1. Name Of The Medicinal Product
Insuman® Rapid 100 IU/ml solution for injection in a cartridge
Insuman® Rapid 100 IU/ml OptiSet® solution for injection
2. Qualitative And Quantitative Composition
Insuman Rapid is a neutral insulin solution (regular insulin).
Each ml of Insuman Rapid contains 100 IU of the active substance insulin human.
Each cartridge contains 3 ml, equivalent to 300 IU insulin.
Insuman Rapid OptiSet is a pre-filled disposable pen. Each pen contains 3 ml, equivalent to 300 IU insulin.
One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.
The human insulin in Insuman Rapid is produced by recombinant DNA technology using K 12 strains of Escherichia coli.
For excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection in a cartridge or pre-filled pen.
4. Clinical Particulars
4.1 Therapeutic Indications
Diabetes mellitus where treatment with insulin is required.
Insuman Rapid cartridges are also suitable for the treatment of hyperglycaemic coma and ketoacidosis, as well as for achieving pre-, intra- and post-operative stabilisation in patients with diabetes mellitus
4.2 Posology And Method Of Administration
The desired blood glucose levels, the insulin preparations to be used and the insulin dosage (doses and timings) must be determined individually and adjusted to suit the patient's diet, physical activity and life-style.
Daily doses and timing of administration
There are no fixed rules for insulin dosage. However, the average insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. The basal metabolic requirement is 40% to 60% of the total daily requirement. Insuman Rapid is injected subcutaneously 15 to 20 minutes before a meal.
Insuman Rapid OptiSet delivers insulin in increments of 2 IU up to a maximum single dose of 40 IU.
Insuman Rapid cartridges: In the treatment of severe hyperglycaemia or ketoacidosis in particular, insulin administration is part of a complex therapeutic regimen which includes measures to protect patients from possible severe complications of a relatively rapid lowering of blood glucose. This regimen requires close monitoring (metabolic status, acid-base and electrolyte status, vital parameters etc.) in an intensive care unit or similar setting.
Transfer to Insuman Rapid
Dosage adjustment may be necessary when transferring patients from one insulin preparation to another. This applies, for example, when transferring from:
- an animal insulin (especially a bovine insulin) to human insulin,
- one human insulin preparation to another,
- a regimen with only regular insulin to one with a longer-acting insulin.
The need to adjust (e.g. reduce) the dose may become evident immediately after transfer. Alternatively, it may emerge gradually over a period of several weeks.
Following transfer from an animal insulin to human insulin, dosage reduction may be required in particular in patients who
- were previously already controlled on rather low blood glucose levels,
- have a tendency to hypoglycaemia,
- previously required high insulin doses due to the presence of insulin antibodies.
Close metabolic monitoring is recommended during the transition and in the initial weeks thereafter. In patients who require high insulin doses because of the presence of insulin antibodies, transfer under medical supervision in a hospital or similar setting must be considered.
Secondary dose adjustment
Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, for example, if
- the patient's weight changes,
- the patient's life-style changes,
- other circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia (see section 4.4).
Use in specific patient groups
In patients with hepatic or renal impairment as well as in the elderly, insulin requirements may be diminished (see section 4.4).
Administration
Cartridges: Insuman Rapid in cartridges has been developed for use in the OptiPen® series. For further details on handling, see section 6.6.
OptiSet: Before using the OptiSet, the Instructions for Use included in the package leaflet must be read carefully (see 6.6).
Insuman Rapid is administered subcutaneously.
Insulin absorption and hence the blood glucose lowering effect of a dose may vary from one injection area to another (e.g. the abdominal wall compared with the thigh). Injection sites within an injection area must be rotated from one injection to the next.
Insuman Rapid cartridges may also be administered intravenously. Intravenous insulin therapy must generally take place in an intensive care unit or under comparable monitoring and treatment conditions (see "Daily doses and timing of administration").
Mixing of insulins
Insuman Rapid cartridges may be mixed with all Sanofi-Aventis human insulins, but NOT with those designed specifically for use in insulin pumps. Insuman Rapid must also NOT be mixed with insulins of animal origin or with insulin analogues.
Insuman Rapid OptiSet must not be mixed with any other insulin or with insulin analogues.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Insuman Rapid cartridges must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing.
4.4 Special Warnings And Precautions For Use
Patients hypersensitive to Insuman Rapid for whom no better tolerated preparation is available must only continue treatment under close medical supervision and – where necessary – in conjunction with anti-allergic treatment.
In patients with an allergy to animal insulin intradermal skin testing is recommended prior to a transfer to Insuman Rapid, since they may experience immunological cross-reactions.
In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism. In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.
In patients with severe hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.
In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered.
Hypoglycaemia
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.
Particular caution should be exercised, and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).
Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:
- in whom glycaemic control is markedly improved,
- in whom hypoglycaemia develops gradually,
- who are elderly,
- in whom an autonomic neuropathy is present,
- with a long history of diabetes,
- suffering from a psychiatric illness,
- receiving concurrent treatment with certain other medicinal products (see section 4.5).
Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia.
If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.
Adherence of the patient to the dosage and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These include:
- change in the injection area,
- improved insulin sensitivity (by, e.g., removal of stress factors),
- unaccustomed, increased or prolonged physical activity,
- intercurrent illness (e.g. vomiting, diarrhoea),
- inadequate food intake,
- missed meals,
- alcohol consumption,
- certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency),
- concomitant treatment with certain other medicinal products.
Intercurrent illness
Intercurrent illness requires intensified metabolic monitoring. In many cases, urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc. and they must never omit insulin entirely.
Handling of the OptiSet pen
Before using OptiSet, the Instructions for Use included in the Package Leaflet must be read carefully. OptiSet has to be used as recommended in these Instructions for Use (see 6.6)
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
A number of substances affect glucose metabolism and may require dose adjustment of human insulin.
Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia include oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.
Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic agents (e.g. epinephrine [adrenaline], salbutamol, terbutaline) and thyroid hormones.
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia which may sometimes be followed by hyperglycaemia.
In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.
4.6 Pregnancy And Lactation
There is no experience with the use of Insuman Rapid in pregnant women. Insulin does not cross the placental barrier.
It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.
There are no restrictions on the use of Insuman Rapid in breast-feeding women. Lactating women may require adjustments in insulin dose and 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 or hyperglycaemia or, for example, as a result of visual impairment. 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 symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.
4.8 Undesirable Effects
Hypoglycaemia
Hypoglycaemia, in general the most frequent undesirable effect of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.
In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.
Eyes
A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.
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. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.
Lipodystrophy
As with any insulin therapy, lipodystrophy may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions.
Injection site and allergic reactions
In rare cases mild reactions at the injection site may occur. Such reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks.
Immediate-type allergic reactions to insulin are very rare. Such reactions to insulin or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening.
Other reactions
Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.
Insulin may cause sodium retention and oedema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
4.9 Overdose
Symptoms
Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.
Management
Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in dosage of the medicinal product, meal patterns, or physical activity may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Antidiabetic agent. Insulins and analogues, fast-acting.
ATC Code: A10AB01,
Mode of action
Insulin:
• lowers blood glucose and promotes anabolic effects as well as decreasing catabolic effects.
• increases the transport of glucose into cells as well as the formation of glycogen in the muscles and the liver, and improves pyruvate utilisation. It inhibits glycogenolysis and gluconeogenesis.
• increases lipogenesis in the liver and adipose tissue and inhibits lipolysis.
• promotes the uptake of amino acids into cells and promotes protein synthesis.
• enhances the uptake of potassium into cells.
Pharmacodynamic characteristics
Insuman Rapid is an insulin with rapid onset and short duration of action. Following subcutaneous injection, onset of action is within 30 minutes, the phase of maximum action is between 1 and 4 hours after injection and the duration of action is 7 to 9 hours.
5.2 Pharmacokinetic Properties
In healthy subjects, the serum half-life of insulin is approximately 4 to 6 minutes. It is longer in patients with severe renal insufficiency. However, it must be noted that the pharmacokinetics of insulin do not reflect its metabolic action.
5.3 Preclinical Safety Data
The acute toxicity was studied following subcutaneous administration in rats. No evidence of toxic effects was found. Local tolerability studies following subcutaneous and intramuscular administration in rabbits gave no remarkable findings. Studies of pharmacodynamic effects following subcutaneous administration in rabbits and dogs revealed the expected hypoglycaemic reactions.
6. Pharmaceutical Particulars
6.1 List Of Excipients
M-cresol, sodium dihydrogen phosphate dihydrate, glycerol, sodium hydroxide, hydrochloric acid, water for injections.
6.2 Incompatibilities
As with all insulin preparations, Insuman Rapid must not be mixed with solutions containing reducing agents such as thioles and sulfites. It must also be remembered that neutral regular insulin precipitates out at a pH of approximately 4.5 to 6.5.
Concerning mixing and incompatibility with other insulins see section 4.2. Care must be taken to ensure that no alcohol or other disinfectants enter the insulin solution.
6.3 Shelf Life
2 years.
Cartridges: Once in use, the cartridges may be kept for up to four weeks. This applies irrespective of whether the cartridges are immediately put into the pen or are first carried as a spare for a while.
OptiSet: Once in use the pens may be kept for up to four weeks. This applies irrespective of whether the pens are immediately used or are first carried as a spare for a while.
6.4 Special Precautions For Storage
Store at 2°C to 8°C. Keep the container in the outer carton. Do not freeze. Ensure that the container is not directly touching the freezer compartment or freezer packs.
Cartridges: Once in use, do not store above 25°C, and protect from direct heat and light. When in use (in the pen) , do not store in a refrigerator.
OptiSet pens: Before first use, Insuman Rapid OptiSet must be kept at room temperature for 1 to 2 hours. Once in use, do not store above 25°C, and protect from direct heat and light. When in use, do not store in a refrigerator.
6.5 Nature And Contents Of Container
Cartridges
3 ml, type 1 colourless glass cartridge with bromobutyl rubber (type 1) plunger and flanged aluminium cap with bromobutyl rubber (type 1) stopper.
Each cartridge contains 3 ml solution (300 IU insulin human). Pack of 5 cartridges are available.
OptiSet
Disposable pen filled with a 3 ml, type 1 colourless glass cartridge with bromobutyl rubber (type 1) plunger and flanged aluminium cap with bromobutyl rubber (type 1) stopper.
Each cartridge contains 3 ml solution (300 IU insulin human). The cartridges are sealed in a disposable pen injector. Needles are not included in the pack. Pack of 5 pens are available.
6.6 Special Precautions For Disposal And Other Handling
Insulin pen
The cartridges are to be used in conjunction with an insulin pen such as OptiPen and other pens suitable for Insuman cartridges and as recommended in the information provided by the device manufacturer
The manufacturer's instructions for using the pen must be followed carefully for loading the partridge, attaching the needle and administering the insulin injection.
If the insulin pen is damaged or not working properly (due to mechanical defects) is has to be discarded and a new insulin pen has to be used.
If the pen malfunctions (see instructions of using the pen), the solution may be drawn from the cartridge into a syringe (suitable for an insulin with 100 IU/ml) and injected.
Cartridges
Before insertion into the pen, Insuman Rapid must be stored at room temperature for 1 to 2 hours. Inspect the cartridge before use. Insuman Rapid must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of a water-like consistency.
Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).
Insuman Rapid cartridges are not designed to allow any other insulin to be mixed in the cartridge.
OptiSet
Insuman Rapid must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of a water-like consistency.
Empty pens must never be reused and must be properly discarded.
To prevent the possible transmission of disease, each pen must be used by one patient only.
Handling of the pen
The Instructions for Use included in the Package Leaflet must be read carefully before using OptiSet.
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Schematic diagram of the pen
Important information for use of OptiSet:
• Before each use, a new needle must be attached and a safety test must be performed.
• The dosage selector must never be turned after the injection button has been pulled out.
• If a problem occurs with OptiSet, the section “Troubleshooting” in the Instructions for Use should be referred to.
• If OptiSet is damaged, or not working properly (due to mechanical defects) it has to be discarded and a new OptiSet has to be used.
General Notes
- The injection button allows checking the actual loaded dose. The button should be pulled out. While holding it out, the last thick bar visible (only the top part can be seen) shows the amount of insulin loaded. If it is difficult to see, the pen may be held at an angle.
- The insulin pen must not be dropped or subjected to impact; otherwise, the insulin cartridge in the transparent insulin reservoir may break and the pen will not work. If this happens, a new pen must be used.
Step 1. Check the Insulin
After removing the pen cap, the label on the insulin reservoir should be checked to make sure it contains the correct insulin. The appearance of insulin should also be checked: the insulin solution must be clear, colourless, with no solid particles visible, and must have a water-like consistency.
Step 2. Attaching the needle
Only needles that have been approved for use with OptiSet should be used.
The needle should be carefully attached straight onto the pen.
Step 3. Safety test
Prior to each injection a safety test has to be performed.
For a new and unused OptiSet, the dose arrow should point to the number 8, as preset by the manufacturer.
Otherwise, the dosage selector should be turned until the dose arrow points to 2.
Then the injection button should be pulled out as far as it will go.
The outer and inner needle caps should be removed.
While holding the pen with the needle pointing upwards, the insulin reservoir should be tapped gently with the finger so that any air bubbles rise up towards the needle
Then the injection button should be pressed in completely.
If insulin has been expelled through the needle tip, then the pen and the needle are working properly.
If no insulin appears at the needle tip, step 3 should be repeated until insulin appears at the needle tip.
Step 4. Setting and loading the insulin dose
The dose can be set in steps of 2 units, from a minimum of 2 units to a maximum of 40 units. If a dose greater than 40 units is required, it should be given as two or more injections.
The dosage selector should be turned in either direction until the dose arrow points to the required dose.
The injection button should be pulled out as far as it will go in order to load the pen.
Step 5. Injecting the insulin dose
The patient should be informed on the injection technique by his health care professional.
The needle should be inserted into the skin.
The injection button should be pressed in completely. Then the injection button should be held down 10 seconds before withdrawing the needle. This ensures that the full dose of insulin has been injected.
Step 6. Removing the needle
The needle should be removed after each injection and discarded. This will prevent contamination as well as leakage, re-entry of air and potential needle blocks. Needles must not be reused.
The pen cap should be replaced on the pen.
Checking the reservoir for remaining insulin
The residual insulin scale on the transparent insulin reservoir shows approximately how much insulin remains in the OptiSet. This scale must not be used to set the insulin dose.
The actual loaded dose should be checked as per “General notes”. In case, the patient is not sure whether enough insulin remains in the reservoir, the OptiSet should be discarded.
Example:If the dose arrow has been set to 30 units and injection button can only be pulled out to as far as 12 units, then only 12 units insulin can be injected with this pen. In this example, either the other 18 units will have to be injected using a new pen, or the entire 30 units dose will have to be injected using a new pen.
7. Marketing Authorisation Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main
Germany
8. Marketing Authorisation Number(S)
5 cartridges of 3 ml: EU/1/97/030/030
5 OptiSet pens of 3 ml: EU/1/97/030/067
9. Date Of First Authorisation/Renewal Of The Authorisation
Cartridge: 11 November 1998
OptiSet: 20 March 2000
10. Date Of Revision Of The Text
June 2006
11. Legal Category
POM
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