Consumer medicine information

Ryzodeg 70/30 FlexTouch 3mL

Insulin degludec; Insulin aspart

BRAND INFORMATION

Brand name

Ryzodeg 70/30

Active ingredient

Insulin degludec; Insulin aspart

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ryzodeg 70/30 FlexTouch 3mL.

What is in this leaflet

This leaflet answers some common questions about Ryzodeg® 70/30 FlexTouch®. It does not contain all the available information. It does not take the place of talking to your doctor, diabetes education nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Ryzodeg® 70/30 FlexTouch® 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 Ryzodeg® 70/30 is used for

Ryzodeg® 70/30 is used to treat diabetes mellitus in patients aged 6 years and older. It helps your body reduce your blood sugar level.

Ryzodeg® 70/30 contains two types of insulin:

  • Basal insulin called insulin degludec – this has a long blood sugar lowering effect.
  • Rapid acting insulin called insulin aspart – this lowers your blood sugar soon after you inject it.

Ryzodeg® 70/30 is a modified insulin, also called an insulin analogue, which is similar to the insulin produced by the pancreas.

Diabetes mellitus is a condition in which 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.

type 2 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.

Ryzodeg® 70/30 may be used in combination with other antidiabetic drugs (for example, diabetes tablets) or with a meal-related short- or rapid-acting insulin, such as NovoRapid®.

Ryzodeg® 70/30 can either be used once or twice each day. Ryzodeg® 70/30 can be used once- or twice-daily with the main meal(s). When needed, you can change the time of dosing as long as Ryzodeg® 70/30 is dosed with the main meal(s). The effect may last for more than 24 hours.

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

FlexTouch® is a pre-filled dial-a-dose insulin pen able to deliver from 1 to 80 units in steps of 1 unit.

This medicine is not addictive.

Ryzodeg® 70/30 FlexTouch® is available only with a doctor’s prescription.

Ask your doctor if you have any questions about why Ryzodeg® 70/30 has been prescribed for you.

Ryzodeg® 70/30 can be used in adolescents and children from the age of 6 years. Ryzodeg® 70/30 should be used with special caution in children and adolescents. The risk for very low blood sugar levels may be higher in children and adolescents. There is no experience with the use of Ryzodeg® 70/30 in children below the age of 2 years.

Before you use Ryzodeg® 70/30 FlexTouch®

When you must not use it

Do not use Ryzodeg® 70/30 if:

  1. you have an allergy to:
  • any medicine containing insulin
  • any of the ingredients listed in the ‘Ingredients’ section 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.
  1. you are experiencing a low blood sugar level (a ‘hypo’) when the dose is due.
If you have a lot of hypos discuss appropriate treatment with your doctor.
  1. the product does not appear clear and colourless, or if the pen is damaged or has not been stored correctly.

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
  • heart disease or stroke.

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if Ryzodeg® 70/30 affects the baby in pregnancy. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. 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. Avoiding too low blood sugar (hypoglycaemia) is particularly important for the health of your baby. 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/pharmacist can discuss with you the risks and benefits involved.

Tell your doctor if you notice any skin changes at the injection site. The injection site should be rotated to help prevent changes to the fatty tissue under the skin, such as skin thickening, skin shrinking or lumps under the skin. The insulin may not work very well if you inject into a lumpy, shrunken or thickened area (see How to use Ryzodeg® 70/30 FlexTouch®). Tell your doctor if you are currently injecting into these affected areas before you start injecting in a different area. Your doctor may tell you to check your blood sugar more closely, and to adjust your insulin or your other antidiabetic medications dose.

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 Ryzodeg® 70/30 may interfere with each other.

Your blood sugar level may fall (hypoglycaemia), if you take:

  • other medicines for diabetes (oral and injectable)
  • sulphonamides - used to treat bacterial infections
  • anabolic steroids - used to promote growth
  • non-selective beta blockers -used to treat high blood pressure and certain heart conditions
  • salicylates e.g. aspirin - used to relieve pain and lower fever
  • 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
  • ACE inhibitors - used to treat high blood pressure, certain heart conditions or elevated protein/albumin in the urine
  • quinine - used to treat malaria and relieve muscle cramps
  • quinidine - used to treat heart problems.

Your blood sugar level may rise (hyperglycaemia), if you take:

  • danazol - used to treat endometriosis, menorrhagia, fibrocystic breast disease and hereditary angioedema
  • 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 - adrenaline and medicines used to treat asthma, such as salbutamol or terbutaline
  • growth hormone - used to treat growth disorders
  • 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.

Your blood sugar level may either fall or rise if you take:

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

Beta-blockers may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.

Thiazolidinediones - some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who were treated with thiazolidinediones in combination with insulin developed heart failure. Inform your doctor immediately if you experience signs of heart failure such as shortness of breath, rapid weight gain or localised swelling.

Tell your doctor about any other medicines that you are taking. This is very important. Your doctor will advise you if it is all right to keep taking them or if you should stop taking them.

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

How to use Ryzodeg® 70/30 FlexTouch®

Your doctor, diabetes education nurse or pharmacist will have shown you how to use your medicine. Carefully follow all the directions. They may differ from the information contained in this leaflet.

If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use the pen without help. Get help from a person with good eyesight who is trained to use the FlexTouch® pen.

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 decide with you:

  • how much Ryzodeg® 70/30 you will need each day and at which meal(s)
  • when to check your blood sugar level and if you need a higher or lower dose.

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

Based on your blood sugar level your doctor may change your dose.

When using other medicines, ask your doctor if your treatment needs to be adjusted.

When to use it

  • Always follow your doctor’s recommendation for dose
  • Ryzodeg® 70/30 can either be used once or twice each day
  • Use with the main meal(s) - you can change the time of dosing as long as Ryzodeg® 70/30 is dosed with the main meal(s)
  • If you want to change your usual diet, check with your doctor, pharmacist or nurse first as a change in diet may alter your need for insulin.

How to use it

  • Inject Ryzodeg® 70/30 under the skin (subcutaneous injection) as shown to you by your doctor or diabetes education nurse. Never inject Ryzodeg® 70/30 into a vein or muscle.
  • Ryzodeg® 70/30 may be injected into the abdomen, thigh or upper arm.
  • Remember to change your injection site regularly as shown to you by your doctor or diabetes education nurse.
  • Always use a new needle for each injection to prevent contamination. Needles must not be shared.
  • Ensure the correct length of needle is selected for use in children.
  • As a precautionary measure, always carry a spare FlexTouch® in case your in-use FlexTouch® is lost or damaged.
  • Do not use Ryzodeg® 70/30 in insulin infusion pumps.

