Consumer medicine information

Semglee

Insulin glargine

BRAND INFORMATION

Brand name

Semglee

Active ingredient

Insulin glargine

Schedule

What is in this leaflet

This leaflet answers some common questions about Semglee.

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

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

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

Keep this leaflet with the medicine. You may need to read it again

What Semglee is used for

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

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

Semglee is a long-acting insulin. Other names for this insulin include insulin glargine and Lantus. Your doctor may tell you to use a rapid- acting human insulin or oral diabetes medication in combination with Semglee.

Semglee is not addictive.

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

Before you use Semglee

When you must not use Semglee

Do not use Semglee:

If you have an allergy to:

any medicine containing insulin
any of the ingredients contained in Semglee listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

redness, swelling, rash and itching at the injection site
rash, itching or hives on the skin
shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body

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

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

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

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

Do not give Semglee to children less than 6 years of age. There is no experience with the use of Semglee in children less than 6 years.

Before you start to use Semglee

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

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

kidney problems
liver problems

Tell your doctor if you are pregnant or plan to become pregnant. Pregnancy may make managing your diabetes more difficult.

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

Tell your doctor if:

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

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

Taking other medicines

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

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

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

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

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

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

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

How to use Semglee

Semglee is a clear solution that does not require shaking before use.

Your doctor, pharmacist or diabetes educator will have shown you how to use Semglee and what injection site to use.

Carefully follow all the directions.

Do not dilute Semglee.

Do not mix Semglee with any other insulin or solution.

Do not inject Semglee into a muscle or vein.

Semglee is intended for injection under the skin. It can be injected at any time during the day, however, at the same time every day.

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

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

How much to use

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

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

When to use Semglee

Your doctor will tell you when to use Semglee.

Semglee should be used once a day, at the same time every day.

How to use Semglee injection pens

Wash your hands with soap and water before using your injection pen.

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

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

Pre-filled disposable pens

Semglee disposable pens are pre- filled and ready to use. Do not attempt to replace the cartridge in a pre-filled disposable pen. Once all the insulin is used you cannot replace the cartridge. Empty disposable pens must never be reused and must be properly discarded

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

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

Becton Dickinson (BD Ultra-Fine™ +) or Novofine needles should be used with the injection pens.

Guide to parts

INJECTING A DOSE

Step 1: Prepare your pen

(A) Inspect the pen. Always check the insulin label on the reusable pen before each injection to make sure:
- It is the correct injection pen
- It is the correct insulin type
- The expiry date has not passed
(B) Hold the pen body with one hand. With the other hand pull off the pen cap. Put the pen cap aside to be used later.

(C) Check the insulin through the cartridge holder to make sure:
- The insulin looks clear and colourless with no visible particles
- There are no cracks, breaks or leaks around the cartridge holder
(D) Wipe the rubber seal (at the front of the cartridge) with a new alcohol wipe.

Step 2: Attach a new needle

(A) Take a new sterile disposable needle and peel off the protective seal. Do not use the needle if the protective seal is damaged or missing as the needle may not be sterile.

(B) While holding the pen body facing upwards, attach the outer needle cap straight on to the cartridge holder as shown. Trying to attach the outer needle cap sideways may bend or damage the needle.

(C) Turn the outer needle cap in a clockwise (right) direction until it feels tightly fixed on the pen.

(D) Carefully pull off the outer needle cap and put it aside. Do not throw it away. You will need the outer needle cap later.

(E) Carefully pull off the inner needle cap and throw it away.

Step 3: Do a safety test on your pen needle

(A) Always do a safety test on a new pen needle before each injection.
(B) Turn the white dose knob to 2 dose units. You will hear a "click" for each unit turned.

If you accidentally turn past 2 units, turn back the dose knob in the opposite direction to the correct number of units.

(C) Hold the pen body facing upwards with one hand.
(D) Tap the cartridge gently with your finger to help any large air bubbles to move to the top of the cartridge. Small bubbles may still be visible. This is normal.

(E) With the pen upright, press the injection button in until it stops moving and the dose window shows "0".
(F) Repeat steps 3B through 3E up to four times until you see drops of insulin at the tip of the needle. The safety test is complete when you can see drops of insulin.

If you do not see any insulin at the needle tip after 4 safety testing attempts the needle may be blocked. If this occurs:
- Go to Step 7 for instructions on safely removing the needle.
- Restart the process at step 2A to attach and do safety testing for a new needle.

Step 4: Select your dose

(A) Check that the dose window shows "0".
(B) Turn the white dose knob until the yellow dose pointer lines up with your required dose

As you turn the white dose knob to set your dose, the white plunger will extend out and you will hear a "click" at each unit dialed.
The dose can be corrected by turning the dose knob in either direction until the correct dose lines up with the yellow dose pointer.
The pen will not let you dial a dose more than the number of units left in the Pen. If your dose is more than the number of units left in the Pen, either:
- Inject the amount left in your pen and use a new pen to give the rest of your dose,
Or
- Get a new pen and inject the full dose.
Do not force the dose knob to turn beyond 80 units.
Do not push the purple injection button when turning the dose knob.

