Consumer medicine information

Apidra

Insulin glulisine

BRAND INFORMATION

Brand name

Apidra 10 mL Vial

Active ingredient

Insulin glulisine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Apidra.

What is in this leaflet

This leaflet answers some common questions about Apidra.

It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or diabetes educator.

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

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

Keep this leaflet with the medicine.

You may need to read it again.

What Apidra is used for

Apidra is used to reduce high blood sugar (glucose) levels in people with diabetes mellitus.

Apidra is a modified insulin that is very similar to human insulin. It is a substitute for the insulin produced by the pancreas.

Apidra is a short-acting insulin. Your doctor may tell you to use a long-acting insulin in combination with Apidra.

Apidra is not addictive.

Ask your doctor if you have any questions about why Apidra has been prescribed for you.

Before you use Apidra

When you must not use Apidra

Do not use Apidra:

- If you have an allergy to:

  • any medicine containing insulin
  • any of the ingredients contained in Apidra listed at the end 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

- If you are experiencing low blood sugar levels (hypoglycaemia - a "hypo").
If you have a lot of hypos discuss appropriate treatment with your doctor.

- After the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.
If you use Apidra after the expiry date has passed, it may not work as well. If it has expired or is damaged, return it to your pharmacist for disposal.

- If the product appears cloudy, discoloured or contains particles, or if the injection pen, cartridge or vial appears damaged.

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

Do not give Apidra to children less than 4 years of age.

There is no experience with the use of Apidra in children less than 4 years.

Before you start to use Apidra

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 of the following medical conditions:

  • kidney problems
  • liver problems

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

Pregnancy may make managing your diabetes more difficult.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Tell your doctor if:

  • you drink alcohol
  • you do not eat regular meals
  • you do a lot of exercise
  • you are ill or feeling unwell

Alcohol, diet, exercise and your general health all affect the control of your diabetes.

If you have not told your doctor about any of the above, tell them before you start using Apidra.

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.

Medicines that may increase the blood sugar lowering effect of Apidra include:

  • oral antidiabetic medicines that are used to treat type 2 diabetes
  • blood pressure, blood flow, cholesterol and heart medications
  • medications for pain and inflammation
  • some antidepressants
  • sulfonamide antibiotics

Medicines that may reduce the blood sugar lowering effect of Apidra include:

  • corticosteroids, glucagon and other hormonal therapies
  • oral contraceptives and gynaecological medications
  • fluid and glaucoma medications
  • tuberculosis and HIV/AIDS treatments
  • some psychiatric medications
  • adrenaline (epinephrine) and asthma medications such as salbutamol, terbutaline

Certain heart medications, especially beta-blockers, may mask the symptoms of hypoglycaemia.

Your doctor and pharmacist have a full list of medicines with which you must be careful or avoid while using Apidra. Please check with your doctor or pharmacist before starting any new medicines or over the counter products.

How to use Apidra

Your doctor, pharmacist or diabetes educator will have shown you how to use Apidra.

Carefully follow all the directions.

Do not inject Apidra into a vein.

Apidra is intended for injection under the skin.

Any change in this medicine should be made cautiously and only under medical supervision.

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

How much to use

Your doctor will tell you how much Apidra you need to use each day. Your doctor may increase or decrease the dose, depending on your blood sugar levels.

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

When to use Apidra

Your doctor will tell you when to use Apidra.

Apidra should be used within 15 minutes before or immediately after a meal.

How to use Apidra

ALWAYS CHECK YOUR APIDRA INJECTION PEN, CARTRIDGE OR VIAL.

Do not use Apidra if it is no longer clear and colourless or if it contains particles.

Make sure you are using the correct injection pen, cartridge or vial.

Always check the insulin label on the SoloStar pen, cartridge or vial before each injection to make sure you are using the right insulin.

Keep the injection pen, cartridge or vial at room temperature for 1 or 2 hours before use. Cold insulin is more painful to inject.

For Apidra injection pens or cartridges

PREPARING A DOSE FOR INJECTION

Always do a safety test before use.

The safety test may highlight a problem with your injection pen. The safety test also removes any air bubbles and helps indicate whether or not a needle is bent or broken.

Becton Dickinson (BD Micro-Fine™+) needles should be used with injection pens.

Reusable pens

We recommend that Apidra cartridges only be used with the AllStar, AllStar Pro, JuniorStar or ClikStar reusable pen.

Carefully follow the instructions provided with the pen, for loading a cartridge, attaching a needle, performing a safety test and administering the insulin injection.

If the reusable injection pen does not work properly, Apidra may be withdrawn from the cartridge into a syringe. Ask your doctor, pharmacist or diabetes educator for help.

Pre-filled disposable pens

Apidra SoloStar disposable pens are pre-filled and ready for use. Once all the insulin is used, you cannot replace the cartridge.

Carefully follow the instructions provided with the Apidra SoloStar pen for attaching a needle, performing a safety test and administering the insulin injection.

Never use an injection pen if it is damaged or if you are not sure that it is working properly. Use a new pen.

INJECTING A DOSE

Apidra should be injected under the skin, being careful not to inject it into a muscle or vein.

Choose a site for injection.

Inject Apidra into the abdomen, thighs or upper arms.

  1. With one hand, stabilise the skin by spreading it or pinching up a large area, as recommended by your healthcare professional.
  2. Insert the needle into the skin as recommended by your healthcare professional.
  3. Inject the full dose of Apidra by pushing the plunger as far as it will go.
  4. Slowly count to 10 before removing the needle from the skin.

Use a different injection site each injection so that the same site is not used more often than once a month.

This will reduce the chance of local skin reactions developing.

AFTER INJECTING

Using the outer needle cap, unscrew the needle and dispose of it safely into a sharps container.

Do not share needles, cartridges or injection devices. Do not reuse needles.

Leave the cartridge in the pen until it needs to be replaced.

Do not attempt to replace the cartridge in a pre-filled disposable pen.

Empty disposable pens must never be reused and must be properly discarded.

For Apidra vials

PREPARING A DOSE FOR INJECTION

Using one insulin type (Apidra)

  1. Wash your hands.
  2. Draw air into a U100 insulin syringe equal to the dose of Apidra to be injected.
  3. Push the needle through the rubber top of the vial and inject the air into the vial.
  4. Leave the needle in the vial. Hold the vial and syringe firmly in one hand, with the vial above the syringe.
  5. Make sure the tip of the needle is in the insulin and withdraw the correct dose into the syringe.
  6. Before removing the needle from the vial, check the syringe for air bubbles. If bubbles are present, hold the syringe vertically (needle pointed upwards) and tap firmly until the bubbles float to the top. Push the bubbles out with the plunger and then withdraw the correct dose. Remove the needle from the vial.
  7. If you need to put the syringe down, make sure the needle does not touch anything.

Mixing Apidra with NPH (isophane) insulin

Only mix Apidra with another insulin if your doctor has instructed you to do so.

Do not mix Apidra with insulins other than NPH (Neutral Protamine Hagedorn) insulin.

Draw Apidra into the syringe first, then NPH insulin.

  1. Wash your hands
  2. Just before use, roll the vial of cloudy (longer acting) NPH insulin between your hands until the liquid is white and uniformly cloudy. Do not shake the vial.
  3. Draw air into a U100 insulin syringe equal to the dose of cloudy NPH insulin you are using. Put the needle through the rubber top of the NPH insulin vial and inject air into the vial. Withdraw the needle without drawing up any insulin.
  4. Draw air into the syringe equal to your dose of Apidra and inject it into the Apidra vial but do not withdraw the needle.
  5. Leave the needle in the vial. Hold the vial and syringe firmly in one hand, with the vial above the syringe.
  6. Make sure the tip of the needle is in the Apidra and withdraw the correct dose into the syringe.
  7. Pull the needle out of the Apidra vial. Expel any air from the syringe and check that the dose is correct.
  8. Insert the needle into the vial of cloudy NPH insulin.
  9. Leave the needle in the vial. Hold the vial and syringe firmly in one hand, with the vial above the syringe.
  10. Make sure the tip of the needle is in the insulin and withdraw your dose of cloudy NPH insulin.
  11. Remove the needle from the vial.
  12. If you need to put the syringe down for a brief moment, make sure the needle does not touch anything.

INJECTING A DOSE

Apidra should be injected under the skin, being careful not to inject it into a muscle or vein.

Choose a site for injection.

Inject Apidra into the abdomen, thighs or upper arms.

Apidra mixed with NPH insulin should be injected immediately after mixing.

  1. With one hand, stabilise the skin by spreading it or pinching up a large area, as recommended by your healthcare professional.
  2. Insert the needle into the skin as recommended by your healthcare professional.
  3. Inject the full dose of Apidra, or Apidra mixed with NPH insulin, by pushing the plunger as far as it will go.
  4. Slowly count to 10 before removing the needle from the skin.

Use a different injection site each injection so the same site is not used more often than once a month.

This will reduce the chance of local skin reactions developing.

AFTER INJECTING

Dispose of your insulin syringes safely into a sharps container.

Do not share vials, needles or syringes. Do not reuse needles.

How long to use Apidra

Continue using Apidra for as long as your doctor recommends.

Make sure you keep enough Apidra to last over weekends and holidays.

If you take too much (overdose) - Hypoglycaemia, a "Hypo"

If you accidentally use too much Apidra your blood sugar level may become too low (hypoglycaemia).

Immediately telephone your doctor or the Poisons Information Centre (13 11 26 in Australia; 0800 POISON or 0800 764 766 in New Zealand) if you think that you or anyone else may have used too much Apidra.

Do this even if there are no signs of discomfort or poisoning.

The risk of hypoglycaemia is increased if you:

  • accidentally use too much Apidra
  • have too much or unexpected exercise
  • delay eating meals or snacks
  • eat too little food
  • are ill

The first symptoms of mild to moderate hypoglycaemia 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 drink with you.