Checking your Ryzodeg® 70/30 FlexTouch® pen

Check your Ryzodeg® 70/30 FlexTouch® pen before each preparation and injection. Check the name and strength on the label of the pen to make sure it is Ryzodeg® 70/30 FlexTouch® 100 U/mL.

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

Read the instructions printed at the end of this leaflet carefully in order to prepare and handle your Ryzodeg® 70/30 FlexTouch® correctly.

Always check your insulin injection device for insulin flow (priming) before each injection. The priming procedure may highlight a malfunction with your insulin injection device. Priming also removes any air bubbles and helps indicate whether or not a needle is broken.

Injecting a dose

Choose a site for injection.

Inject Ryzodeg® 70/30 under the skin (subcutaneous injection) as shown by your doctor or diabetes education nurse. Never inject Ryzodeg® 70/30 into a vein or muscle.

Ryzodeg® 70/30 may be injected into the abdomen, thigh or upper arm.

Change the injection site so that the same position is not used more often than once a month. This will reduce the chance of local skin reactions developing.

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

Keep the needle under the skin for at least 6 seconds. Keep the dose button fully depressed until the needle has been withdrawn from the skin.

Apply gentle pressure over the injection site for several seconds. Do not rub the area.

After injecting

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

Always dispose of the needle after each injection. This reduces the risk of contamination, infection, leakage of insulin, blocked needles and inaccurate dosing.

Healthcare professionals, relatives and other carers should follow general precautionary measures for removal and disposal of needles, to eliminate the risk of needlestick injury. Do not share needles, cartridges and pens.

How long to use it

Do not stop using Ryzodeg® 70/30 FlexTouch® unless your doctor tells you to.

If you take too much (overdose) – Hypoglycaemia

If you use too much insulin, your blood sugar level may get too low (hypoglycaemia).

Immediately telephone your doctor or the Poisons Information Centre (telephone in Australia: 13 11 26; in New Zealand: 0800 764 766) for advice if you think that you or anyone else may have used too much Ryzodeg® 70/30. Do this even if there are no signs of discomfort or poisoning.

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

  • accidentally use too much of this medicine
  • have too much or unexpected exercise
  • delay eating meals or snacks
  • eat too little or miss a meal
  • are ill
  • drink alcohol.

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:

  • Eat glucose tablets or another high sugar snack, like sweets, biscuits or fruit juice (always carry glucose tablets or a high sugar snack, just in case).
  • Measure your blood sugar level if possible and rest. You may need to measure your blood sugar level more than once, as with all basal insulin products improvement from the period of low blood sugar levels may be delayed.
  • Wait until the signs of too low blood sugar levels have gone or when your blood sugar level has settled. Then carry on with your insulin as usual.

Tell your relatives, friends, close workmates, teachers 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, teacher 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. This is because the dosing or timing of your insulin injections, food or exercise may need to be changed. If a severe hypo is not treated, it can cause brain damage and death.

If you miss a dose – Hyperglycaemia

If you forget your insulin dose, test 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 you forget a dose, inject the missed dose with your next large meal on that day, 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
  • drink alcohol.

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

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

Symptoms of mild to moderate hyperglycaemia include:

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

Symptoms of severe hyperglycaemia include:

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

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

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

While you are using Ryzodeg® 70/30 FlexTouch®

Things you must do

Measure your blood sugar level regularly.

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

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

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

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

Tell your doctor if you have trouble recognising the symptoms of hypos. Under certain conditions, the early warning signs of hypos can be different or less obvious. Your doctor may need to adjust your insulin dose.

Make sure that you tell every doctor, dentist, pharmacist or other healthcare 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 your doctor 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.

Tell your doctor if you are having trouble with your eyesight. Visual disturbances in uncontrolled diabetes are reversed during the early stages of treatment. Once established on insulin, if your vision changes, see your doctor as soon as possible.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Ryzodeg® 70/30 FlexTouch®.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not stop using your medicine unless your doctor tells you to. If you stop using your insulin this could lead to a very high blood sugar level and ketoacidosis (a condition with too much acid in the blood).

If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen without help. Get help from a person with good eyesight who is trained to use the FlexTouch® pen.

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

Do not refill your Ryzodeg® 70/30 FlexTouch®.

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.

Having too low or too high blood sugar levels can affect your ability to drive or use any tools or machines. If your blood sugar level is too low or too high your ability to concentrate and react might be affected. This could be dangerous to yourself or others. Ask your doctor whether you can drive if:

  • you often get too low blood sugar levels
  • you find it hard to recognise too low blood sugar levels.

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

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

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

Tell your doctor if your diet changes. Changes in diet may cause your insulin needs to change.

Side effects

Tell your doctor, diabetes education nurse or pharmacist as soon as possible if you do not feel well while you are using Ryzodeg® 70/30 FlexTouch®.

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

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

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

  • hypos (mild to moderate).
  • pain, redness, hives, swelling or itching at the injection site (local allergy). Usually these symptoms disappear within a few weeks during continued use. If you have serious or continuing reactions, you may need to stop using Ryzodeg® 70/30 and use another insulin.
  • 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.

Tell your relatives, friends, close workmates, teachers or carers that you have diabetes.

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
  • signs of heart failure, such as unusual shortness of breath or rapid increase in weight or localised swelling (oedema).

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.

Skin changes at the injection site
If you inject insulin at the same place, the fatty tissue may either shrink (lipoatrophy) or thicken (lipohypertrophy). Lumps under the skin may also be caused by build-up of a protein called amyloid (cutaneous amyloidosis). The insulin may not work very well if you inject into a lumpy, shrunken or thickened area. Change the injection site with each injection to help prevent these skin changes.

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

After using Ryzodeg® 70/30 FlexTouch®

Storage

Before first use:

Store Ryzodeg® 70/30 FlexTouch® 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).

After first opening or if carried as a spare:

When Ryzodeg® 70/30 FlexTouch® is being used or carried as a spare, you can keep it at room temperature (not above 30°C) or in a refrigerator (2°C to 8°C) for up to 28 days.

Discard your Ryzodeg® 70/30 FlexTouch® after 28 days even if there is still some medicine left in it.

Ryzodeg® 70/30 must not be frozen, or exposed to excessive heat and light. Protect the medicine in Ryzodeg® 70/30 FlexTouch® from light by keeping the cap on when not in use.

