Consumer medicine information

NovoRapid Penfill

Insulin, aspart (rys)

BRAND INFORMATION

Brand name

NovoRapid Penfill 3 mL

Active ingredient

Insulin, aspart (rys)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using NovoRapid Penfill.

What is in this leaflet

What NovoRapid® is used for

Before you use NovoRapid® Penfill®

How to use NovoRapid® Penfill®

While you are using NovoRapid® Penfill®

Things to be careful of

Side effects

After using NovoRapid® Penfill®

Product Description

Further Information

This leaflet answers some common questions about NovoRapid® Penfill®. It does not contain all the available information. It does not take the place of talking to your doctor, diabetes education nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using NovoRapid® Penfill® against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor, diabetes education nurse or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What NovoRapid® is used for

The insulin aspart, or “NovoRapid®”, in NovoRapid® Penfill® is a rapid-acting insulin used to treat diabetes mellitus in adults and children. Diabetes mellitus is a condition where your pancreas does not produce enough insulin to control your blood sugar (glucose) level. Extra insulin is therefore needed.

There are two types of diabetes mellitus:

Type 1 diabetes - also called juvenile onset diabetes

Type 2 diabetes - also called maturity onset diabetes

Patients with type 1 diabetes always require insulin to control their blood sugar levels.

Some patients with type 2 diabetes may also require insulin after initial treatment with diet, exercise and tablets.

NovoRapid® lowers your blood sugar level after injection. When injected under your skin, NovoRapid® has a faster onset of action than soluble human insulin. It takes effect within 10 to 20 minutes. Usually, the maximum effect will occur between 1-3 hours after injection and the effect may last for up to 5 hours.

As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. Due to its shorter duration of action, NovoRapid® has a lower risk of causing nocturnal hypoglycaemic episodes.

Penfill® is a pre-filled 3mL glass cartridge designed to be used with Novo Nordisk insulin delivery systems (such as NovoPen®).

NovoRapid® is not addictive.

NovoRapid® Penfill® is available only with a doctor’s prescription.

Ask your doctor, diabetes education nurse or pharmacist if you have any questions about why NovoRapid® Penfill® has been prescribed for you.

Before you use NovoRapid® Penfill®

When you must not use it

Do not use NovoRapid® if:

  1. you have an allergy to:
  • any medicine containing insulin
  • any of the ingredients listed in the “Ingredients” section of this leaflet

Some of the symptoms of an allergic reaction may include:

  • redness, swelling, rash and itching at the injection site
  • rash, itching or hives on the skin
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body.
  1. you are experiencing a low blood sugar level (a “hypo”) when the dose is due.

If you have a lot of hypos discuss appropriate treatment with your doctor.

If you are not sure whether you should start using this medicine, talk to your doctor.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • kidney problems
  • liver problems
  • adrenal, pituitary or thyroid gland problems.

Tell your doctor if you are pregnant or plan to become pregnant.

NovoRapid® can be used during pregnancy. Pregnancy may make managing your diabetes more difficult. Insulin needs usually decrease during the first three months of pregnancy and increase during the last six months. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast-feeding or plan to breast-feed.

Your doctor or pharmacist can discuss with you the risks and benefits involved.

Inform your doctor as soon as possible if you experience signs of heart failure such as unusual shortness of breath or rapid increase in weight or localised swelling (oedema).

Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who are treated with thiazolidinediones in combination with insulin may develop heart failure.

If you have not told your doctor about any of the above, tell them before you use NovoRapid®.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and NovoRapid® may interfere with each other and this may mean that your insulin dose has to change.

If you take any of the medicines below, your blood sugar may fall (hypoglycaemia):

  • other medicines used for the treatment of diabetes
  • monoamine oxidase inhibitors (MAOI) - used for the treatment of depression
  • alpha-blocking agents - used for the treatment of high blood pressure and to relieve difficulty in passing urine caused by an enlarged prostate
  • non-selective beta-blocking agents - used for the treatment of certain heart conditions and high blood pressure which may also mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia
  • angiotensin converting enzyme (ACE) inhibitors - used for the treatment of certain heart conditions, high blood pressure or elevated protein/albumin in the urine
  • salicylates e.g. aspirin - used to relieve pain and lower fever
  • anabolic steroids - used to promote growth
  • sulfonamides - used to treat bacterial infections
  • quinine - used for the prevention of malaria and the relief of muscle cramps
  • quinidine - used for the control of heart problems.

If you take any of the medicines below, your blood sugar level may rise (hyperglycaemia):

  • glucocorticoids (except when applied locally) - used to treat inflammatory conditions
  • oral contraceptives (“the pill”) - used for birth control
  • thiazides, frusemide or ethacrynic acid - used for the treatment of high blood pressure or fluid retention (oedema)
  • thyroid hormones - used for the treatment of malfunction of the thyroid gland
  • sympathomimetics - used for the treatment of asthma
  • growth hormone - used to treat growth hormone disorders
  • danazol - used to treat endometriosis, menorrhagia, fibrocystic breast disease and hereditary angioedema
  • oxymetholone - used to treat certain blood disorders
  • diazoxide - used for the treatment of high blood pressure
  • nicotinic acid - used for the treatment of high cholesterol levels in the blood
  • asparaginase - used to treat leukaemia and lymph gland tumours.

If you take the following medicines, your blood sugar level may rise or fall:

  • octreotide - used to treat gastrointestinal endocrine tumours and enlargement of parts of the body (e.g. hands, feet, head) caused by abnormal growth hormone levels
  • lanreotide – used to treat enlargement of parts of the body (e.g. hands, feet, head) caused by abnormal hormone levels.

Tell your doctor about any other medicines that you are taking.

This is very important. Your doctor will advise you if it is all right to keep taking them or if you should stop taking them.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use NovoRapid® Penfill®

Your doctor, diabetes education nurse or pharmacist will have given you advice on how to use your medicine. Carefully follow all the directions.

They may differ from the information contained in this leaflet.

Your doctor may also want you to use another insulin such as Protaphane® or Levemir®.

Any change in dose or type of insulin should be made cautiously and only under medical supervision.

If you change the type of insulin that you use, you may have to use more or less than before. This may happen with the first dose or over a period of time.

If you do not understand the instructions, ask your doctor, diabetes education nurse or pharmacist for help.

How much to use

Your doctor or diabetes education nurse will tell you how much of this medicine you need to use.

It is very important that you manage your diabetes carefully. Too much or too little insulin can cause serious effects.

When to use it

NovoRapid® should normally be used immediately (up to 10 minutes) before your meal or carbohydrate snack. When necessary NovoRapid® may be used immediately after the meal.

