patient. Humulin I should be given by subcutaneous injection but may although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. Each pack contains a patient information leaflet with instructions on how to inject insulin.


43

4.3 Contraindications Hypoglycaemia. Hypersensitivity to Humulin or to the formulation excipients, unless used as part of a desensitisation programme. Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.


Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin 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 human insulin is considered. If the combination is used, patients should be observed for signs and symptoms


44

of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.











45


4.9 Overdose




Pharmaco-therapeutic group: Humulin I: ATC code A10A C01. Humulin I is an intermediate acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism.


46

In addition insulin has 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. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin I








Time (hours)


47


6.3 Shelf life Unused pre-filled pens 3 years. After first use 28 days.


Unused pre-filled pens Store in a refrigerator (2 C – 8 C). Do not freeze. Do not expose to excessive heat or direct sunlight. After first use Store below 30°C. Do not refrigerate. The pre-filled pen should not be stored with the needle attached.


3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber) in a pre-filled pen. Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Humulin I KwikPen can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A suspension for injection in a pre-filled / disposable pen injector containing a 3ml cartridge. Humulin I KwikPen delivers up to 60 units per dose in single unit increments. a) Preparing a dose Humulin KwikPen containing Humulin I formulation should be rolled in the palms of the hands ten times and inverted 1800 ten times immediately before use to resuspend the insulin until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The pre-filled pen should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge.


48

Cartridges are not designed to be refilled. Follow the instructions with Humulin I KwikPen for attaching the needle and administering the insulin injection. For Humulin I KwikPen, a needle must always be attached before priming, dialing and injecting an insulin dose. Humulin I KwikPen should always be primed before each injection. Failure to prime Humulin I KwikPen may result in an inaccurate dose. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0672




13/08/2014


49


Humulin M3 KwikPen (Mixture 3) 100 IU/ml suspension for injection


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One pre-filled pen contains 3 ml equivalent to 300 IU of biphasic isophane insulin – 30 % soluble insulin / 70 % isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a pre-filled pen. Humulin M3 is a sterile suspension of human insulin in the proportion of 30 % soluble insulin to 70 % isophane insulin.







50







51










52


4.9 Overdose



53



Time (hours)







m-cresol


54




6.3 Shelf life

Unused pre-filled pens 3 years. After first use 28 days.


Unused pre-filled pens Store in a refrigerator (2 C – 8 C). Do not freeze. Do not expose to excessive heat or direct sunlight. After first use Store below 30°C. Do not refrigerate. The pre-filled pen should not be stored with the needle attached


3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber) in a pre-filled pen. Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Humulin M3 KwikPen can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instruction for use and handling A suspension for injection in a pre-filled / disposable pen injector containing a 3ml cartridge. Humulin M3 KwikPen delivers up to 60 units per dose in single unit increments. a) Preparing a dose


55

Humulin KwikPen containing Humulin M3 formulation should be rolled in the palms of the hands ten times and inverted 1800 ten times immediately before use to resuspend the insulin until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The cartridges should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled. Follow the instructions with Humulin M3 KwikPen for attaching the needle and administering the insulin injection. For Humulin M3 KwikPen, a needle must always be attached before priming, dialing and injecting an insulin dose. Humulin M3 KwikPen should always be primed before each injection. Failure to prime Humulin M3 KwikPen may result in an inaccurate dose. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0673




13/08/2014


56


Humulin M3 (Mixture 3) 100 IU/ml suspension for injection in vial


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One vial contains 10 ml equivalent to 1000 IU of biphasic isophane insulin – 30 % soluble insulin / 70 % isophane insulin. For a full list of excipients, see section 6.1.


A suspension for injection in a vial. Humulin M3 is a sterile suspension of human insulin in the proportion of 30 % soluble insulin to 70 % isophane insulin.







57







58










59


4.9 Overdose



60



Time (hours)







m-cresol


61




6.3 Shelf life

Unopened vials 3 years. After first use 28 days.


Do not freeze. Do not expose to excessive heat or direct sunlight. Unopened vials Store in a refrigerator (2°C - 8°C). After first use Store below 30°C.


10 ml of suspension in a vial (type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic). Pack size 1.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles must not be shared. Vials can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings). a) Preparing a dose Vials containing Humulin M3 formulation should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniform cloudy or milky. If not, repeat the above procedure until contents are mixed.


62

Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. The vials should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the vial, giving a frosted appearance. Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse. Use an insulin syringe marked for the strength of insulin being administered. b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0667




13/08/2014


63


Humulin S KwikPen (Soluble) 100 IU/ml solution for injection


1 ml contains 100 IU human insulin (produced in E. coli by recombinant DNA technology). One pre-filled pen contains 3 ml equivalent to 300 IU of soluble insulin. For a full list of excipients, see section 6.1.


A solution for injection in a pre-filled pen. Humulin S is a sterile, clear, colourless, aqueous solution of human insulin.



For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis


The dosage should be determined by the physician, according to the requirement of the patient. Humulin S should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. It may also be administered intravenously. Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques. Each pack contains a patient information leaflet with instructions on how to inject insulin.


Hypoglycaemia.


64

Hypersensitivity to Humulin or to the formulation excipients, unless used as part of a desensitisation programme. Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.


Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), 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. Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and 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. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment. Insulin requirements may be increased during illness or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet. Combination of human insulin 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 human insulin 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.


65









Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise. Local allergy in patients is common (1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few


66

weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause 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. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required. Lipodystrophy at the injection site is uncommon (1/1,000 to < 1/100). Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

4.9 Overdose




Pharmaco-therapeutic group: Humulin S: ATC code A10A B01. Humulin S is a rapidly acting insulin preparation. The prime activity of insulin is the regulation of glucose metabolism. In addition insulin has several anabolic and anti-catabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and


67

protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output. The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. Humulin S

Time (hours)







m-cresol glycerol water for injections. The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.




68

6.3 Shelf life Unused pre-filled pens 2 years. After first use 28 days.


Unused pre-filled pens Store in a refrigerator (2 C – 8 C). Do not freeze. Do not expose to excessive heat or direct sunlight. After first use Store below 30°C. Do not refrigerate. The pre-filled pen should not be stored with the needle attached.


3 ml solution in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber) in a pre-filled pen. Pack size of 5.


Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Humulin S KwikPen can be used until empty, then properly discard. Any unused product or waste material should be disposed of in accordance with local requirements. Instructions for use and handling A solution for injection in a pre-filled / disposable pen injector containing a 3ml cartridge. Humulin S KwikPen delivers up to 60 units per dose in single unit increments. a) Preparing a dose Humulin KwikPen containing Humulin S formulation does not require resuspension and should only be used if it is clear, colourless, with no solid particles visible and if it is of water-like appearance. The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled. Follow the instructions with Humulin S KwikPen for attaching the needle and administering the insulin injection. For Humulin S KwikPen, a needle must always be attached before priming, dialing and injecting an insulin dose. Humulin S KwikPen should always be primed before each injection. Failure to prime Humulin S KwikPen may result in an inaccurate dose.


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b) Injecting a dose Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month. Each pack contains a patient information leaflet with instructions on how to inject insulin.




PL 00006/0671




13/08/2014


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Module 3

Patient Information Leaflet


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Module 4

Labelling


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Module 5 Scientific discussion during initial procedure

I. INTRODUCTION Based on the review of the data on quality the Reference Member State (RMS) and Concerned Member States (CMSs) considered that these line extension applications for Humulin S 100 IU/ml solution for injection in vial (PL 00006/0665-0673) could be approved for the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.

II. ABOUT THE PRODUCT Name of the products in the Reference Member State

Humulin S 100 IU/ml solution for injection in vial Humulin I 100 IU/ml suspension for injection in vial Humulin M3 100 IU/ml suspension for injection in vial Humulin S 100 IU/ml solution for injection in cartridge Humulin I 100 IU/ml suspension for injection in cartridge Humulin M3 100 IU/ml suspension for injection in cartridge Humulin S Kwikpen 100 IU/ml solution for injection Humulin I Kwikpen 100 IU/ml suspension for injection Humulin M3 Kwikpen 100 IU/ml suspension for injection

Name(s) of the active substance(s)

Human insulin

Pharmacotherapeutic classification (ATC code)

A10AB Insulins and analogues, fast-acting

Pharmaceutical form and strength(s)

Solution for injection; suspension for injection 100 units/ml

Reference numbers for the Decentralised Procedure

UK/H/030/062-071

Reference Member State

United Kingdom

Concerned Member States

Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Portugal, Spain, Sweden, The Netherlands

Marketing Authorisation Number(s)

PL 00006/0665-0673

Name and address of the authorisation holder

Eli Lilly & Company Limited, Lilly House, Priestly Road, Basingstoke, Hampshire, RG24 9NL, UK.


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III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS DRUG SUBSTANCE This line extension application is to replace the Master Cell Bank (MCB) for human insulin drug substance. The human insulin manufactured using the new master cell back will be used in the production of all the Humulin formulations listed in this application. The synthesis and specification of the current and proposed active substances are not considered significantly different. The active substance from the proposed source may be considered essentially similar to that currently granted. The line extensions were approved based on agreement from Eli Lilly & Company Limited to adhere to specific commitments regarding validation of materials used in the MCB and stability monitoring of the final product. DRUG PRODUCT The final Humulin insulin formulations are unchanged. III.1 NON-CLINICAL ASPECTS No new non-clinical data was submitted and none are required for applications of these type. III.3 CLINICAL ASPECTS No new non-clinical data was submitted and none are required for applications of these type. IV. OVERALL CONCLUSIONS AND BENEFIT-RISK ASSESSMENT

QUALITY The important quality characteristics of Humulin S 100 IU/vial solution for infusion are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of these type. CLINICAL No new efficacy data were submitted and none are required for applications of these type. As the safety profile of the humulin preparations are well-known, no additional data were required. No new or unexpected safety concerns arose from these applications. The SmPCs, PIL and labelling are satisfactory. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical concerns have been identified. Extensive clinical experience with insulin is considered to have demonstrated


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the therapeutic value of the compound. The benefit risk assessment is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE – SUMMARY

Date submitted Application type Scope Outcome

humulin public assessment report pls 00006 0665-073 · humulin s 100 iu/ml solution for injection...

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