Actrapid Penfill/Actrapid Flexpen: Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces cerevisiae).
1 mL contains 100 IU of insulin human.
1 cartridge and 1 pre-filled pen contains 3 mL equivalent to 300 IU.
One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.
Excipients/Inactive Ingredients: Zinc chloride, glycerol, metacresol, sodium hydroxide/hydrochloric acid (for pH adjustment) and water for injections.
Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, fast-acting, insulin (human). ATC code: A10AB01.
Pharmacology: Pharmacodynamics: The blood glucose lowering effect of insulin is due to the facilitated uptake of glucose following 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 Actrapid reduced mortality by 42% (8% versus 4.6%).
Actrapid is a fast-acting insulin.
Onset of action is within ½ hour, reaches a maximum effect within 1.5-3.5 hours and the entire duration of action is approximately 7-8 hours.
Pharmacokinetics: 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.
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 (t½) 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 t½ of a few minutes). Trials have indicated a t½ of about 2-5 hours.
Children and adolescents: The pharmacokinetic profile of Actrapid has been studied in a small number (n=18) of diabetic children (aged 6-12 years) and adolescents (aged 13-17 years). 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.
Toxicology: 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.
Treatment of diabetes mellitus.
Actrapid is a fast-acting insulin and may be used in combination with long-acting insulin products.
Dosage: 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.
An injection 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. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose. 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.
Administration: For subcutaneous or intravenous use.
Actrapid is administered subcutaneously in the abdominal wall. If convenient, 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 always be rotated within the same region in order to reduce the risk of lipodystrophy.
Intramuscular administrations are possible under guidance by a physician.
Actrapid may also be administered intravenously, which should only be carried out by healthcare professionals.
The intravenous use of Actrapid from any pen or cartridge should be an exception only in situations where vials are not available. In this case, Actrapid should be drawn into an insulin syringe, provided air is avoided, or infused with an infusion system. This procedure should only be carried out by healthcare professionals.
Actrapid Penfill: Actrapid Penfill is designed to be used with Novo Nordisk delivery systems and NovoFine or NovoTwist needles.
Actrapid Flexpen: Actrapid FlexPen is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles of up to a length of 8 mm. FlexPen delivers 1-60 units in increments of 1 unit.
The pens should be primed before injection so that the dose selector returns to zero and a drop of insulin appears at the needle top.
The dose is set by turning the selector, which returns to zero during the injection.
Actrapid is accompanied by a package leaflet with detailed instructions for use to be followed.
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirements are administered: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar containing products.
Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must be given intravenously, if the patient does not respond to glucagon within 10 to 15 minutes.
Upon regaining consciousness, administration of an oral carbohydrate is recommended for the patient in order to prevent a relapse.
Hypersensitivity to the active substance or to any of the excipients.
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 lead to diabetic ketoacidosis, which is potentially lethal.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.
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, origin (human insulin, insulin analogue) and/or method of manufacture may result in a need for a change in dosage. Patients transferred to Actrapid from another type of insulin may require an increased number of daily injections or change in dosage from that used with their usual insulin products. If an adjustment is needed when switching the patient to Actrapid, it may occur with the first dose or during the first few weeks or months.
As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling and itching. 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 Actrapid.
When patients are transferred between different types of insulin medicinal products, the early warning symptoms of hypoglycaemia may change or become less pronounced than 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.
Due to the risk of precipitation in pump catheters, Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.
Combination of thiazolidinediones and insulin medicinal products: Cases of congestive heart failure have been reported when thiazolidinediones were used in combination with insulin, especially in patients with risk factors for development of congestive heart failure.
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 while 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.
There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier.
Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled diabetes therapy, increase the risk of malformations and death in utero. Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy.
Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
There is no restriction on treatment with Actrapid during breast-feeding.
Insulin treatment of the nursing mother presents no risk to the baby. However, the Actrapid dosage, diet or both may need to be adjusted.
Summary of the safety profile:
The most frequently reported adverse reaction during treatment is hypoglycaemia. In clinical trials and during marketed use, the frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemia control, please see Description of selected adverse reactions as follows.
At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur. These reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.
Tabulated list of adverse reactions:
Adverse reactions listed as follows are based on clinical trial data and classified according to MedDRA frequency and System Organ Class. Frequency categories are defined according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See table.)
Click on icon to see table/diagram/image
Description of selected adverse reactions:
Anaphylactic reactions: The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation, reduction in blood pressure and fainting/loss of consciousness) is very rare but can potentially be life threatening.
Hypoglycaemia: The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.
Lipodystrophy: Lipodystrophy is reported as uncommon. Lipodystrophy may occur at the injection site.
A number of medicinal products are known to interact with the glucose metabolism. The following substances may reduce the patient's insulin requirement: Oral anti-diabetic products, monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.
The following substances may increase the patient's insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Octreotide/lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
For intravenous use, infusion systems with Actrapid at concentrations from 0.05 IU/mL to 1.0 IU/mL insulin human in the infusion fluids: 0.9% sodium chloride, 5% dextrose and 10% dextrose inclusive 40 mmol/L potassium chloride, using polypropylene infusion bags, are stable at room temperature for 24 hours. Although stable over time, a certain amount of insulin will initially be absorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during the infusion.
Cartridges and Pens should only be used in combination with products that are compatible with them and allow the cartridge or flexpen to function safely and effectively.
Needles and Actrapid Penfill, Actrapid Flexpen must not be shared. The container must not be refilled.
Insulin preparations which have been frozen must not be used.
Insulin solutions should not be used if they do not appear clear and colourless.
Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion. The patient should be advised to discard the needle after each injection.
In case of emergency in current Actrapid users (hospitalisation or insulin pen malfunction), Actrapid can be withdrawn with an U100 insulin syringe from the cartridge or from the Flexpen.
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.
Store in a refrigerator (2°C - 8°C). Keep away from the cooling element. Do not freeze.
Actrapid must be protected from excessive heat and light.
After first opening or if carried as a spare: Do not refrigerate.
Actrapid Penfill: Keep the cartridge in the outer carton in order to protect from light.
Actrapid Flexpen: Keep the pen cap on Flexpen in order to protect from light.
Shelf-Life: The in-use shelf life is 6 weeks when stored below 30°C.
Actrapid solution for injection in Penfill: Do not use Actrapid: In insulin infusion pumps. If you are allergic (hypersensitive) to human insulin or any of the other ingredients in Actrapid.
If you suspect hypoglycaemia (low blood sugar) is starting.
If the cartridge or the device containing the cartridge is dropped, damaged or crushed.
If it has not been stored correctly or been frozen. If the insulin does not appear clear and colourless.
Before using Actrapid: Check the label to make sure it is the right type of insulin. Always check the cartridge, including the rubber stopper. Do not use it if any damage is seen or if there is a gap between the rubber stopper and the white label band. Take it back to the supplier. See the delivery system manual for further instructions.
Always use a new needle for each injection to prevent contamination.
Needles and Actrapid Penfill must not be shared.
How to use this insulin: Actrapid is for injection under the skin (subcutaneously). Always vary the sites you inject within the same region, to reduce the risk of developing lumps or skin pitting. The best places to give the patient an injection are: the front of your waist (abdomen); your buttocks; the front of your thighs or upper arms. Your insulin will work more quickly if you inject it around the waist.
How to inject this insulin: Inject the insulin under the skin. Use the injection technique advised by the doctor or nurse and described in the delivery system manual.
Keep the needle under your skin for at least 6 seconds. Keep the push button fully depressed until the needle has been withdrawn. This will ensure correct delivery and limit possible flow of blood into the needle or insulin reservoir.
After each injection, be sure to remove and discard the needle and store Actrapid without the needle attached. Otherwise the liquid may leak out which can cause inaccurate dosing.
Do not refill Actrapid Penfill.
Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist needles. If you are treated with Actrapid Penfill and another insulin Penfill cartridge, you should use two insulin delivery systems, one for each type of insulin.
As a precautionary measure, always carry a spare insulin delivery system in case your Penfill is lost or damaged.
Actrapid solution for injection in pre-filled pen: Your FlexPen is a unique dial-a-dose insulin pen. You can select doses from 1 to 60 units in increments of 1 unit. FlexPen is designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. As a precautionary measure, always carry a spare insulin delivery device in case your FlexPen is lost or damaged.
Maintenance: Your FlexPen is designed to work accurately and safely. It must be handled with care. If it is dropped or crushed, there is a risk of damage and leakage of insulin.
You can clean the exterior of the FlexPen by wiping it with a medicinal swab. Do not soak it, wash or lubricate it as it may damage the pen.
Do not refill your Actrapid FlexPen.
Preparing Actrapid FlexPen: Check the label to make sure that your Actrapid FlexPen contains the correct type of insulin: A. Pull off the pen cap.
B. Remove the protective tab from a new disposable needle. Screw the needle straight and tightly onto the FlexPen.
C. Pull off the big outer needle cap and keep it for later.
D. Pull off the inner needle cap and dispose of it. Always use a new needle for each injection to prevent contamination.
Be careful not to bend or damage the needle before use.
To reduce the risk of unexpected needle sticks, never put the inner needle cap back on when you have removed it from the needle.
Checking the insulin flow: Prior to each injection, small amounts of air may collect in the cartridge during normal use. To avoid injection of air and ensure proper dosing: E. Turn the dose selector to select 2 units.
F. Hold the FlexPen with the needle pointing upwards and tap the cartridge gently with your finger a few times to make any air bubbles collect at the top of the cartridge.
G. Keeping the needle upwards, press the push-button all the way in. The dose selector returns to 0.
A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times.
If a drop of insulin still does not appear, the pen is defective, and you must use a new one.
Selecting your dose: Check that the dose selector is set at 0: H. Turn the dose selector to select the number of units needed to inject.
The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer. When turning the dose selector, be careful not to push the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in the cartridge.
Do not use the residual scale to measure the dose of insulin.
Making the injection: Insert the needle into the skin. Use the injection technique shown by the doctor or nurse: I. Inject the dose by pressing the push-button all the way in until 0 lines up with the pointer. Be careful only to push the push-button when injecting.
Turning the dose selector will not inject insulin.
J. Keep the push-button fully depressed after the injection until the needle has been withdrawn from the skin.
The needle must remain under the skin for at least 6 seconds. This will ensure that the full dose has been injected.
K. Lead the needle into the big outer needle cap without touching the big outer needle cap. When the needle is covered, carefully push the big outer needle cap completely on and then unscrew the needle.
Dispose of it carefully and put the pen cap back on.
Always remove the needle after each injection and store your FlexPen without the needle attached.
Otherwise the liquid may leak out which can cause inaccurate dosing.
Caregivers should be most careful when handling used needles to avoid needle sticks.
Dispose of the used FlexPen carefully without the needle attached.
Needles and Actrapid FlexPen must not be shared.
A10AB01 - insulin (human) ; Belongs to the class of fast-acting insulins and analogues. Used in the treatment of diabetes.
Penfill 100 IU/mL (clear colorless, aqueous solution in a cartridge) x 3 mL x 5's. Flexpen 100 IU/mL (clear colorless, aqueous solution in a pre-filled pen) x 3 mL x 5's.