Consumer medicine information

Sandostatin LAR (2.0 mL diluent)

Octreotide

BRAND INFORMATION

Brand name

Sandostatin LAR

Active ingredient

Octreotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sandostatin LAR (2.0 mL diluent).

SUMMARY CMI

SANDOSTATIN LAR®

Consumer Medicine Information (CMI) summary

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

1. Why am I receiving SANDOSTATIN LAR?

SANDOSTATIN LAR contains the active ingredient octreotide. SANDOSTATIN LAR is used to treat a few conditions including acromegaly, advanced neuroendocrine tumours of the gut, and the symptoms of carcinoid tumour and VIPoma. For more information, see Section 1. Why am I receiving SANDOSTATIN LAR? in the full CMI.

2. What should I know before I receive SANDOSTATIN LAR?

Do not use if you have ever had an allergic reaction to SANDOSTATIN LAR (octreotide) 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. SANDOSTATIN LAR is not recommended in these situations. For more information, see Section 2. What should I know before I receive SANDOSTATIN LAR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SANDOSTATIN LAR 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 receive SANDOSTATIN LAR?

  • SANDOSTATIN LAR must only be administered by a doctor or other healthcare professional and only into the muscles of your buttocks. The side you receive SANDOSTATIN LAR will alternate from left to right on each visit you have.
  • SANDOSTATIN LAR requires a healthcare professional to prepare your dose correctly.

More instructions can be found in Section 4. How do I receive SANDOSTATIN LAR? in the full CMI.

5. What should I know while I am receiving SANDOSTATIN LAR?

Things you should do
  • Keep all your doctor's appointments so that your progress and overall health can be checked.
  • Use contraception (birth control) to avoid becoming pregnant.
Things you should not do
  • Do not use SANDOSTATIN LAR if it has been kept out of the fridge for more than 24 hours.
  • Do not give this medicine to someone else.
  • Do not prepare or inject SANDOSTATIN LAR yourself. Your doctor will do this.
Driving or using machines
  • Be careful driving or using machines. May cause dizziness, lightheadedness, or weakness.
Drinking alcohol
  • Tell your doctor if you drink alcohol. May cause dizziness or lightheadedness. Alcohol may make this worse.
Looking after your medicine
  • Keep the vials in the carton until it is time to use them to protect them from light.
  • Keep them in the carton, in the refrigerator at 2°C to 8°C. Do not freeze them.
  • You may remove the carton from the refrigerator on a day you have an injection scheduled. Do not keep them out of the fridge for longer than 24 hours, otherwise it is not safe to use them.

For more information, see Section 5. What should I know while I am receiving SANDOSTATIN LAR? in the full CMI.

6. Are there any side effects?

More common side effects include Feeling sick, tired, or weak, vomiting, diarrhoea/loose stools, discoloured stools, constipation, abdominal pain, cramps, feeling bloated or gassy, indigestion, headache, dizziness, weight changes, redness, swelling or itching at the injection site, rash, hair loss. More serious side effects include signs of an allergic reaction such as trouble breathing, wheezing, swelling of the tongue, lips or face; hives or rash that is spreading, bruising more easily, more bleeding than normal, gall stones, changes to blood sugar (too high, too low), body temperature shifts (too hot, too cold), severe abdominal pain or swelling, yellowing of skin or eyes, trembling, blurred vision, passing very dark urine or little urine, rapid heart rate (palpitations). 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

SANDOSTATIN LAR® (San-do-statin L.A.R)

Active ingredient(s): Octreotide (ok-TREE-oh-tide)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I receiving SANDOSTATIN LAR?

SANDOSTATIN LAR contains the active ingredient octreotide.

SANDOSTATIN LAR is an anti-growth hormone agent, meaning it stops the production of hormones. Sandostatin is derived from somatostatin. Somatostatin is a substance found in the human body which controls the effects of certain hormones such as insulin and growth hormone. SANDOSTATIN LAR is used instead of somatostatin because its effects are stronger and last longer.

SANDOSTATIN LAR is injected into the muscles of your buttocks generally every four weeks by a doctor or healthcare professional; instead of having to inject short-acting Sandostatin more frequently under the skin.

SANDOSTATIN LAR is used to treat the following conditions:

Acromegaly

A condition where the body makes too much growth hormone causing you to have bigger hands and feet than normal. While growth hormone in the body is important as it controls the growth of your organs and body tissues, it may also cause lots of sweating, headaches, stiff joints, loss of feeling in hands and feet and sexual dysfunction if you have too much.

SANDOSTATIN LAR reduces the amount of hormones in your body and may be given to you when other types of treatment for acromegaly (such as surgery or radiotherapy) are not suitable or haven't worked. SANDOSTATIN LAR may also be given to you AFTER radiotherapy, to cover the interim period until the radiotherapy becomes fully effective.

Relieve the symptoms of certain types of cancer - carcinoid tumour and VIPoma

Carcinoid tumours are a type of slow-growing tumour that can start in several places in the body. VIPoma however is a type of tumour that generally starts in the pancreas (the organ that produces insulin). By blocking hormones that are over-produced in these conditions, SANDOSTATIN LAR can relieve symptoms of these tumours such as flushing of the skin and severe diarrhoea.

Advanced Neuroendocrine Tumours

Neuroendocrine cells receive signals from the nervous system (like nerve cells) and respond to this by making hormones (like endocrine cells).