How to use it

  • NovoRapid® Penfill® is designed to be used with Novo Nordisk insulin delivery systems and NovoFine® needles.
  • Carefully follow the instructions on how to use your Novo Nordisk insulin delivery system.
  • Do not use the insulin level indicator on the insulin delivery system to measure your dose of NovoRapid®.
  • If you use more than one type of Penfill® (more than one type of insulin), you must use a separate insulin delivery system for each type of Penfill®.
  • Take care not to drop or knock the insulin delivery system that contains NovoRapid® Penfill®.
  • As a precautionary measure, always carry a spare Penfill® in case your in-use Penfill® is lost or damaged.
  • Inject NovoRapid® under the skin (subcutaneous injection) as shown to you by your doctor or diabetes education nurse.
  • In an emergency, the insulin contained within NovoRapid® Penfill® is suitable for intravenous administration, under medical supervision only. For emergency use, the insulin must first be withdrawn from Penfill® into a syringe. Discard your Penfill® after emergency use.

Checking your NovoRapid® Penfill®

Check your NovoRapid® Penfill® before each preparation and injection. Make sure you are using the correct type of insulin.

Do not use this medicine if it is thickened, coloured, or has solid bits in it.

Always check the cartridge, including the rubber plunger (stopper). Do not use it if any damage is seen or if there is a gap between the plunger and the white label band.

If you note any of the above, return your Penfill® to your pharmacist - do not use your Penfill®.

Preparing a dose

  1. Wash your hands.
  2. If your NovoRapid® Penfill® is already inside your insulin delivery system, check the amount of insulin remaining. If there is insufficient insulin for your dose, follow the relevant instructions in the system user manual.
  3. Alternatively, or if your insulin delivery system does not already carry a Penfill® cartridge, load a new NovoRapid® Penfill®.
  4. Disinfect the rubber membrane of Penfill® with an alcohol swab.
  5. Attach a new NovoFine® needle.

Checking for insulin flow (priming)

Always check your Novo Nordisk insulin delivery system for insulin flow (priming) before each injection, as described in the system user manual.

The priming procedure may highlight a malfunction with your insulin delivery system. Priming also removes any air bubbles and helps indicate whether or not a needle is broken.

Only dial up your required dose after you see a drop of insulin at the needle tip.

After priming, if you need to put the insulin delivery system down, make sure the needle does not touch anything.

Injecting a dose

Choose a site for injection.

Inject NovoRapid® under the skin (subcutaneous injection) as shown by your doctor or diabetes education nurse.

NovoRapid® may be injected into the abdomen, thighs, buttocks or upper arms.

Remember to change your injection site regularly as shown to you by your doctor or diabetes education nurse.

Insert the needle into the skin, and inject the full dose of insulin under the skin.

Keep the needle under the skin for at least 6 seconds. Keep the push button fully depressed until the needle has been withdrawn from the skin. This will ensure correct delivery and limit possible flow of blood into the needle or insulin reservoir.

Apply gentle pressure over the injection site for several seconds.

Do not rub the area.

After injecting

Dispose of your used needle safely into a yellow plastic sharps container after each injection.

If you do not remove it, temperature changes may cause insulin to leak out of the needle, which can cause inaccurate dosing.

Health care professionals, relatives and other carers should follow general precautionary measures for removal and disposal of needles, to eliminate the risk of needlestick injury.

It is recommended that you eat a meal or a snack containing carbohydrate within 10 minutes of the injection.

Do not share needles, cartridges or insulin delivery systems.

Leave Penfill® in the insulin delivery system until it needs to be replaced.

How long to use it

Do not stop using NovoRapid® Penfill® unless your doctor tells you to.

If you use too much (overdose) - Hypoglycaemia

Your blood sugar level may become too low (you may experience hypoglycaemia or a “hypo”) if you:

  • accidentally use too much of this medicine
  • have too much or unexpected exercise
  • delay eating meals or snacks
  • eat too little food
  • are ill.

The first symptoms of mild to moderate hypos can come on suddenly. They may include:

  • cold sweat, cool pale skin
  • fatigue, drowsiness, unusual tiredness and weakness
  • nervousness, anxious feeling, tremor, rapid heart beat
  • confusion, difficulty concentrating
  • excessive hunger
  • vision changes
  • headache, nausea.

Always carry some sugary food or fruit juice with you.

If you experience any of these symptoms of a hypo, immediately eat some sugary food or have a sugary drink, e.g. lollies, biscuits or fruit juice, and measure your blood sugar level.

Tell your relatives, friends, close workmates or carers that you have diabetes. It is important that they recognise the signs and symptoms of a hypo.

Make sure they know to give you some sugary food or fruit juice for mild to moderate symptoms of a hypo.

If you lose consciousness, make sure they know:

  • to turn you on your side and get medical help immediately.
  • not to give you anything to eat or drink.
    This is because you could choke.

An injection of the hormone glucagon may speed up recovery from unconsciousness. This can be given by a relative, friend, workmate or carer who knows how to give it.

If glucagon is used, eat some sugary food or have a sugary drink as soon as you are conscious again.

If you do not feel better after this, contact your doctor, diabetes education nurse, or the closest hospital.

If you do not respond to glucagon treatment, you will require medical attention.

See your doctor if you keep having hypo reactions, or if you have ever become unconscious after using insulin.

Your insulin dose may need to be changed.

If a severe hypo is not treated, it can cause brain damage and even death.

If you miss a dose - Hyperglycaemia

If you forget your insulin dose, test your blood sugar level as soon as possible.

If you are not sure what to do, talk to your doctor, diabetes education nurse or pharmacist.

Do not use a double dose of your insulin.

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to.

Otherwise, use it as soon as you remember - don’t forget to eat some carbohydrate within 10 minutes of your injection - and then go back to using it as you would normally.

Your blood sugar levels may become high (hyperglycaemia) if you:

  • miss doses of insulin or use less insulin than you need
  • have uncontrolled diabetes
  • exercise less than usual
  • eat more carbohydrates than usual
  • are ill or stressed.

High blood sugar levels over a long period of time can lead to too much acid in the blood (diabetic ketoacidosis).

Contact your doctor immediately if your blood sugar level is high or you recognise any of the following symptoms.

Symptoms of mild to moderate hyperglycaemia include:

  • drowsy feeling
  • flushed face
  • thirst, loss of appetite
  • fruity odour on the breath
  • blurred vision
  • passing larger amounts of urine than usual
  • getting up at night more often than usual to pass urine
  • high levels of glucose and acetone in the urine.

Symptoms of severe hyperglycaemia include:

  • heavy breathing
  • fast pulse
  • nausea, vomiting
  • dehydration
  • loss of consciousness.

Severe hyperglycaemia can lead to unconsciousness and in extreme cases death if untreated.

Discuss any worries you may have about this with your doctor, diabetes education nurse or pharmacist.

While you are using NovoRapid® Penfill®

Things you must do

Measure your blood sugar level regularly.

Make sure all friends, relatives, workmates or carers know that you have diabetes.

If your child has diabetes it is important to tell their carers.

Keep using your insulin even if you feel well.

It helps to control your condition, but does not cure it.

Tell your doctor if you often have hypos (low blood sugar levels).

Your doctor may need to adjust your insulin dose.

Always carry some sugary food or fruit juice with you.

If you experience any of the symptoms of a hypo, immediately eat some sugary food or have a drink, e.g. lollies, biscuits or fruit juice.

Tell your doctor if you have trouble recognising the symptoms of hypos.

Under certain conditions, the early warning signs of hypos can be different or less obvious. Your doctor may need to adjust your insulin dose.

Make sure that you tell every doctor, dentist, pharmacist or other health care professional who is treating you that you have diabetes and are using insulin.

Tell your doctor, diabetes education nurse or pharmacist if you are travelling.

Ask them for a letter explaining why you are taking injecting devices with you. Each country you visit will need to see this letter, so you should take several copies.

You may need to inject your insulin and eat your meals at different times because of time differences in and between countries.

You may not be able to get the same type of insulin in the country you are visiting.

Your doctor, diabetes education nurse or pharmacist can provide you with some helpful information.

Things you must not do

Do not stop using your medicine unless your doctor tells you to.

Do not use the medicine if you think it has been frozen or exposed to excessive heat.

It will not work as well.

Do not refill your NovoRapid® Penfill®.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how the insulin affects you.

If your blood sugar is low or high your concentration and ability to react might be affected, and therefore also your ability to drive or operate a machine. Bear in mind that you could endanger yourself or others. Please ask your doctor whether you can drive a car:

  • if you have frequent hypos
  • if you find it hard to recognise hypoglycaemia.

Tell your doctor if you drink alcohol.

Alcohol may mask the symptoms of hypos. If you drink alcohol, your need for insulin may change as your blood sugar level may either rise or fall. Careful monitoring is recommended.

Tell your doctor if you are ill.

Illness, especially with nausea and vomiting, may cause your insulin needs to change. Even if you are not eating, you still require insulin. You and your doctor should design an insulin plan for those times when you are sick.

Tell your doctor if you are exercising more than usual.

Exercise may lower your need for this medicine. Exercise may also speed up the effect of a dose of it, especially if the exercise involves the area of the injection site (e.g. the leg should not be used for injection prior to jogging or running).

Tell your doctor if your diet changes.

Changes in diet may cause your insulin needs to change.

Side effects

Tell your doctor, diabetes education nurse or pharmacist as soon as possible if you do not feel well while you are using NovoRapid® Penfill®.

This medicine helps most people for whom it is prescribed, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, diabetes education nurse or pharmacist to answer any questions you may have.

The most common side effect when using insulin is low blood sugar levels (a hypo).

Tell your doctor if you notice any of the following and they worry you:

  • hypos (mild to moderate).
  • pain, redness, hives, bruising, swelling or itching at the injection site. Usually these symptoms disappear within a few weeks during continued use. If you have serious or continuing reactions, you may need to stop using NovoRapid® and use another insulin.
  • a depression or thickening of the skin around the injection site (lipodystrophy).
  • when you first start your insulin treatment you may get visual problems or swollen hands and feet.

This list includes the more common side effects of your medicine. They are usually mild and short-lived.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

More severe symptoms of low blood sugar levels, including:

  • disorientation
  • seizures, fits or convulsions
  • loss of consciousness.

If a severe hypo is not treated, it can cause brain damage and death.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • skin rashes over a large part of the body
  • shortness of breath, wheezing
  • swelling of the face, lips or tongue
  • fast pulse
  • sweating.

This list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Ask your doctor, diabetes education nurse or pharmacist to answer any questions you have.

After using NovoRapid® Penfill®

Storage

Store NovoRapid® Penfill® cartridges that are not being used between 2°C and 8°C in a refrigerator (not in or too near the freezer section or cooling element).

Do not keep the NovoRapid® Penfill® that you are using in your insulin delivery system, or that you are carrying as a spare, in a refrigerator.

You can use it up to 4 weeks below 30°C after taking it out of the refrigerator. Discard NovoRapid® Penfill® after 4 weeks even if there is still some NovoRapid® left in it.

The NovoRapid® in NovoRapid® Penfill® must not be frozen, or exposed to excessive heat or light.

Protect the NovoRapid® in NovoRapid® Penfill® from light by keeping the cartridges in the carton when not in use.

Never use NovoRapid® Penfill® after the expiry date printed on the label and carton.

Never use NovoRapid® Penfill® if the solution is not clear and colourless.

Keep out of the reach of children.

Disposal

Dispose of used needles safely into a yellow plastic sharps container.

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

NovoRapid® is a clear, colourless solution for subcutaneous injection. NovoRapid® Penfill® is a pre-filled 3mL glass cartridge designed to be used with Novo Nordisk insulin delivery systems.

Ingredients

NovoRapid® contains insulin aspart (rys) 100 units per mL (100 U/mL) as the active ingredient. The abbreviation “rys” indicates the method of genetic engineering used to manufacture this insulin.

NovoRapid® also contains the following inactive ingredients: glycerol, phenol, meta-cresol, zinc chloride, sodium chloride, dibasic sodium phosphate dihydrate, sodium hydroxide, hydrochloric acid and water for injections.

Sponsor

NovoRapid® Penfill® is supplied in Australia by:

Novo Nordisk Pharmaceuticals Pty Ltd.
Level 3
21 Solent Circuit
Baulkham Hills NSW 2153

NovoRapid® Penfill® is supplied in New Zealand by:

Novo Nordisk Pharmaceuticals Ltd.
58 Richard Pearse Drive
Airport Oaks
Mangere
New Zealand.

NovoRapid®, Penfill®, NovoFine®, Protaphane®, Levemir® and NovoCare® are registered trademarks of Novo Nordisk A/S.

This leaflet was prepared on 13 June 2017.

Australian Registration Number:
AUST R 133444

© 2017

Novo Nordisk A/S

Further Information

For further information call the NovoCare Customer Care Centre on 1800 668 626 (Australia) or 0800 733 737 (NZ).

www.novonordisk.com.au

www.novonordisk.co.nz

You can also get more information about diabetes and insulin from Diabetes Australia and Diabetes New Zealand:

  • freecall helpline 1300 136 588 (Australia)
  • www.diabetesaustralia.com.au
  • www.diabetes.org.nz

BRAND INFORMATION

Brand name

NovoRapid Penfill 3 mL

Active ingredient

Insulin, aspart (rys)

Schedule

S4

 

1 Name of Medicine

NovoRapid (insulin aspart (rys)) 100 U/mL solution for injection 10 mL vial.
NovoRapid Penfill (insulin aspart (rys)) 100 U/mL solution for injection 3 mL cartridge.
NovoRapid FlexPen (insulin aspart (rys)) 100 U/mL solution for injection 3 mL cartridge.
NovoMix 30 Penfill (30% soluble insulin aspart (rys) and 70% insulin aspart (rys) crystallised with protamine) 100 U/mL suspension for injection 3 mL cartridge.
NovoMix 30 FlexPen (30% soluble insulin aspart (rys) and 70% insulin aspart (rys) crystallised with protamine) 100 U/mL suspension for injection 3 mL cartridge.

6.7 Physicochemical Properties

Insulin aspart (rys) has the empirical formula C256H381N65O79S6 and a molecular weight of 5,825.8.

Chemical structure.


CAS number.

CAS No.: 16094-23-6.

2 Qualitative and Quantitative Composition

Insulin aspart is a rapid acting analogue of human insulin that rapidly lowers blood glucose. Insulin aspart is homologous with human insulin with the exception of a substitution of the amino acid proline by aspartic acid at position 28 on the B chain. The unique structure of insulin aspart increases the rate of absorption from a subcutaneous injection site, giving a faster onset of action, an earlier peak effect and a shorter duration of action than soluble human insulin. Insulin aspart should be given immediately before a meal or, when necessary, after the start of a meal.
Insulin aspart is produced by recombinant DNA technology using Saccharomyces cerevisiae.
One unit of insulin aspart corresponds to 6 nanomol, 0.035 mg salt free anhydrous insulin aspart.

3 Pharmaceutical Form

NovoRapid is a sterile, clear, colourless, aqueous, neutral solution of insulin aspart (B28 Asp) 100 U/mL. NovoRapid is a solution for injection.
NovoMix 30 is a white suspension for subcutaneous injection consisting of 30% soluble insulin aspart and 70% protamine crystallised insulin aspart. This is a biphasic insulin preparation (NovoMix 30) which produces insulin plasma profiles similar to premixed biphasic human insulin, apart from the initial faster absorption of the soluble component.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Insulin lowers blood glucose levels by binding to insulin receptors to increase glucose uptake and inhibit hepatic glucose output.
As with all insulins in clinical practice, the duration of action of insulin aspart will vary according to the dose, injection site, blood flow, temperature and level of physical activity.
Insulin aspart is equipotent to soluble human insulin on a molar basis.

NovoRapid.

NovoRapid produces a more rapid and pronounced blood glucose lowering effect than soluble human insulin, due to the faster onset of action.
NovoRapid has a shorter duration of action compared to soluble human insulin after subcutaneous injection (see Figure 1).
When administered immediately before a meal, the effect of NovoRapid more closely mimics normal physiological postprandial insulin release than soluble human insulin.
The onset of action of NovoRapid occurs within 10 to 20 minutes of subcutaneous injection. The maximum effect is exerted between one and three hours after injection. The duration of action is 3 to 5 hours. NovoRapid has a more predictable time to peak effect within subjects than soluble human insulin.

NovoMix 30.

NovoMix 30 is a biphasic insulin which contains 30% soluble insulin aspart. This has a rapid onset of action and NovoMix 30 should thus be given closer to a meal than biphasic human insulin. The crystalline phase in NovoMix 30 is 70% insulin aspart protamine, which has an activity profile similar to that of human isophane (NPH) insulin.
The onset of action of NovoMix 30 occurs within 10-20 minutes of subcutaneous injection. The maximum effect is exerted between one and four hours after injection (see Figure 2). The duration of action of NovoMix 30 is up to 24 hours.
When injected immediately before a meal, NovoMix 30 has been demonstrated to better control postprandial hyperglycaemia than a corresponding 30/70 biphasic human insulin (see Figure 3). This improvement in postprandial glycaemia is not of established clinical value.

Clinical trials.

NovoRapid.

Adults.

Clinical trials with NovoRapid have demonstrated an improved postprandial blood glucose control compared to soluble human insulin. In long-term trials, NovoRapid has shown a small but statistically significant improvement in glycosylated haemoglobin with no increase in hypoglycaemic events compared to soluble human insulin. In the pivotal trials, NovoRapid has shown a statistically significant reduction in the number of patients experiencing major nocturnal hypoglycaemia compared to soluble human insulin. Hypoglycaemic events with insulin aspart were seen at two to four hours postdose compared to two to seven hours with soluble human insulin. There were no safety issues with NovoRapid and no evidence of increased immunogenicity with NovoRapid compared with soluble human insulin.
There were four adequate and well controlled clinical trials in the insulin aspart clinical development program: one phase II trial in men with type I diabetes (025/UK) and three phase III trials, two in adults with type 1 diabetes (035/EU and 036/USA) and one in adults with type 2 diabetes (037/USA). In all pivotal efficacy trials, NovoRapid was administered immediately before meals and soluble human insulin was dosed 30 minutes before meals. The phase III trials involved a wide variety of people (aged 18 to 77 years) with type 1 and 2 diabetes.

Elderly.

A randomised, double blind crossover PK/PD (ANA-1416) trial comparing insulin aspart with soluble human insulin was performed in elderly subjects with type 2 diabetes (19 patients aged 65 to 83 years, mean age 70 years). The relative differences in the pharmacodynamic properties between insulin aspart and soluble human insulin in elderly were consistent with those seen in healthy subjects and in younger subjects with diabetes. No safety issues were raised, but careful glucose monitoring and individual dose adjustments of insulin, including insulin aspart, may be necessary in elderly patients.

Children and adolescents.

Limited data suggest that when given to children NovoRapid showed similar glucose control compared to soluble human insulin. A clinical trial (ANA-1415) comparing preprandial soluble human insulin with postprandial insulin aspart was performed in small children (26 patients aged 2 to 6 years), and a single dose PK/PD trial (043/UK) was performed in children (6 to 12 years) and adolescents (13 to 17 years). The pharmacodynamic profile of insulin aspart in children was similar to that seen in adults. Long-term data in children, including the effects on growth and development, are not available.

Continuous subcutaneous insulin infusion (CSII).

Compatibility with NovoRapid was investigated in MiniMed 506 and Disetronic H-TRON plus V-100 infusion pumps, and in MiniMed Polyfin (MMT-106) and Sof-set (MMT-111) and Disetronic Classic and Tender infusion sets. The infusion sets used in compatibility testing employed the same materials as the MiniMed systems registered in Australia. Two clinical trials (ANA 2018/US and ANA 2024/US) were conducted to evaluate the safety and efficacy of NovoRapid when administered by continuous subcutaneous insulin infusion (CSII). Clinical use was investigated in MiniMed 506, 507, 507c and Disetronic H-TRON plus V-100 insulin infusion pumps; of these, Disetronic H-TRON plus V-100, MiniMed 507 and 507c are registered in Australia.

025/UK, 035/EU, 036/USA and 037/USA.

The pivotal phase II and III trials were multicentre, randomised, active controlled studies of one month (025/UK) or six months (035/EU, 036/USA and 037/USA) duration, designed to evaluate short and long-term efficacy and safety of NovoRapid compared to soluble human insulin in type 1 and type 2 diabetes.
In the short-term study, the NovoRapid glucose profiles were lower after meals and higher during the night than soluble human insulin. Overall 24 hour glucose control, as assessed by the excursion of glucose level outside the range 4.0 to 7.0 millimol/L, was significantly improved with NovoRapid. The number of major hypoglycaemic events was significantly lower with NovoRapid than soluble human insulin. The minor hypoglycaemic event rate with NovoRapid was the same as, if not lower than, the soluble human insulin but with fewer events during the night.
In the six month phase III studies, treatment with NovoRapid significantly improved HbA1c in patients with type 1 diabetes. A similar improvement in HbA1c was observed in type 2 patients, but was not significant due to the lower number of patients (see Table 2).
Postprandial glucose levels and mean prandial glucose increments were significantly lower in the NovoRapid treated than in the soluble human insulin treated type 1 patients.
Overall, the relative risk of major hypoglycaemic events was 19% lower with NovoRapid compared to soluble human insulin. The number of mild hypoglycaemic events was similar between insulin groups. Treatment with NovoRapid led to higher glucose levels at night compared to human insulin, resulting in a lower incidence of nocturnal, major hypoglycaemic events. Specifically, compared to soluble human insulin, there was a 50% lower risk of experiencing a major nocturnal hypoglycaemic event with NovoRapid (p = 0.013) in the 036/USA trial and, similarly, a 30% lower risk with NovoRapid (p = 0.076) in the 035/EU trial.

ANA-2024/US.

This was a multicentre, open label, parallel group, phase IIIb study in which 146 adults with type 1 diabetes were randomised 2:2:1 to receive NovoRapid, buffered regular insulin or insulin lispro by CSII over a four week dose adjustment period and 12 week maintenance periods. All subjects had been on other forms of CSII for at least three months prior to study entry. The primary efficacy outcome measure was a comparison against baseline of HbA1c values at 16 weeks. The major endpoints for the safety analysis were comparisons of the numbers of adverse events and hypoglycaemic episodes.
Change from baseline values of HbA1c, blood glucose variability, average daily insulin use or bodyweight were not significantly different between treatment groups at any time point. The adverse event profile of NovoRapid was similar to that of buffered regular insulin and insulin lispro, and the three treatment groups had similar rates of hypoglycaemia. When administered as continuous subcutaneous insulin infusion in a pump, NovoRapid was shown to be as safe and effective as buffered regular human insulin.

ANA/DCD/066.

This phase IIIb, double blind, randomised, crossover, multicentre trial compared the frequency of major hypoglycaemic episodes after 16 weeks treatment with NovoRapid vs 16 weeks treatment with soluble human insulin in 139 adults with well controlled type 1 diabetes treated on a basal bolus regimen. Frequency of major hypoglycaemic episodes during the treatment periods was the primary endpoint.
A statistically nonsignificant (p = 0.119) NovoRapid/ soluble human insulin relative risk for major hypoglycaemia of 0.72 (95% CI: 0.47 to 1.09) was found. A secondary finding was that subjects treated with NovoRapid experienced a significantly (p = 0.001) lower rate of major hypoglycaemic episodes during the night (midnight to 6 am). The estimated NovoRapid/ soluble human insulin relative risk was 0.28 (95% CI: 0.13 to 0.59). This was not a predefined endpoint in the study protocol and this result represents a analysis. A statistically significant (p = 0.048) reduction in the frequency of minor hypoglycaemic episodes was found with NovoRapid treatment (n = 1,590) compared to human soluble insulin (n = 1,752), with the estimated NovoRapid/ soluble human insulin relative risk being 0.93 (95% CI: 0.87 to 1.00). No significant differences between insulin aspart and human soluble insulin were found for the investigated glycaemic control parameters or in the domain scores of the quality of life questionnaires. The statistical testing was not adjusted for the multiple variables examined.

028/UK.

This phase II trial was conducted in 16 subjects with well controlled type 1 diabetes who did not require intravenous therapy. Both NovoRapid and human soluble insulin were given intravenously to determine the blood glucose threshold for autonomic activation during hypoglycaemia. There were no statistically significant differences between NovoRapid and soluble human insulin. No advantage is expected in giving NovoRapid intravenously over soluble human insulin intravenously.

ANA-1415.

A clinical trial investigated the safety and efficacy of insulin aspart (n = 26) vs soluble human insulin (n = 26) in children with type 1 diabetes aged 2 to 6 years. Human NPH insulin was used as the basal insulin in both groups. Similar results for the two primary safety and efficacy endpoints (frequency of hypoglycaemic episodes and postprandial glucose increment, respectively), as well as the secondary endpoints, were observed with both regimens.

ANA-1474 and 2067.

A clinical trial comparing safety and efficacy of insulin aspart vs soluble human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies: insulin aspart, n = 157; human insulin, n = 165) did not detect any adverse effect of insulin aspart on pregnancy or on the health of the foetus/ newborn. Efficacy when measured by HbA1c was observed to be comparable to insulin aspart vs soluble human insulin, while mean prandial glucose increments were significantly improved for insulin aspart during the first and third trimesters. In addition the data from a clinical trial including 27 women with gestational diabetes randomised to treatment with insulin aspart versus soluble human insulin (insulin aspart, N = 14; soluble human insulin, N = 13) showed similar safety profiles between treatments.

NovoMix 30.

038.

In a three month, multicentre, open labelled, randomised, parallel group phase III study, NovoMix 30 was as effective as biphasic human insulin (BHI) in overall glycaemic control (see Table 3).
There were no safety issues with NovoMix 30 compared with human insulin.

1241.

This was a multinational, open label, parallel group trial in 329 subjects with type 2 diabetes. The primary objective of the trial was to compare glycaemic control between the existing gold standard metformin plus add on treatment with sulfonylurea (glibenclamide), against metformin plus add on treatment with NovoMix 30 twice daily (b.i.d.), and against NovoMix 30 b.i.d. monotherapy, in patients inadequately controlled on current metformin monotherapy. Subjects were randomised to receive as add on therapy with metformin either NovoMix 30 b.i.d. (108 subjects exposed) or glibenclamide (114 subjects exposed), or to receive NovoMix 30 b.i.d. monotherapy (107 subjects exposed). After 16 weeks of treatment decreases in mean HbA1c levels relative to baseline of at least 1.5% were observed for all three treatment groups. The mean level of HbA1c at end of trial was statistically significantly lower for the NovoMix 30 plus metformin group than for the NovoMix 30 mono group (by 0.39%, p = 0.0074).

5.2 Pharmacokinetic Properties

Human insulin molecules self associate to form hexamers. The substitution of proline by aspartic acid at position B28 in insulin aspart produces an intermolecular repulsion which reduces the tendency of the insulin molecules to self associate. This increases the rate of dissociation of hexamers into dimers and monomers in the subcutaneous layer.
NovoRapid is more rapidly absorbed from the subcutaneous layer than soluble human insulin. The insulin aspart in the soluble phase of NovoMix 30 comprises 30% of the total insulin: this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as insulin aspart protamine; this has a similar prolonged absorption profile to human NPH (isophane or protamine crystallised) insulin.

NovoRapid.

The Tmax is on average half of that for soluble human insulin. In different studies, the Tmax was reached after 40 to 50 minutes with NovoRapid compared to 80 to 120 minutes for soluble human insulin. The intraindividual variability in Tmax is significantly less for NovoRapid than for soluble human insulin.
The Cmax is on average at least twice as high with NovoRapid than with soluble human insulin. In one study in subjects with type 1 diabetes, the mean Cmax was 492 picomol/L with NovoRapid and 216 picomol/L with soluble human insulin (administered at a dose of 0.15 U/kg bodyweight). The return to baseline insulin levels is faster with NovoRapid than soluble human insulin.
In a clinical study in healthy subjects, the pharmacokinetic differences between NovoRapid and soluble human insulin were maintained independent of the injection site (abdomen, thigh or deltoid).
Insulin aspart has a low binding to plasma proteins, 0 to 9%. After subcutaneous administration, insulin aspart was more rapidly eliminated than soluble human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for soluble human insulin.

NovoMix 30.

The Cmax is, on average, 50% higher with NovoMix 30 than with biphasic human insulin 30/70. The Tmax is, on average, half of that for biphasic human insulin 30/70. A mean maximum serum concentration of 140 ± 32 picomol/L was reached after 60 minutes (interquartile range 45 to 70 minutes) after a subcutaneous dose of 0.20 U/kg bodyweight in healthy volunteers. The mean half-life (t1/2) of NovoMix 30 was about eight to nine hours (interquartile range 6.5 to 17.5 hours). Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose.

Special patient populations.

Children.

The pharmacokinetic and pharmacodynamic properties of soluble insulin aspart were investigated in children (6 to 12 years) and adolescents (13 to 17 years) with type 1 diabetes. The relative difference in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes between soluble insulin aspart and soluble human insulin correlated well with those in healthy adult subjects and adults with type 1 diabetes. The pharmacokinetics of biphasic insulin aspart have not been investigated in children.

Elderly.

The relative differences in pharmacokinetic properties between soluble insulin aspart and soluble human insulin in elderly subjects (65 to 83 years, mean age 70 years) with type 2 diabetes were similar to those observed in healthy subjects and in younger subjects with diabetes; i.e. the significantly earlier and higher Cmax is maintained with soluble insulin aspart. As in younger subjects with type 2 diabetes, Tmax of soluble insulin aspart may be slightly delayed in elderly subjects with type 2 diabetes, though still significantly earlier than for human insulin. The pharmacokinetics of biphasic insulin aspart have not been investigated in the elderly.

Hepatic impairment.

A single dose pharmacokinetic study of soluble insulin aspart was performed in 24 subjects with hepatic function ranging from normal to severely impaired. In subjects with hepatic impairment absorption rate was decreased and more variable, resulting in delayed Tmax from about 50 minutes in subjects with normal hepatic function to about 85 minutes in subjects with moderate and severe hepatic impairment. AUC, Cmax and CL/F were similar in subjects with reduced hepatic function compared with subjects with normal hepatic function. The pharmacokinetics of biphasic insulin aspart have not been investigated in this population.

Renal impairment.

A single dose pharmacokinetic study of soluble insulin aspart in 18 subjects with renal function ranging from normal to severely impaired was performed. No apparent effect of creatinine clearance values on AUC, Cmax and CL of soluble insulin aspart was found. The pharmacokinetics in subjects with renal failure necessitating dialysis treatment was not investigated. Special precautions should be taken in these patients as insulin clearance may be reduced. The pharmacokinetics of biphasic insulin aspart have not been investigated in this population.

5.3 Preclinical Safety Data

Genotoxicity.

Insulin aspart did not cause gene mutations, chromosomal damage or DNA damage in a range of genotoxicity tests.

Carcinogenicity.

Lifetime carcinogenicity studies of insulin aspart have not been performed in animals. In 52-week repeat dose toxicity studies in Sprague-Dawley rats at doses up to 50 U/kg/day subcutaneous (SC), the only significant toxicity findings were related to hypoglycaemia. At a higher dose of 200 U/kg/day SC in female Sprague-Dawley rats, insulin aspart, like human insulin, caused induction of mammary tumours. The clinical relevance of these findings is not known. Neither clinical nor epidemiological studies conducted to date have shown an association between insulin use and carcinogenesis but the available evidence is considered too limited to be conclusive at this time. In vitro studies showed that the mitogenic activity of insulin aspart does not differ from that observed with human insulin.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of diabetes mellitus.

4.3 Contraindications

Hypoglycaemia.
Hypersensitivity to insulin aspart or any of the excipients.

4.4 Special Warnings and Precautions for Use

Avoidance of accidental mix-ups/ medication errors.

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between NovoRapid or NovoMix and other insulins.

Hyperglycaemia.

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. The first symptoms of hyperglycaemia usually develop gradually, over a period of hours or days. They include nausea, vomiting, drowsiness, flushed dry skin, dry mouth, increased frequency of urination, thirst and loss of appetite as well as acetone breath. Untreated hyperglycaemic events may be life threatening.

Hypoglycaemia.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia (see Section 4.8 Adverse Effects (Undesirable Effects) and Section 4.9 Overdose).
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.
Insulin aspart products should be administered immediately before a meal or, when necessary, after the start of a meal. The rapid onset of action should therefore be considered in patients with concomitant diseases or medication where a delayed absorption of food might be expected.
Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements.
Renal or hepatic impairment, or concomitant diseases in the kidney or liver or affecting the adrenal, pituitary or thyroid gland, can require changes in the insulin dose.
Care should be taken, especially in children, to match insulin doses (especially in basal-bolus regimens) with food intake, physical activities and current blood glucose levels in order to minimise the risk of hypoglycaemia.

Injection site reactions.

As with any insulin therapy, injection site reactions may occur and include pain, redness, itching, hives, bruising, swelling and inflammation. Continuous rotation of the injection site within a given area reduces the risk of developing these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of insulin aspart products.
Insulin aspart products contain metacresol which on rare occasions may cause allergic reactions.

Insulin antibodies.

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.

Transfer of patients between insulin types.

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 the need for a change in dosage. Patients transferred to insulin aspart from another type of insulin may require an increased number of daily injections or a change in dosage from that used with their usual insulin products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Combination of thiazolidinediones and insulin.

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. This should be kept in mind if treatment with the combination of thiazolidinediones and insulin medicinal products is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema. Thiazolidinediones should be discontinued if any deterioration in cardiac symptoms occurs.

General.

NovoMix 30 is not to be used in insulin infusion pumps.

Paediatric use.

Safety and effectiveness of NovoMix 30 in children and adolescents under the age of 18 have not been assessed due to limited clinical experience.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A number of drugs are known to interact with glucose metabolism. Possible interactions must, therefore, be taken into account by the physician.
The following substances may reduce the patient's insulin requirements: oral hypoglycaemic agents (OHAs), monoamine oxidase inhibitors (MAOIs), nonselective β-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids (except danazol and oxymetholone), α-adrenergic blocking agents, quinine, quinidine and sulfonamides.
The following substances may increase the patient's insulin requirements: oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol.
β-Blockers may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Octreotide and lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify and prolong, or reduce, the hypoglycaemic effect of insulin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In reproductive toxicity studies, insulin aspart did not affect the fertility of male and female rats but caused a slight increase in pre-implantation loss at subcutaneous doses greater than 10 U/kg/day. Similar effects were seen with human insulin.
(Category A)
Insulin aspart can be used in pregnancy. Data from two randomised controlled clinical trials with NovoRapid (157 + 14 insulin aspart-exposed pregnancies, respectively) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/ newborn when compared to human insulin (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There are no clinical trials with biphasic insulin aspart in pregnancy.
Intensified blood glucose control and monitoring of pregnant women with diabetes (type 1 diabetes, type 2 diabetes or gestational 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 return rapidly to prepregnancy levels.
Although no clinical trial data are available with insulin aspart products during lactation, there are no restrictions on treatment with these medicines during lactation. Insulin treatment of the nursing mother should not affect the baby. However, the dosage of insulin aspart may need to be adjusted.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety profile of insulin aspart products observed in clinical trials is similar to the safety profile reported for the respective Novo Nordisk human insulin products.
Adverse drug reactions observed in patients using insulin aspart products are mainly dose-dependent and due to the pharmacological effect of insulin. As for other insulin products, hypoglycaemia in general is the most frequently occurring undesirable effect. In clinical trials and during marketed use the frequency varies with patient population, dose regimens and level of glycaemic control. Therefore, no specific frequency can be presented (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions).
Refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling and itching at the injection site) may occur upon initiation of insulin therapy. These reactions are usually of a 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. Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Tabulated list of adverse reactions.

Frequencies of adverse drug reactions from clinical trials, which by an overall judgment are considered related to insulin aspart, are listed in Table 1. The frequencies are defined as: very common (≥ 1/10); uncommon (> 1/1,000, < 1/100) and rare (> 1/10,000, < 1/1,000). Isolated spontaneous cases are presented as very rare (defined as < 1/10,000).

Description of selected adverse reactions.

Generalized hypersensitivity reactions.

Symptoms 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.

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.
During clinical trials the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared with human insulin.

Lipodystrophy.

Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular area reduces the risk of developing these reactions.

Antibody production.

In a phase III study of NovoMix 30, the level of antibodies cross-reactive to human insulin and insulin aspart showed an increase during the first three months which persisted at a lower level after 12 and 24 months. After 24 months of treatment a correlation was found between absolute antibody level and absolute insulin dose; no correlation, however, was found between the increase in antibody formation and the increase in insulin dose. There was no significant correlation with glycaemic control attained or adverse event reporting. The long-term clinical significance of insulin antibodies is uncertain.
Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

NovoRapid has a faster onset and a shorter duration of action than soluble human insulin. Similarly, NovoMix 30 has a faster onset of action than biphasic human insulin. Due to the faster onset of action, insulin aspart products should generally be given immediately before a meal or when necessary, soon after the start of a meal.
The dosage of insulin aspart is determined by the physician according to the patient's individual needs. The individual insulin requirement is usually between 0.5 and 1.0 U/kg/day in adults and children. In a meal-related treatment 50-70% of this requirement may be provided by NovoRapid and the remainder provided by an intermediate-acting or long-acting insulin given at least once a day. Alternatively, the daily insulin requirement may be fully or partially supplied with NovoMix 30.
The recommended starting dose of NovoMix 30 in combination with metformin is 0.2 Units/kg/day and should be adjusted depending on individual requirements based on blood glucose response.

Method of administration.

NovoRapid 10 mL vial may be used for continuous subcutaneous insulin infusion (CSII) in pump systems suitable for insulin infusion (see Section 5.1 Pharmacodynamic Properties, Clinical trials). When used in external insulin infusion pumps the initial programming of the pump should be based on the total daily insulin dose on the previous regimen. Approximately 50% of the total dose is to be given as the basal rate and the remainder is to be divided between breakfast, lunch, dinner and snacks. The usual individual daily insulin requirement of between 0.5 and 1.0 U/kg/day also applies when NovoRapid is used in CSII.
When used in an insulin infusion pump NovoRapid should not be mixed with any other medicinal products. Patients using CSII should be comprehensively instructed in the use of the pump system. The infusion and reservoir set should be changed every 48 hours using aseptic technique. Patients administering NovoRapid by CSII must always carry a spare vial of NovoRapid and a U100 syringe, or an alternative insulin delivery system, in case of pump system failure.
Insulin aspart products are administered by SC injection in the abdominal wall, the thigh, the deltoid region or the gluteal region. NovoRapid may also be administered by SC infusion in the abdominal wall. Injection and infusion sites should be rotated within the same region in order to reduce the risk of lipodystrophy. When injected subcutaneously into the abdominal wall, the onset of action for insulin aspart products will occur within 10-20 minutes of injection. For NovoRapid, the maximum effect is exerted between one and three hours after the injection, and the duration of action is 3 to 5 hours. The duration of action of NovoMix 30 is up to 24 hours. As with all insulins the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. Based on studies of soluble insulin aspart and soluble human insulin, SC injection in the abdominal wall is expected to result in a faster absorption than from other injection sites. However, the faster onset of action of insulin aspart products compared to their respective human insulin products is expected to be maintained regardless of injection site. Formal studies on the bioavailability of NovoRapid administered by SC injection in the gluteal region have not been conducted.
NovoRapid may be administered intravenously under medical supervision. For emergency use with Penfill/ FlexPen the NovoRapid must first be withdrawn into a syringe. Discard Penfill/ FlexPen cartridge/ pen after emergency use. NovoRapid has been used intravenously (see Section 5.1 Pharmacodynamic Properties, Clinical trials). No studies have been conducted in critically ill people with diabetes who are likely to require intravenous administration. There is no pharmacokinetic or pharmacodynamic advantage in using NovoRapid over soluble human insulin when these insulins are given intravenously.
NovoMix 30 should never be administered intravenously. Intramuscular administration should be avoided.

Dosage adjustment.

The daily insulin requirement may be higher in patients with insulin resistance (e.g. due to obesity) and lower in patients with residual endogenous insulin production. Adjustment of dosage may also be necessary if patients undertake increased physical activity, change their usual diet, or during concomitant illness. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.
In patients with diabetes mellitus optimised metabolic control effectively delays the onset and slows the progression of diabetic late complications. Optimised metabolic control including glucose monitoring is, therefore, recommended.
As with all insulins, in elderly patients and patients with hepatic or renal impairment, glucose monitoring should be intensified and dosage adjusted on an individual basis.

Transfer of patients to insulin aspart products.

NovoRapid differs from human insulin by its rapid onset and shorter duration of action. NovoMix 30 also differs from human insulin by their faster onset. Because of the rapid onset of action, the injection of insulin aspart products should immediately be followed by a meal.
Insulin aspart products are equipotent to their respective human insulin products in regards to hypoglycaemic effect, receptor affinity and effect on lipogenesis. Patients currently treated with human insulin can be transferred to NovoRapid or NovoMix 30 on a unit for unit basis when administered just before a meal. Although no change in dose is anticipated other than the routine adjustments made in order to maintain stable diabetic control, any change to insulin therapy should be made under medical supervision and blood glucose should be monitored.
When patients are transferred between different types of insulin products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.

Instructions for use and handling.

10 mL vials.

NovoRapid vials are for use with U100 insulin syringes and for use with an infusion pump system. The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling.

Penfill 3 mL cartridges.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling. The leaflet refers to the instructions for using the accompanying Novo Nordisk insulin delivery system.
The suspension contained within NovoMix 30 Penfill must be resuspended after removal from the refrigerator and immediately before use so that it appears uniformly white and cloudy. It is recommended to allow the insulin to reach room temperature before resuspending. The necessity to resuspend immediately before use is to be stressed to the patient.
Insulin aspart Penfill products are for use by one person only. The cartridges must not be refilled.
Insulin aspart Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems and NovoFine needles.
Failure to change the needle may result in needle blockage. The patient should be advised to discard the needle after each injection.

FlexPen 3 mL.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling. Please note that insulin is not delivered if the patient reverse dials the insulin pen by returning the dose selector to zero after inserting the needle. Patients should be instructed that insulin injection only occurs when the push button is depressed.
The suspension contained within NovoMix 30 FlexPen must be resuspended after removal from the refrigerator and immediately before use so that it appears uniformly white and cloudy. It is recommended to allow the insulin to reach room temperature before resuspending. The necessity to resuspend immediately before use is to be stressed to the patient.
Insulin aspart FlexPen products are for use by one person only. The cartridge inside the pen must not be refilled.
NovoFine needles up to a length of 8 mm are designed to be used with insulin aspart FlexPen products.
Failure to change the needle may result in needle blockage. The patient should be advised to discard the needle after each injection.

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 while driving or operating a machine. 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 or operating a machine should be considered in these circumstances.

4.9 Overdose

A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if doses are administered which are too high relative to the patient's requirements.
Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is, therefore, recommended that the person with diabetes always carry products containing sugar with them.
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 medical professional. Glucose must be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes.
Upon regaining consciousness, oral administration of carbohydrate is recommended for the patient in order to prevent relapse.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

NovoRapid contains the following inactive ingredients: glycerol, phenol, metacresol, zinc chloride, dibasic sodium phosphate dihydrate, sodium chloride, sodium hydroxide, hydrochloric acid and water for injections.
NovoMix 30 contains the following inactive ingredients: protamine sulfate, glycerol, phenol, metacresol, zinc chloride, dibasic sodium phosphate dihydrate, sodium chloride, sodium hydroxide, hydrochloric acid and water for injections.

6.2 Incompatibilities

In general, insulin aspart products should only be added to compounds with which they have known compatibility. Drugs added to the insulin may cause degradation of the insulin, e.g. if the drugs contain thiols or sulphites.
NovoMix 30 should not be added to infusion fluids.

6.3 Shelf Life

The shelf-life is 30 months for NovoRapid and 24 months for NovoMix products when stored between 2°C and 8°C. After first opening or carried as a spare: A maximum of 4 weeks, any remainder must then be discarded.

6.4 Special Precautions for Storage

Insulin aspart products should be stored between 2°C and 8°C. Do not freeze. Insulin aspart products which have been frozen must not be used.

NovoRapid FlexPen.

After first opening or carried as a spare: Can be kept at ambient temperature (below 30°C) or stored in a refrigerator (2°C - 8°C).

NovoRapid Vial/Penfill.

After first opening or carried as a spare: Do not refrigerate. Store below 30°C.

NovoMix FlexPen/Penfill.

After first opening or carried as a spare: Do not refrigerate. Store below 30°C.
Insulin aspart products should not be exposed to excessive heat or sunlight. Keep the product in the carton (vial, Penfill) or keep the cap on (FlexPen) when not in use, to protect it from light.
It is recommended that NovoMix 30 products in use or carried as spares be resuspended after removal from the refrigerator and immediately before use. It is recommended to allow the insulin to reach room temperature before resuspending.

6.5 Nature and Contents of Container

NovoRapid contains insulin aspart 100 U/mL. NovoMix 30 products contain biphasic insulin aspart 100 U/mL. The following presentations are available:

10 mL vial.

The 10 mL glass vial is closed with a latex free bromobutyl/ polyisoprene rubber disc and a protective tamper proof plastic cap. One 10 mL vial is packed in a carton.
NovoRapid 10 mL vial.

Penfill 3 mL.

Penfill cartridge is made of glass, contain a bromobutyl rubber piston and is closed with a latex free bromobutyl/ polyisoprene rubber disc. NovoMix 30 Penfill also contains a glass ball within the cartridge to facilitate resuspension. Five 3 mL Penfill cartridges are packed in a carton.
NovoRapid Penfill, NovoMix 30 Penfill.

FlexPen 3 mL.

FlexPen is a pre-filled, multidose, disposable pen consisting of a pen injector and a 3 mL cartridge. The cartridge is made of glass, contains a bromobutyl rubber piston and is closed with a latex free bromobutyl/ polyisoprene rubber disc. The cartridges contained within NovoMix 30 FlexPen also contain a glass ball to facilitate resuspension. The pen injector is made of plastic (polypropylene). Five FlexPen are packed in a carton.
NovoRapid FlexPen, NovoMix 30 FlexPen.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by takin it to your local pharmacy.

Summary Table of Changes