Consumer medicine information

Somatuline Autogel

Lanreotide

BRAND INFORMATION

Brand name

Somatuline Autogel

Active ingredient

Lanreotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Somatuline Autogel.

SUMMARY CMI

Somatuline® Autogel®

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 Somatuline Autogel?

Somatuline Autogel contains the active ingredient lanreotide. Somatuline Autogel is used to treat acromegaly, for the relief of symptoms in patients with carcinoid syndrome/neuroendocrine tumours, or to treat and control the growth of some advanced tumours of the intestine and pancreas.

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

2. What should I know before I use Somatuline Autogel?

Do not use if you have ever had an allergic reaction to lanreotide or any of the ingredients listed at the end of the CMI.

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 Somatuline Autogel? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Somatuline Autogel 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 Somatuline Autogel?

The recommended starting dose is 60 mg to 120 mg every 28 days. Your doctor will decide on the right dose for you.

  • You must follow all the instructions at the end of this leaflet when using Somatuline Autogel.

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

5. What should I know while using Somatuline Autogel?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Somatuline Autogel.
  • Tell your doctor if you are breastfeeding.
  • Tell your doctor if you have diabetes or any heart problems.
Things you should not do
  • Do not stop using this medicine suddenly.
Driving or using machines
  • Be careful before you drive or use any machines or tools.
  • This medicine may cause dizziness in some people.
Looking after your medicine
  • Store Somatuline Autogel at 2°C - 8°C in a refrigerator in its original package. Do not freeze.

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

6. Are there any side effects?

Like all medicines, Somatuline Autogel can cause side effects, although not everybody gets them. 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.

Some side effects may need medical attention, tell your doctor straight away if you notice any of the following:

  • severe and sudden abdominal pain, yellowing of the skin and eyes, high fever, feeling nauseous, vomiting, dark urine or clay-coloured stools. These may be signs of gallbladder stones (very common), or gallstone complications (uncommon).
  • feeling confused, shaky, more hungry or sweating more than usual, more thirsty or tired than usual, dry mouth. These may be signs of low or high blood sugar levels or development of diabetes (common).


FULL CMI

Somatuline® Autogel®

Active ingredient(s): Lanreotide

Consumer Medicine Information (CMI)

This leaflet provides important information about using Somatuline Autogel. 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 Somatuline Autogel.

Where to find information in this leaflet:

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

1. Why am I using Somatuline Autogel?

Somatuline Autogel contains the active ingredient lanreotide. 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).

Somatuline Autogel is used for:

  • the treatment of acromegaly (a condition where your body produces too much growth hormone),
  • the relief of symptoms such as flushing and diarrhoea that sometimes occur in patients with neuroendocrine tumours (NETs),
  • the treatment and control of the growth of some advanced tumours of the intestine and pancreas called gastroenteropancreatic neuroendocrine tumours (GEP-NETs). It is used when these tumours cannot be removed by surgery.

2. What should I know before I use Somatuline Autogel?

Warnings

Do not use Somatuline Autogel if:

  • you are breastfeeding.
  • you are allergic to lanreotide, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, or other parts of the body
  • rash, itching or hives on the skin

Check with your doctor if you:

  • are a diabetic
  • have ever experienced liver or kidney problems
  • have ever experienced gallstones
  • have any thyroid problems
  • have any heart problems
  • take any medicines for any other condition

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 Somatuline Autogel.

Use in children

Somatuline Autogel is not recommended for use in children.

3. What if I am taking other medicines?

Tell your doctor or pharmacist 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.

Some medicines and Somatuline Autogel may interfere with each other, these include (but are not limited to):

  • Medicines used to help prevent transplant rejection or treat problems with the immune system, such as ciclosporin.
  • Medicines used to treat Parkinson's disease, such as bromocriptine.
  • Medicines known as beta-blockers, that are used to treat high blood pressure, heart conditions, glaucoma, and migraine.
  • Medicines that are broken down in the body by liver enzymes, such as quinidine or terfenadine.

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

4. How do I use Somatuline Autogel?

How much to use

  • Acromegaly or symptoms associated with NETs:
    The recommended starting dose is 60 mg to 120 mg injected every 28 days.
  • GEP-NETs:
    The recommended dose is 120 mg every 28 days.
  • Depending on your response to the medicine, your doctor may vary the dose or the injection frequency.

When to use Somatuline Autogel

  • Somatuline Autogel should be used once every 28 days.
  • Your doctor will decide on the length of your treatment with Somatuline Autogel.
  • Use Somatuline Autogel until your doctor tells you to stop.

How to use Somatuline Autogel

  • You must follow the instructions at the end of this leaflet.
  • It is intended for deep injection under the skin.
  • It is for single use only.
  • Your doctor may decide that you or your carer can administer the injection. Your doctor or nurse will give you detailed instructions on how to do this. It is important not to try to inject yourself until you have been trained by a healthcare professional and you are sure of how to do it.
  • Follow all directions given to you by your doctor, nurse or pharmacist carefully. These may differ from the information contained in this leaflet.

This is a long-term treatment. Keep using this medicine for as long as your doctor tells you.

Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If the injection is being given by your doctor, nurse or carer, the injection will usually be given in the upper, outer external quadrant of the buttock.

If you are giving the injection to yourself, the injection should be made in the upper, outer thigh.

The injection site should be alternated between right and left sides with each injection.

Follow the instructions at the end of this leaflet.

If you forget to use Somatuline Autogel

If you miss your dose at the usual time, contact your doctor who will advise when your next injection should be given.

Do not inject a double or extra dose to make up for the dose you missed.

If you use too much Somatuline Autogel

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

However, if you feel you have been given too much, 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 Somatuline Autogel?

Things you should do

Call your doctor straight away if you:

  • feel 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.
  • feel hungry, shaky, sweating more than usual or feel confused. These may be signs of low blood sugar levels.

Remind any doctor, dentist or pharmacist you visit that you are using Somatuline Autogel.

Talk to your doctor or pharmacist if you:

  • have fatty stools, loose stools, abdominal bloating, or weight loss. These may be signs of pancreatic exocrine insufficiency (PEI), a condition where your pancreas doesn't make enough digestive enzymes used to break down food for your body to absorb.

Things you should not do

  • Do not stop using this medicine suddenly.

Diabetes

  • If you are diabetic, your doctor may check your blood sugar levels and possibly alter your anti-diabetic treatment while you are receiving Somatuline Autogel.

Heart problems

  • If you have heart problems, your doctor may check your heart rate and possibly alter your treatment while you are taking Somatuline Autogel.

Gallbladder problems

  • 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 Somatuline Autogel 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 Somatuline Autogel affects you.

This medicine may cause dizziness in some people.

Looking after your medicine

  • Store Somatuline Autogel at 2°C-8°C in a refrigerator in its original package.
  • Do not freeze.
  • The syringe in its sealed pouch can be temporarily stored outside of the refrigerator on up to three occasions for a maximum of 72 hours in total (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.

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

Keep it where young children cannot reach it.

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.

Serious side effects

Serious side effectsWhat to do
Signs of gallbladder stones (cholelithiasis) or complications:
  • severe and sudden abdominal pain, that may spread to the shoulder or back
  • tenderness of the abdomen
  • high fever, fever, chills
  • vomiting, feeling nauseous, loss of appetite
  • yellowing of the skin and eyes (jaundice), itchy skin
  • dark urine, clay-coloured stools
Slowing of the heart rate:
  • dizziness
  • fainting
  • shortness of breath
  • feeling confused
  • fatigue
Signs of low blood sugar levels:
  • feeling confused
  • feeling hungry
  • feeling shaky
  • sweating more than usual
Signs of high blood sugar levels or development of diabetes:
  • feeling more thirsty or tired than usual
  • dry mouth
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.

Less serious side effects

Less serious side effectsWhat to do
Metabolism related:
  • decrease in appetite
Nervous system related:
  • headache
  • lack of energy
Gastrointestinal related:
  • excess fat in the stools
  • bowel problems including diarrhoea or loose stools, abdominal pain, passing wind or constipation
  • feeling sick, vomiting, heartburn, abdominal bloating or discomfort
Skin and hair related:
  • hair loss or no hair growth
Muscle and bone related:
  • pain that affects muscles, ligaments, tendons and bones
General and injection site related:
  • tiredness
  • feeling generally weak
  • moderate and short-lived pain at the injection site, sometimes with redness, swelling (nodule), itching tenderness or abscess
  • weight loss
Blood test related:
  • changes in some liver or pancreas test results
Speak to your doctor if you have any of these less serious side effects and they worry you.