Never use Ryzodeg® 70/30 FlexTouch® after the expiry date printed on the label and carton. The expiry date refers to the last day of that month.

Never use Ryzodeg® 70/30 FlexTouch® if the insulin does not appear 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

Ryzodeg® 70/30 is a clear colourless solution for subcutaneous injection.

Ryzodeg® 70/30 FlexTouch® is a 3mL pre-filled glass cartridge contained in a dial-a-dose insulin pen.

Ingredients

Ryzodeg® 70/30 contains soluble insulin degludec and insulin aspart 100 units per mL (100 U/mL) as the active ingredient, in the ratio of 70:30.

Ryzodeg® 70/30 also contains the following inactive ingredients:

  • glycerol
  • phenol (as preservative)
  • metacresol (as preservative)
  • zinc acetate
  • sodium chloride
  • sodium hydroxide
  • hydrochloric acid
  • water for injections.

Sponsor

Ryzodeg® 70/30 FlexTouch® is supplied in Australia by:

Novo Nordisk Pharmaceuticals Pty. Ltd.
Level 10
118 Mount Street
North Sydney NSW 2060
Australia

Ryzodeg® 70/30 FlexTouch® is supplied in New Zealand by:

Novo Nordisk Pharmaceuticals Ltd.
11-19 Customs Street West
Commercial Bay Tower, Level 18
Office 1834
Auckland 1010
New Zealand.

Ryzodeg®, FlexTouch®, NovoRapid® and NovoFine® are registered trademarks of Novo Nordisk A/S.

Australian Registration Number: AUST R 280432

This leaflet was prepared in April 2023.

Further information

For further information call the Novo Nordisk 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

© 2023
Novo Nordisk A/S

Ryzodeg® 70/30 FlexTouch® 3 mL Instructions For Use

Instructions on how to use Ryzodeg® 70/30 100 U/mL solution for injection in pre-filled pen (FlexTouch®)

Please read these instructions carefully before using your FlexTouch® pre-filled pen. 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.

Do not use the pen without proper training from your doctor or diabetes education nurse.

Start by checking your pen to make sure that it contains Ryzodeg® 70/30 100 U/mL, then look at the illustrations below to get to know the different parts of your pen and needle.

  • If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen without help. Get help from a person with good eyesight who is trained to use the FlexTouch® pre-filled pen.

Your pen is a pre-filled dial-a-dose insulin pen containing 300 units of insulin. You can select a maximum of 80 units per dose, in steps of 1 unit. Your pen is designed to be used with NovoFine® single-use disposable needles up to a length of 8 mm. Needles are not included in the pack.

  • Important information
    Pay special attention to these notes as they are important for correct use of the pen.

1 Prepare your pen

  • Check the name and strength on the label of your pen, to make sure that it contains Ryzodeg® 70/30 100 U/mL. This is especially important if you take more than one type of insulin. If you take a wrong type of insulin, your blood sugar level may get too high or too low.
  • Pull off the pen cap.

  • Check that the insulin in your pen is clear and colourless.
    Look through the insulin window. If the insulin looks cloudy, do not use the pen.

  • Take a new needle and tear off the paper tab.
    Ensure the correct length of needle is selected for use in children.

  • Push the needle straight onto the pen. Turn until it is on tight.

  • Pull off the outer needle cap and keep it for later. You will need it after the injection, to correctly remove the needle from the pen.

  • Pull off the inner needle cap and throw it away. If you try to put it back on, you may accidentally stick yourself with the needle.

A drop of insulin may appear at the needle tip. This is normal, but you must still check the insulin flow.

  • Always use a new needle for each injection.
    This reduces the risk of contamination, infection, leakage of insulin, blocked needles and inaccurate dosing.
  • Never use a bent or damaged needle.

2 Check the insulin flow

Always check the insulin flow before you start. This helps you to ensure that you get your full insulin dose.

  • Turn the dose selector to select 2 units. Make sure the dose counter shows 2.

  • Hold the pen with the needle pointing up.
    Tap the top of the pen gently a few times to let any air bubbles rise to the top.

  • Press and hold in the dose button until the dose counter returns to 0.
    The 0 must line up with the dose pointer.
    A drop of insulin should appear at the needle tip.

A small air bubble may remain at the needle tip, but it will not be injected.

If no drop appears, repeat steps 2A to 2C up to 6 times. If there is still no drop, change the needle and repeat steps 2A to 2C once more.

If a drop of insulin still does not appear, dispose of the pen and 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 counter 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.

3 Select your dose

  • Make sure the dose counter shows 0 before you start.
    The 0 must line up with the dose pointer.
  • Turn the dose selector to select the dose you need, as directed by your doctor or diabetes education nurse.

If you select a wrong dose, you can turn the dose selector forwards or backwards to the correct dose.

The pen can dial up to a maximum of 80 units.

The dose selector changes the number of units. Only the dose counter and dose pointer will show how many units you select per dose.

You can select up to 80 units per dose. When your pen contains less than 80 units, the dose counter stops at the number of units left.

The dose selector clicks differently when turned forwards, backwards or past the number of units left. Do not count the pen clicks.

  • Always use the dose counter and the dose 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 level may get too high or too low.
    Do not use the insulin scale, it only shows approximately how much insulin is left in your pen.

4 Inject your dose

  • Insert the needle into your skin as your doctor or diabetes education nurse has shown you.
  • Make sure you can see the dose counter.
    Do not touch the dose counter with your fingers. This could interrupt the injection.
  • Press and hold down the dose button until the dose counter returns to 0.
    The 0 must line up with the dose pointer.
    You may then hear or feel a click.
  • Leave the needle under the skin for at least 6 seconds to make sure you get your full dose.

  • Pull the needle and pen straight up from your skin.
    If blood appears at the injection site, press lightly with a cotton swab. Do not rub the area.

You may see a drop of insulin at the needle tip after injecting. This is normal and does not affect your dose.

  • Always watch the dose counter to know how many units you inject. The dose counter will show the exact number of units. Do not count the pen clicks. Hold the dose button down until the dose counter returns to 0 after the injection. If the dose counter stops before it returns to 0, the full dose has not been delivered, which may result in too high blood sugar levels.

5 After your injection

  • Lead the needle tip into the outer needle cap on a flat surface without touching the needle or the outer cap.

  • Once the needle is covered, carefully push the outer needle cap completely on.
  • Unscrew the needle and dispose of it carefully.

  • Put the pen cap on your pen after each use to protect the insulin from light.

