Consumer medicine information

Levemir FlexPen

Insulin, detemir (rys)

BRAND INFORMATION

Brand name

Levemir

Active ingredient

Insulin, detemir (rys)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Levemir FlexPen.

What is in this leaflet

What Levemir® is used for

Before you use Levemir® FlexPen®

How to use Levemir® FlexPen®

While you are using Levemir® FlexPen®

Side effects

After using Levemir® FlexPen®

Product description

Further information

Instructions For Use

This leaflet answers some common questions about Levemir® FlexPen®. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Levemir® FlexPen® 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 Levemir® is used for

The insulin detemir (rys), or “Levemir®”, in Levemir® FlexPen® is a long-acting insulin used to treat diabetes mellitus. It may be used in combination with oral antidiabetic medicines (diabetes tablets) or as add-on therapy to liraglutide (Victoza®), which is used to treat type 2 diabetes mellitus in adults. Levemir® can also be used with a meal-related short- or rapid-acting insulin such as NovoRapid®.

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.

Levemir® lowers your blood sugar level after injection. The effect may last for up to 24 hours.

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

FlexPen® is a pre-filled dial-a-dose insulin pen able to deliver from 1 to 60 units of Levemir® in increments of 1 unit.

This medicine is not addictive.

Levemir® FlexPen® is available only with a doctor’s prescription.

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

Before you use Levemir® FlexPen®

When you must not use it

Do not use this medicine if:

  1. you have an allergy to:
  • any medicine containing insulin
  • any of the ingredients listed in the ‘Ingredients’ section of this leaflet.
Some of the symptoms of an allergic reaction may include:
  • redness, swelling, rash and itching at the injection site
  • rash, itching or hives on the skin
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body.
  1. you are experiencing low blood sugar levels (a “hypo”) when your dose is due.
If you have a lot of hypos discuss appropriate treatment with your doctor.

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

Do not use this medicine after the expiry date printed on the pack, or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to use it

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

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

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

Tell your doctor if you are pregnant or plan 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 plan to breast-feed. Your doctor can discuss with you the risks and benefits involved.

Inform your doctor as soon as possible if you experience signs of heart failure such as unusual shortness of breath or rapid increase in weight or localised swelling (oedema). Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who are treated with thiazolidinediones in combination with insulin may develop heart failure.

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

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

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

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

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

  • glucocorticoids (except when applied locally) - used to treat inflammatory conditions
  • oral contraceptives (“the pill”) - used for birth control
  • diuretics e.g. 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
  • growth hormone - used to treat growth disorders.
  • danazol - used to treat endometriosis, menorrhagia, fibrocystic breast disease and hereditary angioedema
  • oxymetholone - used to treat certain blood disorders
  • 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.

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

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

Tell your doctor about any other medicines that you are taking. This is very important. Your doctor will advise you if it is 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 Levemir® FlexPen®

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

Levemir® is either injected once or twice daily. If you require twice daily dosing, the evening dose can be administered either with the evening meal, at bedtime, or 12 hours after the morning dose. Your doctor will tell you when to inject your medicine.

How to use it

  • Inject Levemir® under the skin (subcutaneous injection) as shown to you by your doctor or diabetes education nurse. Never inject Levemir® directly into a vein or muscle.
  • Levemir® may be injected into your abdomen, thigh, buttock or upper arm.
  • Remember to change your injection site regularly as shown to you by your doctor or diabetes education nurse.
  • Do not use Levemir® in insulin pumps.

Checking your Levemir® FlexPen®:

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

Levemir® is a clear colourless solution. Do not use this medicine if it is thickened, coloured, or has solid bits in it.

Read the instructions printed later in this leaflet carefully in order to prepare and handle your Levemir® FlexPen® correctly.

How long to use it

Do not stop using Levemir® FlexPen® 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:

  • use too much insulin
  • miss a meal
  • exercise more than usual
  • are ill.

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

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

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

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

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

If you lose consciousness, make sure they know:

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

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

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

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

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

See your doctor if you keep having hypo reactions, or if you have ever become unconscious after using insulin. The amount or timing of insulin, food or exercise may need to be adjusted.

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

If you miss a dose – Hyperglycaemia

If you forget your insulin dose, check your blood sugar level and test your urine for ketones 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, dry mouth
  • 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 Levemir® FlexPen®

Things you must do

Measure your blood sugar level regularly.

Make sure all friends, relatives, workmates and carers know that you have diabetes and are using insulin. If your child has diabetes it is important to tell their carers.

Keep using your insulin even if you feel well. It helps to control your condition, but does not cure it.

Tell your doctor if you often have hypos (low blood sugar levels). Your doctor may need to adjust your insulin dose.

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

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 Levemir® FlexPen® unless your doctor tells you to.

Do not use this medicine if you think it has been frozen or exposed to excessive heat. It will not work as well.

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.

Do not share needles.

Things to be careful of

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

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

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

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

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

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

Tell your doctor if your diet changes. Insulin is essential to keep your blood sugar levels within acceptable limits. Regular meals and a balanced diet are important factors in the management of diabetes. It is important that you discuss a suitable diet plan with your doctor or diabetes team.

Smoking may increase the chance of complications with your diabetes.

Side effects

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

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

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

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

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

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

  • hypos (mild to moderate)
  • pain, redness, swelling, hives, inflammation, bruising 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 Levemir® and use another insulin.
  • a depression or thickening of the skin around the injection site (lipodystrophy). The fatty tissue under the skin at the injection site may shrink (lipoatrophy) or thicken (lipohypertrophy). Changing the site with each injection reduces the risk of developing such skin changes. If you notice your skin pitting or thickening at the injection site, tell your doctor or nurse. These reactions can become more severe, or they may change the absorption of your insulin, if you inject in such a site.
  • 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 Levemir® FlexPen®

Storage

Before opening:

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

During use or when carried as a spare:

Store Levemir® FlexPen® that you are using, or that you are carrying as a spare up to 4 weeks below 30°C or between 2°C and 8°C in a refrigerator.

Discard Levemir® FlexPen® after 4 weeks even if there is still some medicine left in it.

The Levemir® in Levemir® FlexPen® must not be frozen, or exposed to excessive heat or light. Protect the medicine in Levemir® FlexPen® from light by keeping the pen cap on when not in use.

Do not use Levemir® after the expiry date which is stated on the FlexPen® label and carton after ‘Expiry’.

Never use Levemir® FlexPen® if the solution is not clear and colourless.

Keep out of the reach of children.

Disposal

Dispose of used needles safely into a 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

Levemir® is a clear, colourless, aqueous solution for subcutaneous injection. Levemir® FlexPen® is a 3mL pre-filled glass cartridge contained in a dial-a-dose insulin pen.

Ingredients

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

Levemir® also contains the following inactive ingredients:

  • glycerol
  • phenol
  • metacresol
  • zinc acetate
  • sodium chloride
  • dibasic sodium phosphate dihydrate
  • sodium hydroxide
  • hydrochloric acid
  • water for injections.

Sponsor

Levemir® FlexPen® is supplied in Australia by:

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

Levemir® FlexPen® is supplied in New Zealand by:

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

This leaflet was prepared on: 17 June 2019.

Australian Registration Number: AUST R 172234

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

© 2019

Novo Nordisk A/S

Further information

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

www.novonordisk.com.au
www.novonordisk.co.nz

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

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

Instructions for Use

Introduction

Please read the following instructions carefully before using your FlexPen®. If you do not follow the instructions carefully, you may get too little or too much insulin, which can lead to too high or too low blood sugar levels.

Your FlexPen® is a pre-filled dial-a-dose insulin pen. You can select doses from 1 to 60 units in increments of 1 unit. FlexPen® is designed to be used with NovoFine® disposable needles up to a length of 8mm.

As a precautionary measure, always carry a spare insulin delivery device in case your FlexPen® in use is lost or damaged.

Caring for your pen

Your FlexPen® must be handled with care. If it is dropped, damaged or crushed, there is a risk of insulin leakage. This may cause inaccurate dosing, which can lead to too high or too low blood sugar levels.

You can clean the exterior of your FlexPen® by wiping it with an alcohol swab. Do not soak it, wash or lubricate it as it may damage the pen.

Do not refill your FlexPen®.

Preparing your Levemir® FlexPen®

Check the name and coloured label of your pen to make sure that it contains the correct type of insulin. This is especially important if you take more than one type of insulin. If you take the wrong type of insulin, your blood sugar level may get too high or too low.

A

Pull off the pen cap.

B

Remove the paper tab from a new disposable needle.

Screw the needle straight and tightly onto your FlexPen®.

C

Pull off the big outer needle cap and keep it for later.

D

Pull off the inner needle cap and dispose of it.

Never try to put the inner needle cap back on the needle. You may stick yourself with the needle.

! Always use a new needle for each injection. This reduces the risk of contamination, infection, leakage of insulin, blocked needles and inaccurate dosing.
! Be careful not to bend or damage the needle before use.

Checking the insulin flow

Prior to each injection, small amounts of air may collect in the cartridge during normal use. To avoid injection of air and ensure proper dosing:

E

Turn the dose selector to select 2 units.

F

Hold your FlexPen® with the needle pointing upwards and tap the cartridge gently with your finger a few times to make any air bubbles collect at the top of the cartridge.

G

Keeping the needle upwards, press the push-button all the way in. The dose selector returns to 0.

A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times.

If a drop of insulin still does not appear, the pen is defective, and you must use a new one.

! Always make sure that a drop appears at the needle tip before you inject. This makes sure that the insulin flows. If no drop appears, you will not inject any insulin, even though the dose selector may move. This may indicate a blocked or damaged needle.
! Always check the flow before you inject. If you do not check the flow, you may get too little insulin or no insulin at all. This may lead to too high blood sugar levels.

Selecting your dose

Check that the dose selector is set at 0.

H

Turn the dose selector to select the number of units you need to inject.

The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer. When turning the dose selector, be careful not to push the push-button as insulin will come out.

You cannot select a dose larger than the number of units left in the cartridge.

! Always use the dose selector and the pointer to see how many units you have selected before injecting the insulin.
! Do not count the pen clicks. If you select and inject the wrong dose, your blood sugar levels may get too high or too low. Do not use the residual scale, it only shows approximately how much insulin is left in your pen.

Making the injection

Insert the needle into your skin. Use the injection technique shown by your doctor or nurse.

I

Inject the dose by pressing the push-button all the way in until 0 lines up with the pointer. Be careful only to push the push-button when injecting.

Turning the dose selector will not inject insulin.

J

Keep the push-button fully depressed and let the needle remain under the skin for at least 6 seconds. This will make sure you get the full dose.

Withdraw the needle from the skin then release the pressure on the push-button.

Always make sure that the dose selector returns to 0 after the injection. If the dose selector stops before it returns to 0, the full dose has not been delivered, which may result in too high blood sugar levels.

K

Lead the needle into the big outer needle cap without touching it. When the needle is covered, carefully push the big outer needle cap completely on and then unscrew the needle.

Dispose of it carefully and put the pen cap back on.

! Always remove the needle after each injection and store your FlexPen® without the needle attached. This reduces the risk of contamination, infection, leakage of insulin, blocked needles and inaccurate dosing.

Further important information

! Caregivers must be very careful when handling used needles – to reduce the risk of needle sticks and cross-infection.
! Dispose of your used FlexPen® carefully, without the needle attached.
! Never share your pen or your needles with other people. It might lead to cross-infection.
! Never share your pen with other people. Your medicine might be harmful to their health.
! Always keep your pen and needles out of sight and reach of others, especially children.

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Levemir

Active ingredient

Insulin, detemir (rys)

Schedule

S4

 

1 Name of Medicine

Insulin detemir.

6.7 Physicochemical Properties

Insulin detemir (rys) has the empirical formula C267H402N64O76S6 and a molecular weight of 5916.9.

Chemical structure.


CAS number.

CAS no. 169148-63-4.

2 Qualitative and Quantitative Composition

Levemir is a soluble, basal insulin analogue with a prolonged duration of effect. Insulin detemir (rys) is produced by recombinant DNA technology using Saccharomyces cerevisiae.
One unit of insulin detemir contains 0.142 mg salt-free anhydrous insulin detemir. One unit (U) of insulin detemir corresponds nominally to one IU (international unit) of human insulin.
Levemir also contains the following inactive ingredients: glycerol, phenol, metacresol, zinc acetate, dibasic sodium phosphate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.

3 Pharmaceutical Form

Levemir is a clear, colourless, neutral solution of insulin detemir 100 U/mL. Levemir is a solution for injection.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Levemir is a soluble, basal insulin analogue with a prolonged duration of effect (Figure 1).
The duration of action is up to 24 hours depending on dose, providing an opportunity for once daily administration. Levemir can also be administered twice daily - when administered twice daily, steady state serum concentrations are reached after 2 to 3 dose administrations. For doses of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its total pharmacodynamic effect within the approximate period of 3-14 hours after dose administration.
Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after subcutaneous administration.
The time action profile of Levemir was significantly less variable than NPH (Neutral Protamine Hagedorn) insulin and insulin glargine in a study that enrolled 54 (N=18 per arm) subjects with type 1 diabetes (Table 4).
Lower day-to-day variability in fasting plasma glucose (FPG), a secondary endpoint, was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials in type 1 diabetes, including one in children and adolescents aged 6 to 17 years. The clinical benefit of this has not been demonstrated. Reduced variability in FPG for Levemir versus NPH was not able to be demonstrated consistently in subjects with type 2 diabetes.
Studies in patients with type 2 diabetes treated with basal insulin in combination with oral antidiabetic drugs (OADs) demonstrated that glycaemic control (HbA1c) with Levemir is equivalent to NPH and to insulin glargine. Treatment with Levemir was associated with less weight gain (Table 5), however the trials were not specifically designed to test for this outcome and the clinical benefit has not been demonstrated. In the study versus insulin glargine, Levemir was administered once or twice daily based on patients' needs, whereas insulin glargine was administered once a day.
In a trial investigating add-on insulin detemir with liraglutide and metformin (see Section 5.1 Pharmacodynamic Properties, Clinical trials), weight reduction of 3.5 kg was observed during the initial 12 week run-in period on liraglutide and metformin alone. Adding insulin detemir did not result in any further clinically significant loss of weight but the initial loss was sustained.
In clinical trials in adults using basal bolus insulin therapy, the overall rates of hypoglycaemia with Levemir and NPH insulin were similar. Analyses of nocturnal hypoglycaemia in patients with type 1 diabetes showed a significantly lower risk of minor nocturnal hypoglycaemia (able to self-treat and confirmed by capillary blood glucose less than 2.8 mmol/L or 3.1 mmol/L if expressed as plasma glucose) than with NPH insulin, whereas no difference was seen in type 2 diabetes. Furthermore, the overall risk of nocturnal hypoglycaemia in children and adolescents aged 2 to 17 years with type 1 diabetes was significantly lower with Levemir compared to NPH insulin. In trials with the use of OAD insulin combination therapy in adults with type 2 diabetes, Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH.
The prolonged action of Levemir is thought to be mediated by the strong self-association of insulin detemir molecules at the injection site, and binding to plasma proteins, most likely albumin, via the fatty acyl side-chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to isophane insulin.
The blood glucose lowering effect of Levemir is due to the facilitated uptake of glucose following binding of insulin detemir to receptors on muscle and fat cells and to decreased glucose output from the liver. In vitro testing of insulin detemir's binding to the insulin and IGF-1 receptors has shown that Levemir has reduced affinity to both receptors. The clinical correlates of this have not been established. The molar dose of insulin detemir is approximately fourfold higher compared with human insulin. One unit of Levemir is approximately equipotent to one international unit of human insulin. See Section 5.1 Pharmacodynamic Properties, Clinical trials for dose data observed in randomised clinical trials in types 1 and 2 diabetes.

Clinical trials.

