Consumer medicine information

Actrapid Penfill; Protaphane Penfill; Mixtard 30/70 Penfill; Mixtard 50/50 Penfill

Insulin, neutral (rys); Insulin, isophane (rys)

BRAND INFORMATION

Brand name

Mixtard 30/70 Penfill 3 mL Injection

Active ingredient

Insulin, neutral (rys); Insulin, isophane (rys)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Actrapid Penfill; Protaphane Penfill; Mixtard 30/70 Penfill; Mixtard 50/50 Penfill.

What is in this leaflet

What is in this leaflet

What human insulin is used for

Before you use human insulin Penfill®

How to use human insulin Penfill®

While you are using human insulin Penfill®

Side effects

After using human insulin Penfill®

Product description

Further information

This leaflet answers some common questions about human insulin 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 human insulin 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 human insulin is used for

Human insulin is used to treat diabetes mellitus. 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.

Human insulin lowers your blood sugar level after injection. Each of the following human insulins is available in Penfill®, a 3mL glass cartridge designed to be used with Novo Nordisk insulin delivery devices such as NovoPen®:

Actrapid® is Neutral Insulin Injection, a fast-acting insulin. This means that it will start to lower your blood sugar level about half an hour after you inject it, and the effect will last for approximately 8 hours. Actrapid® is often used in combination with longer-acting insulin products.

Protaphane® is Isophane Insulin Injection, an intermediate-acting insulin. This means that it will start to lower your blood sugar level about one and a half hours after you inject it, and the effect will last for approximately 24 hours. Protaphane® is often used in combination with fast- or rapid-acting insulin products.

Mixtard® 30/70 and Mixtard® 50/50 are Biphasic Isophane Insulin Injection, and each is a mixture of fast- and longer-acting insulins. Mixtard® 30/70 and Mixtard® 50/50 will start to lower your blood sugar level about half an hour after you inject, and the effect will last for approximately 24 hours.

As with all insulins, the duration of action will vary according to the type of insulin, the dose, injection site, blood flow, temperature and level of physical activity.

Actrapid® is also used by doctors to treat some people with diabetes in emergency situations.

Human insulin is not addictive.

Human insulin is available only with a doctor’s prescription.

Ask your doctor if you have any questions about why human insulin Penfill® has been prescribed for you.

Before you use human insulin Penfill®

When you must not use it

Do not use Penfill® 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.
  2. 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 inject Protaphane®, Mixtard® 30/70 or Mixtard® 50/50 into a vein.

Do not use Protaphane®, Mixtard® 30/70 or Mixtard® 50/50 to treat a condition known as diabetic ketoacidotic coma.

Do not use this medicine after the expiry date printed on the label and carton, or if the packaging is torn or shows signs of tampering or does not look quite right.

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 planning to become pregnant.

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 planning 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 localized 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 Penfill®.

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 human insulin may interfere with each other. These include:

  • oral hypoglycaemic agents - used to treat type 2 diabetes
  • monoamine oxidase inhibitors (MAOI) - used to treat depression
  • non-selective beta-blockers - used to treat certain heart conditions and high blood pressure
  • alpha-blockers - used to treat high blood pressure and to relieve difficulty in passing urine caused by an enlarged prostate
  • angiotensin converting enzyme (ACE) inhibitors - used to treat 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
  • glucocorticoids (except when applied locally) – used to treat inflammatory conditions
  • oral contraceptives (“the pill”) - used for birth control
  • thiazides, frusemide or ethacrynic acid - used to treat high blood pressure or fluid retention (oedema)
  • thyroid hormones - used to treat malfunction of the thyroid gland
  • sympathomimetics - used to treat asthma
  • sulphonamides – used to treat bacterial infections

Or other specific medicines including:

  • danazol - used to treat certain female conditions
  • oxymetholone – used to treat certain blood disorders
  • 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 growth hormone levels
  • diazoxide - used to treat high blood pressure
  • nicotinic acid - used to treat high cholesterol levels in the blood
  • asparaginase - used to treat leukaemia and lymph gland tumours
  • quinine – used to treat malaria and relieve muscle cramps
  • quinidine – used to treat heart problems
  • growth hormone – used to treat growth disorders

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

This is very important. Your doctor will advise you if it is alright 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 human insulin 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.

