Consumer medicine information

Mytolac

Lanreotide

BRAND INFORMATION

Brand name

Mytolac

Active ingredient

Lanreotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mytolac.

SUMMARY CMI

Mytolac®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Mytolac?

Mytolac contains the active ingredient lanreotide (as acetate). Mytolac is used for the:

  • treatment of acromegaly when the circulating levels of growth hormone and IGF-1 remain abnormal after surgery and/or radiotherapy, or in patients who do not respond to therapy with medicines called dopamine agonists
  • treatment of symptoms associated with carcinoid syndrome, such as flushing and diarrhoea
  • treatment and control of the growth of some advanced tumours of the intestine and pancreas that cannot be removed by surgery (called gastroenteropancreatic neuroendocrine tumours or GEP-NETs) in adult patients.

For more information, see Section 1. Why am I using Mytolac? in the full CMI.

2. What should I know before I use Mytolac?

Do not use if you have ever had an allergic reaction to lanreotide, somatostatin or medicines from the same family or any of the ingredients listed at the end of the CMI. Do not use Mytolac if you are breastfeeding.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Mytolac? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Mytolac and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Mytolac?

  • Information on how to inject Mytolac can be found in the Instructions for administration of the product at the end of this leaflet.
  • For the treatment of acromegaly or the symptoms of carcinoid syndrome, the recommended starting dose is 60 mg to 120 mg injected every 28 days.
  • For the treatment of advanced tumours of the intestine and pancreas that cannot be removed by surgery (GEP-NETs), the recommended dose is 120 mg every 28 days.

More instructions can be found in Section 4. How do I use Mytolac? in the full CMI.

5. What should I know while using Mytolac?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Mytolac.
  • Tell your doctor if you are diabetic.
  • Tell your doctor if you have any heart problems.
Things you should not do
  • Do not stop using this medicine suddenly.
Driving or using machines
  • Mytolac is unlikely to affect your ability to drive or use machines, however possible side effects such as dizziness may occur with this medicine. If you are affected be careful when driving or using machinery.
Looking after your medicine
  • Store Mytolac at 2°C - 8°C in a refrigerator. Do not freeze. Protect from light.

For more information, see Section 5. What should I know while using Mytolac? in the full CMI.

6. Are there any side effects?

More common side effects of Mytolac are related to the gastrointestinal tract and possible occurrence of gallstones. Serious side effects may be allergic reaction or gallstone complications.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Mytolac®

Active ingredient: lanreotide (as acetate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Mytolac. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Mytolac.

Where to find information in this leaflet:

1. Why am I using Mytolac?
2. What should I know before I use Mytolac?
3. What if I am taking other medicines?
4. How do I use Mytolac?
5. What should I know while using Mytolac?
6. Are there any side effects?
7. Product details

1. Why am I using Mytolac?

Mytolac contains the active ingredient lanreotide (as acetate). Lanreotide is an antigrowth hormone. Lanreotide is an octapeptide, an analogue of a naturally occurring hormone, somatostatin. Lanreotide lowers the levels of hormones in the body such as GH (growth hormone) and IGF-1 (insulin-like growth factor-1).

Mytolac is used for the:

  • treatment of acromegaly when the circulating levels of growth hormone and IGF-1 remain abnormal after surgery and/or radiotherapy, or in patients who do not respond to therapy with medicines called dopamine agonists
  • treatment of symptoms associated with carcinoid syndrome, such as flushing and diarrhoea
  • treatment and control of the growth of some advanced tumours of the intestine and pancreas that cannot be removed by surgery (called gastroenteropancreatic neuroendocrine tumours or GEP-NETs) in adult patients.

2. What should I know before I use Mytolac?

Warnings

Do not use Mytolac if you:

  • are allergic to lanreotide, somatostatin or medicines from the same family (analogues of somatostatin), or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • are breastfeeding.
  • If you have a tumour blocking your intestines
  • Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue.

Check with your doctor if you:

  • are a diabetic
  • have ever experienced liver or kidney problems
  • have ever experienced gallstones as Mytolac may lead to gallstone formation in the gallbladder. In this case, you may need to be monitored periodically. Your doctor may decide to stop treatment with Mytolac if complications arising from gallstones occur.
  • have any thyroid problems, as Mytolac may slightly decrease your thyroid function have any heart problems, as sinus bradycardia (slow heart rate) may occur during lanreotide treatment. Special care should be taken by your doctor when first starting Mytolac if you have bradycardia.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Do not breastfeed if you are taking Mytolac.

Use in children

Mytolac is not recommended for use in children.

3. What if I am taking other medicines?

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

Mytolac may interfere with the effect of other medicines which include:

  • medicines which reduce the heart rate (e.g. beta-blockers)
  • ciclosporin, a medicine used to treat certain problems with the immune system
  • bromocriptine, a medicine used to treat Parkinson's disease
  • medicines broken down by certain liver enzymes such as quinidine or terfenadine.

Dose adjustments of these may be considered by your doctor.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Mytolac.

4. How do I use Mytolac?

How much to use

  • For the treatment of acromegaly or the symptoms of carcinoid syndrome, the recommended starting dose is 60 mg to 120 mg injected every 28 days. Depending on your response to the product, your doctor may vary the dose or the injection frequency.
  • For the treatment of advanced tumours of the intestine and pancreas that cannot be removed by surgery (GEP-NETs), the recommended dose is 120 mg every 28 days. Your doctor will decide how long you should be treated with lanreotide for tumour control.
  • Follow the instructions provided and use Mytolac until your doctor tells you to stop.

How to administer Mytolac

If you forget to use Mytolac

Mytolac should be used regularly every 28 days. If you miss your dose at the usual day, contact your doctor who will then advise when your next injection is to be given.

Do not self-inject extra doses to make up for a forgotten injection without discussing with your doctor.

If you use too much Mytolac

As Mytolac is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. Mytolac comes in a syringe pre-filled with the dose your doctor has prescribed.

However, if you think that you have used too much Mytolac, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Mytolac?

Things you should do

Call your doctor straight away if you:

  • are feeling more thirsty or tired than usual and have a dry mouth. These may be signs that you have high blood sugar levels or are developing diabetes.
  • are feeling hungry, shaky or confused, or are sweating more than usual. These may be signs of low blood sugar levels.

Things you should not do

  • Do not stop using this medicine suddenly.

Monitoring

  • If you are diabetic, your doctor may check your blood sugar levels and possibly alter your anti-diabetic treatment while you are receiving Mytolac.
  • If you have heart problems, your doctor may check your heart rate and possibly alter your treatment while you are taking Mytolac.
  • Due to the possibility of gallbladder problems with this type of medicine, your doctor may want to conduct a gallbladder scan when you start receiving Mytolac and again at regular intervals thereafter.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Mytolac affects you.

Mytolac is unlikely to affect your ability to drive or use machines, however possible side effects such as dizziness may occur with this medicine. If you are affected be careful when driving or using machinery.

Looking after your medicine

  • Store Mytolac at 2°C - 8°C in a refrigerator. Store in its original package to protect from light. Do not freeze.
  • The syringe inside its sealed pouch can be temporarily stored outside of the refrigerator up to a maximum of 24 hours (make sure the temperature stays below 40°C). Return the syringe to the refrigerator as soon as possible for continued storage and use.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Do not use it if the aluminium pouch is damaged or opened.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • bowel problems including diarrhoea or loose stools, abdominal pain
  • nausea, vomiting, heartburn, abdominal bloating or discomfort, passing wind or constipation
  • changes in blood sugar levels (low and high), aggravation of diabetes
  • slowing of the heart rate
  • tiredness
  • headache, dizziness
  • hair loss or no hair growth
  • moderate and short-lived pain at the injection site, sometimes with redness, swelling, itching tenderness or abscess
  • changes in some liver or pancreas test results
  • weight loss
  • lack of energy
  • feeling generally weak
  • decrease in appetite
  • pain that affects muscles, ligaments, tendons and bones
  • excess fat in the stools
  • enlargement of the bile ducts (symptoms may be stomach pain, nausea, jaundice and fever)
  • Pancreatic exocrine insufficiency (PEI)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • gallstones or gallstone complications (signs may be sudden, severe abdominal pain that may spread to the shoulder or back, tenderness of the abdomen, feeling nauseous, vomiting, fever, chills, loss of appetite, itchy skin, having dark urine, clay-coloured stools or yellowing of the skin and eyes (jaundice))
  • allergic reaction (symptoms may include flushed or swollen face, developing spots or a rash, feeling tight in the chest, being short of breath or wheezy, feeling faint)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. In New Zealand, you can report side effects to the Centre for Adverse Reactions Monitoring online at nzphvc.otago.ac.nz/reporting.

By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Mytolac contains

Active ingredient
(main ingredient)		lanreotide (as acetate)
Other ingredients
(inactive ingredients)		glacial acetic acid
water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Mytolac looks like

Mytolac is a semi-solid phase having a gel-like appearance, with viscous characteristics and a colour varying from white to pale yellow

Mytolac is supplied in a pre-filled syringe which is placed in a plastic tray and sealed inside an aluminium pouch. A separately packed automatic single use safety needle is also provided.

One syringe and one safety needle are packaged inside a cardboard box.

Mytolac 60 mg: Aust R 371881
Mytolac 90 mg: Aust R 371880
Mytolac 120 mg: Aust R 371879

Who distributes Mytolac

Distributed in Australia by:

Amdipharm Mercury (Australia) Pty Ltd
Level 9, 76 Berry Street
North Sydney NSW 2060

Ph: 1800 627 680

Distributed in New Zealand by:

Mercury Pharma (NZ)
39 Anzac Road
Browns Bay
Auckland 0753
Ph: 0800 565 633

Amdipharm Mercury (Australia) Pty Ltd is an ADVANZ PHARMA company

This leaflet was revised in February 2024.

Instructions for administration of the product

Your doctor may suggest that the injection can be given by yourself or your carer. Your doctor or nurse will give you or your carer the appropriate training and confirm that you are both motivated and capable of doing this. Your doctor will continue to supervise the long-term management of your condition.

If the injection is being administered by a healthcare professional or your carer, the injection will usually be given as a deep subcutaneous injection in the upper, outer external quadrant of the buttock.

If you are giving the injection to yourself, the deep subcutaneous injection should be given in the upper, outer thigh. The injection site should be alternated between right and left sides.

Instructions for use

A. What's in the box

The following instructions explain how to inject Mytolac. Please read all instructions carefully before starting the injection.

The content of the prefilled syringe is a semi-solid phase having a gel-like appearance, with viscous characteristics and a colour varying from white to pale yellow. The supersaturated solution can also contain micro bubbles that can clear up during injection. These differences are normal and do not interfere with the quality of the product.

B. Before you start

B1. Remove Mytolac from the refrigerator 30 minutes prior to injecting. Keep the aluminium pouch sealed until just before the injection.

B2. Before opening the pouch, check that it is intact and that the medicine has not expired. The expiry date is printed on the outer carton and the pouch.

Do not use if:

  • YOU DROP OR DAMAGE THE PRE-FILLED SYRINGE
  • THE PRE-FILLED SYRINGE OR POUCH APPEAR DAMAGED IN ANY WAY.
  • THE PRODUCT HAS EXPIRED

B3. Wash hands with soap and dry hands thoroughly before starting.

B4. Make sure there is a clean surface for preparation.

B5. Choose injection site - the sites are shown below.

B6. Make sure to clean the injection site.

B7. Tear open the pouch and take out the pre-filled syringe.

If you are injecting someone else:

Inject into the upper outer area of the buttock.

If you are injecting yourself:

Inject into the upper outer part of your thigh.

Alternate the injection site between the right and left side each time you have an injection of Mytolac.

C. Get the syringe ready

C1: Remove the cap from the syringe

  • With one hand, hold the syringe barrel steady (not the plunger).
  • With the other hand, remove the cap by twisting it.

C2: Open the needle pack

  • Hold the needle pack and pull the lid off.

Caution: Do not touch the open end of the needle pack. This needs to stay clean.

C3: Put the end of the syringe into the open end of the needle pack

  • Hold the needle pack with one hand.
  • With the other, hold the syringe barrel steady (not the plunger) and twist until the syringe and needle are fully locked together.
  • They are fully locked when you cannot turn it any further.

Important: Tighten the syringe firmly to avoid drug leakage.

C4: Remove the needle from the pack

  • Hold the syringe barrel (not the plunger).
  • Pull the needle straight out from the needle pack without twisting or turning to make sure that the syringe is well connected to the safety needle.

Caution: The needle is partially exposed from this step onwards.

  • NEVER TOUCH OR TRY TO OPEN THE GREEN NEEDLE SHIELD throughout the course of operation of the device.

  • Green needle shield is NOT a removable cap or cover for the needle.
  • Green needle shield will automatically activate once the injection is complete.
  • Green needle shield will automatically cover and lock around the needle once the injection is complete
  • Green needle shield is a self-operating safety lock mechanism.

D. Perform injection

D1: Position the syringe

  • To check which site you should use, refer to section B.
  • Stretch the skin around the injection site flat and tight using your thumb and index finger.
  • Hold the lower part of the syringe barrel (not the plunger) with your other hand.
  • Position the syringe at a 90-degree angle to the skin.

D2: Insert the needle

  • Without folding or pressing on the skin at the injection site, push the needle firmly against the skin.
  • The Green needle shield will retract and The safety mechanism will activate.
  • Keep going until only the collar of the Green needle shield is visible.
  • Do not push the plunger in this step. Hold the syringe in this position for the next step.

D3: Push the top of the plunger

  • Move your hand from the skin to the plunger.
  • Push the plunger slowly until the top touches the syringe barrel (it is easier to depress the plunger with your dominant hand).
  • This should take around 20 seconds.

E. Remove and throw away syringe

E1: Remove from the skin

  • Lift the syringe straight up and away from your body.
  • The Green needle shield will cover the needle.

E2: Apply gentle pressure

  • Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding.
  • Do not rub or massage the injection site after administration.

E3: Throw away

  • Dispose of the used syringe and needle in the syringe disposal container as instructed by your doctor or healthcare professional.
  • The needles are not reusable.
  • Do not dispose of the syringe or needle in your general household rubbish.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Mytolac

Active ingredient

Lanreotide

Schedule

S4

 

1 Name of Medicine

Lanreotide acetate.

2 Qualitative and Quantitative Composition

Lanreotide (as acetate) 60 mg, 90 mg and 120 mg solution for injection in a pre-filled syringe.
Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 24.6 mg of lanreotide base per 100 mg of solution. Each syringe delivers an injection dose of 60 mg, 90 mg and 120 mg of lanreotide base, respectively.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection in a pre-filled syringe.
It is a white to pale-yellow semi-solid formulation and is formulated as a prolonged-release solution of lanreotide acetate for deep subcutaneous injection. Prolonged release of the peptide is achieved by the physical nature of the supersaturated solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Mytolac is indicated for:
the treatment of acromegaly when the circulating levels of growth hormone and IGF-1 remain abnormal after surgery and/or radiotherapy or in patients who are dopamine agonist treatment refractory;
the treatment of symptoms of carcinoid syndrome associated with carcinoid (neuroendocrine) tumours;
the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adult patients with unresectable locally advanced or metastatic disease.

4.2 Dose and Method of Administration

Dose.

Acromegaly.

In patients receiving a somatostatin analogue for the first time, the recommended starting dose is 60 mg of lanreotide administered every 28 days.
In patients previously treated with lanreotide microparticle formulation* once every 14 days, the initial dose of Mytolac should be 60 mg every 28 days; in patients previously treated with lanreotide microparticle formulation once every 10 days, the initial dose of Mytolac should be 90 mg every 28 days, and in patients treated with lanreotide microparticle formulation once every 7 days, the initial dose of Mytolac should be 120 mg every 28 days.
* Lanreotide microparticle formulation is unavailable in this brand.
Thereafter, in all patients, the dosage strength (60 mg, 90 mg and 120 mg) should be individualised according to the response to treatment (as judged by a reduction in GH and/or IGF-1 levels).
If the desired response is not obtained, the dose may be increased.
If complete control is obtained (based on GH levels under 1 microgram/L, normalised IGF-1 levels and/or disappearance of symptoms), the dose may be decreased.
Patients well controlled on lanreotide can be treated with Mytolac 120 mg every 42-56 days.
Long term monitoring of symptoms, GH and IGF-1 levels should be undertaken as clinically indicated.

Symptoms of carcinoid syndrome.

The recommended starting dose is 60 to 120 mg administered every 28 days. The dose should be adjusted according to the degree of symptomatic relief obtained.

Treatment of gastroenteropancreatic neuroendocrine tumours in adult patients with unresectable locally advanced or metastatic disease.

The recommended dose of Mytolac is one injection of 120 mg administered every 28 days. The treatment with Mytolac should be continued for as long as needed for tumour control.

Special populations.

Patients with renal or hepatic impairment.

In patients with hepatic/renal dysfunction, kidney and liver function should be regularly monitored. Due to the wide therapeutic window of lanreotide, it is not necessary to adjust the dose in these circumstances.

Method of administration.

Mytolac should be injected via the deep subcutaneous route in the superior external quadrant of the buttock by a healthcare professional. The deep subcutaneous injection should be given at varying places in the buttock or in the upper outer thigh.
For patients who are controlled on Mytolac, the product may be administered either by the patient or their carer, who both must be motivated and competent to perform the injection following appropriate training. In the case of self-injection, the injection should be given in the upper outer thigh.
The decision regarding administration of Mytolac by the trained patient/ carer should be taken by a health professional. A monitoring system should be in place for such patients to ensure the maintenance of their disease control in the long term.
Regardless of the site of injection, the skin should not be folded and the needle should be inserted rapidly to its full length, perpendicularly to the skin. The injection site should be alternated between the right and left side.
Pharmaceutical precautions. Do not use if the aluminium pouch is damaged or opened.
Instructions for use/ handling. The solution for injection in a pre-filled syringe is ready for use.
After opening the protective aluminium pouch, the product should be administered immediately.
For use in one patient on one occasion only. Discard any residue. Contains no antimicrobial preservative.

NB.

It is important that injection of this product is performed according to the instructions in the package insert.

4.3 Contraindications

Mytolac should not be prescribed during lactation, nor in patients presenting with hypersensitivity to the peptide or related peptides or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Hyperglycaemia and hypoglycaemia.

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and its analogues inhibit secretion of insulin and glucagon. Hence, patients treated with lanreotide may experience hypoglycaemia or hyperglycaemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and treatment of diabetic patients should be accordingly adjusted. In insulin-dependent patients, insulin requirements may be reduced.

Hypothyroidism.

Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare. Thyroid function tests are recommended where clinically indicated.

Cholelithiasis and complications of cholelithiasis.

Lanreotide may reduce gall bladder motility and therefore, gall bladder echography is advised at the start of treatment and every six months thereafter. There have been post-marketing reports of gallstones resulting in complications, including cholecystitis, cholangitis, and pancreatitis, requiring cholecystectomy in patients taking lanreotide. If complications of cholelithiasis are suspected, discontinue lanreotide and treat appropriately.
In patients with hepatic/ renal dysfunction, kidney and liver function should be regularly monitored (see Section 4.2 Dose and Method of Administration, Patients with renal or hepatic impairment).

Bradycardia.

Lanreotide may lead to a decrease of heart rate without necessarily reaching the threshold of bradycardia in patients without an underlying cardiac problem. In patients suffering from cardiac disorders prior to lanreotide initiation, sinus bradycardia may occur and therefore heart rate should be monitored. Care should be taken when initiating treatment with lanreotide in patients with bradycardia.
In 81 patients with baseline heart rates of ≥ 60 beats per minute (bpm) treated with lanreotide in Study 726 in GEP NET patients, the incidence of heart rate < 60 bpm was 23% (19/81) as compared to 16% (15/94) of placebo treated patients; ten patients (12%) had documented heart rates < 60 bpm on more than one visit. The incidence of documented episodes of heart rate < 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia.

Pancreatic function.

Pancreatic exocrine insufficiency (PEI) has been observed in some patients receiving lanreotide therapy for gastroenteropancreatic neuroendocrine tumours. Symptoms of PEI can include steatorrhea, loose stools, abdominal bloating and weight loss. Screening and appropriate treatment for PEI according to clinical guidelines should be considered in symptomatic patients.

Use in hepatic impairment.

In subjects with moderate to severe hepatic impairment a reduction in clearance (30%) and an increase in volume of distribution and mean residence time are observed.
No GEP-NET patients with hepatic impairment (as per Child-Pugh score) were studied.

Use in renal impairment.

Subjects with severe renal impairment show an approximately two-fold decrease in total serum clearance of lanreotide, with a consequent increase in half-life and AUC.
No effect on clearance of lanreotide was observed in a population PK analysis of GEP-NET patients including 165 with mild and moderate renal impairment (106 and 59 respectively) treated with lanreotide. GEP-NET patients with severe renal impaired function were not studied.

Use in the elderly.

Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. Due to the wide therapeutic window of lanreotide, it is not necessary to adjust the dose in these circumstances.
In a population PK analysis of GEP-NET patients including 122 patients aged 65 to 85 years, no effect of age on clearance and volume of distribution of lanreotide was observed.

Paediatric use.

As there is no experience of the use of the product in children, the use of lanreotide in children cannot be advised.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on lanreotide.

Concomitant administration of bradycardia-inducing drugs (i.e. beta blockers) may have an additive effect on the slight reduction of heart rate associated with lanreotide. Dose adjustments of such concomitant medications may be necessary.

Effect of lanreotide on other medicinal products.

The gastrointestinal effects of lanreotide may result in the reduction of the intestinal absorption of co-administered drugs. As with other somatostatin analogues, lanreotide may reduce the intestinal absorption of ciclosporin A.
Concomitant administration of ciclosporin with lanreotide may decrease the relative bioavailability of ciclosporin and therefore may necessitate the adjustment of ciclosporin dose to maintain therapeutic levels.
Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins (78% mean serum binding).
Limited published data indicate that concomitant administration of somatostatin analogues and bromocriptine may increase the availability of bromocriptine.
The limited published data available indicate that somatostatin analogues may decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in normal male and female rats showed that lanreotide decreased fertility index, increased pre-implantation loss and duration of gestation, and decreased the number of delivered pups in the F1 and F2 generations at a systemic exposure level approximately two times higher than in humans.
(Category C)
There is a limited amount of data (less than 300 pregnancy outcomes) from the use of lanreotide in pregnant women. Studies in animals have shown reproductive toxicity but no evidence of teratogenic effects. The potential risk for humans is unknown.
As a precautionary measure, it is preferable to avoid the use of lanreotide during pregnancy.
This drug may produce foetal growth retardation in normal animals, probably due to the suppression of the growth hormone. No teratogenic effects were observed in rats or rabbits dosed subcutaneously with lanreotide at doses up to 2 mg/kg/day. Systemic exposure at this dose level was not measured in rabbits, but in rats was about 14 times higher than that expected in humans. In rabbits, embryofetal survival was reduced at doses greater than 0.1 mg/kg/day.
 It is not known whether lanreotide is excreted in the milk of animals or humans. A study in rats dosed with lanreotide during lactation showed transitory growth retardation of the offspring prior to weaning, and reduced performance of male offspring in a test of learning and memory. Lanreotide must not be administered to breast feeding women (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Lanreotide has minor or moderate influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, dizziness has been reported with lanreotide. If a patient is affected he/ she should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

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.
The adverse effects related to lanreotide solution for injection during clinical trials are consistent with those seen with other prolonged release formulations of lanreotide, and are predominantly gastrointestinal. In clinical trials of lanreotide solution for injection in acromegalic patients, up to 80% of patients experienced at least one adverse effect. More than 50% of these adverse effects were classified as gastrointestinal system disorders. The most commonly reported adverse effects are gastrointestinal disorders and cholelithiasis. The profile of undesirable effects is similar for other indications.
Undesirable effects reported by patients suffering from acromegaly and GEP-NETs, treated with lanreotide solution for injection or the microparticle formulation of lanreotide 30 mg in clinical trials are listed under the corresponding body organ systems according to the following classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100): not known (cannot be estimated from the available data). See Table 1.
Rarely post-injection episodes of malaise with signs of dysautonomia were reported

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 for Australia and National Poisons Centre on 0800 POISON (0800 764766) for New Zealand.
Animal data do not predict any effects other than those on insulin and glucagon secretion and the gastrointestinal system. If overdosage occurs, symptomatic management is indicated.
One spontaneous report of an overdose of a microparticle formulation of lanreotide was reported in a 52 year old patient, with a medical history of diabetes mellitus and hypertension, who had received as a result of drug misuse 30 mg lanreotide per day for 2 months. No acute symptoms or pharmacological signs of overdose were reported. The patient died of an acute myocardial infarction, one week after the last dose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antigrowth hormones.
ATC code: H01C B03.

Mechanism of action.

Like natural somatostatin, lanreotide is a peptide inhibitor of a number of endocrine, neuroendocrine, exocrine and paracrine functions. It shows good affinity for peripheral somatostatin receptors (anterior pituitary and pancreatic). In contrast, its affinity for central receptors is much lower. This profile confers a good specificity of action at the level of growth hormone secretion.
Lanreotide shows a much longer duration of action than natural somatostatin. In addition, its marked selectivity for the secretion of growth hormone, compared to that of insulin, makes it a suitable candidate for the treatment of acromegaly.
Additionally, in the pivotal trial Study 726, lanreotide decreased the levels of plasma chromogranin A and urinary 5-HIAA (5 Hydroxyindolacetic acid) by at least 50% in 42.2% and 53.3%, respectively, of patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and with elevated levels of these tumour markers.

Clinical trials.

Acromegaly.

One open multicentre clinical study was conducted in order to evaluate the efficacy of three repeated deep subcutaneous administrations of lanreotide solution for injection (60, 90 or 120 mg) at fixed doses in acromegalic patients previously treated with the 30 mg prolonged release microparticle formulation of lanreotide. This study was of a switch design in which acromegalic patients were given lanreotide microparticle formulation in a first period and lanreotide solution for injection in a second period. In the second period, patients received either lanreotide solution for injection 60, 90 or 120 mg for three months depending on their respective dosing interval of lanreotide microparticle formulation, as follows:
dosing interval of lanreotide microparticle formulation between 12 and 16 days at the end of the first period: switch to lanreotide solution for injection 60 mg;
dosing interval of lanreotide microparticle formulation between 8 and 11 days at the end of the first period: switch to lanreotide solution for injection 90 mg;
dosing interval of lanreotide microparticle formulation between 5 and 7 days at the end of the first period: switch to lanreotide solution for injection 120 mg.
This ensured that patients continued to receive the same monthly total lanreotide dose. The lanreotide serum levels in patients at the end of the 3rd interval of lanreotide solution for injection administration were similar to those obtained at the end of the 4th interval of administration of lanreotide microparticle formulation, all strengths combined (2.17 ± 0.92 microgram/L and 2.37 ± 1.13 microgram/L, respectively). It should be noted that lanreotide serum levels fell in the first interval following changeover to the solution for injection formulation, with associated increases in GH and IGF-1 levels.
The study demonstrated that the efficacy of lanreotide solution for injection after three injections given every 28 days is not inferior to lanreotide microparticle formulation (administered every 7 to 14 days) after four injections. Median GH and median IGF-1 were similar at the end of the 3rd interval of lanreotide solution for injection and at the end of the 4th interval of lanreotide microparticle formulation administration. Similar safety was observed after three injections of lanreotide solution for injection and after four injections of lanreotide microparticle formulation. (See Table 2.)

Carcinoid syndrome.

One open multicentre clinical study was conducted to evaluate the efficacy of lanreotide solution for injection (60 mg, 90 mg or 120 mg) administered once monthly for 6 months in the relief of the clinical symptoms associated with carcinoid syndrome. Each patient's target symptom (diarrhoea or flushing) was chosen by the investigator as the symptom which most troubled the patient. Responders were defined as having a reduction of ≥ 50% (compared to baseline) in the average number of daily episodes of diarrhoea or moderate to severe flushing.
27 out of 71 patients (38%) in the ITT population and 14 out of 35 (40%) patients in the PP population were target symptom responders at month 6. Of 40 patients whose target symptom was diarrhoea, seven (18%) responded at month 6. Of 31 patients whose target symptom was flushing, twenty (65%) responded at month 6. Lanreotide solution for injection was generally well tolerated.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs).

A Phase III, 96-week, fixed duration, randomized, double-blind, multi-centre, placebo-controlled trial of lanreotide solution for injection (Study 726) was conducted in patients with gastroenteropancreatic neuroendocrine tumours to assess the antiproliferative effect of lanreotide.
Patients had metastatic and/or locally advanced inoperable disease with histologically confirmed well or moderately well differentiated tumours primarily localized in the pancreas, mid-gut, hind-gut or of unknown primary location.
Randomization was stratified by previous therapy at entry and the presence/absence of progression at baseline as assessed by RECIST 1.0 (Response Evaluation Criteria in Solid Tumours) during a 3 to 6 month screening phase.
The primary endpoint was progression-free survival (PFS) measured as time to either disease progression by RECIST 1.0 or death within 96 weeks after first treatment administration. Analysis of PFS utilized independent centrally-reviewed radiological assessment of progression. Secondary endpoints included safety, overall survival, percentage of patients alive and progression free at weeks 48 and 96 and effect on tumour markers.
Patients were randomized 1:1 to receive either lanreotide solution for injection 120 mg every 28 days (n=101) or placebo (n=103). In terms of age and sex demographics were well balanced (median age 62.7 years, 52.5% male). Additionally, 96% of the patients were Caucasian, 69% of the patients had Grade 1 tumours and 30% had Grade 2, 50.5% of the patients had Ki67 ≤ 2% and 29% had a Ki67 between 2 and 10% (the information on Ki67 was not available in 20% of the patients), 52.5% of the patients had hepatic tumour load ≤ 10%, 14.5% had hepatic tumour load > 10 and ≤ 25% and 33% had hepatic tumour load > 25%.
Crossover from placebo to open-label lanreotide solution for injection, in the extension study, occurred in 45.6% (47/103) of the patients. Monthly treatment with lanreotide demonstrated a statistically significant improvement in PFS resulting in a 53% reduction in risk of disease progression or death when compared to placebo (p=0.0002). The median duration of PFS for lanreotide solution for injection was not reached at 96 weeks, while the median duration of PFS for placebo was 72 weeks as shown in Table 3 and Figure 1.
Based on the Kaplan Meier (KM) estimates at the time of the last scan performed 78% of subjects treated with placebo had progressed or died compared with 38% of subjects treated with lanreotide solution for injection.
The beneficial effect of lanreotide in reducing the risk of progression or death was statistically confirmed in some pre-planned baseline covariates (Figure 2).
A clinically-relevant benefit of treatment with lanreotide solution for injection was seen in patients with tumours of pancreatic, midgut and other/unknown origin as in the overall study population. The limited number of patients with hindgut tumours (14/204) contributed to difficulty in interpreting the results in this subgroup. The available data suggested no benefit of lanreotide in these patients.
A beneficial effect of lanreotide in reducing the risk of progression or death could not be shown for some covariates - progression at baseline (n=9, p=0.29), previous therapy at entry (n=32, p=0.68), hind-gut (n=14, p=0.73), BMI > median value (n=97, p=0.05), hepatic tumour load categories = 0% or > 10% (n's ≤ 35, p > 0.05), as shown in Figure 3.
Changes in tumour size were also assessed during the study. Forty-nine (50.5%) patients in the lanreotide solution for injection group compared to 18 (17.8%) in the placebo group experienced tumour shrinkage at some time during the study. Eighteen (18.6%) patients in the lanreotide solution for injection group compared to 20 (19.8%) in the placebo group experienced a minimal change in tumour size of less than 1%. An increase in tumour size was observed in 30 (30.9%) in the group treated with lanreotide solution for injection and in 63 (62.4%) patients in the placebo group.
No significant difference in overall survival was found in the pivotal Study 726 between the placebo arm and the lanreotide solution for injection arm.

5.2 Pharmacokinetic Properties

Absorption.

After a single subcutaneous injection of lanreotide solution for injection 60 mg in healthy volunteers, a maximum serum concentration (Cmax) of 5.8 ± 4 nanogram/mL was reached after 6 hours, followed by a slow decrease (mean residence time: 30 ± 6 days, apparent half-life: 33 ± 14 days). The absolute bioavailability was 63 ± 10%.
After a single intramuscular injection of lanreotide solution for injection 60 mg in healthy volunteers, a maximum serum concentration (Cmax) of 6.8 ± 3 nanogram/mL was reached after 15 hours, followed by a slow decrease (mean residence time: 23 ± 11 days, apparent half-life: 23 ± 9 days). The absolute bioavailability was 79 ± 10%.
Therefore, the route of administration (subcutaneous or intramuscular) does not show any marked influence on the lanreotide pharmacokinetic profile.
After a single intramuscular injection of lanreotide solution for injection 90 mg in healthy volunteers, a maximum serum concentration (Cmax) of 9.8 ± 5 nanogram/mL was reached after 10 hours, followed by a slow decrease (mean residence time: 26 ± 4 days, apparent half-life: 31 ± 16 days). The absolute bioavailability was 58 ± 10%.
After a single intramuscular injection of lanreotide solution for injection 120 mg in healthy volunteers, a maximum serum concentration (Cmax) of 12.8 ± 7 nanogram/mL was reached after 16 hours, followed by a slow decrease (mean residence time: 29 ± 3 days, apparent half-life: 28 ± 6 days). The absolute bioavailability was 55 ± 10%.
Therefore, lanreotide serum concentration after intramuscular administration of lanreotide solution for injection 60, 90 and 120 mg shows an almost log-linear first order lanreotide release profile.
In an open, comparative, multicentre, switch design study, lanreotide solution for injection 120 mg was administered every 56, 42 or 28 days to those given lanreotide microparticle formulation 30 mg every 14, 10 or 7 days at least for 2 months prior to the study. This study demonstrated that trough levels obtained after the switch were similar to levels with lanreotide microparticle formulation treatment. Furthermore, the serum levels obtained after administration of lanreotide solution for injection 120 mg every 56, 42 or 28 days are comparable, at equivalent cumulative dose, to those obtained after three deep subcutaneous injections of lanreotide solution for injection 60, 90 or 120 mg, respectively given every 28 days.

Distribution.

Pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 13 L. Total clearance was 20 L/h, terminal half-life was 2.5 hours and mean residence time was 0.68 hours.

Excretion.

In a population PK analysis in 290 GEP-NET patients receiving lanreotide solution for injection 120 mg, rapid initial release was seen with mean Cmax values of 7.49 ± 7.58 nanogram/mL reached within the first day after a single injection. Steady-state concentrations were reached after 4 to 5 injections of lanreotide solution for injection 120 mg every 28 days and were sustained up to the last assessment (up to 96 weeks after the first injection). At steady-state the mean Cmax values were 13.9 ± 7.44 nanogram/mL and the mean trough serum levels were 6.56 ± 1.99 nanogram/mL. The mean apparent clearance was 513 L/day (21.4 L/H) for a typical 74 kg individual and the mean apparent terminal half-life was 43.6 days.

5.3 Preclinical Safety Data

Genotoxicity.

Lanreotide did not show mutagenic or clastogenic activity in a standard battery of in vitro and in vivo tests.

Carcinogenicity.

Two carcinogenicity studies were conducted by the subcutaneous route in mice and rats at doses up to 30 and 0.5 mg/kg/day respectively. Lanreotide did not increase tumour incidences at doses up to 5 mg/kg/day in male mice and 1.5 mg/kg/day in female mice (relative exposure based on animal:human serum AUC, ≤ 12) and at 0.1 mg/kg/day in rats (relative exposure, ≤ 1). Injection site tumours (fibroma, fibrosarcoma and/or malignant fibrous histiocytoma) were increased in incidence at higher doses (relative exposure, ≥ 18 in mice and ≥ 2 in rats). The development of these tumours is consistent with chronic irritation/ inflammation in rodents from repeated injection and they are not considered to indicate a carcinogenic hazard to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mytolac contains glacial acetic acid (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

Store at 2°C - 8°C (refrigerate, do not freeze). Protect from light.
Once removed from the refrigerator, product left in its sealed pouch may be returned to the refrigerator (the number of temperature excursions must not exceed three times) for continued storage and later use, provided it has been stored for no longer than a total of 24 hours at below 40°C.

6.5 Nature and Contents of Container

Mytolac is supplied in a pre-filled syringe (polypropylene with thermoplastic elastomer rubber plunger stopper sealed with polypropylene cap) which is placed in a plastic tray and sealed inside an aluminium pouch. A separately packed automatic single use safety needle (stainless steel) is also provided. Both are packaged inside a cardboard box.
Box of one 0.5 mL pre-filled syringe and one safety needle (1.2 mm x 20 mm).

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

The pH of Mytolac solution is 5.7 to 6.3.

Chemical structure.

Lanreotide is a peptide containing eight amino acids as shown below:
Molecular formula: C54H69N11O10S2.

CAS number.

108736-35-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes