Velosulin - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae ).

1 ml contains 100 IU of insulin human.

1 vial contains 10 ml equivalent to 1000 IU.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion in a vial.

Clear, colourless, aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

4.1 Therapeutic indications

Treatment of diabetes mellitus.

4.2 Posology and method of administrati

4.2 Posology and method of administrati

This phosphate-buffered soluble insulin is intended for continuous subcutaneous insulin infusion (CSII) in external insulin infusion pumps.

Velosulin is a fast-acting insulin and may be used in combination with certain long-acting insulin products. For incompatibilities see section 6.2.

Dosage

Dosage is individual and determined by the physician in accordance with the needs of the patient. Usually, 40–60% of the total daily dose is given as a continuous basal rate and the remaining 40–60% as boluses divided between the three main meals.

In general, when patients are transferred from injection to infusion therapy, it may be advisable to reduce the dosage by initiating the patient at 90% of the previous total daily dosage, with 40% as basal rate and 50% as boluses divided between the three main meals.

Dosage is individual and determined in accordance with the needs of the patient. The individual insulin requirement is usually between 0.3 and 1.0 IU/kg/day. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty or due to obesity) and lower in patients with residual, endogenous insulin production.

In patients with diabetes mellitus optimised glycaemic control delays the onset of late diabetic complications. Close blood glucose monitoring is therefore recommended.

An injection or infusion should be followed within 30 minutes by a meal or snack containing carbohydrates.

Dosage adjustment

Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirement.

Renal or hepatic impairment may reduce insulin requirement.

Adjustment of dosage may also be necessary if patients change physical activity or their usual diet. Dosage adjustment may be necessary when transferring patients from one insulin preparation to another (see section 4.4 ).

Administration

For subcutaneous or intravenous use.

Insulin infusion (CSII):

Continuous subcutaneous insulin infusion (CSII) in external insulin infusion pumps is usually

administered in the abdominal wall. Velosulin should never when used in a pump.

Patients started on CSII must receive comprehensive instruction in the use of the pump, and the necessary actions in case of illness, hypoglycaemia, hyperglycaemia or pump failure.

The patient should read and follow the instructions that accompany the infusion pump and use the correct reservoir and catheter for the pump (see section 6.6).

The infusion set should be changed every 48 hours using aseptic technique when inserting the infusion set.

When filling a new syringe, no large air bubbles should be left in either the syringe or the catheter. The patient should follow the instructions from the physician about the basal infusion rate and the mealtime insulin boluses to be taken.

etect possible malfunction of the pump, the patient should measure his blood glucose level regularly.

In the event of a hypoglycaemic episode, the infusion should be stopped until the episode is resolved. If repeated or severe low blood glucose levels occur, the patient should notify the health care professional and the need to reduce or stop the insulin administration should be considered. A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If the patient suspects an interruption to insulin flow the patient should notify the health care professional.

Patients administering Velosulin by CSII must have injection syringes and alternative insulin readily available in case of emergency or pump interruption or failure, in order that insulin can be administered by subcutaneous injection.

Insulin injection:

Administration of Velosulin is also possible by subcutaneous or intravenous injection. Intravenous administration should only be carried out by health care professionals.

Velosulin is administered subcutaneously in the abdominal wall. The thigh, the gluteal region or the deltoid region may also be used.

Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites.

Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.

The needle should be kept under the skin for at least 6 seconds to make sure the entire dose is injected.

Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.

The vials may be used with insulin syringes with a corresponding unit scale. When two types of insulin are mixed, draw the amount of fast-acting insulin first, followed by the amount of long-acting insulin.

Velosulin is accompanied by a package leaflet with detailed instruction for use to be followed.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Hypoglycaemia.

4.4 Special warnings and precautions for use

Inadequate dosage or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia.

Usually, the first symptoms of hyperglycaemia set in gradually, over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry

mouth, loss of appetite as well as acetone odour of breath.

In type 1 diabetes, untreated hyperglycaemic events eventually potentially lethal.

Due to the lack of long-acting insulin, patients receiving continuous subcutaneous insulin infusion via an insulin pump are at risk of fast development of ketoacidosis in case of prolonged interruption of continuous subcutaneous insulin infusion.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see sections 4.8 and 4.9).

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.

Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly.

Usual warning symptoms may disappear in patients with longstanding diabetes.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting insulin etc.), origin (animal, human or analogue insulin) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in a need for a change in dosage. If an adjustment is needed when switching the patients to Velosulin, it may occur with the first dose or during the first several weeks or months.

As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, swelling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Velosulin.

A few patients who have experienced hypoglycaemic reactions after transfer from animal source insulin have reported that early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin.

Before travelling between different time zones, the patient should be advised to consult the physician, since this may mean that the patient has to take insulin and meals at different times.

Patients using CSII may be more prone to infection at the site of infusion. Infections can be minimised by careful attention to personal hygiene of the hands and infusion site and by frequent changes of catheter (maximum usage 2 days).

Velosulin contains metacresol, which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

4.5 Interaction with other medicinal products and other forms of interaction

A number of medicinal products are known to interact with glucose metabolism. The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.

The following substances may reduce insulin requirement:

Oral hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective betablocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids or sulphonamides.

The following substances may increase insulin requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones and beta-sympathomimetics, growth hormone and danazol.

hypoglycaemia.

Octreotide/lan­reotide may both decrease and increase insulin requirement.

Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

4.6 Pregnancy and lactation

4.6 Pregnancy and lactation

There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier.

a, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero. Intensified control in the treatment of pregnant women with diabetes is therefore recommended throughout pregnancy and when contemplating pregnancy.

Insulin requirements usually fall in the first trimester and subsequently increase during the second and third trimesters.

After delivery, insulin requirements return rapidly to pre-pregnancy values.

Insulin treatment of the nursing mother presents no risk to the baby. However, the Velosulin dosage may need to be adjusted.

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.

4.8 Undesirable effects

As for other insulin products, in general, hypoglycaemia is the most frequently occurring undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement. In clinical trials and during marketed use, the frequency varies with patient population and dose regimens. Therefore, no specific frequency can be presented. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Frequencies of adverse drug reactions from clinical trials that are considered related to fast-acting human insulin (Actrapid) are listed below. The frequencies are defined as: uncommon (£ 1/1,000 to <1/100). Isolated spontaneous cases are presented as very rare defined as <1/10,000 including isolated reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders

Uncommon – Peripheral neuropathy

Fast improvement in blood glucose control may be associated with a condition termed “acute painful neuropathy”, which is usually reversible.

Eye disorders

Uncommon – Refraction disorders

Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Very rare – Diabetic retinopathy

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy.

Skin and subcutaneous tissue disorders

Uncommon – Lipodystrophy

Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

General disorders and administration site conditions

Uncommon – Injection site reactions

Injection site reactions (redness, swelling, itching, pain and haematoma at the injection site) may occur during treatment with insulin. Most reactions are transitory and disappear during continued treatment.

Uncommon – Oedema

Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory

Immune system disorders

Uncommon – Urticaria, rash

Very rare – Anaphylactic reactions

Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation, reduction in blood pressure and fainting/loss of consciousness. Generalised hypersensitivity reactions are potentially lifethreatening.

4.9 Overdose

A specific overdose of insulin cannot be defined. However, hypoglycaemia may develop over sequential stages:

• • Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patients carry some sugar lumps, sweets, biscuits or sugary fruit juice.
• • Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a person who has received appropriate instruction, or by glucose given intravenously by a medical professional. Glucose must also be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: insulins and analogues for injection, fast-acting, insulin (human). ATC code: A10A B01.

The blood glucose lowering effect of insulin is due to the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

A clinical trial in a single intensive care unit treating hyperglycaemia (blood glucose above 10 mmol/l) in 204 diabetic and 1344 non-diabetic patients undergoing major surgery showed that normoglycaemia (blood glucose 4.4 – 6.1 mmol/l) induced by intravenous treatment with another fast acting human insulin (Actrapid) reduced mortality by 42% (8% versus 4.6%).

Velosulin is a fast-acting insulin.

When Velosulin is administered as a bolus injection onset of action is within % hour, reaches a maximum effect within 1.5–3.5 hours and the entire duration of action is approximately 7–8 hours.

5.2 Pharmacokinetic properties

Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of an insulin preparation is determined solely by its absorption characteristics.

This process is influenced by several factors (e.g. insulin dosage, injection route and site, thickness of subcutaneous fat, type of diabetes). The pharmacokinetics of insulin products are therefore affected by significant intra- and inter-individual variation.

Continuous subcutaneous infusion eliminates some of the variations/fluc­tuations inherent to injection therapy.

The relatively fast absorption of soluble insulin ensures a constant supply of insulin to the blood from a relatively small pool under the skin.

Absorption

The maximum plasma concentration is reached within 1.5–2.5 hours after subcutaneous administration.

Distribution

No profound binding to plasma proteins, except circulating insulin antibodies (if present) has been observed.

Metabolism

Human insulin is reported to be degraded by insulin protease or insulin-degrading enzymes and possibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the human insulin molecule have been proposed; none of the metabolites formed following the cleavage are active.

Elimination

The terminal half-life is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life (ty2) is therefore a measure of the absorption rather than of the elimination per se of insulin from plasma (insulin in the blood stream has a ty2 of a few minutes). Trials have indicated a ty2 of about 2–5 hours.

Chrildren and adolescents

The pharmacokinetic profile has been studied in a small number (n=18) of diabetic children (aged 612 years) and adolescents (aged 13–17 years) using another fast-acting human insulin, (Actrapid). The data are limited but suggest that the pharmacokinetic profile in children and adolescents may be similar to that in adults. However, there were differences between age groups in Cmax, stressing the importance of individual dose titration.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Zinc chloride

Glycerol

Metacresol

Disodium phosphate dihydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

Insulin products should only be added to compounds with which it is known to be compatible.

Medicinal products added to the insulin solution may cause degradation of the insulin, e.g. if the medicinal products contain thiols or sulphites.

Concerning compatibility with insulin infusion pumps, reservoirs, catheters and needles, see section 6.6.

6.3 Shelf life

30 months when stored between 2°C – 8°C.

6 weeks when used or stored at room temperature (below 25°C).

After first use as infusion, the insulin solution may be stored in the pump reservoir for six days at up to 37°C (close to the body).

6.4 Special precautions for storage

Before use: store in a refrigerator (2°C – 8°C).

Do not store them in or too near the freezer section or cooling element.

Do not freeze.

During use: do not refrigerate. Do not store above 25°C.

After first use as infusion: the insulin solution may be stored in the pump reservoir at up to 37°C (close to the body).

Keep the vial in the outer carton in order to protect from light. Protect from excessive heat and sunlight.

6.5 Nature and contents of container 10 ml glass vial (type 1) closed with a bromobutyl/polyisoprene rubber stopper and a protective tamper-proof cap.

Pack sizes: 1 and 5 vials x 10 ml and a multipack with 5 x (1 × 10 ml) vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handlin

6.6 Special precautions for disposal and other handlin

Upon mixing Velosulin with infusion fluids an unpredictable amount of insulin will be absorbed to the infusion material. Monitoring of the patient's blood glucose during infusion is therefore recommended.

When administered by CSII no other medicinal products or other insulin products should be mixed in the reservoir of the infusion pump with Velosulin.

When combination with long-acting insulin is necessary it is only possible to mix Velosulin with isophane or premixed insulin products. Velosulin should not be mixed with insulin zinc suspensions since the phosphate buffer may interact with the zinc in the suspension and alter the timing of action of the insulin in an unpredictable way.

Insulin preparations which have been frozen must not be used.

Insulin solutions should not be used if they do not appear water clear and colourless.

Insulin infusion (CSII):Insulin infusion (CSII):

Use only syringes made of polyethylene, polypropylene or glass.

Use only catheters where the material in contact with the insulin is made of polyethylene or polypropylene.

Use only teflon-coated or stainless steel needles.

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

7. MARKETING AUTHORISATION HOLDER

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/232/001–003