If you experience any of these symptoms of hypoglycaemia, you need to raise your blood sugar urgently. You can do this by taking one of the following:

  • 5-7 jelly beans
  • 3 teaspoons of sugar or honey
  • 1/2 can of a sugar-containing soft drink (not a diet soft drink)
  • 2-3 concentrated glucose tablets

Follow up with extra carbohydrates, e.g. plain biscuits, fruit or milk, when over the initial symptoms.

Taking this extra carbohydrate will prevent a second drop in your blood sugar level.

If not treated quickly, the initial symptoms of hypoglycaemia may progress to loss of co-ordination, slurred speech, confusion, loss of consciousness and seizures.

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

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 turn you on your side and get medical help immediately if you lose consciousness.

Make sure they know not to give you anything to eat or drink if you are unconscious.

This is because you could choke.

Provide them with the telephone number for your doctor, the Poisons Information Centre (13 11 26 in Australia; 0800 POISON or 0800 764 766 in New Zealand) and Emergency Services.

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, have some sugary food or drink as soon as you are conscious again.

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

If you do not respond to glucagon treatment, you will have to be treated in a hospital.

See your doctor if you keep having "hypos", or if you have ever become unconscious after using Apidra.

Your dose of Apidra or other medicines may need to be changed.

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

If you miss a dose - Hyperglycaemia

If you forget to take your insulin dose check your blood sugar level as soon as possible.

Your blood sugar level may become high (hyperglycaemia).

Do not take an extra dose at a later time just because you have missed a dose.

If you miss taking your dose at the regular scheduled time, taking a dose at another time can increase your risk of having a hypo. You should therefore plan in advance with your doctor or healthcare professional so that you know what to do in case you miss a dose.

If you have missed a dose and are not sure what to do, contact your doctor or healthcare professional for specific advice.

Do NOT use a double dose of your insulin.

If you double a dose, this may cause low blood sugar levels.

The risk of hyperglycaemia is increased if you:

  • miss doses of Apidra or other insulins, or use less Apidra than you need
  • have uncontrolled diabetes
  • exercise less than usual
  • eat more carbohydrates than usual
  • are ill or stressed
  • take certain other medicines

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

Contact your doctor immediately if your blood sugar level is very high or you experience 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, pharmacist or diabetes educator.

While you are using Apidra

Things you must do

Measure your blood sugar level regularly.

This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

It is important to keep using Apidra even if you feel well.

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

Tell your doctor if you often have hypoglycaemia or if you have ever become unconscious after using Apidra.

Your doctor may need to adjust your dose of Apidra or of other medicines you are taking.

Always carry some sugary food or drink with you.

If you experience any of the symptoms of hypoglycaemia, immediately eat some sugary food or have a drink, e.g. jelly beans, sugar, honey, sugar-containing soft drink, glucose tablets. Diet and low calorie soft drinks do NOT contain sugar and are unsuitable to take for hypoglycaemia.

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

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

Ask your doctor for a letter explaining why you are taking injecting pens and needles with you.

Each country you visit will need to see this letter, so you should take several copies.

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

If you are travelling, it is a good idea to:

  • wear some form of identification showing you have diabetes
  • carry some form of sugar to treat hypoglycaemia if it occurs, e.g. sugar sachets or jelly beans
  • carry emergency food rations in case of a delay, e.g. dried fruit, biscuits or muesli bars
  • keep Apidra readily available; take enough Apidra for your expected needs whilst travelling - you may not be able to get Apidra in the country you are visiting

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

Tell your doctor if you are having trouble or difficulty with your eyesight.

Visit your doctor for regular checks of your eyes, feet, kidneys, heart, circulation, blood and blood pressure.

Carefully follow your doctor's and/or dietician's advice on diet, drinking alcohol and exercise.

Things you must not do

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

Do not skip meals while using Apidra.

Do not use Apidra if you think it has been frozen or exposed to excessive heat (temperatures above 25°C).

Do not re-use empty cartridges.

Do not give Apidra 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 Apidra affects you. Be careful not to let your blood sugar levels fall too low.

Tell your doctor if you drink alcohol.

Alcohol may mask the symptoms of hypoglycaemia.

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.

If you become sick with a cold or flu, it is very important to continue using Apidra, even if you feel unable to eat your normal meal. If you have trouble eating solid foods, use sugar-sweetened drinks as a carbohydrate substitute or eat small amounts of bland food.

Your diabetes educator or dietician can give you a list of foods to use for sick days.

Tell your doctor if you are exercising more than usual.

Exercise may lower your need for Apidra. Exercise may also speed up the effect of a dose of Apidra, 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, pharmacist or diabetes educator as soon as possible if you do not feel well while you are using Apidra.

Apidra helps most people with diabetes, 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 attention 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, pharmacist or diabetes educator to answer any questions you may have.

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

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

  • hypoglycaemia (mild to moderate)
  • redness, swelling or itching at the injection site; usually these symptoms disappear within a few weeks during continued use
  • a depression or thickening of the skin around the injection site (lipodystrophy); this can often occur if you inject too often at the same injection site

The above 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 hypoglycaemia, including:

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

- Signs of a serious allergic reaction, including:

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

The above list includes some 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.

After using Apidra

Storage

All medicines should be kept where children cannot reach them.