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

Your doctor or diabetes education nurse will tell you when and how often to inject the insulin. If you are using Actrapid®, Mixtard® 30/70 or Mixtard® 50/50, it is recommended that you eat a meal or a snack containing carbohydrate within 30 minutes of the injection.

How to use it

  • Penfill® cartridges are designed to be used with Novo Nordisk insulin delivery devices (such as NovoPen®), and NovoFine® or NovoTwist® needles.
  • Make sure you are using the correct type and strength of insulin. Carefully follow the instructions on how to use your Penfill® in the Novo Nordisk insulin delivery device.
  • If you use more than one type of Penfill® (more than one type of insulin), you must use a separate insulin delivery device for each type of Penfill®.
  • Do not use the insulin level indicator on the device to measure your dose of insulin.
  • You should inject human insulin under the skin (subcutaneous injection) as shown to you by your doctor or diabetes education nurse.
  • In an emergency, the insulin contained within Actrapid® Penfill® is suitable for intramuscular administration under medical guidance. In an emergency, the insulin contained within Actrapid® Penfill® is also suitable for intravenous administration, but only if administered by a physician. For emergency use, the insulin must first be withdrawn from Penfill® into a syringe. Discard your Penfill® after emergency use.
  • In an emergency, the insulins contained within Protaphane®, Mixtard® 30/70 and Mixtard® 50/50 Penfill® are suitable for intramuscular administration under medical guidance. For emergency use, the resuspended insulin must first be withdrawn from Penfill® into a syringe. Discard your Penfill® after emergency use.
  • Do not use Penfill® in insulin pumps.
  • Take care not to drop or knock the device that contains Penfill®.

Checking your human insulin Penfill®:
Check your Penfill® before each preparation and injection to make sure you are using the correct type and strength of insulin. Disinfect the rubber membrane with a medicinal swab.

Do not use your Actrapid® Penfill® unless the insulin appears clear and colourless. Do not use it if the insulin appears thickened or has bits in it.

Do not use your Protaphane®, Mixtard® 30/70 or Mixtard® 50/50 Penfill® if the insulin is no longer a cloudy, white suspension after shaking, or if it has bits in it.

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

If these observations are noted, return your Penfill® to your pharmacist. See the insulin delivery device user manual for further instructions.

Preparing a dose:

  1. Wash your hands.
    IMPORTANT - If your Penfill® contains cloudy insulin please read and follow points 2-5 carefully:
  2. On the Penfill® cartridge is a coloured band. Do not start an injection with a Penfill® cartridge you have emptied beyond the coloured band. The glass ball must have adequate space to resuspend the insulin. Resuspending is easier when the insulin has reached room temperature.
  3. Before you put Penfill® into the Novo Nordisk insulin delivery device, move it up and down between positions a and b – see picture below - so that the glass ball in the cartridge moves from one end to the other at least 20 times. The movement must always be repeated until the liquid appears uniformly white and cloudy (‘resuspended’).
  4. If Penfill® is already inside the Novo Nordisk insulin delivery device, turn the delivery device upside-down at least 10 times with the cartridge inside it. Do this again before each subsequent injection.
  5. Complete the remaining stages of injection without delay.

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

The priming procedure may highlight a malfunction with your insulin delivery device. 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 device down, make sure the needle does not touch anything.

Injecting a dose:
Choose a site for injection.

Inject the medicine into the abdomen, thighs, upper arms or buttocks.

Your insulin will work more quickly if you inject into the abdomen.

Change the injection site so that the same position is not used more often than once a month.

This will reduce the chance of local skin reactions developing.

Pinch the skin between two fingers, push the needle into the raised skin, and inject the full dose of insulin under the skin.

Slowly count to 6 before pulling the needle out.

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 are using Actrapid® or Mixtard® insulins, it is recommended that you eat a meal or a snack containing carbohydrate within 30 minutes of the injection.

Do not share needles, insulin cartridges or insulin delivery devices.

How long to use it

Do not stop using human insulin 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.

Do not inject any insulin if you feel a hypo coming on.

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 convulsions, brain damage and even death.

If you miss a dose – Hyperglycamia

If you forget to inject 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 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 human insulin 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 sugary 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 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.

Tell your doctor if you drink alcohol.

Alcohol may mask the symptoms of hypos.

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 human insulin.

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)
  • redness, 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 your current insulin 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 human insulin Penfill®

Storage

Penfill® that are not being used should be stored between 2°C and 8°C in the refrigerator (away from the cooling element). Protect the insulin in Penfill® from light by keeping the cartridges in the carton when not in use.

The Penfill® that you are using in your device, or that you are carrying as a spare, does not need to be kept in a refrigerator. You can use it for up to 4 weeks after taking it out of the refrigerator if it is kept below 25ºC. Discard Penfill® after 4 weeks even if there is still some insulin left in it.

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

Never use insulin after the expiry date printed on the label and carton after ‘Expiry’.

The expiry date refers to the last day of that month.

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

Never use Protaphane®, Mixtard® 30/70 or Mixtard® 50/50 Penfill® if the suspension does not become white and uniformly cloudy after shaking.

Keep out of the reach of children.

Disposal

Dispose of your 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

A coloured band is located on the Penfill® cartridge. The colour of the band is specific for the insulin preparation.

Actrapid® is a clear, colourless solution for subcutaneous injection.

Actrapid® Penfill® 3mL is a glass cartridge.

Protaphane®, Mixtard® 30/70 and Mixtard® 50/50 are white, cloudy suspensions for subcutaneous injection. Protaphane®, Mixtard® 30/70 and Mixtard® 50/50 Penfill® 3mL are glass cartridges.

Ingredients

Human insulin (rys) is characterised by being identical to natural human insulin. The abbreviation “rys” indicates the method of genetic engineering used to manufacture the insulin.

Actrapid® is a neutral solution of human insulin (rys) 100 IU/mL. Also contains: glycerol, meta-cresol, zinc chloride, water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Protaphane® is a neutral suspension of isophane human insulin (rys) 100 IU/mL. Also contains: glycerol, meta-cresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate, water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Mixtard® 30/70 is a pre-mixed neutral suspension of human insulin (rys) 100 IU/mL, consisting of neutral insulin injection (30%) and isophane insulin injection (70%). Also contains: glycerol, meta-cresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate, water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Mixtard® 50/50 is a pre-mixed neutral suspension of human insulin (rys) 100 IU/mL, consisting of neutral insulin injection (50%) and isophane insulin injection (50%). Also contains: glycerol, meta-cresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate, water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Sponsor

Penfill® is supplied in Australia by:

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

This leaflet was prepared on 30 August 2012.

Australian Registration Numbers:

Actrapid® Penfill® 3mL: AUST R 169623

Protaphane® Penfill® 3mL: AUST R 169635

Mixtard® 30/70 Penfill® 3mL: AUST R 169629

Mixtard® 50/50 Penfill® 3mL: AUST R 169630

Penfill®, NovoFine®, NovoTwist®, NovoPen®, Actrapid®, Protaphane®, Mixtard® and NovoCare® are registered trademarks of Novo Nordisk A/S.

© 2012

Further information

For further information call the NovoCare® Customer Care Centre on 1800 668 626.

www.novonordisk.com.au

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

  • freecall helpline 1300 136 588
  • www.diabetesaustralia.com.au

BRAND INFORMATION

Brand name

Mixtard 30/70 Penfill 3 mL Injection

Active ingredient

Insulin, neutral (rys); Insulin, isophane (rys)

Schedule

S4

 

1 Name of Medicine

Insulin (rys).

2 Qualitative and Quantitative Composition

Actrapid.

1 mL solution contains 100 international units insulin (rys). Also contains: glycerol, metacresol, zinc chloride, water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Protaphane.

1 mL suspension contains 100 international units isophane insulin (rys). Also contains: glycerol, metacresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate (a fish product), water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Mixtard 30/70.

1 mL suspension contains 100 international units soluble insulin (rys)/isophane insulin (rys) in the ratio 30/70. Also contains: glycerol, metacresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate (a fish product), water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.

Mixtard 50/50.

1 mL suspension contains 100 international units soluble insulin (rys)/isophane insulin (rys) in the ratio 50/50. Also contains: glycerol, metacresol, phenol, dibasic sodium phosphate dihydrate, zinc chloride, protamine sulfate (a fish product), water for injections. Hydrochloric acid and sodium hydroxide are used to adjust the pH.
One IU (International Unit) of insulin corresponds to 0.035 mg of anhydrous insulin (rys).
Insulin (rys) is produced by recombinant DNA technology using Saccharomyces cerevisiae.
Actrapid, Protaphane, Mixtard 30/70 and Mixtard 50/50 contain less than 1 mmol sodium (23 mg) per dose, i.e. these products are essentially 'sodium-free'.

3 Pharmaceutical Form

Actrapid.

Solution for injection. The solution is clear, colourless and aqueous.

Protaphane.

Suspension for injection. The suspension is cloudy, white and aqueous.

Mixtard 30/70.

Suspension for injection. The suspension is cloudy, white and aqueous.

Mixtard 50/50.

Suspension for injection. The suspension is cloudy, white and aqueous.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of insulin-requiring diabetes.

4.2 Dose and Method of Administration

Dosage.

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 diabetes lies between 0.5 and 1.0 IU/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1.0 IU/kg/day, 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 diabetes are often lower, e.g. 0.3 to 0.6 IU/kg/day. This should be adjusted slowly until optimum glycaemic control is reached. The total daily insulin requirement for maintenance therapy in type 2 diabetes is usually higher than the initial dose.
In people 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.
In the elderly the primary aim of treatment may be symptom relief and avoidance of hypoglycaemic events.

Method of administration.

Insulin is usually administered subcutaneously by injection in the abdominal wall, the thigh, the gluteal region or the deltoid region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimises the risk of intramuscular injection. Keep the needle under the skin for at least 6 seconds to make sure the entire dose is injected.

Insulin solution - Actrapid.

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. In an emergency, Actrapid is suitable for intramuscular administration under medical guidance. In an emergency, Actrapid is also suitable for intravenous administration but only if administered by a physician. For emergency use with Penfill, the insulin must first be withdrawn into a syringe. Discard Penfill cartridge after emergency use.
Actrapid may also be administered when insulin is required in the following situations:
Initial stabilisation of diabetes.
Treatment of diabetic ketoacidosis and hyperosmolar nonketotic syndrome.
Insulin given as a continuous intravenous infusion or intramuscular injection regime is part of the overall management of both diabetic ketoacidosis and hyperosmolar nonketotic syndrome.
During stress situations such as severe infection.
Clinical management of severe infections may require higher doses of insulin than normal, intravenous insulin or short-term insulin treatment in patients normally taking oral hypoglycaemic agents.
Major trauma and/or surgery in people with diabetes.
Management of the patient is determined by the nature and severity of the trauma and/or surgery, the duration of peri-operative fasting and the patient's ability to produce insulin. People normally treated with insulin will generally require insulin administration. People with poorly controlled type 2 diabetes or those undergoing major surgery will generally require insulin. Frequent blood glucose monitoring is required during and after surgery. When the patient is able to eat normally, their usual therapy can be reinstated.
Due to the risk of precipitation in pump catheters, Actrapid should not be used in insulin pumps for continuous subcutaneous insulin infusion.
For intravenous use, infusion systems with Actrapid at concentrations 0.05 IU/mL-1.0 IU/mL insulin in the following infusion fluids; 0.9% sodium chloride, 5% dextrose and 10% dextrose inclusive 40 mmol/L potassium chloride, using polypropylene infusion bags, are stable at room temperature for 24 hours. Although stable over time, a certain amount of insulin will initially be absorbed to the material of the infusion bag. Monitoring of blood glucose is necessary during the infusion.

Pre-mixed insulin suspensions - Mixtard 30/70 and Mixtard 50/50.

Mixtard (pre-mixed) insulins are usually given once or twice daily when a rapid initial effect together with a more prolonged effect is required. Mixtard 50/50 has the strongest initial effect followed by Mixtard 30/70. An injection should be followed by a meal or snack containing carbohydrates within 30 minutes.

Insulin suspension - Protaphane.

The physician determines whether one or more daily injections are necessary. Protaphane is usually given once or twice daily. The preparation may be used alone or mixed with short acting soluble insulin (e.g. Actrapid, NovoRapid). In intensive insulin therapy the suspensions may be used as basal insulin (evening and/or morning injection) with soluble insulin given at meals. Protaphane may also be used in combination with oral antidiabetic drugs (OADs) when OADs alone have not given satisfactory control of blood glucose.
Protaphane, Mixtard 30/70 and Mixtard 50/50 are suitable for intramuscular administration in emergency under medical guidance only. For such use with Penfill/ InnoLet, the insulin must first be withdrawn into a syringe. Discard Penfill/ InnoLet cartridge/ syringe after emergency use. Insulin suspensions are never to be administered intravenously. Insulin suspensions are not to be used in insulin infusion pumps.
Preparations containing cloudy insulins should be gently agitated by rolling between the hands (10 mL vials only) or gently shaken (Penfill and InnoLet only) before use to ensure that the insulin is uniformly distributed throughout the liquid and the injection should be given immediately thereafter.

Mixing with other insulins.

Insulin preparations may be admixed in the syringe. The insulin mixture should be injected immediately after preparation. When short acting soluble insulin is mixed with longer acting insulin, the short acting insulin should be drawn into the syringe first to prevent contamination of the vial by the longer acting preparation.
If an intermediate acting or long acting insulin is mixed with NovoRapid (insulin aspart, a short acting insulin analogue), NovoRapid should be drawn into the syringe first. The injection should be made immediately after mixing.

Instructions for use and handling.

10 mL vials.

Insulin vials are for use with U100 insulin syringes. A Consumer Medicine Information leaflet is available with instructions for use and handling. The insulin suspensions must be resuspended immediately before use so that they appear uniformly white and cloudy.

Penfill 3 mL cartridges.

The Consumer Medicine Information leaflet is available with instructions for use and handling. The insulin suspensions must be resuspended immediately before use so that they appear uniformly white and cloudy.
Penfill preparations are for use by one person only. The cartridge must not be refilled.
Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems and NovoFine needles. The patient should be advised to discard the needle after each injection.

InnoLet 3 mL.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling. The insulin suspensions must be resuspended immediately before use so that they appear uniformly white and cloudy.
InnoLet preparations are for use by one person only. The cartridge inside the pre-filled insulin delivery device must not be refilled. InnoLet are designed to be used with NovoFine needles.
Cartridges/pre-filled delivery devices should only be used in combination with products that are compatible with them and that allow the cartridge/ device to function safety and effectively.
Penfill and InnoLet are for use by one person only. The container must not be refilled.

4.3 Contraindications

Hypoglycaemia.
Hypersensitivity to insulin or any of the excipients.
Insulin suspensions should not be administered intravenously.
Insulin suspensions are not suitable for the treatment of diabetic ketoacidotic coma.

4.4 Special Warnings and Precautions for Use

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 come on gradually over a period of hours or days. They include nausea, vomiting, drowsiness, flushed dry skin, dry mouth, increased urination, thirst and loss of appetite as well as acetone breath. In type 1 diabetes, untreated hyperglycaemic events lead to diabetic ketoacidosis which is potentially lethal.

Hypoglycaemia.

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).
Concomitant illness, especially infections and conditions with fever, usually increases the patient's insulin requirements.
Under certain circumstances, e.g. insufficient food intake, increased physical activity, etc, the daily dose administered to the patient may represent an overdose leading to hypoglycaemia. A change in insulin dosage may be necessary to correct recurrent 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.

Transfer from other insulin products.

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, intermediate-acting, long-acting, etc.), and/or species (animal, insulin analogue) may result in the need for a change in dose.
If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
Patients currently stabilised on bovine insulins may require a dosage reduction, depending upon the dosage, purity and formulation of the insulin(s) currently administered. Variations in glycaemic control may occur and adjustments in therapy should be made under the guidance of a physician. Any patient receiving over 100 units per day may need to be referred to hospital for transfer. These guidelines are general indications only.
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.
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.

Skin and subcutaneous tissue disorders.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered.

Travelling with insulin.

Before travelling between different time zones, the patient should be advised to consult their doctor or diabetes education nurse, since this may mean that the patient has to inject their insulin and eat their meals at different times.

Combination of thiazolidinediones and insulin medicinal products.

Cases of congestive heart failure have been reported when thiazolidinediones were used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. 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.

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 Actrapid/Protaphane/Mixtard 30/70/Mixtard 50/50 and other insulin products.

Use in renal and hepatic impairment.

Renal or hepatic impairment may reduce 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.

Use in the elderly.

Data were not assessed as part of this medicine registration.

Paediatric use.

Data were not assessed as part of this medicine registration.

Effects on laboratory tests.

Data were not assessed as part of this medicine registration.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A number of drugs are known to interact with glucose metabolism. The physician must therefore take possible interactions into account.
The following substances may reduce the patient's insulin requirements: oral hypoglycaemic agents (OHAs), octreotide, lanreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids (except danazol and oxymetholone), alpha-adrenergic blocking agents, quinine, quinidine and sulphonamides.
The following substances may increase the patient's insulin requirements: oral contraceptives, thiazides, frusemide, ethacrynic acid diuretics, glucocorticoids, thyroid hormones, sympathomimetics, octreotide, lanreotide, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol.
Beta blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Alcohol may intensify and prolong, or reduce, the hypoglycaemic effect of insulin.
Hypoglycaemia in the presence of concomitant use of a beta-adrenergic blocking agent may precipitate a hypertensive crisis.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Data were not assessed as part of this medicine registration.
(Uncategorised)
It is essential to maintain continuous good control of insulin requiring diabetes throughout pregnancy. 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 occur with inadequately controlled diabetes therapy, increase the risk of malformations and death in utero.
Intensified treatment and monitoring of pregnant women with diabetes is recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy levels, leading to the risk of hypoglycaemia if the patient's insulin dose is not adjusted. Blood glucose levels should be monitored closely during the post-partum period and the patient's insulin dose adjusted accordingly.
There are no restrictions on treatment of diabetes with insulin during lactation. Insulin treatment of the nursing mother should not affect the baby. However the insulin dosage, or diet, or both, may need to be reduced.

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. People should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery. 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 machinery should be considered in these circumstances.

4.8 Adverse Effects (Undesirable Effects)

Post marketing data.

Hypoglycaemia is a frequently occurring undesirable effect of insulin therapy. It may occur if the insulin dose is too high in relation to the insulin requirement. Symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, nervousness or tremor, anxious feeling, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, temporary vision changes, headache, nausea and palpitations. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.
Oedema and refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually transitory in 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.
Lipodystrophy is reported as uncommon. Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see Section 4.4 Special Warnings and Precautions for Use).
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 may help to reduce these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of a particular brand or brands of insulin.
Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally they disappear during continued treatment.
Generalised hypersensitivity reactions may rarely occur. Generalised hypersensitivity reactions are potentially life threatening.

Hypersensitivity and skin.

Uncommon: lipodystrophy.
Rare: hypersensitivity reactions.
Not known: cutaneous amyloidosis (see description above).

Endocrine.

Rare: insulin resistance.

Reporting suspected adverse effects.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

A specific overdose of 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 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 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).

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.
In clinical practice the duration of insulin action may be shorter or longer than the duration specified below. Variations between and within patients may occur depending upon injection site and technique, insulin dosage, diet and exercise.
Actrapid is a short acting insulin preparation. Its hypoglycaemic effect after subcutaneous administration begins after approximately 0.5 hour, is maximal between 2.5 and 5 hours, and terminates after approximately 8 hours.
Protaphane is an intermediate acting insulin preparation. Its hypoglycaemic effect after subcutaneous administration begins after approximately 1.5 hours, is maximal between 4 and 12 hours, and lasts up to approximately 24 hours.
Mixtard 30/70 is an intermediate acting insulin preparation. Its hypoglycaemic effect after subcutaneous administration begins after approximately 0.5 hour, is maximal between 2 and 12 hours and terminates after approximately 24 hours. Mixtard 30/70 is not exactly equivalent to its component insulins.
Mixtard 50/50 is an intermediate acting insulin preparation. Its hypoglycaemic effect after subcutaneous administration begins after approximately 0.5 hour, is maximal between 4 and 8 hours and terminates after approximately 24 hours. Mixtard 50/50 is not exactly equivalent to its component insulins.

Clinical trials.

Data were not assessed as part of this medicine registration.

5.2 Pharmacokinetic Properties

Data were not assessed as part of this medicine registration.

5.3 Preclinical Safety Data

Genotoxicity.

Data were not assessed as part of this medicine registration.

Carcinogenicity.

Data were not assessed as part of this medicine registration.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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.
Insulin suspensions should not be added to infusion fluids.

6.3 Shelf Life

The shelf life is 30 months when stored between 2°C and 8°C.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Storage conditions.

Before opening.

Insulin preparations should be stored between 2°C and 8°C (in a refrigerator), not in or near the freezing compartment. Do not freeze. Insulin preparations which have been frozen must not be used. Insulin preparations should be protected from excessive heat and light. When not in use, the product should be kept in the carton, or stored with its cap on (prefilled devices only), to protect the insulin from light.
Insulin solutions should not be used if they do not appear water-clear and colourless. Insulin suspensions should not be used if they do not appear uniformly white and cloudy after suspension.

During use or when carried as a spare.

Vial: Store at room temperature (below 25°C) for up to 4 weeks.
Penfill and InnoLet: Store at room temperature (below 25°C) for up to 4 weeks.
Insulin products should not be exposed to excessive heat or light. Keep the product in the carton (vial, Penfill) or keep the cap on (InnoLet) when not in use, to protect it from light.

6.5 Nature and Contents of Container

Insulin (rys) 100 IU/mL.

Penfill 3 mL.

Penfill cartridges are made of glass, contain a rubber piston and are closed with a rubber disc. The insulin suspension cartridges contain a glass ball to facilitate resuspension. Five cartridges are packed in a carton.
Actrapid Penfill 3 mL, Protaphane Penfill 3 mL, Mixtard 30/70 Penfill 3 mL, Mixtard 50/50 Penfill 3 mL.

InnoLet 3 mL.

Insulin delivery device containing a 3 mL cartridge. The cartridge is made of glass, contains a rubber piston and is closed with a rubber disc. Five prefilled insulin delivery devices are packed in a carton. The device is made of plastic and is disposable.
Protaphane InnoLet 3 mL, Mixtard 30/70 InnoLet 3 mL.

10 mL vial.

The 10 mL glass vial is closed with a rubber disc. One vial is packed in a carton.
Actrapid, Protaphane 10 mL vial.
Not all presentations are marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Insulin (rys) is characterised by being identical to natural human insulin. Insulin has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.

CAS number.

11061-68-0.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes