Data Sheet
ACTRAPID®
NOVO NORDISK
Neutral insulin 100 IU/ml
Presentation
Actrapid® is a clear colourless solution containing 100% neutral human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc, or in 10 ml glass vials. The Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems.
Uses
Actions
ATC code A10A B01
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.
Pharmacokinetics
Insulin in the bloodstream 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), which is why considerable intra- and inter-patient variations are seen.
For Actrapid the fast absorption is due to the product being a solution
An average action profile after subcutaneous injection indicates:
Onset: within ½ hour
Maximum: between 2.5 and 5 hours
Duration: approximately 8 hours
No profound binding to plasma proteins, except circulating insulin antibodies (if present) has been observed.
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.
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.
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 phamacokinetic 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.
Indications
Treatment of diabetes mellitus. Furthermore indicated for the initial stabilisation of diabetes, during treatment of diabetic ketoacidosis and the hyperosmolar non ketotic syndrome, and during stress situations such as severe infections and major surgery in diabetic patients.
Dosage and Administration
Dosage is individual and determined by the physician in accordance with the needs of the patient.
The individual insulin requirement is usually between 0.5 and 1.0 IU/kg. The daily insulin requirement may be higher in patients with insulin resistance (e.g. during puberty in the young 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 recommended.
Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirement. Renal or hepatic impairment may reduce insulin requirement.
Adjustment of the 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 Warnings and Precautions).
Actrapid is usually administered subcutaneously in the abdominal wall. The thigh, the gluteal region or the deltoid region may also be used. Intramuscular administrations are possible under guidance by a physician. Intravenous administrations are only suitable for vial products and should only be carried out by a physician.
In order to avoid lipodystrophy, injection sites for a given insulin preparation should be rotated within an anatomic region.
Actrapid is a-short-acting insulin and is often used in combination with intermediate- or long acting insulins.
An injection should be followed by a meal or snack containing carbohydrates within 30 minutes.
Subcutaneous injection into the abdominal wall ensures a faster absorption than from other regions of the body. Injection into a lifted skin fold minimises the risk of intramuscular injection. Keep the needle under the skin for at least 6 seconds to make sure the entire dose is injected.
Contraindications
Insulin should never be given to patients with hypoglycaemia.
Hypersensitivity to human insulin or any of the excipients.
Warnings and Precautions
Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia. The first symptoms of hyperglycaemia usually 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 breath. In type 1 diabetes, untreated hyperglycaemic events eventually leads to diabetic ketoacidosis which is potentially lethal.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see Adverse Effects and Overdosage). 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, my 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 (rapid acting insulin, dual acting insulin, intermediate and long acting insulin etc.), species (animal, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dosage.
If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
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 doctor, 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.
Actrapid contains metacresol, which may cause allergic reactions.
Pregnancy and lactation
There are no restrictions on the 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 control in the treatment of pregnant women with diabetes is recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase during the second and third trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy values.
Insulin treatment of the nursing mother involves no risk to the baby. However, the insulin dosage, diet or both may need to be reduced.
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.
Adverse Effects
Adverse drug reactions observed in patients using Actrapid are mainly dose-dependent and due to the pharmacologic effect of insulin. As for other insulin products, hypoglycaemia, in general is the most frequently 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. During clinical trials the overall rates of hypoglycaemia did not differ between patients treated with human insulin compared to insulin aspart.
Frequencies of adverse drug reactions from clinical trials, which by an overall judgement are considered related to Actrapid are listed below. The frequencies are defined as: Uncommon (>1/1,000 < 1/100). Isolated spontaneous cases are presented as very rare defined as < 1/10,000.
Immune system disorders
Anaphylactic responses - Very rare
Urticaria rash, - Uncommon
Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life threatening
Nervous system disorders
Peripheral neuropathy - Uncommon
Fast improvement in blood glucose control may be associated with a condition termed acute painful neuropathy, which is usually reversible.
Eye disorders
Refraction disorder - Uncommon
Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
Diabetic retinopathy - Very rare
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
Lipodystrophy - Uncommon
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
Injection site reaction - Uncommon
Injection site reactions (redness, swelling, itching, pain and haematoma at the injection site) may occur during treatment with insulin. Must reactions are transitory and disappear during continued treatment.
Oedema - Very rare
Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
Interactions
Concomitant use of other drugs may influence insulin requirements.
The following substances may reduce the insulin requirements:
- Oral hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates and alcohol.
The following substances may increase the insulin requirements:
- Thiazides, glucocorticoids, thyroid hormones and beta-sympathomimetics, growth hormone and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia. Octreotide/lanreotide may both increase and decrease insulin requirement. Alcohol may intensify and prolong the hypoglycaemic effect of insulin.
Overdosage
Insulins have no specific overdose definitions. 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 patient constantly carry some sugar lumps, sweets, biscuits or a 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 trained person or glucose given intravenously by a medical professional. Glucose must also be given i.v, if the patient does not respond to glucagon within 10 to 15 minutes.
Upon regaining consciousness administration of oral carbohydrate is recommended for the patient in order to prevent relapse.
Pharmaceutical Precautions
Insulin preparations should be stored between 2°C and 8°C (in a refrigerator), not in or near a freezing compartment. Insulin preparations which have been frozen must not be used.
Insulin preparations should be protected from excessive heat or sunlight. Insulin solutions should not be used if they do not appear water-clear and colourless. Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.
After first use Actrapid vials may be kept at room temperature (below 25°C) for 6 weeks. Actrapid Penfill, can be used or carried as a spare (below 25°C) for 6 weeks.
Medicine Classification
Prescription Medicine
Package Quantities
Actrapid is available as a Penfill® of 3 ml in cartons of five, or in glass vials of 10 ml.
Further Information
Incompatibilities
In general terms, insulin should only be added to compounds with which it has known compatibility. Drugs added to the insulin solution may cause degradation of the insulin, e.g. if the drugs contain thiols or sulphites. Upon mixing Actrapid with infusion fluids an unpredictable amount of insulin will be adsorbed to the infusion material. Monitoring of the patient's blood glucose during infusion is therefore recommended.
Instructions for use/handling
The carton contains a package leaflet with instructions for use and handling. For Actrapid Penfill, the leaflet carries reference to the instructions for use accompanying the administration device.
Actrapid vials are for use with insulin syringes with the 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.
Actrapid Penfill is for single person use only. The container must not be refilled.
ACTRAPID Penfill are designed to be used with Novo Nordisk insulin delivery systems and NovoFine® needles.
Excipients
Glycerol
Metacresol
Zinc chloride
Sodium hydroxide
Hydrochloric acid
Water for injections
Name and Address
Novo Nordisk Pharmaceuticals Ltd
PO Box 51-268
Pakuranga
Auckland
Tel: (09) 916 5590
Fax: (09) 916 5595
Date of Preparation
6 April 2006
SPC version 8 March 2004
Actrapid, PenFill and NovoFine are trademarks owned by Novo Nordisk A/S, Denmark