CARTRIDGES

Keep unopened cartridges of Apidra in a refrigerator where the temperature is between 2-8°C. Do not allow it to freeze. Discard if frozen.

When the cartridge has been inserted in the injection pen, the cartridge-pen combination should not be put in the refrigerator and should be kept below 25°C. Do not leave it near heat or in direct light. Discard the cartridge within 28 days of first use. Cartridges that are first carried as a spare for a while must also be discarded 28 days after being removed from the refrigerator.

PRE-FILLED DISPOSABLE PENS
Before use, keep unopened Apidra pre-filled pens in a refrigerator where the temperature is between 2-8°C. Do not allow to freeze. Discard if frozen.

Before first use, store the pre-filled pen at room temperature for 1 to 2 hours. Once in use, the pre-filled pen should not be put in the refrigerator and it should be kept below 25°C. Do not leave it near heat or in direct light. Discard the pre-filled pen within 28 days of first use. Pre-filled pens that are first carried as a spare for a while must also be discarded 28 days after being removed from the refrigerator.

VIALS

Keep Apidra in a refrigerator where the temperature is between 2-8°C. Do not allow it to freeze. Discard if frozen.

Once opened, the vial should be refrigerated between 2-8°C, but may be kept unrefrigerated for up to 28 days as long as it is kept below 25°C. Do not leave it near heat or in direct light. Discard the vial within 28 days of first use. Vials that are first carried as a spare for a while must also be discarded 28 days after being removed from the refrigerator.

Disposal

Dispose of your needles and disposable injection devices safely into a sharps container.

If your doctor tells you to stop using Apidra 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

Apidra is a clear, colourless solution available in 3mL cartridges and 10mL vials.

Apidra SoloStar is a pre-filled disposable pen containing a 3mL cartridge of Apidra.

Ingredients

Active ingredient:

  • insulin glulisine (100IU/mL)

Inactive ingredients:

  • metacresol
  • trometamol
  • sodium chloride
  • polysorbate 20
  • hydrochloric acid
  • sodium hydroxide
  • water for injections

Supplier

Apidra is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park, NSW 2113
Freecall No: 1800 818 806

Apidra is supplied in New Zealand by:

sanofi-aventis new zealand limited
Level 8, 56 Cawley Street
Ellerslie, Auckland
Freecall No: 0800 283 684

®= Registered Trademark

Apidra SoloStar 3mL injector pen AUST R 132816

Apidra 3mL cartridge AUST R 99146

Apidra 10mL vial AUST R 99145

This leaflet was prepared in October 2017.

Further information

You can get more information about diabetes and insulin from:

  • Diabetes Australia: Freecall helpline 1300 136 588
    www.diabetesaustralia.com.au
  • Diabetes NZ: 0800 369 636
    www.diabetes.org.nz

apidra-ccdsv11-cmiv11-25oct17

BRAND INFORMATION

Brand name

Apidra 10 mL Vial

Active ingredient

Insulin glulisine

Schedule

S4

 

Name of the medicine

Insulin glulisine.

Excipients.

Metacresol, trometamol, sodium chloride, polysorbate 20, hydrochloric acid, sodium hydroxide for adjustment to pH 7.3 and water for injections.

Description

Chemical name: 3B-Lys-29B-Glu-human insulin. Molecular formula: C258H384N64O78S6. MW: 5,823. CAS: 207748-29-6. Apidra (insulin glulisine injection (rDNA origin)) is a recombinant human insulin analogue produced by recombinant DNA technology. Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid.
Apidra is a sterile clear, colourless solution of insulin glulisine in vials and cartridges for use as an injection. Apidra contains 100 IU/mL (3.49 mg/mL) insulin glulisine. It also contains metacresol, trometamol, sodium chloride, polysorbate 20, hydrochloric acid and sodium hydroxide for adjustment to pH 7.3, and water for injections.

Pharmacology

Mode of action.

The primary activity of insulins and insulin analogues, including insulin glulisine, is regulation of glucose metabolism. Insulins lower blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis in the adipocyte, inhibit proteolysis and enhance protein synthesis.

Pharmacodynamics.

The glucose lowering activities of Apidra and of regular human insulin are equipotent when administered by the intravenous route.
Studies in healthy volunteers and patients with diabetes demonstrated that Apidra has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.
In a study in patients with type 1 diabetes (n = 20), the glucose lowering profiles of Apidra and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0.15 IU/kg. (See Figures 1, 2 and 3.)

Pharmacokinetic properties.

Absorption and bioavailability.

Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or 2) demonstrated that absorption of insulin glulisine was about twice as fast with a peak concentration approximately twice as high compared to regular human insulin.
In a study in patients with type 1 diabetes (n = 20) after subcutaneous administration of 0.15 IU/kg, the Tmax was 55 minutes and Cmax was 82 microIU/mL for insulin glulisine compared to a Tmax of 82 minutes and a Cmax of 46 microIU/mL for regular human insulin. The mean residence time of insulin glulisine was shorter (98 min) than for regular human insulin (161 min). (See Figure 4.)
When Apidra was injected subcutaneously into different areas of the body, the time concentration profiles were similar with a slightly faster absorption when administered in the abdomen compared to the deltoid or thigh. The absolute bioavailability of insulin glulisine after subcutaneous administration is about 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

Distribution and elimination.