Step 5: Select and clean the injection site

(A) Select the injection site as explained to you by your doctor, pharmacist or diabetes educator, clean with a new alcohol wipe and let your skin dry before you inject your dose.

Injection sites include your arms, hips, thighs, buttocks and abdomen. You should change your injection site for each injection.

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

Step 6: Inject your dose

(A) If instructed by your doctor, pharmacist or diabetes educator, you can stabilise the cleaned skin by spreading it or pinching up a large area between your fingers.
(B) Push the needle straight into the skin as shown by your doctor, pharmacist or diabetes educator.

Do not inject with the needle at an angle

(C) Press the purple injection button all the way in. The white dose knob will turn and you will hear "clicks" as you press down.

(D) Hold the purple injection button down for 10 seconds after the dose window shows "0" to make sure all of the insulin is injected. If you do not keep the injection button pressed down for 10 seconds after "0" is displayed you may get the wrong dose of medicine.

Do not push the injection button sideways or block the white dose knob with your fingers as this will stop you from injecting the medicine.

Step 7: After your injection

(A) Take the outer needle cap that you had saved in step 2D, hold it at the widest part and carefully cover the needle without touching it.

(B) Squeeze the wide part of the outer needle cap and unscrew the needle in a counter-clockwise (left) direction. Keep twisting the needle until it comes off the pen. It may take several twists to release the needle.

(C) Dispose of the needle safely into a sharps container or as instructed by your healthcare professional.

(D) Replace the pen cap over the cartridge.

(E) Store the pen at room temperature (below 30°C). Do not store the pen with a used needle attached

How long to use Semglee

Continue using Semglee for as long as your doctor recommends.

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

Always carry an extra Semglee prefilled pen injector as recommended by your healthcare professional in case your pen gets lost or damaged.

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

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

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

The risk of hypoglycaemia is increased if you:

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

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

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

Always carry some sugary food or drink with you.

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

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

Follow up with extra carbohydrates, e.g. plain biscuits, fruit or milk, when over the initial symptoms. Taking this extra carbohydrate will prevent a second drop in your blood sugar level.

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

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

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

Make sure they know to turn you on your side and get medical help immediately if you lose consciousness.

Make sure they know not to give you anything to eat or drink if you are unconscious. This is because you could choke.

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

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

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

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

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

See your doctor if you keep having "hypos" or if you have ever become unconscious after using Semglee. Your dose of Semglee or other medicines may need to be changed.

If you miss a dose - Hyperglycaemia

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

Semglee is a long-acting insulin that works for 24 hours and should be injected regularly at the same time each day. If you miss injecting your dose at the regular scheduled time, your blood sugar levels may become high (hyperglycaemia).

However, injecting a dose of Semglee at another time may increase your risk of having a hypo. You should therefore plan in advance with your doctor or healthcare professional so that you know what to do in case you miss a dose.

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

Do NOT use a double dose of your insulin. If you double a dose, this may cause low blood sugar levels.

The risk of hyperglycaemia is increased if you:

miss doses of Semglee or other insulin, or use less Semglee than you need
have uncontrolled diabetes
exercise less than usual
eat more carbohydrates than usual
are ill or stressed
take certain other medications

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

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

Symptoms of mild to moderate hyperglycaemia include:

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

Symptoms of severe hyperglycaemia include:

heavy breathing
fast pulse
nausea, vomiting
dehydration
loss of consciousness

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

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

While you are using Semglee

Things you must do

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

It is important to keep using Semglee even if you feel well. Semglee helps to control your condition, but does not cure it.

Tell your doctor if you often have hypoglycaemia or if you have ever become unconscious after using Semglee. Your doctor may need to adjust your dose of Semglee or of other medicines you are taking.

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

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

Tell your doctor, pharmacist or diabetes educator if you are travelling. Ask your doctor for a letter explaining why you are taking injecting pens and needles with you. Each country you visit will need to see this letter, so you should take several copies.

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

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

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

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

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

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

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

Things you must not do

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

Do not skip meals while using Semglee.

Do not use Semglee if you think it has been frozen or exposed to excessive heat (temperatures above 30°C).

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

Do not share needles or injection devices with other people, even if the needle has been changed. Do not reuse needles. You may give other people a serious infection, or get a serious infection from them.

Things to be careful of

Be careful driving or operating machinery until you know how Semglee affects you. Be careful not to let your blood sugar levels fall too low.

Tell your doctor if you drink alcohol. Alcohol may mask the symptoms of hypoglycaemia.

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

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

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

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

Side effects

Tell your doctor, pharmacist or diabetes educator as soon as possible if you do not feel well while you are using Semglee.

Semglee helps most people with diabetes, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

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

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

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

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

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

More severe symptoms of hypoglycaemia, including:
- disorientation
- seizures, fits or convulsions
- loss of consciousness
Signs of a serious allergic reaction, including:
- skin rashes over a large part of the body
- shortness of breath, wheezing
- swelling of the face, lips or tongue
- fast pulse
- sweating

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

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

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

After using Semglee

Storage

All medicines should be kept where children cannot reach them.

PRE-FILLED DISPOSABLE PENS

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

Before first use, store the pre-filled pen at room temperature for 1 to 2 hours.

Once in use, the opened, pre-filled pen should not be put in the refrigerator. It should be kept below 30°C away from direct heat and light.

Do not leave the needle attached to the pre-filled pen during storage

Always store the pre-filled pen with the cap on, to prevent contamination.

Discard the pre-filled pen within 28 days of first use. Pre-filled pens that are first carried as a spare for a while must also be discarded 28 days after being removed from the refrigerator.

Maintenance

Protect your pen from dust and dirt. You can clean the outside of your Semglee pen by wiping it with a damp cloth.

Do not soak, wash or lubricate the pen as this may damage it.

Handle your Semglee pen with care and avoid situations where it may be damaged. Dropping your pen can cause the cartridge to break or can damage the pen.

If you are concerned that your pen may be damaged, do not try to fix it. Use a new pen instead.

Disposal

Dispose of your insulin needles and disposable injection devices safely into a sharps container or as instructed by your healthcare professional. The used Semglee pen cannot be recycled.

If your doctor tells you to stop using Semglee 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

Semglee is a pre-filled disposable pen containing a 3mL cartridge.

Each cartridge contains a clear, colourless solution.

Ingredients

Semglee contains the following active ingredient:

insulin glargine (100 IU/mL)

It also contains the following inactive ingredients:

meta-cresol
glycerol
zinc chloride
hydrochloric acid
sodium hydroxide
water for injection

Supplier

Semglee is supplied in Australia by:

Alphapharm Pty Ltd (Mylan Australia)
(ABN 93 002 359 739)
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.mylan.com.au

Australian registration number:

Semglee pre-filled injection pen with 3 mL cartridge: AUST R 286207

This leaflet was prepared in March 2018.

Further information

You can get more information about diabetes and insulin from:

Diabetes Australia:
freecall helpline 1300 136 588
www.diabetesaustralia.com.au

Semglee_cmi\Mar18/01

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Semglee

Active ingredient

Insulin glargine

Schedule

1 Name of Medicine

Insulin glargine.
Semglee is a biosimilar medicine to Lantus. The comparability of Semglee to Lantus has been demonstrated with regard to physiochemical characteristics, efficacy and safety outcomes. The evidence for comparability supports the use of Semglee for the listed indications.

2 Qualitative and Quantitative Composition

Semglee [insulin glargine injection {rDNA origin}] is a recombinant human insulin analogue produced by DNA technology.
The Semglee injector pen provides insulin glargine for subcutaneous injection.
The 3 mL cartridge inside the injector pen contains 100 IU/mL (3.64 mg/mL) of insulin glargine as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Semglee is a sterile, clear, colourless solution free from particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Insulin glargine is an insulin analogue indicated for once-daily subcutaneous administration in the treatment of type 1 diabetes mellitus in adults and children and type 2 diabetes mellitus in adults who require insulin for the control of hyperglycaemia.

4.2 Dose and Method of Administration

Semglee is an insulin analogue, equipotent to human insulin, with a peakless glucose lowering profile and a prolonged duration of action that permits once daily dosing.
Semglee is for individual patient use only.
Semglee is given subcutaneously once a day. It may be administered at any time during the day, however, at the same time every day.
Semglee is not intended for intravenous administration.
The desired blood glucose levels as well as the doses and timing of any antidiabetic medication, including Semglee, must be determined and adjusted individually. In a clinical study in insulin-naïve patients with type 2 diabetes, insulin glargine was started at a dose of 10.8 ± 4.9 IU (mean ± SD; median dose 10 IU) insulin glargine once daily and subsequently adjusted individually. Blood glucose monitoring is recommended for all individuals with diabetes.
Dose adjustment may also be required, for example, if the patient's weight or lifestyle change, change in timing of insulin dose or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Any change of insulin dose should be made cautiously and only under medical supervision.
Although absorption of Semglee does not differ between abdominal, thigh or deltoid subcutaneous injection sites, as with all insulins, injection sites must be rotated from one injection to the next in order to reduce the risk of lipodystrophy and localised cutaneous amyloidosis. Do not inject into areas of lipodystrophy and localised cutaneous amyloidosis. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).)

Paediatric use.

Semglee can be safely administered to paediatric patients > 6 years of age. In a study comparing insulin glargine to NPH insulin in children from 2-5 years, non-inferiority was not demonstrated in relation to the primary outcome of hypoglycaemia (see Section 5.1 Pharmacodynamic Properties, Clinical trials for details). Efficacy in terms of HbA1C (a secondary efficacy endpoint) was similar between groups.
Based on the result of a study in paediatric patients, the dose recommendation for changeover to Semglee is the same as described for adults.

Changeover to Semglee.

The initial dose of Semglee should be determined individually, depending on the desired blood glucose levels.
When changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Semglee, the amount and timing of a short-acting insulin or fast-acting insulin analogue or the dose of any oral antidiabetic drug may need to be adjusted.
To reduce the risk of hypoglycaemia, when patients are transferred from once daily insulin glargine 300 units/mL to once daily Semglee, the recommended initial Semglee dose is approximately 80% of the insulin glargine 300 units/mL that is being discontinued.
In clinical studies, when adult patients were transferred from once daily NPH human insulin or ultralente human insulin to once daily insulin glargine, the initial dose was usually not changed. In studies when patients were transferred from twice-daily NPH human insulin to insulin glargine once daily at bedtime, the initial dose (IU) was usually reduced by approximately 20% (compared to total daily IU of NPH human insulin) within the first week of treatment and then adjusted based on patient response. There was also a slightly higher rate of injection site pain seen with insulin glargine, possibly related to the acidic nature of insulin glargine when compared with NPH insulin. The majority of injection site reactions were mild, with only one subject in each of the insulin glargine and NPH treatment groups discontinuing study medication due to injection site adverse events.
A programme of close metabolic monitoring under medical supervision is recommended during changeover and in the initial weeks thereafter. As with all insulin analogues, this is particularly true for patients who, due to antibodies to human insulin, need high insulin doses and may experience markedly improved insulin response with insulin glargine.
With improved metabolic control and resultant increase in insulin sensitivity (reduced insulin requirements) further adjustment of the dose of Semglee and other insulin or oral antidiabetic agents in the regimen may become necessary.

Preparation and handling.

Unopened pre-filled pens.

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

Open (in use) or unrefrigerated pre-filled pens.

Semglee pre-filled pens, whether or not refrigerated, must be discarded after 28 days from first use. Do not freeze. Discard if frozen.
Unrefrigerated pre-filled pens, whether or not in use, must be discarded after 28 days. This applies irrespective of whether the pre-filled pen is used immediately or is first carried as a spare for a while.
Once in use, pre-filled pens must not be stored in the refrigerator. Semglee that is in use in pre-filled pens may be kept unrefrigerated for up to 28 days, as long as the temperature is not greater than 30°C and it is kept away from direct heat and light. It must be used within a 28 day period or must be discarded 28 days after commencement of use.
An empty pre-filled pen must never be reused and must be properly discarded.
Manufacturer instructions for using Semglee in pre-filled pens must be followed carefully for attaching the needle, performing the safety test and administering the insulin injection. If the injection device is damaged, it should be discarded and a new injection device should be used.
Semglee must not be mixed with any other insulin nor be diluted. Mixing or diluting can change its time/action profile and mixing can cause precipitation.

4.3 Contraindications

Semglee must not be used in patients hypersensitive to insulin glargine or any of its excipients.

4.4 Special Warnings and Precautions for Use

Semglee must not be diluted or mixed with any other insulin or solution.
Semglee is not intended for intravenous administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous space. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycaemia.
Semglee is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, intravenous regular insulin is recommended in such cases.
As with all insulins, the time course of Semglee action may vary in different individuals or at different times in the same individual and the rate of absorption is dependent on blood supply, temperature and physical activity.
Patients, and if appropriate, their relatives, must also be alert to the possibility of hyper- or hypoglycaemia, and know what actions to take.
In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's compliance with all prescribed treatment regimens, injection sites and proper injection technique, the handling of the pen and all other relevant factors must be reviewed before dose adjustment is considered.
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and localised 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, and dose adjustment of antidiabetic medications may be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).
Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of insulin glargine.

Traceability.

In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product should be clearly recorded.

Hypoglycaemia.

Hypoglycaemia is the most common adverse effect of insulins. The incidence of nocturnal hypoglycaemia in regimens that include insulin glargine is significantly reduced in patients with type 2 diabetes compared with regimens containing NPH human insulin. The time of occurrence of hypoglycaemia depends on the action profile of the insulins and may, therefore, change when the treatment regimen is changed.
As with all insulins, particular caution (including intensified blood glucose monitoring) should be exercised in patients who are at greater risk of clinically significant sequelae from hypoglycaemic episodes.
The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia.
In clinical studies, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar after insulin glargine and human insulin both in healthy volunteers and patients with type I diabetes. However, the warning symptoms of hypoglycaemia may be changed, be less pronounced, or be absent in certain risk groups, as for example, in patients whose glycaemic control is markedly improved; in elderly patients; where an autonomic neuropathy is present; in patients with a long history of diabetes; in patients receiving concurrent treatment with certain other drugs.
Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia.

Use in renal impairment.

In patients with renal impairment, insulin requirements may be diminished because of reduced insulin metabolism.

Use in the elderly.

Progressive deterioration of renal function may lead to a steady decrease in insulin requirements. Furthermore, the warning signs of hypoglycaemia may be changed, diminished or absent in elderly patients. See Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in hepatic impairment.

Although no studies have been performed in patients with diabetes and hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

Intercurrent conditions.

Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances or stress.

Information for patients.

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and hypoglycaemia and hyperglycaemia management. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate food intake or skipped meals.
Patients must be advised that Semglee must not be diluted or mixed with any other insulin or solution.
Accidental mix-ups between insulin glargine and other insulins, particularly short-acting insulins, have been reported. To avoid medication errors between insulin glargine and other insulins, patients should be instructed to always check the insulin label before each injection.
As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycaemia or hyperglycaemia.
Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating becoming pregnant.

Paediatric use.

In general, the safety profile for patients ≤ 18 years of age is similar to the safety profile for patients > 18 years. The adverse events reports received from postmarketing surveillance included relatively more frequent injection site reactions (injection site pain, injection site reaction) and skin reactions (rash, urticaria) in patients ≤ 18 years of age than in patients > 18 years.
Data from pooled clinical trials in adults and children aged 6 to 18 years did not show a greater incidence of either injection site reaction or skin reactions in the paediatric population compared to adults.
Pharmacokinetics in children aged 2 to less than 6 years of age with type 1 diabetes mellitus was assessed in one clinical study. Plasma "trough" levels of insulin glargine and its main metabolites M1 and M2 were measured in children treated with insulin glargine, revealing plasma concentration patterns similar to adults, and providing no evidence for accumulation of insulin glargine or its metabolites with chronic dosing.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a combined fertility, prenatal and postnatal study in male and female rats at subcutaneous doses up to 10 IU/kg/day (approximately 5 times anticipated clinical exposure based on BSA), insulin glargine was maternotoxic due to dose-dependent hypoglycaemia leading to death at the highest dose. There were no effects of treatment on fertility. Similar effects were seen with NPH insulin.
(Category B3)
There are no randomized controlled clinical studies of the use of insulin glargine in pregnant women.
A large number (more than 1000 retrospective and prospective pregnancy outcomes with insulin glargine) of exposed pregnancies from postmarketing surveillance indicate no specific adverse effects on pregnancy or on the health of the foetus and newborn child.
Furthermore a meta-analysis of eight observational clinical studies including 331 women using insulin glargine and 371 women using insulin NPH was performed to assess the safety of insulin glargine and insulin NPH in gestational or pregestational diabetes. No significant differences in safety related maternal or neonatal outcomes were seen between insulin glargine and insulin NPH during pregnancy.
It is essential to maintain good control of the insulin-treated patient (insulin-dependent or gestational diabetes) throughout pregnancy to prevent adverse outcomes associated with hyperglycaemia. Insulin requirements usually fall during the first trimester, increase during the second and third trimesters and rapidly decline after delivery. Careful monitoring of glucose control is essential.
Patients with diabetes must inform their doctor if they are pregnant or are contemplating pregnancy and insulin glargine should be used during pregnancy only if the potential benefits outweigh potential risk.
Embryofetal development studies in rats and rabbits have been performed at subcutaneous doses up to 20 IU/kg/day and 2 IU/kg/day, respectively (approximately 10 times and twice anticipated clinical exposure, respectively, based on BSA). The effects of insulin glargine generally did not differ from those observed with NPH insulin in rats or rabbits. However, in rabbits dosed with 2 IU/kg/day there was an increased incidence of dilatation of the cerebral ventricles.
It is not known whether insulin glargine is excreted in significant amounts in human milk or animal milk. Many drugs, including insulin, are excreted in human milk. For this reason, caution should be exercised when insulin glargine is administered to a nursing mother. Lactating women may require adjustments in insulin dose and diet.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects of Semglee include hypoglycaemia which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

See Tables 1, 2, and 3.

Over the course of this 6 year study severe hypoglycaemia was reported in 5.7% of the insulin glargine group compared to 1.9% of the standard care group. The rates (per 100 patient-years) of confirmed all hypoglycaemia events, severe hypoglycaemia events and non-severe symptomatic hypoglycaemia are shown in Table 4.
Over the course of this 6-year study, 42% of the insulin glargine group and 74% of the standard care group did not experience any hypoglycaemia.

The median of the change in body weight from baseline to the last on-treatment visit was 2.2 kg greater in the insulin glargine group than in the standard care group i.e. weight gain of 1.4 kg in insulin glargine group compared to weight loss of 0.8 kg in standard care group.

Hypoglycaemia.

Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.
As with all insulins, severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.
In many patients, the signs and symptoms of neuroglycopaenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.

Eyes.

A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.
As with all insulin regimens, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary visual impairment or worsening of diabetic retinopathy. However, long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.
In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient partial or complete blindness.
Retinopathy was evaluated in clinical studies by means of retinal adverse events reported and fundus photography. The numbers of retinal adverse events reported for insulin glargine and NPH treatment groups were similar for patients with type 1 and type 2 diabetes. Progression of retinopathy was investigated by fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Study (ETDRS). In a 5-year NPH-controlled study, the primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. The results of this analysis are shown in Table 5 for both the per-protocol (primary) and intent-to-treat (ITT) populations, and indicate non-inferiority of insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome.

Skin and subcutaneous tissue disorders.

As with any insulin therapy, lipodystrophy may occur at the injection site and delay local insulin absorption. In clinical studies, in regimens, which included insulin glargine, lipohypertrophy was observed in 1 to 2% of patients, whereas lipoatrophy was uncommon.
Localised cutaneous amyloidosis at the injection site has occurred with insulins. Hyperglycaemia has been reported with repeated insulin injections into areas of cutaneous amyloidosis; hypoglycaemia has been reported with a sudden change to an unaffected injection site.
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.)

Injection site and allergic reactions.

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy include redness, pain, itching, hives, swelling and inflammation. Most minor reactions to insulins usually resolve in a few days to a few weeks.
Immediate-type allergic reactions are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalised skin reactions, angioedema, bronchospasm, hypotension, or shock and may be life threatening.
Animal studies with insulin glargine have identified significant local tolerance toxicity at the injection site following repeat subcutaneous administration. Care should be taken to rotate the site of injection.

Antibody production.

Insulin administration may cause the formation of antibodies to insulin. In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed in both NPH human insulin and insulin glargine treatment groups with similar incidences. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycaemia or hypoglycaemia.

Other reactions.

Insulin may cause sodium retention and oedema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Medication errors have been reported in which other insulins have been accidentally administered instead of insulin glargine.

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

Symptoms.

An excess of insulin relative to food intake, energy expenditure or both may lead to severe and sometimes prolonged and life-threatening hypoglycaemia.

Management.

Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.
More severe episodes with coma, seizure or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 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 Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Pharmacodynamics.

Insulin glargine is a human insulin analogue that has been designed to have low solubility at neutral pH. At pH 4, the pH of the Semglee injection solution, it is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralised, leading to formation of microprecipitates from which small amounts of insulin glargine are continuously released, providing a smooth, peakless, predictable time/concentration profile and a prolonged duration of action. This allows once daily dosing to meet a patient's basal insulin needs.
Insulin glargine is metabolised into 2 active metabolites M1 and M2.

Insulin receptor binding.

In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to the one of human insulin.

IGF-1 receptor binding.

The affinity of insulin glargine for the human IGF-1 receptor is approximately 5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to human insulin.
The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half maximal occupation of the IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in Semglee therapy, are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.
In clinical studies, intravenous insulin glargine and human insulin have been shown to be equipotent when given at the same doses.
In euglycaemic clamp studies in healthy subjects or in patients with type I diabetes, the onset of action of subcutaneous insulin glargine was slower than NPH (neutral protamine hagedorn) human insulin. The effect profile of insulin glargine was smooth and peakless, and the duration of its effect was prolonged compared to NPH human insulin. Figure 1 shows results from a study in patients with type I diabetes. The median time between injection and the end of pharmacological effect was 14.5 hours for NPH human insulin, and 24 hours (the end of the observation period) for insulin glargine.

The longer duration of Semglee is directly related to its slower rate of absorption and supports once daily subcutaneous administration. The time course of action of insulin and insulin analogues such as Semglee may vary considerably in different individuals or within the same individual but is, due to the lack of a peak, less variable with insulin glargine than with NPH insulin.

Clinical trials.

The following clinical trial information has been generated on the reference medicine.

Efficacy studies.

The overall efficacy of once-daily insulin glargine on metabolic control was compared to that of once-daily and twice-daily NPH human insulin in open-label, randomised, active-control, parallel studies of 2327 adult patients and 349 paediatric patients with type 1 diabetes mellitus and 1563 patients with type 2 diabetes mellitus.

Type 1 diabetes in adults (see Table 8).

In Phase 3 studies, patients with type 1 diabetes (Studies 3001 and 3004, n=1119) were randomised to basal-bolus treatment with insulin glargine once daily or to NPH human insulin once or twice daily and treated for 28 weeks. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH human insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily. Insulin glargine had a larger effect in reducing fasting glucose than NPH human insulin administered twice daily, but was comparable with NPH human insulin twice daily in its effect on glycohaemoglobin (GHb) and incidence of nocturnal and severe hypoglycaemia. Compared to once daily NPH human insulin, insulin glargine had a similar effect on fasting glucose and GHb. Hypoglycaemia was reported with similar frequency during the first month of the studies (during initial titration period) after starting treatment with insulin glargine compared to NPH human insulin.
In another Phase 3 study, patients with type 1 diabetes (Study 3005, n=619) were treated for 16 weeks with a basal-bolus insulin regimen where insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Insulin glargine and NPH human insulin had a similar effect on GHb, with similar numbers of patients reporting a hypoglycaemic episode.

Type 1 diabetes in children (see Table 9).

In a randomised, controlled clinical study, paediatric patients (ranging in age from 6 to 15 years) with type 1 diabetes (Study 3003, n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on GHb and the incidence of hypoglycaemia were observed in both treatment groups.

Type 1 paediatric diabetes (2 to 6 years).

A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus aged 1 to 6 years (61 children from 2 to 5 in the insulin glargine group and 64 children from 1 to 6 in the NPH insulin group), comparing insulin glargine given once daily in the morning to NPH insulin given once or twice daily as basal insulin. Both groups received bolus insulin before meals.
Comparison of the two treatment regimens in terms of hypoglycaemia was the primary objective of the study. The composite primary outcome consisted of: continuous glucose monitoring excursions below 3.9 mmol/L, confirmed by fingerstick blood glucose (FSBG) measurements; other FSBG measurements < 3.9 mmol/L; and episodes of symptomatic hypoglycaemia.
Overall, the event rate ratio of this composite outcome for once daily insulin glargine compared to NPH (given twice daily in most patients) was 1.18 (95% CI: 0.97-1.44), therefore, not meeting the non-inferiority margin of 1.15.
The rate of symptomatic hypoglycaemia events is the most commonly used and clinically relevant component of the composite outcome. Rates of symptomatic hypoglycaemia events were numerically lower in the insulin glargine group, both overall (25.5 episodes per patient-year, vs 33.0 for NPH) and overnight (2.38 episodes per patient-year, vs 3.65 for NPH).
Glycohaemoglobin and glucose variabilities were comparable in both treatment groups. No new safety signals were observed in this trial.
Table 6 summarises the primary outcome results between insulin glargine and NPH insulin.

Semglee has not been studied in children below 2 years.

Type 2 diabetes in adults (see Table 9).

In one Phase 3 study (Study 3002, n=570), insulin glargine was evaluated for 52 weeks as part of a regimen of combination therapy with insulin and oral antidiabetic agents (a sulfonylurea, metformin, acarbose, or combinations of these drugs). Insulin glargine administered once daily at bedtime was as effective as NPH human insulin administered once daily at bedtime in reducing GHb and fasting glucose. However, fewer patients treated with insulin glargine reported a nocturnal hypoglycaemic episode after initial titration, from study month 2 to end of study (see Table 7).

In another Phase 3 study in patients with type 2 diabetes not using oral antidiabetic agents (Study 3006, n=518), a basal-bolus regimen of insulin glargine once daily at bedtime or NPH human insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals as needed. Insulin glargine had similar effectiveness as either once or twice-daily NPH human insulin in reducing GHb and fasting glucose. Fewer patients treated with insulin glargine reported nocturnal hypoglycaemia from study month 2 to end of study (Table 8).

Type 1 and type 2 adult diabetes.

Table 9 compares regimens of insulin glargine once daily to NPH human insulin either once or twice daily in subgroups of patients from Phase 3 studies based upon prior basal insulin regimens.

Type 1 diabetes in children.

Table 10 compares regimens of insulin glargine once daily to NPH human insulin either once or twice daily in subgroups of patients from Phase 3 studies based upon prior basal insulin regimens.

ORIGIN trial (study HOE901/4032).

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) trial was an international, multicenter, randomised, open-label, 2x2 factorial design study conducted in 12,537 participants with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or early type 2 diabetes mellitus and evidence of CV disease. Participants were randomised to receive insulin glargine (n=6264) (participants with IFG and/or IGT = 11.7%, early type 2 diabetes mellitus = 88.3%), titrated to a FPG of 5.3 mmol/L or less, or standard care (n = 6273) (participants with IFG and/or IGT = 11.4%, early type 2 diabetes mellitus = 88.6%). At baseline participants had a mean age of 63.5 years, mean duration of diabetes of 5.8 years in those with pre-existing diabetes, and median HbA1c of 6.4%. Median duration of follow-up was approximately 6.2 years. At the end of the trial 81% of participants randomised to take insulin glargine were still on treatment.
The primary objective of the trial was to demonstrate that insulin glargine use could significantly lower the risk of major cardiovascular endpoints compared to standard care. There were two co-primary composite efficacy outcomes. The first one was the time to the first occurrence of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, and the second one was the time to the first occurrence of any of the first co-primary events, or revascularization procedure (cardiac, carotid, or peripheral), or hospitalization for heart failure.
Secondary endpoints were:
all-cause mortality;
a composite microvascular outcome;
development of type 2 diabetes, in participants with IGT and/or IFG at baseline.
After a median treatment duration of 6.2 years, insulin glargine did not alter the relative risk for CV disease and CV mortality when compared with standard care. There were no significant differences between insulin glargine and standard care for the two co-primary outcomes, for any individual components of the co-primary outcomes, for all-cause mortality or for the composite microvascular outcomes. The results are displayed in Table 11.

Median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulin glargine group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up. Median FPG at the end of study in the insulin glargine group was 5.4 mmol/L, and for the standard care group was 6.8 mmol/L.
Over the course of this 6 year study severe hypoglycaemia was reported in 5.7% of the insulin glargine group compared to 1.9% of the standard care group. The rates (per 100 Patient-Years) of confirmed all hypoglycaemia events, severe hypoglycaemia events and non-severe symptomatic hypoglycaemia are shown in Table 12.
Over the course of this 6-year study, 42% of the insulin glargine group and 74% of the standard care group did not experience any hypoglycaemia.

Cancer.

In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancers was similar between the treatment groups as shown in Table 13.

5.2 Pharmacokinetic Properties

After subcutaneous injection of insulin glargine in healthy subjects and patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a lack of a peak in comparison to NPH human insulin. However, the assay was unable to differentiate between the two forms of insulin (native human insulin and insulin glargine). Concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.
After subcutaneous injection of 0.3 IU/kg insulin glargine in patients with type I diabetes, a flat concentration-time profile has been demonstrated; this is also reflected in the wide range of T_max values (0 to 22.5 h) compared to 0.3 IU/kg NPH human insulin (2.5 to 10.5 h).
There were no relevant differences in serum insulin glargine levels and the duration of action after abdominal, deltoid or thigh subcutaneous administration.
In a randomised, controlled, double-blind, four-way crossover trial in healthy male volunteers, insulin glargine with polysorbate 20 was found to be bioequivalent to insulin glargine.

Metabolism.

After subcutaneous injection of insulin glargine in healthy subjects and diabetic patients, insulin glargine is rapidly metabolised at the carboxyl terminus of the beta-chain with formation of two active metabolites M1 (21^A-gly-insulin) and M2 (21^A-gly-des-30^B-thr-insulin). In plasma, the principal circulating compound is the metabolite M1. The exposure to M1 increases with the administered dose of insulin glargine. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulin glargine is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose of insulin glargine.

Special populations.

Age and gender.

There were no phase 1 studies to evaluate the effects of age and race. In clinical trials, subgroup analysis based on age and gender did not indicate any difference in safety and efficacy in insulin glargine treated patients compared to the total study population.

Obesity.

In clinical trials, subgroup analysis based on BMI showed no differences in safety and efficacy in insulin glargine treated patients compared to the total study population. The same was true for NPH insulin.

Renal and hepatic impairment.

No studies were performed in patients with renal or hepatic impairment. Careful glucose monitoring and dose adjustments of insulin or insulin analogues including insulin glargine may be necessary.

5.3 Preclinical Safety Data

Genotoxicity.

Insulin glargine was negative in tests for mutagenicity in bacterial and mammalian cells and for clastogenicity (in vitro in V79 cells and in vivo in Chinese hamsters).

Carcinogenicity.

Two year carcinogenicity studies were performed in mice and rats at subcutaneous doses up to 12.5 IU/kg/day (approximately 3 and 7 times anticipated clinical exposure based on BSA). Malignant fibrous histiocytomas were found at insulin glargine injection sites in male rats and mice. The incidence of these tumours was not dose-dependent and tumours were also present at acid vehicle control injection sites but not at saline control injection sites or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown.
Other insulin preparations are known to cause an increase in mammary tumours in female rats. No such increase in tumours was seen with insulin glargine probably because of the lower doses of insulin glargine used in the mouse and rat carcinogenicity studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

Semglee contains metacresol, glycerol, zinc chloride, hydrochloric acid and sodium hydroxide for adjustment to pH 4.0, 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

Store unopened pre-filled pens in a refrigerator at 2 to 8°C. Do not freeze.
Store open (in use) pre-filled pens below 30°C. Do not refrigerate open pre-filled pens. Avoid direct heat and light. Use unrefrigerated pre-filled pens within a 28 day period or discard any remaining contents 28 days after commencement of use.

6.5 Nature and Contents of Container

Semglee 100 IU/mL solution for injection for subcutaneous use is available as 3 mL, Type 1, colourless glass cartridges inside pre-filled, disposable pen devices.
Semglee is available in cartons with the following pack sizes:
1 pre-filled injection pen with 1 x 3 mL cartridge.
5 pre-filled injection pens with 1 x 3 mL cartridge each.
Some pack sizes may not be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Chemical name: 21^A-Gly-30^Ba-L-Arg-30^Bb-L-Arg-human insulin.
Structural formula: Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. The changes relative to the human insulin sequence are highlighted within the balloons. The structural formula is shown below:

Molecular formula: C₂₆₇H₄₀₄N₇₂O₇₈S₆. Molecular weight: 6063.

CAS number.

160337-95-1.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Log in

Consumer medicine information

Semglee

Insulin glargine

Keep track of your medicines

BRAND INFORMATION