Always dispose of the needle after each injection. This reduces the risk of contamination, infection, leakage of insulin, blocked needles and inaccurate dosing. If the needle is blocked, you will not inject any insulin.

When the pen is empty, throw it away without a needle on as instructed by your doctor, diabetes education nurse, pharmacist or local authorities.

  • Never try to put the inner needle cap back on the needle. You may stick yourself with the needle.
  • Always remove the needle after each injection and store your pen without a needle attached. This may prevent blocked needles, contamination, infection, leakage of insulin, blocked needles and inaccurate dosing.

6 How much insulin is left?

  • The insulin scale shows you approximately how much insulin is left in your pen.

  • To see precisely how much insulin is left, use the dose counter:
    Turn the dose selector until the dose counter stops.
    If it shows 80, at least 80 units are left in your pen.
    If it shows less than 80, the number shown is the number of units left in your pen.

  • Turn the dose selector back until the dose counter shows 0.
  • If you need more insulin than the units left in your pen, you can split your dose between two pens.
    - Be very careful to calculate correctly if splitting your dose. If in doubt, take the full dose with a new pen. If you split the dose incorrectly, you will inject too little or too much insulin, which can lead to too high or too low blood sugar levels.
    - Further important information
  • Always keep your pen with you.
  • Always carry an extra pen and new needles with you, in case of loss or damage.
  • Always keep your pen and needles out of sight and reach of others, especially children.
  • 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.
  • Caregivers must be very careful when handling used needles – to reduce the risk of needle injury and cross-infection.

Caring for your pen

Treat your pen with care. Rough handling or misuse may cause inaccurate dosing, which can lead to too high or too low blood sugar levels.

  • Do not leave the pen in a car or other place where it can get too hot or too cold.
  • Do not expose your pen to dust, dirt or liquid.
  • Do not wash, soak or lubricate your pen. If necessary, clean it with mild detergent on a moistened cloth.
  • Do not drop your pen or knock it against hard surfaces.
    If you drop it or suspect a problem, attach a new needle and check the insulin flow before you inject.
  • Do not try to refill your pen. Once empty, it must be disposed of.
  • Do not try to repair your pen or pull it apart.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Ryzodeg 70/30

Active ingredient

Insulin degludec; Insulin aspart

Schedule

S4

 

1 Name of Medicine

Insulin degludec (rys) and insulin aspart (rys).

2 Qualitative and Quantitative Composition

Ryzodeg 70/30 is a soluble insulin product consisting of insulin degludec (ultra-long acting basal insulin) and insulin aspart (rapid acting mealtime insulin) administered in one injection.
1 mL of the solution contains 100 U insulin degludec/insulin aspart (70% soluble insulin degludec and 30% soluble insulin aspart) equivalent to 2.56 mg salt-free anhydrous insulin degludec and 1.05 mg salt-free anhydrous insulin aspart. One pre-filled pen or cartridge contains 3 mL, equivalent to 300 U of insulin degludec/insulin aspart.
Insulin degludec and insulin apart are produced by recombinant DNA technology in Saccharomyces cerevisiae.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ryzodeg 70/30 is a solution for injection.
Ryzodeg 70/30 is a ready-to-use, clear, colourless, neutral solution in pre-filled pen or cartridge. Ryzodeg 70/30 has a pH of approximately 7.4.

4 Clinical Particulars

4.1 Therapeutic Indications

For use in diabetes mellitus in patients aged 6 years and older.

4.2 Dose and Method of Administration

Dosage.

Ryzodeg 70/30 is a soluble insulin product consisting of the ultra-long acting basal insulin degludec and the rapid acting prandial insulin aspart in a ratio of 70:30.
Ryzodeg 70/30 can be administered once- or twice-daily with the main meal(s). However, if advised by a healthcare professional, when needed, the patient can change the time of administration as long as Ryzodeg 70/30 is dosed with the main meal when taken once daily.
The potency of insulin analogues, including Ryzodeg 70/30 is expressed in units (U). 1 unit (U) of Ryzodeg 70/30 corresponds to 1 international unit (IU) of human insulin and one unit of most other insulin analogues.
In patients with type 2 diabetes mellitus, Ryzodeg 70/30 can be administered alone, in combination with oral antidiabetic products approved for use with insulin, and in combination with bolus insulin.
In type 1 diabetes mellitus, Ryzodeg 70/30 is combined with short-/rapid-acting insulin at the remaining meals.
Ryzodeg 70/30 is to be dosed in accordance with individual patients' needs. Pre-meal plasma glucose levels should be used to evaluate the adequacy of the preceding dose.

Initiation.

Adults with type 2 diabetes.

The recommended total daily starting dose of Ryzodeg 70/30 is 10 units with meal(s) followed by individual dosage adjustments.

Patients with type 1 diabetes.

The recommended starting dose of Ryzodeg 70/30 is 60-70% of the total daily insulin requirements.
Ryzodeg 70/30 is to be used once daily at mealtime in combination with short-/rapid-acting insulin at the remaining meals followed by individual dosage adjustments.

Transfer from other insulin medicinal products.

As with all insulin products, close glucose monitoring is recommended during transfer and in the following weeks. Doses and timing of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetic treatment may need to be adjusted.

Patients with type 2 diabetes.

Patients switching from once daily basal or premix insulin therapy can be converted unit-to-unit to once daily Ryzodeg 70/30 at the same total insulin dose as the patient's previous total daily insulin dose, or twice daily Ryzodeg 70/30 using half the total daily dose twice daily.
Patients switching from more than once daily basal or premix insulin therapy can be converted unit-to-unit to once daily or twice-daily Ryzodeg 70/30 at the same total insulin dose as the patient's previous total daily insulin dose.
Patients switching from basal-bolus insulin therapy to Ryzodeg 70/30 will need to convert their dose based on individual needs. In general, patients are initiated on the same number of basal units.

Patients with type 1 diabetes.

The recommended starting dose of Ryzodeg 70/30 is 60-70% of the total daily insulin requirements in combination with short-/rapid-acting insulin at the remaining meals followed by individual dosage adjustments.

Flexibility in dosing time.

Ryzodeg 70/30 allows for some flexibility in the timing of insulin administration as long as it is dosed with the main meal(s).
Patients should not take an extra dose to make up for a missed dose. If a dose of Ryzodeg 70/30 is missed, the patient can take the missed dose with the next main meal of that day and thereafter resume the usual dosing schedule.

Avoidance of accidental mix-ups.

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Ryzodeg 70/30 and other insulin products.

Special populations.

Elderly (≥ 65 years old).

Ryzodeg 70/30 can be used in elderly patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Renal impairment.

Ryzodeg 70/30 can be used in renal impaired patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Hepatic impairment.

Ryzodeg 70/30 can be used in hepatic impaired patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Paediatric population.

Ryzodeg 70/30 can be used in children and adolescents from the age of 6 years (see Section 5.1, Clinical trials). When changing from another insulin regimen to Ryzodeg 70/30, dose reduction of total insulin needs to be considered on an individual basis in order to minimise the risk of hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use).
Ryzodeg 70/30 should be used with special caution in paediatric patients because data from the clinical trial indicate that there may be a higher risk for severe hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1, Clinical trials).

Method of administration.

Ryzodeg 70/30 combines the ultra-long acting basal insulin degludec and the rapid acting prandial insulin aspart in one injection.
Ryzodeg 70/30 is for subcutaneous administration only. Ryzodeg 70/30 must not be administered intravenously as it may result in severe hypoglycaemia. Ryzodeg 70/30 must not be administered intramuscularly as it may change the absorption. Ryzodeg 70/30 must not be used in insulin infusion pumps.
Ryzodeg 70/30 is administered subcutaneously by injection in the abdominal wall, the upper arm or the thigh. Injection sites are always to be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Ryzodeg 70/30 FlexTouch is a pre-filled pen designed to be used with NovoFine disposable needles. FlexTouch delivers 1-80 units in increments of 1 unit.
Ryzodeg 70/30 Penfill is designed to be used with Novo Nordisk insulin delivery systems and NovoFine disposable needles.

Dosage adjustment.

As with all insulin products adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Instructions for use and handling.

Ryzodeg 70/30 FlexTouch.

The pre-filled pen is designed to be used with NovoFine disposable needles. FlexTouch delivers 1-80 units in increments of 1 unit. The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling.

Ryzodeg 70/30 Penfill.

The cartridge is designed to be used with Novo Nordisk delivery systems, such as NovoPen (durable devices for repeated use) and NovoFine disposable needles. 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 delivery system.
Ryzodeg 70/30 FlexTouch and Ryzodeg 70/30 Penfill is for use by one person only. The cartridge must not be refilled.
Ryzodeg 70/30 must not be used if the solution does not appear clear and colourless. Ryzodeg 70/30 which has been frozen must not be used.
The patient should discard the needle after each injection.

4.3 Contraindications

Hypersensitivity to insulin degludec, insulin aspart or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Hypoglycaemia.

Ryzodeg 70/30 must be taken with a carbohydrate containing meal. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.
Dose reductions and increased frequency of glucose monitoring may be required when Ryzodeg 70/30 is co-administered with insulin secretagogues or GLP-1 agonists as they may potentiate the risk of hypoglycaemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement.
In children, extra care should be taken to match insulin doses with food intake and physical activities in order to minimise the risk of hypoglycaemia.
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 must be advised accordingly. Usual warning symptoms may disappear in patients with long-standing diabetes mellitus.
Concomitant illness, especially infections and fever, usually increases the patient's insulin requirement. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes in the insulin dose.
As with other basal insulin products or insulin products with a basal component, the prolonged effect of Ryzodeg 70/30 may delay recovery from hypoglycaemia.

Hyperglycaemia.

Administration of rapid-acting insulin is recommended in situations with severe hyperglycaemia.
Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead to hyperglycaemia and potentially to diabetic ketoacidosis. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased insulin requirement.
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, and loss of appetite as well as acetone odour of breath. In type 1 diabetes mellitus, untreated hyperglycaemic events may lead to diabetic ketoacidosis, which is potentially lethal.

Insulin antibodies.

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia.

Eye disorder.

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.

Weight gain.

Weight gain can occur with any insulin therapy, including Ryzodeg 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Administration.

Ryzodeg 70/30 is for subcutaneous administration only. Ryzodeg 70/30 must not be administered intravenously as it may result in severe hypoglycaemia. Ryzodeg 70/30 must not be administered intramuscularly as it may change the absorption. Ryzodeg 70/30 must not be used in insulin infusion pumps.

Skin and subcutaneous tissue disorders.

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

Transfer of patients between insulin types.

Transferring a patient to another type, brand or manufacturer of insulin must be done under medical supervision and may result in the need for a change in dosage.

Use in hepatic impairment.

Ryzodeg 70/30 can be used in hepatic impaired patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Use in renal impairment.

Ryzodeg 70/30 can be used in renal impaired patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Use in elderly.

Ryzodeg 70/30 can be used in elderly patients. As with all insulin products, glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis.

Paediatric use.

Safety and efficacy of Ryzodeg 70/30 in children less than 2 years have not been established.

Avoidance of accidental mix-ups.

Ryzodeg 70/30 has a unique PK/PD profile and cannot be automatically substituted for any other insulin. Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between Ryzodeg 70/30 and other insulin products.
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision, must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

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 requirement: oral antidiabetic drugs (OADs), GLP-1 receptor agonists, monoamine oxidase inhibitors (MAOIs), nonselective 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 requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol.
Beta-blocking agents 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.

Combination of thiazolidinediones and insulin.

Cases of cardiac failure have been reported when thiazolidinediones were used in combination with insulin, especially in patients with risk factors for development of cardiac failure. This should be kept in mind if treatment with the combination of thiazolidinediones and Ryzodeg 70/30 is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Thiazolidinediones should be discontinued if any deterioration in cardiac function occurs.

Incompatibilities.

Substances added to Ryzodeg 70/30 may cause degradation of insulin degludec and/or insulin aspart. Ryzodeg 70/30 must not be added to infusion fluids. Ryzodeg 70/30 must not be mixed with other medicinal products insulin products or solutions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility.
In a combined fertility and embryofetal study in male and female rats, treatment with subcutaneous doses of insulin degludec up to 21 U/kg/day (yielding 5-6 times the AUC in humans at a clinical dose of 0.8 U/kg/day) prior to mating and in female rats during gestation had no effect on mating performance or fertility.
In reproductive toxicity studies, insulin aspart did not affect the fertility of male and female rats but caused a slight increase in pre-implantation loss at subcutaneous doses greater than 10 U/kg/day. Similar effects were seen with human insulin.
(Category B3)
There is no clinical experience with Ryzodeg 70/30 in pregnant women.
In rats, decreased fetal weight was observed following treatment with insulin degludec and insulin aspart in combination at a subcutaneous dose of 30 U/kg/day (resulting in 8 and 24 times the AUC in humans for the respective insulins at a dose of 1.08 U/kg Ryzodeg 70/30). In addition, an increase in fetal skeletal abnormalities was found in a rat embryofetal study conducted with insulin degludec alone. In both cases, similar effects were seen with human insulin, and are probably secondary to maternal hypoglycaemia.
Animal reproduction studies have not revealed any differences between insulin degludec and human insulin regarding embryotoxicity and teratogenicity.
In general, intensified blood glucose control and monitoring of pregnant women with diabetes mellitus are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually decrease in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements usually return rapidly to pre-pregnancy values.
 There is no clinical experience with Ryzodeg 70/30 during breast-feeding. In rats, insulin degludec and its metabolites were secreted in milk; the peak concentration of insulin degludec in milk was less than half of that in plasma. It is unknown whether Ryzodeg 70/30 is excreted in human milk. No metabolic effects of Ryzodeg 70/30 are anticipated in the breast-fed newborn/infant.

4.7 Effects on Ability to Drive and Use Machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machines). Patients must 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 have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

More than 2000 subjects have been exposed to Ryzodeg 70/30 in the clinical development programme.
Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin, including Ryzodeg 70/30.

Tabulated list of adverse events and adverse reactions.

See Tables 1, 2 and 3.

Adverse reactions from clinical trials.

Adverse reactions listed in Table 4 are based on clinical trial data and classified according to MedDRA 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).

Adverse reactions from post-marketing sources.

Adverse reactions listed below are based on post-marketing source data and classified according to MedDRA System Organ Class. See Table 5.

Description of selected adverse reactions.

Immune system disorders.

As with any insulin therapy, allergic reactions may occur. Immediate type allergic reactions to either insulin itself or the excipients may potentially be life threatening. With Ryzodeg 70/30 hypersensitivity (manifested with swelling of tongue and lips, diarrhoea, nausea, tiredness and itching) and urticaria were reported rarely.

Hypoglycaemia.

As with any insulin therapy, hypoglycaemia 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.

Injection site reactions.

As may occur with any insulin therapy, injection site reactions (including injection site haematoma, pain, haemorrhage, erythema, nodules, swelling, discolouration, pruritus, warmth and injection site mass) occurred in subjects treated with Ryzodeg 70/30. These reactions are usually mild and transitory and they normally disappear during continued treatment.

Skin and subcutaneous tissue disorders.

As with any insulin therapy, lipodystrophy (including lipohypertrophy and lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see Section 4.4 Special Warnings and Precautions for Use).

Peripheral oedema.

Insulin, including Ryzodeg 70/30, may cause sodium retention and oedema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Antibody production.

There was no clinically relevant development of insulin antibodies after long-term treatment with Ryzodeg 70/30.

Paediatric population.

Ryzodeg 70/30 has been administered to children (6-11 years) and adolescents (12-18 years) for the investigation of pharmacokinetic properties (see Section 5.2 Pharmacokinetic Properties). Clinical trials have been performed in children aged 2 to 18 years. The frequency, type and severity of adverse reactions in the paediatric population do not indicate differences to the experience in the general diabetes population with the exception of a signal of higher occurrence of severe hypoglycaemia compared to a basal-bolus regimen in the paediatric population (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Other special populations.

Based on results from clinical trials, the frequency, type and severity of adverse reactions observed in the elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

A specific overdose 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. It is therefore recommended that the patient always carries glucose-containing products. Adjustments in drug dosage, meal patterns, or exercise may be needed.
Severe hypoglycaemic episodes, including 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 healthcare 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 reoccurrence of hypoglycaemia.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: A10AD06.

Mechanism of action.

Insulin degludec and insulin aspart bind to the human insulin receptor, resulting in the same pharmacological effects as human insulin. The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
The pharmacodynamic effect of Ryzodeg 70/30 is distinctively separated for the two components (Figure 1) and the resulting action profile reflects the individual components, the rapid acting insulin aspart and the ultra-long acting insulin degludec. The ultra-long acting basal component of Ryzodeg 70/30 (insulin degludec) forms soluble multi-hexamers upon subcutaneous injection of Ryzodeg 70/30 resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect. This effect is maintained in the co-formulation with insulin aspart and does not interfere with the rapid acting insulin aspart monomers.
Ryzodeg 70/30 has a rapid onset of action occurring soon after injection providing mealtime coverage while the basal component has a flat, stable and ultra-long action profile providing continuous coverage of the basal insulin requirements. The duration of action of a single dose of Ryzodeg 70/30 is beyond 24 hours.
The total and maximum glucose-lowering effects of Ryzodeg 70/30 increase linearly with increasing doses. Steady-state will occur after 2-3 days of dose administration.
There is no difference in the pharmacodynamic effect of Ryzodeg 70/30 between elderly and younger subjects.

Clinical trials.

Five (plus one extension) multi-national, randomised, controlled, open-label, treat-to-target clinical trials of 26 weeks or 52 weeks duration were conducted exposing a total of 1360 subjects with diabetes mellitus (362 subjects in type 1 diabetes mellitus and 998 subjects in type 2 diabetes mellitus) to Ryzodeg 70/30.
Ryzodeg 70/30 administered once daily plus oral antidiabetic drugs (OADs) was compared to insulin glargine (IGlar) once daily plus OADs in two trials in type 2 diabetes mellitus. Ryzodeg 70/30 once daily plus insulin aspart (IAsp) was also compared to once daily or twice-daily insulin detemir (IDet) plus IAsp in type 1 diabetes mellitus. Ryzodeg 70/30 twice daily plus OADs was compared to biphasic insulin aspart 30 (BIAsp 30) twice daily plus OADs in two trials in type 2 diabetes mellitus. BIAsp 30 is a white suspension for subcutaneous injection consisting of 30% soluble insulin aspart and 70% protamine-crystallised insulin aspart, marketed as NovoMix 30.
Efficacy and safety of once daily and twice daily mealtime dosing of Ryzodeg 70/30 either for insulin initiation or insulin intensification were confirmed. Ryzodeg 70/30 effectively improved glycaemic control as measured by HbA1c. Non-inferiority of change from baseline to end-of-trial of HbA1c was confirmed in all trials against all comparators, when treating subjects to target. All trials comparing insulin products were carried out using a treat-to-target design, where titration of basal insulin was based on pre-breakfast glucose values in order to achieve similar degrees of glycaemic control allowing for objective comparison of overall safety profile of the tested insulins, including risk of hypoglycaemia.
In a non-blinded, treat-to-target clinical trial (trial 3590), insulin-naïve adult subjects with type 2 diabetes mellitus were randomised to 26 weeks of treatment with Ryzodeg 70/30 + metformin (Met) or IGlar + Met. Ryzodeg 70/30 was administered once daily at breakfast. IGlar was administered once daily according to approved labelling. All subjects started on 10 U of either Ryzodeg 70/30 or IGlar. Ryzodeg 70/30 and IGlar groups had similar HbA1c levels with IGlar resulting in lower fasting plasma glucose (FPG) levels. Treatment with Ryzodeg 70/30 resulted in higher rates of confirmed hypoglycaemia but lower rates of nocturnal confirmed hypoglycaemia compared to IGlar (see Table 6).
In a non-blinded, treat-to-target clinical trial (trial 3593), adult subjects with type 2 diabetes mellitus who were inadequately controlled with basal insulin once daily + OADs were randomised to 26 weeks of treatment with Ryzodeg 70/30 once daily or IGlar once daily, both in combination with Met ± pioglitazone (Pio) ± DPP-4 inhibitor. All subjects initiated trial insulin treatment by switching on a unit-to-unit basis from the basal insulin they received before randomisation. Subjects administered Ryzodeg 70/30 once daily with either the evening meal or the largest meal or administered IGlar once daily according to approved labelling. Ryzodeg 70/30 and IGlar groups had similar HbA1c and FPG levels. Treatment with Ryzodeg 70/30 resulted in higher rates of confirmed hypoglycaemia but similar rates of nocturnal confirmed hypoglycaemia compared to IGlar (see Table 6).
The use of Ryzodeg 70/30 in combination with sulphonylureas, GLP-1 agonists, alpha-glucosidase inhibitors and SGLT-2 inhibitors has not been studied.
In a non-blinded, treat-to-target clinical trial (trial 3592), adult subjects with type 2 diabetes mellitus who were inadequately controlled on once daily or twice daily premixed or self-mixed insulin regimen ± OADs were randomised to 26 weeks of treatment with Ryzodeg 70/30 twice daily or BIAsp 30 twice daily, both ± Met, ± DPP-4 inhibitor, ± Pio. Ryzodeg 70/30 and BIAsp 30 were administered before the breakfast and main evening meals. Subjects on premixed insulin twice daily transferred their doses unit-to-unit to trial insulin. Subjects on a self-mixed regimen transferred to trial insulin at doses corresponding to their respective self-mixed pre-meal dose. Subjects previously receiving premixed or self-mixed insulin once daily were to divide their dose into 2 equal doses. Ryzodeg 70/30 and BIAsp 30 groups had similar HbA1c levels with Ryzodeg 70/30 resulting in significantly lower FPG levels. Treatment with Ryzodeg 70/30 resulted in significantly lower rates of confirmed hypoglycaemia and lower rates of nocturnal confirmed hypoglycaemia compared to BIAsp 30 (see Table 7).
In a non-blinded, treat-to-target clinical trial (trial 3597), Asian adult subjects with type 2 diabetes mellitus who were inadequately controlled on basal insulin, premixed or self-mixed insulin in an once daily or twice daily insulin regimen ± Met were randomised to 26 weeks of treatment with Ryzodeg 70/30 twice daily or BIAsp 30 twice daily, with or without Met. Subjects on once daily insulin split the total dose of their previous insulin treatment into 2 equal doses of trial insulin for twice daily administration. Subjects on twice daily insulin transferred their doses on a unit-to-unit basis to the trial insulin. Ryzodeg 70/30 and BIAsp 30 was administered at the breakfast and main evening meal. Ryzodeg 70/30 and BIAsp 30 groups had similar HbA1c levels with Ryzodeg 70/30 resulting in significantly lower FPG levels. Treatment with Ryzodeg 70/30 resulted in similar rates of confirmed hypoglycaemia and nocturnal confirmed hypoglycaemia compared to BIAsp 30 (see Table 7).
In a non-blinded, treat-to-target clinical trial (trial 3594), adult subjects with type 1 diabetes mellitus were randomised to 26 weeks of treatment with Ryzodeg 70/30 and IAsp or IDet and IAsp. Ryzodeg 70/30 was administered once daily with any main meal while allowing for a switch to another main meal. IAsp was administered for the remaining insulin requiring meals. IDet was administered once daily at evening meal or bedtime. A second dose of IDet was added to breakfast after 8 weeks in cases of inadequate glycaemic control (mean pre-dinner PG > 6.0 mmol/L, deterioration of HbA1c from baselines < 8.0% or improvement of HbA1c < 0.5% when baseline HbA1c ranges from 8.0-10%). Ryzodeg 70/30 and IDet groups had similar HbA1c and FPG levels and similar rates of confirmed hypoglycaemia. Treatment with Ryzodeg 70/30 resulted in lower rates of nocturnal confirmed hypoglycaemia compared to IDet (see Table 8).

Paediatric population.

The efficacy and safety of Ryzodeg 70/30 have been studied in a randomised, controlled clinical trial in children and adolescents with diabetes mellitus type 1 for a period of 16 weeks (n=362). Patients in the Ryzodeg 70/30 arm included 40 exposed children aged 2-5 years, 61 children aged 6-11 years and 80 adolescents aged 12-17 years. Ryzodeg 70/30 dosed once daily with the main meal plus insulin aspart for the remaining meals showed similar reduction in HbA1c at week 16 and no differences in FPG and SMPG compared to comparator insulin detemir dosed once or twice daily plus mealtime insulin aspart. At week 16, the mean total daily insulin dose was 0.88 vs 1.01 units/kg in the Ryzodeg 70/30 and insulin detemir arms, respectively. See Tables 9 and 10.
Efficacy and safety evaluation for adolescent patients with type 2 diabetes mellitus has been made using data from adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. This assessment supports the use of Ryzodeg 70/30 in adolescent patients with type 2 diabetes mellitus.

Cardiovascular evaluation.

DEVOTE was a randomised, double-blind, active-controlled, treat-to-target and event-driven clinical trial with a median duration of 2 years comparing the cardiovascular safety of insulin degludec versus insulin glargine (100 units/mL) in 7,637 patients with type 2 diabetes mellitus at high risk of cardiovascular events. Patients eligible to enter the trial were 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure (85% of the enrolled population) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (15% of the enrolled population).
The primary analysis was time from randomisation to first occurrence of a 3-component major adverse cardiovascular event (MACE) defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The trial was designed as a non-inferiority trial to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE comparing insulin degludec to insulin glargine. The cardiovascular safety of insulin degludec as compared to insulin glargine was confirmed (Figure 2).
The cardiovascular safety of insulin degludec as compared to insulin glargine (100 units/mL) was confirmed (HR: 0.91; 95% CI [0.78;1.06], p = 0.209).
Similar improvements in HbA1c were achieved with insulin degludec and insulin glargine, and a greater reduction in FPG was achieved with insulin degludec.
Insulin degludec was superior compared to insulin glargine in terms of a lower rate of severe hypoglycaemic events and a lower proportion of subjects experiencing severe hypoglycaemia. The rate of nocturnal severe hypoglycaemia was significantly lower for insulin degludec compared to insulin glargine.

5.2 Pharmacokinetic Properties

Absorption.

After subcutaneous injection, soluble and stable multi-hexamers of insulin degludec are formed creating a depot in the subcutaneous tissue, while not interfering with the rapid release of insulin aspart monomers into the circulation. Insulin degludec monomers gradually separate from the multi-hexamers resulting in a slow and continuous delivery of insulin degludec into the circulation. Steady-state serum concentrations of the ultra-long acting component (insulin degludec) is reached after 2-3 days of daily Ryzodeg 70/30 administration. The rapid absorption characteristics of the well established insulin aspart are maintained by Ryzodeg 70/30. The pharmacokinetic profile for insulin aspart appears 14 minutes after injection with a peak concentration after 72 minutes.

Distribution.

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of > 99% in human plasma. Insulin aspart has a low binding to plasma proteins, < 10%, similar to that seen with regular human insulin.

Metabolism.

Degradation of insulin degludec and insulin aspart is similar to that of human insulin.

Excretion.

The half-life after subcutaneous administration of Ryzodeg 70/30 is determined by the rate of absorption from the subcutaneous tissue. The half-life of the basal component, insulin degludec, at steady-state is approximately 25 hours independent of dose.

Linearity.

Total exposure with Ryzodeg 70/30 increases proportionally with increasing dose of the basal component (insulin degludec) and the mealtime component (insulin aspart) in type 1 and type 2 diabetes mellitus.

Special populations.

Elderly, race, renal and hepatic impairment.

There are no clinically relevant differences in the pharmacokinetics of Ryzodeg 70/30 between elderly and younger adult subjects, between races or between healthy subjects and subjects with renal or hepatic impairment.

Gender.

There are no gender differences in the pharmacokinetic properties of Ryzodeg 70/30.

Paediatric population.

The pharmacokinetic properties of Ryzodeg 70/30 in type 1 diabetes mellitus were investigated in children (6-11 years) and adolescents (12-18 years) and compared to adults after single dose administration.
The steady state pharmacokinetics properties of the insulin degludec component of Ryzodeg 70/30 were investigated using population pharmacokinetic analysis in children down to 1 year of age.
Total exposure and peak concentration of insulin aspart were higher in children than in adults and were similar for adolescents and adults.
At steady state, the pharmacokinetic properties of insulin degludec in children (1-11 years) and adolescents (12-18 years) were comparable to those observed in adults with type 1 diabetes mellitus. Total exposure of insulin degludec after single dose administration was, however, higher in children and adolescents than in adults with type 1 diabetes mellitus.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been carried out with insulin degludec. Insulin aspart did not cause gene mutations, chromosomal damage or DNA damage in a range of genotoxicity tests.

Carcinogenicity.

Standard 2-year carcinogenicity studies in animals have not been performed with insulin degludec and insulin aspart, either alone or in combination.
In a 52-week study with insulin degludec, rats received subcutaneous doses of up to 10 U/kg/day (resulting in 5 times the AUC in humans at a dose of 0.8 U/kg/day). No treatment-related increases in incidences of hyperplasia, benign or malignant tumours were recorded, and no treatment-related changes in female mammary gland cell proliferation were found using BrdU incorporation. In vitro studies showed the ratio of mitogenic relative to metabolic potency for insulin degludec is unchanged compared to human insulin.
In 52-week repeat dose toxicity studies with insulin aspart in Sprague-Dawley rats at subcutaneous doses up to 50 U/kg/day, the only significant toxicity findings were related to hypoglycaemia. At a higher dose of 200 U/kg/day in female Sprague-Dawley rats, insulin aspart, like human insulin, caused induction of mammary tumours. The clinical relevance of these findings is not known. Neither clinical nor epidemiological studies conducted to date have shown an association between insulin use and carcinogenesis but the available evidence is considered too limited to be conclusive at this time. In vitro studies showed that the mitogenic activity of insulin aspart does not differ from that observed with human insulin.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ryzodeg 70/30 contains the following inactive ingredients: glycerol, metacresol, phenol, sodium chloride, zinc acetate, hydrochloric acid and sodium hydroxide for pH adjustment, and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Before use.

FlexTouch and Penfill.

Store at 2°C to 8°C. Refrigerate. Do not freeze. Store Ryzodeg 70/30 away from the freezing element in the refrigerator.

In-use or carried as a spare.

FlexTouch.

Store below 30°C or in the refrigerator between 2°C to 8°C for up to 28 days. Keep the cap on the pen in order to protect from light. Protect from heat.

Penfill.

Store below 30°C for up to 28 days. Do not refrigerate. Keep cartridges in the outer carton in order to protect from light. Protect from heat.

6.5 Nature and Contents of Container

Ryzodeg 70/30 FlexTouch: 3 mL solution in cartridge (type 1 glass) with a plunger (halobutyl) and a stopper (halobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.
Pack sizes: 1 x 3 mL, 5 x 3 mL.
Ryzodeg 70/30 Penfill: 3 mL solution in cartridge (type 1 glass) with a plunger (halobutyl) and a stopper (halobutyl/polyisoprene) in a carton.
Pack size: 5 x 3 mL.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Insulin degludec.

Insulin degludec differs from human insulin in that the threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached (chemical name: LysB29(Nepsilon-hexadecandioyl-γ-Glu) des(B30) human insulin).

Insulin aspart.

Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28.

Chemical structure.

Insulin degludec.

Insulin degludec has a molecular formula of C274H411N65O81S6 and a molecular weight of 6103.97 daltons.

Insulin aspart.

Insulin aspart has a molecular formula of C256H381N65O79S6 and a molecular weight of 5825.8 daltons.

CAS number.

Insulin degludec.

844439-96-9.

Insulin aspart.

116094-23-6.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes