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

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

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

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

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

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

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

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

1ml contains 100IU human insulin (produced in E. coli by recombinant DNA technology).

For a full list of excipients, see section 6.1.

HUMULIN S: A solution for injection in a cartridge or vial. HUMULIN S is a sterile, clear, colourless, aqueous solution of human insulin.

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

HUMULIN M3: A suspension for injection in a cartridge, vial or pre-filled pen. HUMULIN M3 is a sterile suspension of human insulin in the proportion of 30% soluble insulin to 70% isophane 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.

HUMULIN I and 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.

HUMULIN I (Isophane) may be administered in combination with HUMULIN S (Soluble). (See 'Instructions for use and handling' for 'Mixing of insulins'.)

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.

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.

Some medicinal products are known to interact with glucose metabolism. The physician should take possible interactions into account and ask patients about their other medications in addition to human insulin.

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.

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.

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

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving; this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g., a patient's level of diet and exercise.

Local allergy in patients is common (1/100 to <1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, 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).

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.

Pharmaco-therapeutic group:

HUMULIN S: ATC code, A10A B01

HUMULIN I: ATC code, A10A C01

HUMULIN M3: ATC code, A10A D01

HUMULIN S is a rapidly-acting insulin preparation.

HUMULIN I is an intermediate-acting insulin preparation.

HUMULIN M3 (Mixture 3) 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.

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.

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.

For HUMULIN S preparations:

m-cresol

Glycerol

Water for injections

The following may be used to adjust pH:

Hydrochloric acid and/or

Sodium hydroxide

For HUMULIN I and HUMULIN M3 preparations:

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

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

Vials: The shelf-life for HUMULIN S, HUMULIN I and HUMULIN M3 presentations is two years.

Once in use the vials may be used for up to 28 days. Do not use beyond this period. When in use the vials should not be stored above 30°C.

Cartridges: The shelf-life for the HUMULIN S presentation is two years. The shelf-life for HUMULIN I and HUMULIN M3 presentations is 3 years.

After insertion of the cartridge in the pen, the solution or suspension should be used in 28 days. Do not use beyond this period. When in use the cartridges should not be stored above 30°C.

Pre-filled pens: The shelf-life for HUMULIN I- and M3 KwikPen presentations is 3 years.

Once in use HUMULIN I- and M3 KwikPen may be used for up to 28 days. Do not use beyond this period. When in use HUMULIN I- and M3 KwikPen should not be stored above 30°C.

Store in a refrigerator (2°C-8°C).

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

Keep the container in the outer carton.

Vials: 10ml of solution or 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 or 2.

Cartridges: 3ml solution or 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.

Pre-filled pens: 3ml 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.

HUMULIN I- and M3 KwikPen: Pack size of 5, or 2 x 5 x 3ml.

Not all pack sizes may be marketed.

Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Vials, cartridges and HUMULIN I- and 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.

Instructions for use and handling

A Vials

A solution or suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings).

B Cartridges

A solution or suspension for injection in a 3ml cartridge to be used with a CE marked pen as recommended in the information provided by the device manufacturer.

C Pre-filled pens

A suspension for injection in a pre-filled /disposable pen injector containing a 3ml cartridge. HUMULIN I- and M3 KwikPen delivers up to 60 units per dose in single unit increments.

a) Preparing a dose

Vials or 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.

Vials containing HUMULIN I or the HUMULIN M3 formulations should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. Cartridges and pre-filled pens containing HUMULIN I and HUMULIN M3 formulations should be rolled in the palms of the hands ten times and inverted 180° ten times immediately before use to resuspend the insulin until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.

The vials, cartridges, and pre-filled pens 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 or cartridge, giving a frosted appearance.

HUMULIN S and I Vials: 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.

Vials:

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.

Cartridges and pre-filled pens:

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.

Follow the instructions with HUMULIN I- and M3 KwikPen for attaching the needle and administering the insulin injection.

For HUMULIN I- and M3 KwikPen, a needle must always be attached before priming, dialling, and injecting an insulin dose. HUMULIN I- and M3 KwikPen should always be primed before each injection. Failure to prime HUMULIN I- and 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 site is not used more than approximately once a month.

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

Eli Lilly and Company Limited

Lilly House

Priestley Road

Basingstoke

Hampshire, RG24 9NL

02 June 2010

POM

HUMULIN* (human insulin [prb]) is a trademark of Eli Lilly and Company. HU29M