The confirmatory therapeutic clinical development programme to evaluate the efficacy and safety of Levemir consisted of 15 phase 3, randomised, parallel-group (versus isophane insulin and/or insulin glargine), open-label, multicentre clinical trials. The trial programme randomised a total of 1945 adult patients with type 1 diabetes and a total of 2433 adult patients with type 2 diabetes. Ten of the studies employed the marketed formulation, and the remaining five employed a less concentrated (but nevertheless bioequivalent) ‘early-development’ formulation. In addition, the efficacy and safety of Levemir were demonstrated in two studies in children and adolescents with type 1 diabetes. One of these studies, of 6 months' duration, investigated children aged 6 to 17 years (N=347). The second of these studies, of 12 months' duration (N=347) plus an extension phase to 24 months (N=146), investigated children and adolescents aged from 2 to 17 years. The efficacy component of the clinical trials were designed primarily to test non-inferiority to the comparator, not equivalence.
In intermediate and long-term treatment trials intended to demonstrate the non-inferiority of the marketed formulation of Levemir to human insulin, the primary outcome was HbA1c. Secondary outcomes included FPG levels, multi-point blood glucose profiles, within-subject variation for fasting blood/plasma glucose (FBG or FPG), hypoglycaemia, quality of life, antibody levels, daily doses and safety profiles as measured by adverse events, laboratory safety parameters, physical examination, weight and vital signs. Levemir provides equivalent glycaemic control as measured by HbA1c and better glycaemic control as measured by FPG, although not at some other times as determined by 9 point blood glucose profiles, compared to human isophane insulin treatment in type 1 diabetes. Intensive therapy with Levemir is also associated with lower day to day FBG variation in type 1 diabetes, and equivalent safety profiles except for weight. Reduced variability in FPG for Levemir versus human isophane insulin was not able to be demonstrated consistently in subjects with type 2 diabetes.
Levemir is not associated with weight gain over 4-6 months in type 1 diabetes, however the trials were not designed to test for this outcome and the clinical benefit of this has not been demonstrated.

Clinical studies in type 1 diabetes.

In three large randomised, controlled clinical studies, adult patients with type 1 diabetes (1335 study, N=749; 1447 study, N=400; 1448 study, N=409) were randomised to basal/bolus treatment with once- or twice-daily Levemir (marketed formulation insulin detemir) or with NPH insulin once- or twice-daily, for 4 to 6 months. The bolus (mealtime) treatment was soluble human insulin (1335 study) or insulin aspart (1447 and 1448 studies). In these studies, Levemir and NPH had a similar effect on the primary outcome of HbA1c (Table 6). In the secondary outcomes, Levemir demonstrated significantly improved FPG (Table 6) and within-subject variation (1335 study p < 0.001, 1447 study p < 0.001; 1448 study p < 0.001), with similar overall rates of hypoglycaemia and safety profiles including adverse events, laboratory safety parameters, physical examination, and vital signs, compared with NPH insulin. In a 9 point blood glucose profile (1335 study), the overall profiles were significantly different between Levemir and NPH insulin (p=0.006), with blood glucose concentrations being lower from before breakfast and throughout the day until after bedtime, in the Levemir group. In 10 point blood glucose profiles (1447 and 1448 studies), the overall profiles were similar during the day but tended to differ at night, with lower night-time blood glucose concentrations in some of the Levemir groups. In the 1335 study, antibody formation was increased with Levemir but did not compromise glycaemic control.
Two additional multicentre, open-label, randomised, confirmatory clinical trials were conducted in adult subjects with type 1 diabetes to assess HbA1c response during treatment for up to 6 months. Twice daily Levemir (early-development formulation insulin detemir) or NPH insulin were compared when combined with bolus insulin aspart (1205 study; N=448) or with bolus soluble human insulin (1181 study; N=461). At the end of 6 months of treatment, the primary outcomes of mean HbA1c values were equivalent for Levemir and NPH in both studies. In the 1205 study, the secondary outcomes which were statistically different between treatment groups included lower within-subject variation in FBG with Levemir compared with NPH insulin (p < 0.001), lower relative risk (0.78) of hypoglycaemia with Levemir compared with NPH insulin [95% CI: 0.62, 0.97], and a significant difference in the 9 point blood glucose profile, with blood glucose concentrations lower before breakfast and higher from lunch through 02:00 hours in the Levemir group compared with the NPH insulin group (p=0.036). The mean doses of both basal and bolus insulins were higher after 6 months in the Levemir group compared with the NPH group.
Both 1205 and 1181 clinical trials were extended for an additional 6 months (as trial IDs 1316 and 1243 respectively) to assess maintenance of Levemir efficacy up to a period of 1 year of treatment. At the end of extension trials 1316 and 1243, HbA1c values for Levemir treatment were equivalent to those of the NPH parallel treatment group.

Clinical studies in children and adolescents with type 1 diabetes.

Study 1379 was a multicentre, open-label, randomised, confirmatory clinical trial conducted in subjects (N=347) with type 1 diabetes aged between 6 and 17 years. After 26 weeks of treatment with Levemir or NPH, both given once or twice daily in combination with bolus insulin aspart, the primary endpoint (HbA1c) for Levemir was non-inferior to NPH (Table 7). Other secondary outcomes measured included within-subject variability in FPG, 8-point PG profiles, nocturnal PG, overall safety profiles as measured by adverse events and laboratory measures including weight (in terms of change in body mass index (BMI)) and vital signs, rates of overall and (pre-defined) sub-categories of hypoglycaemia, incidences of diabetic ketoacidosis requiring hospitalisation, and antibody formation. The secondary outcomes which were statistically different between treatment groups included lower within-subject variation in FPG with Levemir compared with NPH insulin (p < 0.001), lesser increase in BMI with Levemir (p < 0.001), and lower overall risk of nocturnal hypoglycaemia with Levemir (p=0.011) compared to NPH insulin, although hypoglycaemic episodes in general occurred with similar frequencies in both groups (see Section 4.8 Adverse Effects (Undesirable Effects)). The study had no subgroup analysis by once daily/twice daily Levemir. Levels of Levemir-specific and cross-reacting antibodies increased in the Levemir but not the NPH insulin group, and the levels of Levemir-specific antibodies correlated with dose per kg body weight. Doses of basal and bolus insulins were equivalent in both treatment groups.
Study 1689 was a 12-month, multinational, multi-centre, open-labelled, randomised, parallel, efficacy and safety clinical trial comparing Levemir and NPH Insulin in 348 children and adolescents 2-16 years with type 1 diabetes on a basal-bolus regimen with insulin aspart as bolus insulin. Glycaemic control (HbA1c) with Levemir was similar to NPH insulin when given as basal-bolus therapy. A lower risk of 24h and nocturnal hypoglycaemia and a lower rate (number of events/1000 exposure years) of severe adverse events were observed with Levemir than with NPH. Furthermore, less weight gain was observed with Levemir than with NPH insulin. The change in mean weight at 52 weeks from baseline in the Levemir group was 3.2 kg and 4.1 kg in the NPH group. No severe nocturnal hypoglycaemic episodes were reported with Levemir in this trial.
Study 1689 was extended for an additional 12 months (total of 24 months' treatment data; extension designated as ‘study 1690’) to assess antibody formation after long-term treatment with Levemir. After an increase in the levels of insulin antibodies during the first year, the levels decreased during the second year to those slightly higher than observed pre-trial. There was slight increase in HbA1c during the extension period for all the age groups: mean% (SD) 0.10% (0.77) for the 2 to 5 year age group, 0.27% (1.08) for the 6 to 12 year, 0.11% (1.60) for the 13 to 16 year and 0.17% (1.22) for the overall population. Of the total population, 15 (10.3%) patients were within the target range for pre-prandial PG of ≥ 4 to ≤ 7 mmol/L.

Clinical studies in type 2 diabetes.

Combination therapy with oral antidiabetic drugs (OADs) (studies 1337, 1373, 1530, 1632).

Four phase 3, multicentre, open, randomised studies of Levemir versus NPH and/or insulin glargine, all in combination with one or more OADs, have been conducted in patients with type 2 diabetes inadequately controlled on OADs (or, in the case of study 1337, inadequately controlled on basal monotherapy). The studies (N=2029 total) were conducted with durations between 20 weeks and 1 year, and in all studies the primary efficacy measure was HbA1c and secondary endpoints included FPG, multi-point blood glucose profiles, within-subject variability, hypoglycaemia, weight and safety profiles.
In study 1337 (N=467), the earliest of the aforementioned combination with OAD studies, Levemir was inferior to NPH insulin for HbA1c (mean difference (Levemir-NPH) [95% CI] was 0.56 [0.33, 0.78]). In the studies performed subsequently (N=1562 total), Levemir was non-inferior to the NPH/insulin glargine comparator for HbA1c (Table 8). Secondary endpoints were similar between Levemir and comparators with the exception of weight (see Section 5.1 Pharmacodynamic Properties).
In study 1373, a comparison with insulin glargine, the results of the primary efficacy endpoint was for the ITT group 0.045 (-0.114 to 0.205), indicating that the predefined non-inferiority criteria were met. In the ITT group, the mean (SE) HbA1c at end of treatment was 7.16 (0.078) for the Levemir group and 7.12 (0.078) for the glargine group. For the once daily Levemir group, the difference was 0.061 (-0.142 to 0.263) and for the twice daily group, 0.003 (-0.189 to 0.195). There was no significant difference in fasting plasma glucose at 52 weeks. The ratio of final daily dose (U/kg Levemir/glargine) was 1.16 for the once daily Levemir group and 2.26 for the twice daily group, and 1.77 overall.
In study 1632, there was less risk of nocturnal hypoglycaemia with morning Levemir than evening Levemir.

Add-on therapy to liraglutide plus OADs (studies 1842, 1842 ext.).

An open-label randomised study in patients with type 2 diabetes not reaching target with OADs was conducted. The trial started with a 12 week run-in period with liraglutide+metformin, where 61% reached an HbA1c < 7%. The 39% of patients not achieving target were randomised to have Levemir once-daily added or continue on liraglutide + metformin for 52 weeks. Addition of Levemir provided a further reduction of HbA1c from 7.6% to 7.1% after 52 weeks, no major hypoglycaemic episodes were reported with Levemir (see Table 9). Adding Levemir did not result in any further clinically significant loss of weight but the initial loss obtained with liraglutide + metformin dual therapy during the run-in period was maintained.

Basal/bolus therapy (study 1336).

Study 1336 (N=505) was a 6 month, phase 3, multicentre, open, randomised, parallel study of Levemir (marketed formulation insulin detemir) and NPH in patients with type 2 diabetes treated with a basal/bolus regimen. Insulin aspart was employed as the bolus insulin. The primary endpoint was HbA1c, and after 6 months the reduction in HbA1c was non-inferior for Levemir versus NPH (mean difference (Levemir-NPH) [95% CI] was 0.157 [0.003, 0.312]). Secondary endpoints such as FPG, 9 point blood glucose profiles, hypoglycaemia (total and nocturnal), quality of life and most of the safety profiles were all similar between the two treatment groups. The within-subject variation in FBG (p=0.021) was significantly lower for Levemir compared with NPH insulin. At end of study, the mean basal insulin doses were 36.4 units per day for Levemir, and 35.3 IU per day for NPH, and the mean bolus insulin doses were 40.2 U and 35.8 U per day respectively.
Results of other ongoing studies supporting the basal/bolus use of Levemir in patients with type 2 diabetes mellitus are not yet available.

Basal monotherapy (study 1166).

Study 1166 (N 439) was a 6 month, phase 3 basal monotherapy study of twice-daily Levemir (early development formulation insulin detemir) versus NPH, in patients aged 35 years or more with type 2 diabetes receiving ≤ 120 IU total insulin per day. The primary endpoint was HbA1c, and after 6 months Levemir was inferior to NPH insulin (mean difference (Levemir-NPH) [95% CI] was 0.660 [0.436, 0.885]). Secondary endpoints included FPG, 9 point blood glucose profiles, within-subject variability, hypoglycaemia and weight control. FPG and 9 point blood glucose profiles were inferior with Levemir compared with NPH. Within-subject variability and hypoglycaemia were similar between the two treatment arms. Withdrawals due to lack of efficacy were seen in 10.7% of Levemir subjects versus 0.7% of NPH subjects.

Clinical studies in pregnancy.

In a randomised controlled clinical trial (study 1687), pregnant women with type 1 diabetes (N=310) were treated in a basal-bolus regimen where Levemir (N=152) was compared to NPH insulin (N=158), with insulin aspart as meal time insulin. Levemir was shown to be non-inferior to NPH insulin measured by HbA1c at gestational week 36 (treatment difference in the full analysis set, -0.06% [95% CI -0.21 to 0.08]). The changes in mean HbA1c through pregnancy were similar for subjects in the Levemir and NPH insulin groups. The target of HbA1c ≤ 6.0% at both gestational week 24 and 36 was reached by 41% of the subjects in the Levemir group and by 32% in the NPH insulin group. At gestational weeks 24 and 36, mean FPG was statistically significantly lower in the Levemir group than in the NPH insulin group. The estimated treatment difference was -0.94 mmol/L (95% CI: [-1.67 ; 0.21], p=0.012) at 24 gestational weeks and -0.65 mmol/L (95% CI: [-1.19 ; -0.12], P=0.017) at 36 gestational weeks.
The rate of hypoglycaemic episodes during pregnancy was similar between the Levemir and NPH groups. The overall frequencies of maternal adverse events during pregnancy were similar for Levemir and NPH insulin treatment groups; however, a numerically higher frequency of serious adverse events during pregnancy in the mothers (61 (40%) vs. 49 (31%)) and in the offspring during pregnancy and after birth (36 (24%) vs. 32 (20%)) was seen for Levemir compared to NPH insulin. The number of live born children of women becoming pregnant after randomisation were 50 (83%) for Levemir and 55 (89%) for NPH insulin. The frequency of children with congenital malformations was 4 (5%) in the Levemir group and 11 (7%) in the NPH insulin group. Thereof, 3 (4%) children in the Levemir group and 3 (2%) children in the NPH insulin group had major malformations (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

5.2 Pharmacokinetic Properties

Absorption.

Maximum serum concentration is reached 6 to 8 hours after administration. When administered twice daily, steady state serum concentrations are reached after 2 to 3 dose administrations. Intra-subject variation in absorption is lower for Levemir in type 1 diabetes than for other basal insulin preparations.

Distribution.

An apparent volume of distribution for Levemir (approximately 0.1 L/kg) indicates that a high fraction of insulin detemir is circulating in the blood.
The results of the in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between Levemir and fatty acids or other protein bound drugs.

Metabolism.

Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are likely to be inactive.

Excretion.

The terminal half-life after subcutaneous administration is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life is between 5 and 7 hours depending on dose.

Linearity.

Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after subcutaneous administration in the therapeutic dose range.
No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and Levemir when administering a single dose of Levemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.

Special populations.

Elderly, renal and hepatic impairment.

There was no clinically relevant difference in pharmacokinetics of Levemir between elderly and young subjects, or between subjects with renal or hepatic impairment and healthy subjects.

Gender.

There was no clinically relevant difference between genders in pharmacokinetic parameters of Levemir.

Paediatric use.

The pharmacokinetic properties of Levemir were investigated in children (6-12 years) and adolescents (13-17 years) with type 1 diabetes, and compared to adults with type 1 diabetes. A total of 16 males and 18 females were studied. No difference in pharmacokinetics was observed between the three age groups.

5.3 Preclinical Safety Data

Genotoxicity.

Insulin detemir was not genotoxic in assays for reverse gene mutation in bacterial or chromosomal damage in cultured human lymphocytes. An in vivo micronucleus test in mice was also negative.

Carcinogenicity.

The carcinogenic potential of insulin detemir has not been investigated in long-term animal studies.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of diabetes mellitus. (See Section 5 Pharmacological Properties; Section 5.1 Pharmacodynamic Properties, Clinical trials.)

4.3 Contraindications

Hypersensitivity to insulin detemir or any of the excipients.

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. Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).
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).
Patients whose blood glucose control is greatly improved, for example 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.
Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements. Concomitant diseases in the kidney, liver or affecting the adrenal, pituitary or thyroid gland can require changes in the insulin dose.

Administration.

Levemir is for subcutaneous administration only. Intramuscular administration should be avoided. Levemir is not to be administered intravenously as it may result in severe hypoglycaemia.
Levemir is not to be used in insulin infusion pumps.

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 Levemir and other insulin products.

Injection site reactions.

As with any insulin therapy, injection site reactions may occur and include pain, itching, redness, hives, bruising, swelling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Levemir.
Levemir contains metacresol, which may cause allergic reactions.

Transfer of patients between insulin types.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (human insulin, insulin analogue) and/or method of manufacture may result in the need for a change in dosage. Patients transferred to Levemir from another type of insulin may require a change in dosage from that used with their usual insulin products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Travelling with insulin.

Before travelling between different time zones, the patient should seek the doctor's advice since this means that the patient has to take the insulin and meals at different times.

Combination of thiazolidinediones and insulin.

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

Incompatibilities.

Substances added to Levemir may cause degradation of insulin detemir, for example if the medicinal product contains thiols or sulphites. Levemir should not be added to infusion fluids.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

See Section 5.2 Pharmacokinetic Properties.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A number of medicinal products are known to interact with glucose metabolism. Possible interactions must therefore be taken into account by the physician.
The following substances may reduce the patient's insulin requirements.
Oral antidiabetic drugs (OADs), GLP-1 receptor agonists, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, 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, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol.
Insulin detemir is greater than 97% protein-bound in plasma, independent of gender. The results of in vitro studies do not suggest any clinically relevant albumin binding interactions between insulin detemir and fatty acids or other protein-bounds drugs (such as warfarin, frusemide, tolbutamide, diazepam, glibenclamide, nicardipine, repaglinide, aspirin or valproic acid) or other drugs known to bind to domains IIA and IIIA of the albumin molecule. As there is a vast excess (about 400 000) of albumin binding sites available in plasma per insulin detemir molecule, there would be little risk that lower albumin concentrations resulting from some disease states like nephrotic syndrome might affect the ratio of bound to free insulin detemir or that acute displacement could occur. This is supported by in vitro studies as well as subgroup analyses from the clinical trial programme. Nevertheless, there are limited data in patients with severe hypoalbuminaemia.
Beta blockers may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Octreotide and lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify and prolong, or reduce, the hypoglycaemic effect of insulin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on male or female fertility were apparent in a study in rats dosed at levels up to 50 U/kg/day s.c.
(Category A)
Treatment with Levemir can be considered during pregnancy, if the benefit justifies possible risks.
In a randomised controlled clinical trial (study 1687), pregnant women with type 1 diabetes were treated in a basal-bolus regimen where Levemir (N=152) was compared to NPH insulin (N=158), with insulin aspart as meal time insulin. A total of 470 women were randomised to two parallel treatment groups (233 and 237 subjects in Levemir and NPH groups, respectively). The Full Analysis Set consisted of 152 women in the Levemir group (79 pregnant (gestational age 8-12 weeks) at randomisation; 73 became pregnant post randomisation) and 158 women in the NPH group (83 pregnant (gestational age 8-12 weeks) at randomisation; 75 became pregnant post randomisation). Levemir was shown to be noninferior to NPH insulin measured by HbA1c at gestational week 36.
There was no statistically significant difference between Levemir and NPH insulin treatment groups in the rate of hypoglycaemic episodes during pregnancy. The overall frequencies of maternal adverse events during pregnancy were similar for Levemir and NPH insulin treatment groups; however, a numerically higher frequency of serious adverse events during pregnancy in the mothers (61 (40%) vs. 49 (31%)) and in the offspring during pregnancy and after birth (36 (24%) vs. 32 (20%)) was seen for Levemir compared to NPH insulin. The number of live born children of women becoming pregnant after randomisation were 50 (83%) for Levemir and 55 (89%) for NPH insulin. The frequency of children with congenital malformations was 4 (5%) in the Levemir group and 11 (7%) in the NPH insulin group. Thereof, 3 (4%) children in the Levemir group and 3 (2%) children in the NPH insulin group had major malformations. Pre-eclampsia is a syndrome defined by symptoms of hypertension and proteinuria. Pre-eclampsia was reported at an incidence of 10.5% with Levemir compared to 7% in NPH group.
The clinical trial results showed similar efficacy of Levemir and NPH insulin (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in pregnancy).
Post-marketing data (approximately 300 outcomes from pregnant women exposed to Levemir) indicate no adverse effect of Levemir on pregnancy and no malformative or feto/neonatal toxicity of insulin detemir.
Animal reproduction studies showed increases in post-implantation loss and fetal anomalies in rats following treatment with insulin detemir at doses of 25-50 U/kg/day s.c. A teratology study in rabbits revealed increased in utero deaths and post-implantation losses following dosing with 37.5 U/kg/day s.c. Lower doses were not tested. Similar effects have also been reported for human insulin and other human insulin analogues. These effects are probably secondary to maternal hypoglycaemia.
In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
There is currently no clinical experience with insulin detemir during lactation. Lactating women may require adjustments in insulin dose and diet.

4.8 Adverse Effects (Undesirable Effects)

a. Summary of the safety profile.

Adverse drug reactions observed in patients using Levemir are mainly dose-dependent and due to the pharmacologic effect of insulin. The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.
Injection site reactions are seen more frequently during treatment with Levemir than with human insulin. These reactions include pain, redness, hives, inflammation, bruising, swelling and itching at the injection site. Most of the injection site reactions are minor and of a transitory nature, i.e. they normally disappear during continued treatment in a few days to a few weeks.
At the beginning of the insulin treatment, refraction anomalies and oedema may occur; these reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

b. Tabulated list of adverse events and adverse reactions.

See Table 2.
Adverse reactions listed in Table 3 are based on clinical trial data and classified according to MedDRA frequency and system organ class. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

c. Description of selected adverse reactions.

Allergic reactions, potentially allergic reactions, urticaria, rash and eruptions.

Allergic reactions, potentially allergic reactions, urticaria, rash and eruptions are uncommon when Levemir is used in basal-bolus regimen. In three clinical studies with subjects treated in combination with OADs a higher frequency (2.2%) of allergic reactions and potentially allergic reactions has been observed compared with the frequency observed across all studies (0.1-1.0%; see below).

Anaphylactic reactions.

The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.

Hypoglycaemia.

The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.

Lipodystrophy.

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

Antibody development.

Antibody development has been observed with the use of Levemir in adults and children, however no discernible impact on glycaemic control dose has been noted. In a 12 month clinical trial in children and adolescents aged 6-17 years with type 1 diabetes (1689 study), rises in insulin detemir specific and cross-reacting antibodies were observed in the Levemir but not the NPH comparator groups. In the 1690 extension study to 24 months, insulin antibody levels decreased during the second year to those slightly higher than pre-trial levels (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

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.

4.2 Dose and Method of Administration

Dosage.

Levemir is a long-acting insulin analogue used alone as a basal insulin or in combination with bolus insulin. It can also be used in combination with oral antidiabetic drugs (OADs) or as add-on therapy to liraglutide.
For patients with type 1 diabetes mellitus, Levemir must be used in combination with rapid- or short-acting insulin.
When Levemir is used as part of a basal-bolus insulin regimen Levemir should be administered once or twice daily depending on patients' needs. Dosage of Levemir should be adjusted individually. For patients who require twice daily dosing to optimise blood glucose control, the evening dose can be administered either with the evening meal, at bedtime, or 12 hours after the morning dose.
In combination with OADs or as add on therapy to liraglutide in type 2 diabetes it is recommended to initiate Levemir treatment with once daily administration at a dose of 10 U or 0.1-0.2 U/kg. The dose of Levemir should be titrated based on individual patients' needs. Based on study results, the following titration guideline is recommended (Table 1).
In combination with OADs in type 2 diabetes, where optimisation of blood glucose control is not achieved with once daily injection, consideration should be given to adding a mealtime bolus injection of short-/rapid-acting insulin, or to transferring the patient to a pre-mixed insulin.
As with all insulins, adjustment of dosage may also be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Special populations.

Elderly, renal and hepatic impairment.

As with all insulins, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin detemir dosage adjusted on an individual basis.

Paediatric use.

Specific nonclinical studies in juvenile animals have not been conducted.
The efficacy and safety of Levemir were demonstrated in adolescents and children aged 2 years' and above in studies up to 24 months in duration (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
As with all insulins, in children and adolescents, glucose monitoring should be intensified and the Levemir dose adjusted on an individual basis.

Pregnancy.

In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.

Hypoalbuminaemia.

There are limited data in patients with severe hypoalbuminaemia. Careful monitoring is recommended in these patients.

Transfer from other insulins.

Transfer to Levemir from intermediate or long-acting insulins may require adjustment of dose and timing of administration (see Section 4.4 Special Warnings and Precautions for Use). As with all insulins, close glucose monitoring is recommended during the transition and in the initial weeks thereafter.
Concomitant antidiabetic treatment may need to be adjusted (dose and/or timing of concurrent short/rapid-acting insulins or OADs). An increase in soluble insulin requirements has been demonstrated in some individuals who have been transferred from human insulin to Levemir.

Method of administration.

Levemir is for subcutaneous administration only by injection in the thigh, abdominal wall, the upper arm, or the gluteal region. As with human insulin, the rate and extent of absorption of insulin detemir may be higher when administered subcutaneously in the abdomen or upper arm as opposed to the thigh. Injection sites should be rotated within the same region in order to reduce the risk of lipodystrophy. Formal studies with administration in the gluteal region have not been conducted. As with all insulin products, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Instructions for use and handling.

Levemir FlexPen and Levemir Penfill are for use by one person only. Levemir must not be used if it has been frozen. Levemir must not be used if the solution does not appear clear and colourless.

Levemir FlexPen.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling. Please note that insulin is not delivered if the patient reverse dials the insulin pen by returning the dose selector to zero after inserting the needle. Patients should be instructed that insulin injection only occurs when the pushbutton is depressed.
The cartridge inside Levemir FlexPen must not be refilled. NovoFine needles up to a length of 8 mm are designed to be used with Levemir FlexPen. The patient should be advised to discard the needle after each injection.

Levemir Penfill.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling. The leaflet refers to the instructions for using the accompanying Novo Nordisk insulin delivery system (durable device for repeated use).
Levemir Penfill cartridges must not be refilled. Levemir Penfill cartridges are designed to be used with Novo Nordisk insulin delivery systems and NovoFine disposable needles. The patient should be advised to discard the needle after each injection.

4.7 Effects on Ability to Drive and Use Machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (for example, driving a car or operating machinery). Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or who have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

4.9 Overdose

A specific overdose for insulin cannot be defined, however hypoglycaemia may develop over sequential stages if doses are administered which are too high relative to the patient's requirements.
Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the person with diabetes always carry products containing sugar with them. Adjustments in drug dosage or meal patterns may be needed.
Severe hypoglycaemic episodes, where the patient is not able to treat themselves, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by a medical professional. Glucose must be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes. After apparent clinical recovery from hypoglycaemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycaemia.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

If Levemir is mixed with other insulin preparations the profile of action of one or both individual components may change. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections.

6.3 Shelf Life

Before opening.

30 months.

During use or when carried as a spare.

The product can be stored for a maximum of 4 weeks.

6.4 Special Precautions for Storage

Before opening.

Levemir products should be stored in a refrigerator between 2°C and 8°C. Keep away from the cooling element. Do not freeze.

During use or when carried as a spare.

Levemir FlexPen: Store below 30°C or in a refrigerator (2°C-8°C) for up to 4 weeks. Do not freeze.
Levemir Penfill: Store below 30°C for up to 4 weeks. Do not refrigerate. Do not freeze. Keep the cartridges in the outer carton in order to protect from light.
After 4 weeks, any remaining insulin must be discarded. Levemir products should not be exposed to excessive heat or light.

6.5 Nature and Contents of Container

Levemir contains insulin detemir 100 U/mL. The following presentations are registered. Not all presentations may be marketed.

Levemir FlexPen.

Levemir FlexPen is a pre-filled, multidose, disposable syringe consisting of a pen injector and a 3mL cartridge. The cartridge is made of glass, contains a bromobutyl rubber piston and is closed with a latex-free bromobutyl/polyisoprene rubber disc. The pen injector is made of plastic (polypropylene, POM). Five Levemir FlexPen are packed in a carton.

Levemir Penfill.

Levemir Penfill is a 3mL cartridge made of glass, containing a bromobutyl rubber piston and closed with a latex-free bromobutyl/polyisoprene rubber disc. Five Levemir Penfill cartridges are packed in a carton.

6.6 Special Precautions for Disposal

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

Summary Table of Changes