The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar, with volumes of distribution of 13 L and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous administration in diabetic and nondiabetic subjects, insulin glulisine is eliminated more rapidly than regular human insulin, with an elimination half-life ranging from 37 to 75 minutes, compared to 86 minutes for regular human insulin.

Special populations.

Paediatric patients.

The pharmacokinetic and pharmacodynamic properties of Apidra and regular human insulin were assessed in a study conducted in paediatric patients with type 1 diabetes (children (7-11 years, n = 10) and adolescents (12-16 years, n = 10)). The relative differences in pharmacokinetics and pharmacodynamics between Apidra and regular human insulin in paediatric patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.

Race and gender.

Information on the effect of race and gender on the pharmacokinetics of Apidra is not available. However, in phase 3 clinical trials in adults (n = 1617), subgroup analyses based on gender did not show differences in safety and efficacy between Apidra and regular human insulin or other rapid acting insulin formulations.

Obesity.

The pharmacokinetic and pharmacodynamic properties of Apidra, regular human insulin and insulin lispro were compared in a study conducted in obese (30-40 kg/m2), otherwise healthy nondiabetic subjects (n = 18). The more rapid onset of action and shorter duration of activity of Apidra and insulin lispro compared to regular human insulin were maintained in this population. The rapid onset of action was better maintained with insulin glulisine than with insulin lispro. (See Figure 5.)

Renal impairment.

Studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study performed in 24 nondiabetic subjects covering a wide range of renal function (ClCr > 80 mL/min; 30-50 mL/min; < 30 mL/min), the pharmacokinetic properties of Apidra were generally maintained. (See Precautions, Renal impairment.)

Hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of Apidra has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. (See Precautions, Hepatic impairment.)

Pregnancy.

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Apidra has not been studied. (See Precautions, Use in pregnancy.)

Clinical Trials

Efficacy studies.

The safety and efficacy of Apidra was studied in adult patients with type 1 and type 2 diabetes (n = 1,617) and in children and adolescents with type 1 diabetes (n = 572). The primary efficacy parameter was glycaemic control, as measured by glycated haemoglobin (GHb) and expressed as either GHb or haemoglobin A1c equivalents (HbA1c).

Type 1 diabetes in adults.

A 26 week, randomised, open label, active control study (study 3001, n = 672) was conducted in patients with type 1 diabetes to assess the safety and efficacy of Apidra compared to insulin lispro when administered subcutaneously within 15 minutes prior to a meal. Lantus (insulin glargine) was administered once daily in the evening as the basal insulin. Before start of the study there was a 4 week run-in period combining insulin lispro and Lantus followed by randomisation. Glycaemic control and the rates of hypoglycaemia requiring intervention from a third party were comparable for the two treatment regimens. The number of daily insulin injections and the total daily doses of Apidra and insulin lispro were similar. The decrease in HbA1c was observed in patients treated with Apidra without an increase in the basal insulin dose. (See Table 1). The change in basal insulin dose (p = 0.0001) and total insulin dose (p = 0.0123) at endpoint was statistically significantly different between the two groups. The clinical value of this difference was not assessed in this study.

Type 1 diabetes in children and adolescents.

In a 26 week phase III clinical study (study D3001, n = 572) comparing Apidra with insulin lispro, both injected subcutaneously shortly (0-15 minutes) before a meal in children and adolescents with type 1 diabetes mellitus (4-17 years of age, inclusive), using Lantus or NPH human insulin as basal insulin, Apidra was comparable to insulin lispro for glycaemic control, as reflected by changes in GHb from baseline to endpoint. (See Table 2). A slightly higher percentage of subjects reached GHb < 8.5% at endpoint in the insulin glulisine group (62.0%) compared to the insulin lispro group (57.4%). A higher percentage of adolescents (13-17 years) reached GHb < 7.5% at endpoint in the insulin glulisine group (31.1% versus 21.2%) and overall, for all age groups together, the percentage of subjects reaching their age dependent GHb goals was significantly greater in the insulin glulisine group than in the insulin lispro group (38.4% versus 32.0%, p = 0.0386). Comparable self monitored blood glucose values were observed. To achieve similar glycaemic control, subjects in the Apidra group required significantly less increase in basal (p = 0.0084), rapid acting (p = 0.0465) and total (p = 0.0074) insulin doses as compared to subjects treated with insulin lispro. (See Table 2). The majority of subjects had an average number of rapid acting insulin injections between 3 and 4, in both groups, and this number remained stable throughout the study.

Type 2 diabetes in adults.

A 26 week, randomised, open label, active control study (study 3002, n = 876) was conducted in insulin treated patients with type 2 diabetes to assess the safety and efficacy of Apidra given within 15 minutes prior to a meal compared to regular human insulin administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the basal insulin. All patients participated in a 4 week run-in period combining regular human insulin and NPH human insulin. The average body mass index (BMI) of patients was 34.55 kg/m2. At randomisation, 58% of the patients were on an oral antidiabetic agent and were instructed to continue use of their oral antidiabetic agent at the same dose. The majority of patients (79%) mixed their rapid acting insulin with NPH human insulin immediately prior to injection. A larger reduction from baseline HbA1c was seen in the Apidra group. The adjusted mean difference was statistically significant (p = 0.0029). At end of treatment period, postprandial blood glucose levels in the Apidra group were lower than in the regular human insulin group. The clinical value of these differences was not assessed in this study. The rates of hypoglycaemia, requiring intervention from a third party, were comparable for the two treatment regimens. No differences between Apidra and regular human insulin groups were seen in the number of daily injections or basal or rapid acting insulin doses. (See Table 3).

Premeal and postmeal administration (Type 1 diabetes).

A 12 week, randomised, open label, active control study (study 3004, n = 860) was conducted in patients with type 1 diabetes to assess the safety and efficacy of Apidra administered at different times with respect to a meal. Apidra was administered subcutaneously either within 15 minutes prior to a meal or immediately after a meal and regular human insulin was administered subcutaneously 30 to 45 minutes prior to a meal. The comparisons performed in this study were premeal Apidra compared to regular human insulin, postmeal Apidra compared to regular human insulin, and postmeal Apidra compared to premeal Apidra. Lantus was (insulin glargine) administered once daily at bedtime as the basal insulin. Before start of the study there was a 4 week run-in period combining regular human insulin and Lantus followed by randomisation. Glycaemic control and the rates of hypoglycaemia requiring intervention from a third party were comparable for the treatment regimens. Significant reductions from baseline in HbA1c were observed in all three treatment regimens. No changes from baseline between the treatments were seen in the total daily number of insulin injections. An increase in daily rapid acting insulin dose was seen with regular human insulin. At endpoint, the change in the rapid acting insulin dose in the regular human insulin group was statistically significant compared to the changes seen in either the premeal Apidra group (p = 0.0001) or postmeal Apidra group (p = 0.0012). (See Table 4). The clinical value of this difference was not assessed in this study.

Indications

Apidra is indicated for the treatment of type 1 and type 2 diabetes mellitus in adults and children of 4 years or above who require insulin for the control of hyperglycaemia.

Contraindications

Apidra is contraindicated in patients hypersensitive to insulin glulisine or any of its excipients.

Precautions

Because of the short duration of action of Apidra, patients with diabetes also require a longer-acting insulin or basal insulin analogue to maintain adequate glucose control.
As with all insulins, the time course of action of Apidra may vary in different individuals or at different times in the same individual and the rate of absorption is dependent on blood supply, temperature and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan.
Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances or stress.
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g. regular, NPH, analogues), species (animal, human) or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage. Concomitant oral antidiabetic treatment may need to be adjusted.
Glucose monitoring is recommended for all patients with diabetes.
Medication errors have been reported in which other insulins, particularly long acting insulins, have been accidentally administered instead of insulin glulisine.

Hypoglycaemia.

Hypoglycaemia is the most common adverse effect of insulins and may occur if the insulin dose is too high in relation to the insulin requirement. The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may, therefore, differ among various different insulin formulations.
As with all insulins, the warning symptoms of hypoglycaemia may be changed, less pronounced or absent, in certain risk groups, as for example, in patients whose glycaemic control is markedly improved or in whom hypoglycaemia is developing gradually; in elderly patients; where an autonomic neuropathy is present; in patients with a long history of diabetes; in patients receiving concurrent treatment with certain drugs. (See Interactions with Other Medicines.)
Such situations may result in severe hypoglycaemia (and possibly, loss of consciousness) prior to the patient's awareness of hypoglycaemia.

Renal impairment.

The pharmacokinetic properties of Apidra were generally maintained in subjects with renal impairment. However, as with all insulins, the requirements for Apidra may be reduced in patients with renal impairment. (See Pharmacology, Pharmacokinetics, Special populations.) In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.

Hepatic impairment.

In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

Injection site and allergic reactions.

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Local allergy in patients occasionally occurs as redness, swelling and itching at the site of insulin injection. These reactions usually resolve in a few days to a few weeks. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.
Systemic allergic reactions to insulin (including insulin glulisine), may be associated with rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse or sweating. Severe cases of generalised allergy, including anaphylactic reaction, may be life threatening.
Localised reactions and generalised myalgias have been reported with the use of cresol as an injectable excipient.

Information for patients.

For all patients.

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique and hypoglycaemia and hyperglycaemia management. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress or emotional disturbances), an inadequate food intake or skipped meals and missed doses.
Accidental mix-ups between insulin glulisine and other insulins, particularly long-acting insulins, have been reported. To avoid medication errors between insulin glulisine and other insulins, patients should be instructed to always check the insulin label before each injection.
As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycaemia or hyperglycaemia, or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.
Women with diabetes should be advised to inform their doctor if they are pregnant or are contemplating becoming pregnant.

Pens to be used with Apidra cartridges.

Apidra cartridges should only be used with the following pens: AllStar and AllStar Pro which deliver Apidra in 1 unit dose increments; or JuniorSTAR which delivers Apidra in 0.5 unit dose increments from 1 unit; or ClikSTAR, which delivers Apidra in 1 unit dose increments.
Apidra cartridges should not be used with any other reusable pen as dosing accuracy has only been established with the listed pens.

Carcinogenicity, mutagenicity and impairment of fertility.

Long-term carcinogenicity studies in animals have not been conducted with Apidra. Results from a 12 month toxicity study in normal (non-diabetic) rats, and from other control studies, did not show any effect of treatment on incidences of mammary gland tumours. Subcutaneous doses tested were up to 50 IU/kg twice daily (plasma AUC approximately 150-fold that expected in patients). Insulin glulisine did not show any genotoxicity in tests for bacterial gene mutation and V79 cell chromosomal aberrations in vitro, or in an in vivo rat micronucleus test for clastogenicity.
Subcutaneous treatment of normal (non-diabetic) male and female rats with Apidra doses of up to 10 IU/kg/day had no effect on fertility (plasma AUC approximately 5-fold that expected in patients).

Use in pregnancy.

(Category B3)
Embryofoetal toxicity studies in normal (non-diabetic) pregnant rats did not show any effects specific to Apidra. A subcutaneous dose of 10 IU/kg/day did not affect embryofoetal development in rats (plasma AUC approximately 5-fold that expected in patients). Increased post-implantation losses were seen in rabbits treated with doses of 0.5 and 1.5 IU/kg/day (plasma AUC approximately 0.5-fold and 3-fold that expected in patients, respectively). Foetal skeletal defects (including scoliosis) seen in rabbits treated with 1.5 IU/kg/day also occurred with human insulin treatment, and were associated with maternal hypoglycaemia.
There are no well-controlled clinical studies of the use of Apidra (insulin glulisine) in pregnant women. As animal reproduction studies are not always predictive of human response, insulin glulisine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters and rapidly decline after delivery. Careful monitoring of glucose control is essential in such patients. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy.

Use in lactation.

Offspring development was unaffected after subcutaneous treatment of rats from early gestation and through the lactation period with doses of up to 8 IU/kg/day (plasma AUC approximately 4-fold that expected in patients). It is not known whether insulin glulisine is excreted in human milk. Many drugs, including insulin, are excreted in human milk. For this reason, caution should be exercised when Apidra is administered to a nursing mother. Lactating women may require adjustments in insulin dose and diet.

Use in children.

The relative differences in pharmacokinetic and pharmacodynamic properties of Apidra compared with regular human insulin observed in healthy adult subjects and adults with type 1 diabetes are similar in paediatric patients with type 1 diabetes (7 to 16 years). (See Pharmacology, Pharmacokinetics, Special populations, Paediatric patients.) Apidra can be administered to children ≥ 4 years of age. Administration to children < 4 years has not been studied.

Geriatric use.

In phase 3 clinical trials (n = 1617), Apidra was administered to 147 patients ≥ 65 years of age and 27 patients ≥ 75 years of age. The majority of these were patients with type 2 diabetes. The change in HbA1c values and hypoglycaemia frequencies did not differ by age, but greater sensitivity of some older individuals cannot be ruled out. Hypoglycaemia may be difficult to recognise in the elderly.

Interference with laboratory or diagnostic tests.

None known.

Abuse and dependence.

No risk of abuse or dependence is likely to occur with Apidra.

Interactions

A number of substances affect glucose metabolism and may require dose adjustment of human insulin.
Substances that may enhance the blood glucose lowering effect and increase susceptibility to hypoglycaemia include: oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline (oxpentifylline), propoxyphene, salicylates, sulfonamide antibiotics.
Substances that may reduce the blood glucose lowering effect include: atypical antipsychotic medications (e.g. olanzapine, clozapine), corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens (e.g. in oral contraceptives), phenothiazine derivatives, protease inhibitors, somatotropin, sympathomimetic agents (e.g. adrenaline (epinephrine), salbutamol, terbutaline), thyroid hormones.
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood glucose lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia.
In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation induced by hypoglycaemia may be reduced or absent.

Mixing of insulins.

A clinical study in healthy volunteers (n = 32) showed that mixing of Apidra with NPH human insulin immediately before injection did not affect the time to peak and that the total bioavailability was similar. There was some attenuation in peak concentration.
Mixtures should not be administered intravenously.
No data are available on mixing Apidra with insulin preparations other than NPH. (See Clinical Trials.) Apidra should not be mixed with insulin preparations other than NPH.

Adverse Effects

The adverse events observed are those known in this pharmacological class and consequently common to insulins. Hypoglycaemia, the most frequent undesirable effect of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.
Medication errors have been reported in which other insulins have been accidentally administered instead of insulin glulisine.
Overall, clinical studies comparing Apidra with rapid acting insulins in adults or children and adolescents did not demonstrate a difference in frequency of adverse events. (See Table 5).
The following related adverse reactions from clinical investigations were listed below by system organ class and in order of decreasing incidence (very common: > 1/10; common > 1/100, < 1/10; uncommon: > 1/1,000, < 1/100; rare: > 1/10,000, < 1/1,000; very rare: < 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Metabolism and nutrition disorders.

Very common: hypoglycaemia.
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. Hypoglycaemia can become severe and may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Skin and subcutaneous tissue disorders.

Common: injection site reactions and local hypersensitivity reactions.
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.
Rare: lipodystrophy.
Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.

General disorders.

Uncommon: systemic hypersensitivity reactions.
Systemic hypersensitivity reactions may include urticaria, chest tightness, dyspnoea, allergic dermatitis and pruritus. Severe cases of generalised allergy, including anaphylactic reaction, may be life threatening.

Dosage and Administration

Apidra is a recombinant human insulin analogue that has been shown to be equipotent to human insulin. After subcutaneous administration it has a more rapid onset and a shorter duration of action than regular human insulin.
Apidra is for single patient use only.
Apidra should be given by injection within 15 minutes before or immediately after a meal.
The dosage of Apidra should be individualised and determined based on the doctor's advice in accordance with the needs of the patient. Apidra should normally be used in regimens that include a longer acting insulin or basal insulin analogue.
Apidra should be administered by subcutaneous injection in the abdominal wall, the thigh or deltoid. As with all insulins, injection sites within an injection area (abdomen, thigh, deltoid) should be rotated from one injection to the next.
As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by injection site, exercise and other variables. Blood glucose monitoring is recommended for all patients with diabetes.

Mixing of insulins for subcutaneous injection.

Apidra can be mixed with NPH human insulin. If Apidra is mixed with NPH human insulin, Apidra should be drawn into the syringe first. Injection should be made immediately after mixing. Mixtures should not be administered intravenously.

Preparation and handling.

Unopened vials, cartridges and prefilled pens.

Unopened vials, cartridges and prefilled pens (such as Apidra SoloStar) should be stored in a refrigerator where the temperature is between +2°C and +8°C. Do not freeze. Discard if frozen. Keep in the outer carton in order to protect from light. Do not store next to the freezer compartment or freezer packs.
Before first use, Apidra must be kept at room temperature for 1 to 2 hours.
Apidra must only be used if the solution is clear, colourless, with no solid particles visible and if it is of water-like consistency.

Open (in use) or unrefrigerated vials, cartridges and prefilled pens.

Apidra vials, cartridges or prefilled pens, whether or not refrigerated, must be discarded after 28 days from first use.
Unrefrigerated vials, cartridges or prefilled pens, whether in use or not, must be discarded after 28 days. This applies irrespective of whether the vial, cartridge or prefilled pen is used immediately or is first carried as a spare for a while.
An empty vial, cartridge or prefilled pen must never be reused and must be properly discarded.

Vials.

Before withdrawing Apidra from the vial for the first time, remove the plastic protective cap. Do not shake the vial vigorously as this may cause frothing. Froth may interfere with the correct measurement of dose.
Once in use, vials of Apidra should be stored away from direct light between 2 and 8°C. Do not freeze. Discard if frozen. If refrigeration is not possible, the vial of Apidra in use may be kept unrefrigerated for up to 28 days, as long as the temperature is not greater than 25°C and it is kept away from direct heat and light. Whether or not it is refrigerated, the vial that is in use must be used within a 28 day period. Any unused contents must be discarded 28 days after opening.

Cartridges and prefilled pens.

Apidra cartridges are not designed to allow any other insulin to be mixed in the cartridge.
Once in use, prefilled pens (such as Apidra SoloStar) or a reusable injection pen containing a cartridge of Apidra must not be stored in the refrigerator. Apidra that is in use in injection pens may be kept unrefrigerated for up to 28 days, as long as the temperature is not greater than 25°C and it is kept away from direct heat and light. It must be used within a 28 day period or must be discarded 28 days after commencement of use.
Manufacturer instructions for using Apidra in reusable or prefilled disposable injection devices must be followed carefully for loading the cartridge into a reusable pen, and for attaching the needle, performing the safety test and administering the insulin injection. If the injection device is damaged, it should be discarded and a new injection device should be used.
If the reusable injection device malfunctions (see instructions for using the pen), or no pen is available, Apidra may be withdrawn from the cartridge into a U100 syringe and injected subcutaneously. The syringe must not contain any other medicinal product or residue.

Overdosage

Symptoms.

Hypoglycaemia may occur as a result of an excess of insulin relative to food intake energy expenditure or both.

Management.

Mild/ moderate episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns or exercise may be needed.
More severe episodes with coma, seizure or neurologic impairment may be treated with intramuscular/ subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

Presentation

Solution for injection, 100 units/mL (U100) (sterile, clear, colourless): 3 mL cartridge with reusable injection device; 3 mL cartridge in SoloStar prefilled disposable injection device; 10 mL vial: 5's.

Storage

Unopened vials, cartridges and prefilled pens (such as Apidra SoloStar) should be stored in a refrigerator where the temperature is between +2°C and +8°C. Do not freeze. Discard if frozen. Keep in the outer carton in order to protect from light. Do not store next to the freezer compartment or freezer packs.

Poison Schedule

S4.