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. 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 Somatuline Autogel contains

Active ingredient
(main ingredient)		Lanreotide acetate
Other ingredients
(inactive ingredients)		Sterile water
Acetic acid
Potential allergensn/a

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

What Somatuline Autogel looks like

Somatuline Autogel is a pre-filled syringe is packed in a laminated pouch and a cardboard box.

Each box contains one 0.5 mL syringe with an automatic safety system and one needle (1.2 mm x 20 mm). (AUST R 95260, 95261, 95262).

Australian Sponsor of Somatuline Autogel

Ipsen Pty Ltd
Level 5, 627 Chapel Street
South Yarra Victoria 3141

Somatuline® Autogel® is a registered trademark of Ipsen Pharma S.A.S.

This leaflet was prepared in January 2024.

8. Instructions for use

These instructions explain how to inject Somatuline Autogel.

Please read all the instructions carefully before starting the injection.

The injection is a deep subcutaneous injection that requires a specific technique different to normal subcutaneous injections.

Somatuline Autogel is supplied in a ready to use pre-filled syringe fitted with an automatic safety system. The needle will retract automatically following the full administration of the product, to prevent needle stick injury.

  1. Ensure that the medication has been refrigerated in its original package.
    Remove Somatuline Autogel from the refrigerator 30 minutes prior to administration. Injection of cold medication may be painful. Keep laminated pouch sealed until just prior to injection.

  1. Before opening the pouch, check that it is intact and that the medication has not expired. The expiration 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.

If any of the above apply you should contact your doctor or pharmacist.

  1. Wash hands with soap and ensure there is a clean area for preparation.
  2. Tear open the pouch along the dotted line and take out the pre-filled syringe.
    The content of the pre-filled syringe is semi-solid with a gel-like appearance, and a colour varying from white to pale yellow. The solution can also contain very small bubbles that can clear up during injection. These differences are normal and do not interfere with the quality of the product.

After opening the protective laminated pouch, the product should be administered immediately.
  1. Select an injection site:
5a. If a healthcare professional (HCP) or someone else like a trained family member or friend is doing the injection: use the superior external (upper, outer) quadrant of the buttock for injection, or
5b. If you are injecting yourself: use the upper outer part of your thigh.

Alternate the injection site between the right and left side each time you receive an injection of Somatuline Autogel. Avoid areas with moles, scar tissue, reddened skin, or skin that feels bumpy.
  1. Clean the injection site without rubbing the skin excessively and let it dry.
  2. Before injecting, remove the pre-filled syringe from its tray. Discard the tray.

  1. Remove the needle cap by pulling it off and discard it.

  1. Flatten injection area using the thumb and index finger of the hand not holding the pre-filled syringe to stretch the skin. Do not pinch the skin. Use a strong, straight dart-like motion to quickly insert the needle perpendicular to the skin (90° angle), all the way into the skin.
    It is very important that you insert the needle completely. You should not see any needle once it is fully inserted.
    Do not aspirate (do not draw back).

  1. Release injection site that has been flattened by your hand. Push plunger with steady very firm pressure. The medication is thicker and harder to push than you might expect. Typically, 20 seconds are needed. Inject the full dose and give a final push to make sure you cannot depress it any further.

Note: maintain pressure on the plunger with your thumb to avoid activation of the automatic safety system.

  1. Without releasing the pressure on the plunger, withdraw the needle from the injection site.

  1. Then release the pressure on the plunger. The needle will automatically retract into the needle guard where it will be locked permanently.

  1. 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.
  2. Dispose of the used syringe in the syringe disposal container as instructed by your doctor or healthcare provider. Do not dispose of the device in your general household rubbish.
    Keep the disposal container and Somatuline Autogel out of reach and sight of children.

Published by MIMS June 2024

BRAND INFORMATION

Brand name

Somatuline Autogel

Active ingredient

Lanreotide

Schedule

S4

 

1 Name of Medicine

Lanreotide acetate.

2 Qualitative and Quantitative Composition

Each Somatuline Autogel pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 24.6 mg of lanreotide base per 100 mg of solution, which ensures an actual injection dose of 60 mg, 90 mg or 120 mg of lanreotide, respectively. 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.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Somatuline Autogel is a white to pale-yellow semi-solid formulation solution for injection in a pre-filled clear polypropylene syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Somatuline Autogel 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

Acromegaly.

In patients receiving a somatostatin analogue for the first time, the recommended starting dose is 60 mg of Somatuline Autogel administered every 28 days.
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 Somatuline Autogel 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 Somatuline Autogel is one injection of 120 mg administered every 28 days. The treatment with Somatuline Autogel 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.

Somatuline Autogel 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 Somatuline Autogel, 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 Somatuline Autogel 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 laminated 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 laminated 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 leaflet.

4.3 Contraindications

Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel. 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 Somatuline Autogel 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 Somatuline Autogel may result in the reduction of the intestinal absorption of co-administered drugs. As with other somatostatin analogues, Somatuline Autogel may reduce the intestinal absorption of ciclosporin A.
Concomitant administration of ciclosporin with lanreotide may decrease the relative bioavailability of cyclosporine and therefore may necessitate the adjustment of cyclosporine 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

Somatuline Autogel 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 Somatuline Autogel. 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 Somatuline Autogel during clinical trials are consistent with those seen with other prolonged release formulations of lanreotide, and are predominantly gastrointestinal. In clinical trials of Somatuline Autogel 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 Somatuline Autogel or a 30 mg lanreotide microparticle formulation 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 (Australia).
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 Somatuline Autogel (60, 90 or 120 mg) at fixed doses in acromegalic patients previously treated with a 30 mg prolonged release microparticle lanreotide formulation. This study was of a switch design in which acromegalic patients were given the microparticle lanreotide formulation in a first period and Somatuline Autogel in a second period. In the second period, patients received either Somatuline Autogel 60, 90 or 120 mg for three months depending on their respective dosing interval of the microparticle lanreotide 30 mg formulation, as follows:
dosing interval of microparticle lanreotide 30 mg between 12 and 16 days at the end of the first period: switch to Somatuline Autogel 60 mg;
dosing interval of microparticle lanreotide 30 mg between 8 and 11 days at the end of the first period: switch to Somatuline Autogel 90 mg;
dosing interval of microparticle lanreotide 30 mg between 5 and 7 days at the end of the first period: switch to Somatuline Autogel 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 Somatuline Autogel administration were similar to those obtained at the end of the 4th interval of administration of the microparticle lanreotide 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 Autogel formulation, with associated increases in GH and IGF-1 levels.
The study demonstrated that the efficacy of Somatuline Autogel after three injections given every 28 days is not inferior to the microparticle lanreotide 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 Somatuline Autogel and at the end of the 4th interval of the microparticle lanreotide formulation administration. Similar safety was observed after three injections of Somatuline Autogel and after four injections of the microparticle lanreotide formulation. See Table 2.

Carcinoid syndrome.

One open multicentre clinical study was conducted to evaluate the efficacy of Somatuline Autogel (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.
Twenty seven out of 71 patients (38%) in the ITT population and 14/35 (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. Somatuline Autogel was generally well tolerated.

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs).

A Phase III, 96-week, fixed duration, randomised, double-blind, multicentre, placebo-controlled trial of Somatuline Autogel (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 localised in the pancreas, mid-gut, hind-gut or of unknown primary location.
Randomisation 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 utilised 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 randomised 1:1 to receive either Somatuline Autogel 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 Somatuline Autogel, in the extension study, occurred in 45.6% (47/103) of the patients. Monthly treatment with Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel.
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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel arm.

5.2 Pharmacokinetic Properties

Absorption.

After a single subcutaneous injection of Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 60, 90 and 120 mg shows an almost log-linear first order lanreotide release profile.
In an open, comparative, multicentre, switch design study, Somatuline Autogel 120 mg was administered every 56, 42 or 28 days to those given microparticle lanreotide 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 microparticle lanreotide treatment. Furthermore, the serum levels obtained after administration of Somatuline Autogel 120 mg every 56, 42 or 28 days are comparable, at equivalent cumulative dose, to those obtained after three deep subcutaneous injections of Somatuline Autogel 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 Somatuline Autogel 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 Somatuline Autogel 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

Water for injections.
Glacial acetic acid (for pH adjustment).

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) in the original package.
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 72 hours at below 40°C.

6.5 Nature and Contents of Container

Somatuline Autogel is supplied in a pre-filled syringe (polypropylene) fitted with an automatic safety system with a plunger stopper (bromobutyl rubber), and a needle (stainless steel) covered by a plastic cap.
Each ready to use pre-filled syringe is placed into a plastic tray and packed in a laminated pouch and is contained in a cardboard box.
Box of one 0.5 mL pre-filled syringe with an attached 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 by taking to your local pharmacy.

6.7 Physicochemical Properties

The pH of Somatuline Autogel solution is around 6.1.

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)

S4.

Summary Table of Changes