Neuroendocrine tumours can be found in different parts of the body, however SANDOSTATIN LAR treats rare tumours located in the gut (e.g. small intestine, colon, or appendix) by blocking these hormones and controlling the growth.

2. What should I know before I receive SANDOSTATIN LAR?

Warnings

Do not receive SANDOSTATIN LAR if:

  • you are allergic to octreotide, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can receive 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 have/have had:

  • gallstones
  • problems with your liver
  • diabetes or problems with blood sugar being too high or too low
  • low vitamin B12
  • blood pressure issues
  • problems with your thyroid
  • problems with your pancreas
  • 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?

Monitoring while on treatment

If you are going to be receiving SANDOSTATIN LAR for a while, your doctor may want to monitor your blood sugar, gallbladder, thyroid, and liver function from time to time to prevent unwanted side effects from happening.

Your doctor may also want to monitor your pancreas function, especially if you are taking other medicines to control your blood sugar.

Your doctor may send you for blood tests to monitor your liver enzymes, hormones, and vitamin B12 as well.

Gallstones

Your doctor will want to know if you have experienced any complications like fever, chills, abdominal pain, or yellowing of your skin or eyes as prolonged use of SANDOSTATIN LAR may result in gallstone formation.

Taking other medicines

Your doctor will want to know if you are taking medicines to control blood pressure (beta-blockers or calcium channel blockers) or agents to control fluid and electrolyte balance. They may change your dose or treatment plan based on this.

Children

There is very little information on the use of SANDOSTATIN LAR in children.

Contraception

You should avoid becoming pregnant while you are receiving SANDOSTATIN LAR. Your doctor may recommend you take birth control to prevent this.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant, think you may be pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if SANDOSTATIN LAR passes into breast milk. You should not breastfeed while undergoing treatment with SANDOSTATIN LAR.

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 can buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interfere with SANDOSTATIN LAR and affect how it works.

These medicines can include:

  • bromocriptine, a medicine which is also used to treat acromegaly
  • medicines for diabetes
  • cimetidine, a medicine for ulcers
  • cyclosporin, a medicine used to suppress the immune system
  • quinidine, a medicine used to prevent irregular heartbeats
  • medicines to control blood pressure (beta-blockers or calcium channel blockers)
  • agents to control fluid and electrolyte balance
  • some radiotherapies such as those used for neuroendocrine tumours

You may need to take different amounts of your medicines, or you may need to take different medicines.

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

4. How do I receive SANDOSTATIN LAR?

Your doctor or other healthcare professional will administer your treatment directly into the muscles of your buttocks after they have combined the contents of the packet. It must ONLY be administered in this location and generally, the side you have it injected in will alternate each visit.

How much SANDOSTATIN LAR will I receive

Your doctor will decide how much SANDOSTATIN LAR you will receive based on your overall health, your condition and how you respond to therapy.

Generally

  • The usual amount of SANDOSTATIN LAR you will receive is 20 mg, injected every 4 weeks.
  • After about 3 months, the dose may be lowered to 10 mg or increased to 30 mg depending on how you respond to treatment. Your doctor will decide this.
  • If receiving SANDOSTATIN LAR for the treatment of neuroendocrine tumours
  • If you are receiving SANDOSTATIN LAR for the treatment of neuroendocrine tumours located in the gut, the usual dose is 30 mg every 4 weeks. Your doctor will decide how long you will receive SANDOSTATIN LAR.
  • If you are currently taking short-acting Sandostatin
  • Depending on your condition you may also need to continue injecting short-acting Sandostatin under the skin for about 2 weeks after your first injection of SANDOSTATIN LAR. Your doctor will tell you if this is the case.

When to receive SANDOSTATIN LAR

  • Your doctor or other healthcare professional will discuss with you how often to get your injection.

If you forget to receive SANDOSTATIN LAR

If you miss your injection or cannot make your appointment for the injection, have it as soon as you can and then go back to your normal schedule. It will not do any harm if a dose is a few days late, but you could get some temporary re-appearance of symptoms until you get back on schedule.

Do not ask your doctor to give you a double dose to make up for the dose you missed.

If you receive too much SANDOSTATIN LAR

If you think that you have received too much SANDOSTATIN LAR, you may need urgent medical attention.

  • Some of the symptoms that you have received too much may include hot flushes, fatigue, depression (sad mood), anxiety, lack of concentration and needing to urinate more frequently than usual.

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 I am receiving SANDOSTATIN LAR?

Things you should do

  • Keep all your doctor's appointments so that your progress and overall health can be checked. These include appointments to check on your liver, gall bladder, thyroid, pancreas, and blood sugar.
  • Get your blood and urine tested promptly when asked by your doctor.
  • Use contraception (birth control) to avoid becoming pregnant.

Call your doctor straight away if you:

  • Become pregnant or think you may be pregnant. SANDOSTATIN LAR is not recommended in pregnancy because there is not much information about whether it is safe for you or your unborn baby.

Remind any doctor, dentist, or pharmacist you visit that you are receiving SANDOSTATIN LAR.

Things you should not do

  • Do not take this medicine after the expiry date printed on the packaging, or if it is damaged, or shows signs of tampering.
  • Do not take this medicine if it has been left out of the fridge for more than 24 hours.
  • Do not give this medicine to someone else.

Driving or using machines

Be careful before you drive or use any machines or tools requiring your attention until you know how SANDOSTATIN LAR affects you.

This medicine may cause dizziness, lightheadedness, or weakness in some people. If you have any of these symptoms, do not drive or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

This medicine may cause dizziness or lightheadedness in some people. Alcohol may make this worse.

Looking after your medicine

While you will generally receive SANDOSTATIN LAR at a hospital administered by doctor or other healthcare professional, you may be asked to store SANDOSTATIN LAR at home between visits.

Keep the vials in the carton until it is time to use them as this will protect them from light.

  • If you are storing the vials for longer than one day, keep them in the carton, in the refrigerator between 2°C to 8°C. Do not freeze them.
  • If you are scheduled to receive a SANDOSTATIN LAR injection that day, you can take it out of the fridge, but you must store it in a cool dry place (below 25°C) away from moisture, heat, or sunlight.

For example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.
  • SANDOSTATIN LAR should only be administered by your Doctor or other healthcare professional
  • SANDOSTATIN LAR requires a healthcare professional to prepare your dose correctly.
  • SANDOSTATIN LAR carton contents should reach room temperature (20°C to 25°C) before the contents are mixed to prepare for the injection. This will be a minimum of 30 minutes.
  • The suspension (the mixture that occurs after the powder is combined with the liquid) must only be made up right before the injection.

Your doctor will have more detailed information about this if you have questions since you will not need to prepare or administer this yourself.

Keep it where young children cannot reach it.

When to discard your medicine

If any vials have been left out of the fridge for longer than one day (24 hours), do not use them.

The reconstituted suspension (mixture) contains no preservative. This medicine is for single use in one patient only. Your doctor or other healthcare professional will dispose of anything that is left over, after the injection, in a sharps container.

Getting rid of any unwanted medicine

After your doctor or other healthcare professional has administered your treatment, they will dispose of anything left over in a sharps container.

If your doctor has told you that you no longer need to receive this medicine or it is out of date or been left out of the fridge for too long, 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
General wellness
  • Feeling tired or weak
  • Headache
  • Temporary hair loss
  • Feeling a little short of breath
Gut problems
  • Abdominal pain/cramps
  • Constipation or diarrhoea
  • Bloating, wind, or change in bowel movements
  • Indigestion, nausea, vomiting
  • Loss of appetite
Skin problems
  • Pain, irritation, redness, rash or swelling at the injection site.
  • Dry skin
Speak to your doctor if you have any of these less serious side effects and they worry you or are making you feel unwell.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction
  • Red, itchy rash that is spreading.
  • Itchy hives
  • Swelling of the face, lips, tongue, or other parts of the body
  • Trouble breathing, wheezing, shortness of breath
Signs of low blood sugar:
  • Excessive sweating, trembling, dizziness, hungry all the time.
  • Feeling weak, irregular heartbeat (palpitations), feeling really tired.
Signs of high blood sugar:
  • Blurred vision
  • Passing much less urine than normal or very dark urine
Thyroid problems:
  • Cold sweats, feeling hot and cold, feeling anxious
  • Swelling of the neck
  • Significant weight gain
Gall bladder/liver problems:
  • Severe pain, tenderness or swelling in the stomach or abdomen while feeling/being sick
  • Yellowing of the skin and eyes, loss of appetite, generally feeling unwell
  • Light coloured urine
  • Gallstones, may present with back pain
Bleeding problems:
  • Increased bleeding or bruising (could be low level of platelets in blood).
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. 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 SANDOSTATIN LAR contains

SANDOSTATIN LAR vials contain 10 mg, 20 mg or 30 mg of the active ingredient, octreotide (as acetate).

Active ingredient
(main ingredient)		Octreotide
Other ingredients
(inactive ingredients)		Vial contents
  • mannitol
  • polyglactin glucose
Syringe contents
  • mannitol
  • carmellose sodium
  • poloxamer
  • water for injections
Potential allergens-

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

What SANDOSTATIN LAR looks like

SANDOSTATIN LAR is a white to white with yellowish tint powder packed in a glass vial. The diluent (liquid) is a clear, colourless to slightly yellow or brown solution.

Each box of SANDOSTATIN LAR contains one 6mL glass vial of powder, a 3mL glass syringe already containing the diluent (liquid) to mix with the powder, a vial adaptor and safety injection needle.

The vial contents need to be suspended in diluent prior to injection. Your doctor will do this before they administer your treatment. If you have any questions about the contents of the pack, speak to your doctor.

SANDOSTATIN LAR is available as:

  • SANDOSTATIN LAR octreotide (as acetate) 10 mg modified release injection plus diluent (AUST R 227962)
  • SANDOSTATIN LAR octreotide (as acetate) 20 mg modified release injection plus diluent (AUST R 227963)
  • SANDOSTATIN LAR octreotide (as acetate) 30 mg modified release injection plus diluent (AUST R 227964)

Who distributes SANDOSTATIN LAR

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1800 671 203

® = Registered Trademark

This leaflet was prepared in June 2024.

Internal document code

(smsL110624c_v2) based on PI (smsL110624i)

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Sandostatin LAR

Active ingredient

Octreotide

Schedule

S4

 

1 Name of Medicine

Octreotide.

2 Qualitative and Quantitative Composition

Sandostatin LAR octreotide (as acetate) 10 mg modified release injection plus diluent.
Sandostatin LAR octreotide (as acetate) 20 mg modified release injection plus diluent.
Sandostatin LAR octreotide (as acetate) 30 mg modified release injection plus diluent.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release, injection.

Sandostatin LAR is a modified release injection of octreotide. The octreotide is distributed within polymer microspheres. The powder is a white to white with yellowish tint.

Diluent.

The vehicle is a clear, colourless to slightly yellow or brown solution. The pH of the reconstituted suspension is 5-8.
Single glass vials of 10, 20 or 30 mg octreotide modified release injection to be suspended in 2 mL diluent prior to injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Acromegaly.

For the symptomatic control and reduction of growth hormone and IGF-1 plasma levels in patients with acromegaly, including those who are inadequately controlled by surgery, radiotherapy, or dopamine agonist treatment but who are adequately controlled on s.c. treatment with Sandostatin. Sandostatin LAR is also indicated in acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.

Gastroenteropancreatic tumours.

For the relief of symptoms associated with the following functional tumours of the gastroenteropancreatic endocrine system:
carcinoid tumours with features of the carcinoid syndrome;
vasoactive intestinal peptide secreting tumours (VIPomas) in patients who are adequately controlled on subcutaneous treatment with Sandostatin.
Sandostatin LAR is not curative in these patients.

Advanced neuroendocrine tumours of the midgut.

Treatment of patients with progression of well differentiated, advanced neuroendocrine tumours of the midgut or suspected midgut origin.

4.2 Dose and Method of Administration

Sandostatin LAR may only be administered by deep intragluteal injection. Each injection is for single use only. The site of repeat intragluteal injections should be alternated between the left and right gluteal muscle. Deltoid injections are to be avoided because of significant discomfort at the injection site when given in that area.

Acromegaly.

Patients controlled with subcutaneous octreotide.

In patients who are adequately controlled with the usual therapeutic range of subcutaneous octreotide, it is recommended to start treatment with the administration of 20 mg Sandostatin LAR at 4 week intervals for 3 months. Treatment with Sandostatin LAR can be started the day after the last dose of s.c. Sandostatin. Subsequent dosage adjustment should be based on serum GH and IGF-1 concentrations and clinical symptoms.
In patients in whom clinical symptoms and biochemical parameters (GH, IGF-1) are not fully controlled (GH concentrations still above 2.5 microgram/L) within this 3 month period, the dose may be increased to 30 mg every 4 weeks.
The monitoring of GH concentrations is recommended for another 3 months. If, after 6 months of treatment, the response is judged to be inadequate from clinical and biological points of view, Sandostatin LAR should be discontinued.
For patients whose GH concentrations are consistently below 1 microgram/L, whose IGF-1 serum concentrations are normalised, and in whom most reversible signs/ symptoms of acromegaly have disappeared after 3 months of treatment with 20 mg, 10 mg of Sandostatin LAR may be administered every 4 weeks. However, particularly in this group of patients, it is recommended to closely monitor adequate control of serum GH and IGF-1 concentrations, as well as clinical signs/ symptoms at this low dose of Sandostatin LAR.
For patients on a stable dose of Sandostatin LAR, assessment of biochemical markers should be made periodically.

Patients not previously treated with octreotide.

For patients in whom surgery, radiotherapy or dopamine agonist treatment is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective, a short treatment period of subcutaneous octreotide is recommended to assess the response and systemic tolerability of octreotide prior to initiating treatment with Sandostatin LAR as described above.

Gastroenteropancreatic endocrine tumours.

Patients controlled with subcutaneous octreotide.

For patients whose symptoms are adequately controlled with s.c. Sandostatin, it is recommended to start treatment with the administration of 20 mg Sandostatin LAR at 4 week intervals. The treatment with s.c. Sandostatin should be continued at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR.
For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10 mg Sandostatin LAR every 4 weeks. For patients whose symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30 mg Sandostatin LAR every 4 weeks.
For days when symptoms associated with gastroenteropancreatic tumours may increase during treatment with Sandostatin LAR, additional administration of s.c. Sandostatin is recommended at the dose used prior to the Sandostatin LAR treatment. This may occur mainly in the first 2 months of treatment until therapeutic concentrations of octreotide are reached.

Patients not previously treated with octreotide.

For patients who were not previously treated with s.c. Sandostatin, it is recommended to start with the administration of s.c. Sandostatin at a dosage of 0.1 mg (100 micrograms) three times daily for a short period (approximately 2 weeks) to assess the response and systemic tolerability of octreotide before initiating the treatment with Sandostatin LAR as described above.

Advanced neuroendocrine tumours of the midgut or suspected midgut origin.

The recommended dose of Sandostatin LAR is 30 mg administered every 4 weeks. Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.

Instructions for preparation and intramuscular injection for Sandostatin LAR.

Procedure kit with vial adapter and safety needle. For deep intragluteal injection only.
The reconstituted suspension contains no preservative. This medicine is for single use in one patient only. Discard any residue.

Content.

a. One vial containing Sandostatin LAR powder.
b. One prefilled syringe containing the vehicle solution for reconstitution.
c. One vial adapter for drug product reconstitution.
d. One safety injection needle.
Follow the instructions below carefully to ensure proper reconstitution of Sandostatin LAR before deep intragluteal injection.
There are 3 critical actions in the reconstitution of Sandostatin LAR. Not following them could result in failure to deliver the drug appropriately.
The injection kit must reach room temperature. Remove the injection kit from the fridge and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours.
After adding the diluent solution, ensure that the powder is fully saturated by letting the vial stand for 5 minutes.
After saturation, shake the vial moderately in a horizontal direction for a minimum of 30 seconds until a uniform suspension is formed. The Sandostatin LAR suspension must only be prepared immediately before administration.
Sandostatin LAR should only be administered by a trained health professional.
Step 1. Remove the Sandostatin LAR injection kit from refrigerated storage.

Attention.

It is essential to start the reconstitution process only after the injection kit reaches room temperature. Let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours.

Note.

The injection kit can be re-refrigerated if needed.
Step 2. Remove the plastic cap from the vial and clean the rubber stopper of the vial with an alcohol wipe.
Remove the lid film of the vial adapter packaging, but do not remove the vial adapter from its packaging.
Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place, confirmed by an audible 'click'.
Lift the packaging off the vial adapter with a vertical movement.
Step 3. Remove the cap from the syringe prefilled with diluent solution and screw the syringe onto the vial adapter.
Slowly push the plunger all the way down to transfer all the diluent solution in the vial.
Step 4.

Attention.

It is essential to let the vial stand for 5 minutes to ensure that the diluent has fully saturated the powder.

Note.

It is normal if the plunger rod moves up as there might be a slight overpressure in the vial.
At this stage prepare the patient for injection.
Step 5. After the saturation period, make sure that the plunger is pushed all the way down in the syringe.

Attention.

Keep the plunger pressed and shake the vial moderately in a horizontal direction for a minimum of 30 seconds so that the powder is completely suspended (milky uniform suspension). Repeat moderate shaking for another 30 seconds if the powder is not completely suspended.
Step 6. Prepare injection site with an alcohol wipe.
Turn syringe and vial upside down, slowly pull the plunger back and draw the entire contents from the vial into the syringe.
Unscrew the syringe from the vial adapter.
Step 7. Screw the safety injection needle onto the syringe.
Gently reshake the syringe to ensure a milky uniform suspension.
Pull the protective cover straight off the needle.
Gently tap the syringe to remove any visible bubbles and expel them from the syringe. Verify that injection site has not been contaminated.
Proceed immediately to Step 8 for administration to the patient. Any delay may result in sedimentation.
Step 8. Sandostatin LAR must be given only by deep intragluteal injection, never intravenously.
Insert the needle fully into the left or right gluteus at a 90° angle to the skin.
Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated).
Depress the plunger with steady pressure until the syringe is empty. Withdraw the needle from the injection site and activate the safety guard (see Step 9).
Step 9. Activate the safety guard over the needle in one of the 2 methods: either press the hinged section of the safety guard down onto a hard surface; or push the hinge forward with your finger.
An audible 'click' confirms the proper activation.
Dispose of syringe immediately (in a sharps container).

4.3 Contraindications

Hypersensitivity to octreotide or any components of the formulation.

4.4 Special Warnings and Precautions for Use

Pancreatic function.

Pancreatic exocrine insufficiency (PEI) has been observed in some patients receiving octreotide 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.

Cardiovascular related events.

Cases of bradycardia have been reported (frequency: common). Medical review including dose adjustment of this agent and dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.

Gallbladder and related events.

Cholelithiasis is a very common event during Sandostatin treatment and may be associated with cholecystitis and biliary duct dilatation (see Section 4.8 Adverse Effects (Undesirable Effects)). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients taking Sandostatin LAR in the post-marketing setting. Ultrasonic examination of the gallbladder before and at 6 to 12 monthly intervals during Sandostatin LAR therapy is recommended.

GH secreting pituitary tumours.

As GH secreting pituitary tumours may sometimes expand, causing serious complication (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.

Gastroenteropancreatic tumours.

In the treatment of gastroenteropancreatic endocrine tumours with subcutaneous Sandostatin, sudden escape from symptomatic control may occur infrequently, with rapid recurrence of severe symptoms. To date, in patients with gastroenteropancreatic endocrine tumours treated with Sandostatin LAR, there is no evidence of a sudden escape from symptomatic control with abrupt recurrence of severe symptoms.

Effects on glucose regulation.

In patients with concomitant type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation, and insulin requirements may be reduced. In nondiabetics and type II diabetics with partially intact insulin reserves, Sandostatin s.c. administration may result in increases in postprandial glycaemia. It is, therefore, recommended to monitor glucose tolerance and antidiabetic treatment.
In patients with concomitant hypersecretion of insulin, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycaemia. These patients should be closely monitored.

Nutrition.

Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR in patients who have a history of vitamin B12 deprivation.

Thyroid function.

Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.

Use in hepatic impairment.

In a study with octreotide administered subcutaneously and intravenously it was shown that the elimination capacity was reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. Due to the wide therapeutic window of octreotide, no dose adjustment of Sandostatin LAR is necessary in patients with liver cirrhosis.

Use in renal impairment.

Impaired renal function did not affect the total exposure (AUC) to octreotide when administered subcutaneously. Therefore, no dose adjustment of Sandostatin LAR is necessary.

Use in the elderly.

In a study with octreotide administered subcutaneously no dose adjustment was necessary in patients 65 years of age or older. Therefore, no dose adjustment is necessary in this group of patients with Sandostatin LAR.

Paediatric use.

There is very limited experience with the use of Sandostatin LAR in children.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Nutrition earlier in this section.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dose adjustment of medicinal products such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary when Sandostatin LAR is administered concomitantly (see Section 4.4 Special Warnings and Precautions for Use).
Octreotide has been found to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine. Since octreotide has also been associated with alterations in nutrient absorption, its effect on absorption of any orally administered drugs should be carefully considered.
Adjustment of the dosage of drugs affecting glucose metabolism, such as insulin and oral hypoglycaemic agents, may be required during Sandostatin LAR therapy.
Concomitant administration of octreotide and bromocriptine increased the bioavailability of bromocriptine.
Limited published data indicate that somatostatin analogues might decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinidine) should, therefore, be used with caution.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

It is not known whether octreotide has an effect on human fertility. Reproduction studies have been performed in rats and rabbits at doses up to 1 mg/kg octreotide and have revealed no evidence of any adverse effect of subcutaneous octreotide on fertility or morphogenesis (see Use in pregnancy).
(Category C)
There are no adequate and well controlled studies in pregnant women. In the postmarketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 micrograms/day of Sandostatin s.c. or 20 to 30 mg/month of Sandostatin LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies. In most of the cases with known outcome, normal newborns were reported but also several spontaneous abortions during the first trimester, and a few induced abortions.
There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.
Sandostatin should only be prescribed to pregnant women under compelling circumstances.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with octreotide.
Reproduction studies have been performed in rats and rabbits at doses up to 1 mg/kg octreotide and have revealed no evidence of any adverse effect of subcutaneous octreotide on fertility or morphogenesis. Foetal and postnatal growth retardation was seen in rats, probably due to suppression of growth hormone.
 It is unknown whether octreotide is transferred into human breast milk. Animal studies have shown transfer of octreotide into breast milk. Patients should not breast-feed during Sandostatin treatment.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.
The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse reactions were dizziness, localised pain, biliary sludge, thyroid dysfunction (e.g. decreased thyroid stimulating hormone (TSH), decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycaemia.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions (see Table 1) from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions (see Table 2) have been derived from postmarketing experience with octreotide via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Description of selected adverse drug reactions.

Gastrointestinal disorders and nutrition.

Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

Gallbladder and related reactions.

Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. In clinical trials (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin for 1 month or less developed gallstones.
The prevalence in the general population (aged 40 to 60 years) is estimated from reviews to be about 5-20%. Long-term exposure of patients with acromegaly or gastro-entero-pancreatic tumours to Sandostatin LAR suggests that treatment with Sandostatin LAR does not increase the incidence of gallstone formation as compared to subcutaneous treatment. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

Pancreatitis.

In rare instances, acute pancreatitis has been reported within the first hours or days of s.c. Sandostatin treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term s.c. Sandostatin treatment.

Cardiac disorders.

Bradycardia is a common adverse reaction with somatostatin analogues. In both acromegalic and carcinoid syndrome patients arrhythmia and ECG changes such as QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression and nonspecific ST-T wave changes were observed. The relationship of these events to octreotide acetate is however not established because many of these patients have underlying cardiac diseases (see Section 4.4 Special Warnings and Precautions for Use).

Hypersensitivity and anaphylactic reactions.

Hypersensitivity and allergic reactions have been reported during postmarketing experience. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.

Injection site reactions.

Local injection site reactions to Sandostatin LAR may occur, and are usually mild and of short duration. They include local pain and, occasionally, swelling, irritation and rash.

Thrombocytopenia.

Thrombocytopenia has been reported during postmarketing experience, particularly during treatment with Sandostatin (i.v.) in patients with cirrhosis of the liver, and during treatment with Sandostatin LAR. This is reversible after discontinuation of treatment.

Reporting suspected adverse effects.

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

4.9 Overdose

Symptoms.

A limited number of accidental overdoses of Sandostatin in adults and children have been reported. In adults, the doses ranged from 2,400-6,000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms t.i.d.). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly and lactic acidosis.
A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100 mg to 163 mg/month of Sandostatin LAR. The only adverse event reported was hot flushes.
Cancer patients receiving doses of Sandostatin LAR up to 60 mg/month and up to 90 mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety and lack of concentration.

Treatment.

The management of overdosage is symptomatic. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

In healthy subjects octreotide, like somatostatin, has been shown to inhibit:
release of GH stimulated by arginine, exercise and insulin induced hypoglycaemia;
postprandial release of insulin, glucagon, gastrin, other peptides of the GEP system, and arginine stimulated release of insulin and glucagon;
thyrotropin releasing hormone (TRH) stimulated release of thyroid stimulating hormone (TSH).
Unlike somatostatin, octreotide inhibits GH preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).
In patients with acromegaly, Sandostatin LAR, an injectable galenical formulation of octreotide suitable for repeated administration at intervals of 4 weeks, delivers consistent and therapeutic octreotide serum concentrations thus consistently lowering GH and normalising insulin-like growth factor-1/ somatomedin-C (IGF-1) serum concentrations in the majority of patients. In most patients, Sandostatin LAR markedly reduces the clinical symptoms of the disease, such as headache, perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel syndrome.
For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastroenteropancreatic tumours are as follows.

Carcinoid tumours.

Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

Vasoactive intestinal peptide secreting tumours (VIPomas).

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computer tomography scanning suggests a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Mechanism of action.

Pharmacotherapeutic group: anti-growth hormone. ATC code H01CB02.
Octreotide is a synthetic octapeptide analogue of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits the secretion of serotonin and the gastroenteropancreatic (GEP) peptides: gastrin, vasoactive intestinal peptide, insulin, glucagon, secretin, motilin and pancreatic polypeptide, and of growth hormone (GH). Octreotide, like somatostatin, decreases splanchnic blood flow.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin, with greater selectivity for GH and glucagon suppression.

Clinical trials.

Acromegaly.

Sandostatin LAR was evaluated in three clinical trials in acromegalic patients. In these studies, greater than 50% of patients achieved satisfactory serum concentrations of GH (< 2.5 nanogram/mL) and IGF-1 (< 500 nanogram/mL). In two of the clinical trials and their open label extensions, a total of 101 patients were entered who had, in most cases, achieved a GH level < 5 nanogram/mL on subcutaneous Sandostatin given in doses of 100 micrograms or 200 micrograms three times a day. Most patients were switched to 20 mg or 30 mg doses of Sandostatin LAR given once every 4 weeks for up to 27 to 28 injections. A few patients received doses of 10 mg and a few required doses of 40 mg. Growth hormone and IGF-1 levels were at least as well controlled with Sandostatin LAR as they had been on subcutaneous Sandostatin and this level of control remained for the entire duration of the trials.
A third trial was a 12 month open label study that enrolled 151 patients who had GH level < 10 nanogram/mL after treatment with subcutaneous Sandostatin (most had levels < 5 nanogram/mL). The starting dose of Sandostatin LAR was 20 mg every 4 weeks for three doses. Thereafter, patients received 10, 20 or 30 mg every 4 weeks depending on the degree of GH suppression. Growth hormone and IGF-1 were at least as well controlled on Sandostatin LAR as they had been on subcutaneous Sandostatin. For the 122 patients who received all 12 injections in this trial, a mean GH level of 2.5 nanogram/mL was observed in 66% receiving Sandostatin LAR. Over the course of the trial, 57% of patients maintained mean growth hormone levels of < 2.5 nanogram/mL and mean normal IGF-1 levels.
Antibodies to octreotide have been noted in some patients (up to 25%) after treatment with octreotide. Such antibody positive patients were also observed in two clinical studies with Sandostatin LAR. The results for these patients suggest that there are no significant differences in efficacy and local or systemic tolerability between antibody positive and antibody negative subjects.
Two exploratory open label phase IV studies investigated a 24 and 48 week treatment with Sandostatin LAR in previously untreated acromegalic patients. The median reduction in tumour volume was 20.6% in study B2402 at 24 weeks (n = 46) and 29.9% at 48 weeks (n = 29) and 24.5% in study B2401 at 24 weeks (n = 91) and 36.2% at 48 weeks (n = 84). The percentage change in tumour volume during the course of the investigation was assessed by MRI for the intent to treat population.

Carcinoid syndrome.

A six month parallel group clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to subcutaneous Sandostatin. Sixty-seven patients were randomised at baseline to receive double blind doses of 10 mg, 20 mg or 30 mg Sandostatin LAR every 28 days and 26 patients continued, unblinded, on their previous subcutaneous Sandostatin regimen (100 to 300 micrograms three times a day). Sandostatin LAR was as efficacious as subcutaneous Sandostatin in the control of the symptoms of carcinoid syndrome (diarrhoea, flushing). In patients treated with Sandostatin LAR, the need for supplementary doses of subcutaneous octreotide was comparable to that seen in the patients that continued on subcutaneous Sandostatin, but was somewhat higher in the 10 mg per 28 day group for the first few months.
In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin LAR on tumour size, rate of growth and development of metastases has not been determined.

Advanced neuroendocrine tumours of the midgut or unknown primary tumour location.

An interim analysis of Phase III, randomised, double blind, placebo controlled study (PROMID) demonstrated that Sandostatin LAR prolongs TTP in patients with advanced, well differentiated neuroendocrine tumours of the midgut as compared to placebo, across all 3 efficacy analysed populations.
No conclusions could be drawn from the PROMID study regarding an important secondary endpoint; overall survival.
85 patients were randomised to receive Sandostatin LAR 30 mg every 4 weeks (n = 42) or placebo (n = 43) for 18 months, or until tumour progression or death.
Main inclusion criteria were: treatment naïve; histologically confirmed; locally inoperable or metastatic well differentiated; functionally active or inactive neuroendocrine tumours/ carcinomas; with primary tumour located in the midgut or unknown origin believed to be of midgut origin if a primary within the pancreas, chest, or elsewhere was excluded.
The primary endpoint was time to tumour progression or tumour related death (TTP). The TTP results by analysis populations is presented in Table 3 and described below.
In the intent to treat analysis population (ITT) (all randomised patients), 26 and 41 progressions or tumour related deaths were seen in the Sandostatin LAR and placebo groups, respectively (HR = 0.32; 95% CI, 0.19 to 0.55; p-value = 0.000015).
In the conservative ITT (cITT) analysis population in which 3 patients were censored at randomisation, 26 and 40 progressions or tumour related deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR = 0.34; 95% CI, 0.20 to 0.59; p-value = 0.000072; see Figure 1). Median time to tumour progression was 14.3 months (95% CI, 11.0 to 28.8 months) in the Sandostatin LAR group and 6.0 months (95% CI, 3.7 to 9.4 months) in the placebo group.
In the per protocol analysis population (PP) in which additional patients were censored at end study therapy, tumour progression or tumour related death was observed in 19 and 38 Sandostatin LAR and placebo recipients, respectively (HR = 0.24; 95% CI, 0.13 to 0.45; p-value = 0.0000036).
Subgroup analyses on the per protocol analysis population demonstrated that treatment effect was similar in patients with functionality active (HR = 0.23; 95% CI, 0.09 to 0.57), or inactive tumours (HR = 0.25; 95% CI, 0.10 to 0.59).
After 6 months of treatment, stable disease was observed in 66% of patients in the Sandostatin LAR group and 37% of patients in the placebo group.
Both treatment groups had comparable levels of global QoL at random assignment and after 6 months of follow-up.
Based on the significant benefit of Sandostatin LAR observed in this preplanned interim analysis the recruitment was stopped, after over half (52%) of its intended participants were enrolled (85/162).
In this study, there were limitations in the estimation of the true magnitude of time to tumour progression and disease stabilisation with Sandostatin LAR. Documented progressive disease was not a requirement for study entry and there was a significant imbalance between the groups in time since diagnosis which was a median 7.5 months in the Sandostatin LAR group and 3.3 months in the placebo group (p = 0.01). As the treatment effect was relatively large after analysis of tumour progression or tumour related death in the analysed populations, these factors are not likely to affect the significance of the result.
The safety of Sandostatin LAR in this trial was consistent with its established safety profile.

5.2 Pharmacokinetic Properties

Absorption.

After a single i.m. injection of Sandostatin LAR, the octreotide serum concentration reaches a peak within 1 hour after administration, the area under the peak not being larger than 0.5% of the total AUC, followed by a progressive decrease to low octreotide levels within 24 hours. After this initial peak, the octreotide concentration remains at sub-therapeutic levels for the majority of the patients for the following 7 days after the injection of Sandostatin LAR. This initial peak is lower than that observed when administering octreotide subcutaneously. Octreotide levels necessary for relevant and significant suppression of hormone secretion build up subsequently and remain quite stable from days 14 to 42. After day 42, the octreotide concentration decreases slowly.
In patients with acromegaly, mean plateau octreotide concentrations are about 358 nanogram/L, 926 nanogram/L and 1710 nanogram/L for single 10 mg, 20 mg and 30 mg dose respectively. Steady-state octreotide serum concentrations, reached after 3 injections at 4 week intervals, are higher by a factor of 1.6 to 1.8 (when determined on day 28 after the third injection) as compared to the plateau octreotide levels noted after the first injection (at day 28). During the plateau phase, the peak-trough fluctuation is much lower than that observed for subcutaneously administered octreotide. Octreotide did not accumulate in the body, as monitored over a duration of up to 28 monthly injections of Sandostatin LAR.
In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of 10 mg, 20 mg and 30 mg of Sandostatin LAR given at 4 week intervals also increased linearly with dose and were 1231 (894) nanogram/L, 2620 (2270) nanogram/L and 3928 (3010) nanogram/L, respectively.
Following doses of 20 and 30 mg Sandostatin LAR, the bioavailability of octreotide in cholecystectomised volunteers (measured over 107 days) relative to that seen after the same total doses of subcutaneously administered octreotide was shown to be 60% and 63%, respectively.

Distribution.

According to data obtained with intravenously administered octreotide, the volume of distribution of octreotide is 0.27 L/kg. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.

Excretion.

According to data obtained with intravenously and subcutaneously administered octreotide, the total body clearance is 160 mL/min.

5.3 Preclinical Safety Data

Genotoxicity.

In the postmarketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). In most of the cases with known outcome, normal newborns were reported but also several spontaneous abortions during the first trimester, and a few induced abortions. There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.

Carcinogenicity.

In repeat dose toxicity studies in rats of 52 weeks duration and longer, predominantly in males, sarcomas were noted at the subcutaneous injection site of octreotide in an acidic vehicle and at a lower incidence with the acidic vehicle alone. These did not occur in a mouse carcinogenicity study, nor did hyperplastic or neoplastic lesions occur at the subcutaneous injection site in a 52 week dog toxicity study. There have been no reports of tumour formation at the injection sites in patients treated for up to 3 years with subcutaneous octreotide. All information available at present indicates that the finding of injection site sarcomas in rats is species specific and has no significance for the use of the drug in humans. The 116 week rat carcinogenicity study also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest dose of 1.25 mg/kg per day. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumours were associated with oestrogen dominance in the aged female rats which does not occur in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Modified release injection (vial).

Polyglactin glucose, mannitol.

Diluent (prefilled syringe).

Carmellose sodium, poloxamer, mannitol, 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

Storage conditions.

Store at 2 to 8°C. Do not freeze. Protect from light. Sandostatin LAR can remain below 25°C on the day of injection. However, the suspension must only be prepared immediately prior to injection.

6.5 Nature and Contents of Container

Each composite pack contains one 6 mL glass vial of powder, one 3 mL prefilled glass syringe containing 2 mL diluent, one vial adaptor and one safety injection needle. Vial contents to be suspended in diluent prior to injection.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Molecular weight: 1019.3 (free peptide).
Chemical name: D-Phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl) propyl]-L-cysteinamide cyclic (2→7)-disulfide.

CAS number.

79517-01-4 (as acetate).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes