INFORMATION FOR HEALTH PROFESSIONALS
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PENMIX® 10 is a cloudy or milky suspension containing 10% neutral human insulin and 90% isophane human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc.
PENMIX® 20 is a cloudy or milky suspension containing 20% neutral human insulin and 80% isophane human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc.
PENMIX® 30 is a cloudy or milky suspension containing 30% neutral human insulin and 70% isophane human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc.
PENMIX® 40 is a cloudy or milky suspension containing 40% neutral human insulin and 60% isophane human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc.
PENMIX® 50 is a cloudy or milky suspension containing 50% neutral human insulin and 50% isophane human insulin in 3 ml Penfill® cartridges made of glass, closed with a rubber disc.
MIXTARD® 30 is a cloudy or milky suspension containing 30% neutral human insulin and 70% isophane human insulin in 10 ml glass vials.
MIXTARD® 50 is a cloudy or milky suspension containing 50% neutral human insulin and 50% isophane human insulin in 10 ml glass vials.
PROTAPHANE® is a cloudy or milky suspension containing isophane insulin suspension 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 and are also included in the Novolet, Flexpen and InnoLet pre-filled syringes.
ATC code A10A D01
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.
Insulin in the bloodstream has a half-life of only 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 PENMIX and MIXTARD the absorption profile is caused by the product being a mixture of insulins with protracted and fast absorption respectively.
An average action profile for PENMIX and MIXTARD after subcutaneous injection indicates:
Onset: within ½ hour
Maximum: 2 - 8 hours
Duration: up to 24 hours
For PROTAPHANE the protracted absorption is caused by the product being a suspension.
An average action profile for PROTAPHANE after subcutaneous injection indicates:
Onset: 1.5 hours
Maximum: 4 - 12 hours
Duration: up to 24 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 5-10 hours.
Treatment of diabetes mellitus.
PENMIX and MIXTARD are dual-acting insulins. They are bi-phasic formulations containing fast-acting and long-acting insulin.
PROTAHANE is a long-acting insulin.
Dosage is individual and determined by the physician in accordance with the needs of the patient.
The average range of total daily insulin requirement for maintenance therapy in type 1 diabetic patients lies between 0.5 and 1.0 IU/kg. However, in pre-pubertal children it usually varies from 0.7 to 1.0 IU/kg, but can be much lower during the period of partial remission. In insulin resistance, e.g. during puberty or due to obesity, the daily insulin requirement may be substantially higher.
Initial dosages for type 2 diabetic patients are often lower, e.g. 0.3 to 0.6 IU/kg/day.
In patients with diabetes mellitus optimised metabolic control delays the onset and slows the progression of late diabetic complications. Optimised metabolic control, including glucose monitoring, is therefore recommended.
In the elderly the primary aim of treatment may be symptom relief and avoidance of hypoglycaemic events.
The preparations are administered subcutaneously in the thigh or abdominal wall. If convenient the gluteal region or deltoid region may be used.
Insulin suspensions are never to be administered intravenously.
Injection into a lifted skin fold minimises the risk of intramuscular injection.
A subcutaneous injection into the abdominal wall results in a faster absorption than from other injection sites
In order to avoid lipodystrophy injection sites for a given insulin preparation should be rotated, within an anatomic region.
Premixed insulins such as PENMIX or MIXTARD are usually given once or twice daily when a rapid initial effect together with a more prolonged effect is desired.
An injection of PENMIX or MIXTARD should be followed by a meal or snack containing carbohydrates within 30 minutes.
Hypoglycaemia.
Hypersensitivity to human insulin or any of the excipients.
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, 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 (rapid acting insulin, intermediate acting insulin, long acting insulin etc.), species (animal, human insulin analogue insulin) and/or method of manufacturer (recombinant DNA versus animal source insulin) may result in 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.
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.
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.
Insulin suspensions are not to be used in insulin infusion pumps.
PENMIX, MIXTARD and PROTAPHANE contain metacresol, which may cause allergic reactions.
There are no restrictions on the treatment of diabetes with insulin during pregnancy as insulin does not pass the placental barrier. Both hypoglycaemia add 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 therefore recommended throughout pregnancy and when contemplating pregnancy.
Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements return rapidly to pre-pregnancy values
There are no restrictions on the treatment of diabetes with insulin during lactation, as insulin treatment of the nursing mother involves no risk to the baby. However, the insulin dosage, diet or both may need to be reduced.
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 drug reactions observed in patients using PENMIX, MIXTARD and PROTAPHANE 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 PEMIX, MIXTARD or PROTAPHANE 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 - Very rare
Fast improvement in blood glucose control may be associated with a condition
termed acute painful neuropathy, which is usually reversible.
Eye disorders
Refraction disorder - Very rare
Refraction anomalies may occur upon initiation of insulin therapy. These
symptoms are usually of transitory nature.
Diabetic retinopathy - Uncommon
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 - Uncommon
Oedema may occur upon initiation of insulin therapy. These symptoms are usually
of transitory nature.
A number of drugs are known to interact with the glucose metabolism. Possible interactions must therefore be taken into account by the physician.
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 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.
Insulins have no specific overdose definitions. However, hypoglycaemia may develop over sequential stages:
Upon regaining consciousness administration of oral carbohydrate is recommended for the patient in order to prevent relapse.
Insulin preparations should be stored between 2ºC and 8ºC, (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.
After first use MIXTARD and PROTAPHANE vials may be kept at room temperature (up to 25ºC) for 6 weeks. PENMIX and PROTAPHANE Penfill, NovoLet, FlexPen and InnoLet may be used or carried as a spare (below 25ºC) for 6 weeks.
Insulin suspensions should not be used if they do not appear uniformly white and cloudy after suspension.
Prescription Medicine
PENMIX® 10, 20, 30, 40 and 50 are available as a Penfill® of 3 ml in cartons of five.
MIXTARD® 30 and 50 are available in glass vials of 10 ml.
PROTAPHANE® is available as a Penfill® of 3 ml in cartons of five, or in glass vials of 10 ml.
PROTAPHANE NovoLet® 3 ml, FlexPen 3 ml and InnoLet 3 ml prefilled syringes are registered but not marketed.
PENMIX® 10, 20, 40 and 50 NovoLet® 3 ml are registered but not marketed.
PENMIX® 30 NovoLet® 3 ml, FlexPen® 3 ml and Innolet® 3 ml prefilled syringe is registered but not marketed.
In general terms, insulin should only be added to compounds with which it has known compatibility. Insulin suspensions should not be added to infusion fluids.
The carton contains a package leaflet with instructions for use and handling. The necessity of re-suspending the insulin suspension immediately before use is to be stressed to the patient. The re-suspended liquid shall appear uniformly white and cloudy.
For PENMIX and PROTAPHANE Penfill, the leaflet carries reference to the instructions for use accompanying the pen administration device.
MIXTARD and PROTAPHANE vials are for use with insulin syringes with the corresponding unit scale.
PENMIX and PROTAPHANE Penfill, NovoLet, FlexPen and InnoLet: are for single person use only. The container must not be refilled.
PENMIX and PROTAPHANE Penfill are designed to be used with Novo Nordisk insulin delivery systems and NovoFine® needles. NovoFine needles are designed to be used with the NovoLet, FlexPen and InnoLet.
Glycerol
Disodium phosphate dihydrate
Metacresol
Phenol
Zinc chloride
Protamine sulphate
Sodium hydroxide
Hydrochloric acid
Water for injections
Novo Nordisk Pharmaceuticals Ltd
PO Box 51-268
Pakuranga
Auckland
Tel: (09) 5790653
Fax: (09) 5790654
9 August 2004
SPC April 2004
PenMix, Protophane, Mixtard, PenFill, NovoLet, FlexPen, Innolet and NovoFine are trademarks owned by Novo Nordisk A/S, Denmark