Consumer medicine information

Octreotide SUN

Octreotide

BRAND INFORMATION

Brand name

Octreotide Sun

Active ingredient

Octreotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Octreotide SUN.

What is in this leaflet

This leaflet answers some common questions about Octreotide SUN. The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you using Octreotide SUN against the benefits they expect it will have for you.

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

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

What Octreotide SUN is used for

Octreotide SUN has three uses:

  1. Octreotide SUN is used to treat acromegaly.
In people with acromegaly the body makes too much growth hormone, which controls the growth of tissues, organs and bones. This leads to enlargement of the bones, especially of the hands and feet. Other symptoms include headaches, increased sweating, tiredness, numbness of the hands and feet, pain and stiffness in the joints and loss of sexual function. By blocking the excess growth hormone, Octreotide SUN can relieve many of these symptoms.
  1. Octreotide SUN is used to relieve symptoms of certain types of cancer such as carcinoid syndrome and VIPoma.
By blocking hormones that are over-produced in these conditions, Octreotide SUN can relieve symptoms such as flushing of the skin and severe diarrhoea.
  1. Octreotide SUN is used for people who are having surgery on the pancreas. This medicine helps to lower the chance of complications after the surgery.
Octreotide SUN contains octreotide, a man-made medicine derived from somatostatin, a substance found in the human body. Octreotide is used instead of somatostatin because its effects are stronger and last longer so that it needs to be given only 2 or 3 times a day.

Ask your doctor if you have any questions about why Octreotide SUN has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is only available with a doctor's prescription. It is not addictive.

There is very little information on the use of this medicine in children.

Before you use Octreotide SUN

When you must not use it

Do not use Octreotide SUN if you have an allergy to:

  • octreotide (the active ingredient in Octreotide SUN) or any of the other ingredients listed at the end of this leaflet.

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.

Do not use Octreotide SUN after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to use it

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

  • gallstones
  • diabetes, as Octreotide SUN can affect blood sugar levels. If you are diabetic, your sugar levels should be checked regularly
  • problems with your liver
  • a history of vitamin B 12 deprivation

Your doctor may want to take special precautions if you have any of the above conditions.

Tell your doctor if you are taking other medicines to control blood pressure (beta-blockers or calcium channel blockers) or agents to control fluid and electrolyte balance.

Dose adjustment may be necessary.

Tell your doctor if you are pregnant or intend to become pregnant or wish to breast-feed your baby. There is not much information on the use of Octreotide SUN during pregnancy or breast-feeding. If it is necessary for you to use this medicine, your doctor will discuss with you the benefits and risks involved. They may recommend that you use a method of contraception to prevent pregnancy during your treatment. It is not known if Octreotide SUN passes into breast milk. Breastfeeding is not recommended during treatment with Octreotide SUN.

If you have not told your doctor about any of these things, tell him/her before you use Octreotide SUN.

Taking other medicines

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

Some medicines and Octreotide SUN may interfere with each other. Some of these medicines 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.

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

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

How to use Octreotide SUN

Follow all directions given to you by your doctor and pharmacist carefully. These directions may differ from the information contained in this leaflet.

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

How it is given

Octreotide SUN cannot be taken by mouth because it is rapidly broken down in the stomach. Instead it is given as a subcutaneous injection. That means that it is injected into the fat layer just under the skin.

How much is given

The dose of Octreotide SUN depends on the condition being treated.

  1. Acromegaly: treatment is usually started with injections of 0.05 to 0.1 mg every 8 or 12 hours. The dose can then be adjusted depending on how well it blocks growth hormone and relieves symptoms such as tiredness, sweating and headache.
  2. Carcinoid syndrome and VIPoma: treatment is usually started with injections of 0.05 mg once or twice a day. The dose can be increased if symptoms such as diarrhoea are not relieved.
  3. Surgery on the pancreas: injections of 0.1 mg are usually given three times a day for one week, starting about an hour before the operation.

If you are giving the injections yourself

If you will be giving the injections yourself, your doctor or nurse will teach you how to do it properly.

Before using a Octreotide SUN ampoule, check the liquid for particles or a change in colour. If you notice anything unusual, do not use the ampoule.

Once an ampoule is opened, use it immediately and throw out any liquid that remains. The ampoule does not contain any preservative.

Give the injections between meals or at bedtime. Avoid having meals around the time of the injections. This will help to reduce the chance of stomach upset.

To help prevent irritation or pain at the injection site:

  • Choose a new site for each injection. The upper arms, thighs and abdomen are good areas for injection.
  • Make sure the ampoule is at room temperature before you use it. If it has been in the fridge, take it out half an hour before using it. You can warm it up in your hand but don't try to heat it.

If you notice pain, stinging, tingling, burning, redness or swelling at the injection site after the injection, gently rub the site for a few seconds. These side effects rarely last more than 15 minutes after an injection.

If you forget to use it

Inject the dose as soon as you remember, and then go back to using it as you would normally. It won't do any harm if you miss a dose but some of your symptoms may come back temporarily until you get back on schedule.

Do not use a double dose to make up for the one that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you use too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that an overdose has happened. Do this even if there are no signs of discomfort or poisoning.

Some of the symptoms of an overdose may include hot flushes, fatigue, depression (sad mood), anxiety, lack of concentration and needing to pass water more frequently than usual.

No life-threatening reactions have been reported after an overdose of this medicine.

While you are using Octreotide SUN

Things you must do

Keep all of your doctor's appointments so that your progress can be checked. If you must use this medicine for a long time, your doctor may want to check your blood sugar, gallbladder, thyroid and liver functions from time to time to prevent unwanted side effects from happening.

If your doctor recommends it, make sure you use a method of contraception to prevent pregnancy during your treatment. Tell your doctor if you become pregnant while you are receiving this medicine.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Octreotide SUN.

Tell any other doctor, dentist or pharmacist who treats you that you are using Octreotide SUN.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem to be the same as yours.

Do not use it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how Octreotide SUN 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Octreotide SUN.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice:

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other parts of the body; shortness of breath, wheezing or troubled breathing
  • severe pain, tenderness or swelling in the stomach or abdomen, which may be accompanied by fever, nausea and vomiting, yellowing of the skin and eyes, loss of appetite, generally feeling unwell, itching, light coloured urine (symptoms of a possible problem with your liver, pancreas or gall bladder)
  • symptoms of low blood glucose (hypoglycaemia), including sweating, trembling, dizziness, weakness, hunger, palpitations (feeling of fast or irregular heartbeat) and fatigue
  • symptoms of high blood glucose (hyperglycaemia), including lethargy or tiredness, headache, thirst, passing large amounts of urine, and blurred vision
  • unusually slow or fast heartbeat

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

  • pain, irritation, redness, rash or swelling at the injection site
  • loss of appetite
  • indigestion, nausea or vomiting
  • cramps
  • feeling of bloating or wind
  • constipation, diarrhoea or other change in bowel motions
  • headache
  • dizziness or light headedness
  • swelling of hands or feet due to excess fluid
  • tiredness or weakness
  • flushing of the skin
  • temporary hair loss
  • changes in the rhythm of your heartbeat
  • shortness of breath
  • symptoms of changes in the activity of the thyroid gland (hyper or hypothyroidism) including changes in heart rate, appetites or weight, tiredness, feeling cold or sweating too much, anxiety or swelling at the front of the neck.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

After using Octreotide SUN

Storage

  • Keep the ampoules in the original container until it is time to use them.
  • You can store the ampoules for up to 2 weeks at room temperature.
  • For longer than 2 weeks, keep them in the refrigerator. Do not freeze them.
  • Do not store Octreotide SUN or any other medicine in the bathroom or near a sink.
  • Do not leave them in the car or on window sills.

Keep the medicine where children cannot reach it.

Disposal

If any ampoules have been left out of the fridge for longer than 2 weeks, do not use them.

If your doctor tells you to stop using this medicine or you find that the expiry date has passed or the ampoules have been left out of the fridge for too long, ask your pharmacist what to do with any medicine you have left over.

Product description

What it looks like

Octreotide SUN comes in 1 mL glass ampoules containing a clear, colourless liquid; boxes of 5

Ingredients

Octreotide SUN ampoules contain 0.05 mg, 0.1 mg or 0.5 mg of the active ingredient, octreotide (as octreotide acetate). They also contain glacial acetic acid, sodium acetate trihydrate, sodium chloride and water for injections.

Sponsor:

Sun Pharma ANZ Pty Ltd.
Macquarie Park
Sydney NSW 2113

Australian registration numbers:

Octreotide SUN 50 microgram/1mL (i.e. 0.05mg/1mL): 311226

Octreotide SUN 100 microgram/1mL (i.e. 0.1 mg/1mL): 311225

Octreotide SUN 500 microgram/1mL (i.e. 0.5 mg/1mL): 311224

This leaflet was last prepared in April 2019.

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Octreotide Sun

Active ingredient

Octreotide

Schedule

S4

 

1 Name of Medicine

Octreotide (as acetate).

6.7 Physicochemical Properties

Chemical structure.


CAS number.

79517-01-4 (octreotide acetate).
MW: 1019.3 (free peptide).
Chemical name: D-Phenylalanyl-L-cysteinyl- L-phenyalanyl-D-tryptophyl- L-lysyl-L-threonyl- N-[2-hydroxy-1- (hydroxymethyl)propyl]- L-cysteinamide cyclic (2→7)-disulfide.

2 Qualitative and Quantitative Composition

Each 1 mL ampoule contains 0.05 mg, 0.1 mg or 0.5 mg octreotide (as octreotide acetate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
The solution is clear and colourless.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Octreotide Sun is octreotide, a synthetic octapeptide analogue of somatostatin.

Mechanism of action.

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 gastro-entero-pancreatic 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 growth hormone, glucagon and insulin release than somatostatin with greater selectivity for GH- and glucagon-suppression.
In healthy subjects octreotide, like somatostatin, has been shown to inhibit:
release of growth hormone (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 secretion 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 (including those who have failed to respond to surgery, radiation or dopamine agonist treatment), octreotide lowers plasma levels of GH and Insulin-like Growth Factor-l/Somatomedin C (IGF-1). A reduction in plasma GH (by 50% or more) occurs in almost all patients, and a plasma GH < 5 nanogram/mL can be achieved in about half of the cases. Most patients with symptoms such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paraesthesia report a reduction in these symptoms. In patients with a large pituitary adenoma, octreotide treatment may result in some shrinkage of the tumour mass.
In patients with functional tumours of the gastro-entero-pancreatic endocrine system, octreotide, because of its diverse endocrine effects, modifies different clinical features. Clinical improvement and symptomatic benefit occur in patients who have severe symptoms related to their tumours despite previous therapies which include surgery, hepatic artery embolisation and various chemotherapies, e.g. streptozotocin and 5-fluorouracil.
Octreotide's effects in the different tumour types are as follows:

Carcinoid tumours.

Administration of octreotide may result in improvement of symptoms, particularly of flush episodes and severe diarrhoea. In some cases this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid. In the event of no beneficial response to octreotide treatment, continuation of therapy beyond one week at the maximum tolerated dose is not recommended, although in non-responders no serious sustained adverse drug effects have been reported.

Vasoactive intestinal peptide secreting tumours (VIPomas).

The biochemical characteristic of these tumours is overproduction of vaso-active 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.
In patients with carcinoid syndrome and VIPomas, the effect of octreotide LAR on tumour size, rate of growth and development of metastases, has not been determined.
For patients undergoing pancreatic surgery, the peri- and post-operative administration of octreotide reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).
A large multi-centre study in patients with acute bleeding due to gastric or duodenal ulcer showed no benefit of octreotide over placebo in the control of haemorrhage.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.5 nanogram/mL (100 microgram dose) were reached 0.4 hours after dosing. In a single dose study, the absolute bioavailability after s.c. administration was found to be significantly different for different doses, however the interindividual variability was large. Relative to an equivalent intravenous dose, the bioavailability of a subcutaneous dose was estimated to be 80-135%. This was established based on the respective plasma concentrations determined by a radioimmunoassay. Peak concentrations and area under the curve values were dose proportional both after s.c. or i.v. single doses up to 400 microgram and with multiple doses of 200 microgram t.i.d. (600 microgram/day).
Clearance was reduced by about 66% suggesting non-linear kinetics of the drug at daily doses of 600 microgram/day as compared to 150 microgram/day. The relative decrease in clearance with doses above 600 microgram/day is not defined.

Distribution.

The distribution of octreotide from plasma was rapid (t½α = 0.2 h) and the volume of distribution after i.v. dosing was estimated to be 0.27 L/kg body weight. 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.

The elimination of octreotide from plasma had an apparent half-life of 1.5 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of octreotide is variable but extends up to 12 hours depending upon the type of tumour. About 32% of the dose is excreted unchanged into the urine.

Effect of renal and hepatic dysfunction on pharmacokinetics.

Impaired renal function did not affect the total exposure (AUC) to octreotide administered as a subcutaneous injection. Therefore, no dose adjustment is necessary. In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in normal subjects (from approximately 10 L/h to 4.5 L/h).
The elimination capacity may be reduced in patients with liver cirrhosis (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment), but not in patients with fatty liver disease.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

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. 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. There have been no reports of tumour formation at the injection sites in patients treated for up to 15 years with 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 presence of endometriosis 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.

4 Clinical Particulars

4.1 Therapeutic Indications

For 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. Octreotide treatment is also indicated in acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.
For the relief of symptoms associated with the following functional tumours of the gastro-entero-pancreatic endocrine system:
Carcinoid tumours with features of the carcinoid syndrome;
Vasoactive intestinal peptide secreting tumours [VIPomas]. Octreotide is not curative in these patients.
For reduction of the incidence of complications following pancreatic surgery.

4.3 Contraindications

Hypersensitivity to octreotide or to any component of the formulation.

4.4 Special Warnings and Precautions for Use

Cardiovascular related events.

Uncommon cases of bradycardia have been reported. 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.

Development of gallstones.

Development of gallstones has been reported in 15-30% of long-term recipients of octreotide. The prevalence in the general population (aged 40 to 60 years) is estimated from reviews to be about 5-20%. Ultrasonic examination of the gallbladder before and at 6 to 12 monthly intervals during octreotide therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

GH secreting pituitary tumours.

As GH secreting pituitary tumours may sometimes expand, thereby causing serious complications (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.

Gastro-entero-pancreatic endocrine tumours.

In the treatment of gastro-entero-pancreatic endocrine tumours sudden escape from symptomatic control by octreotide may occur infrequently, with rapid recurrence of severe symptoms.

Effects on glucose regulation.

In patients with concomitant hypersecretion of insulin, octreotide, because of its greater relative potency in inhibiting secretion of growth hormone and glucagon than of insulin, and its shorter duration of action on inhibition of the latter, may increase the depth of, and prolong the duration of hypoglycaemia. Such patients should be closely observed on introduction of octreotide therapy and at each change of dosage. Marked fluctuations of blood glucose concentration may possibly be reduced by more frequent administration of octreotide.
Patients with type I diabetes mellitus requiring insulin therapy may have their insulin requirements reduced by administration of octreotide. In non-diabetic patients and patients with type II diabetes mellitus who have partially intact insulin reserves, octreotide administration can result in prandial increases in glycaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.

Oesophageal varices.

Octreotide administration to patients who have concomitant bleeding gastro-oesophageal varices due to underlying hepatic cirrhosis increases the risk of development of insulin-dependent diabetes or of changes in insulin requirements in the presence of pre-existing diabetes. Therefore, appropriate monitoring of blood glucose levels is mandatory.

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 octreotide 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 patients with liver cirrhosis, the half-life of the drug may be increased. If this occurs, adjustment of the maintenance dose may be considered.

Use in renal impairment.

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

Use in the elderly.

In elderly patients treated with octreotide, there was no evidence for reduced tolerability or altered dosage requirements.

Paediatric use.

Experience with octreotide in children is very limited.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Many patients with carcinoid syndrome or VIPomas being treated with octreotide have also been, or are being, treated with many other drugs to control the symptomatology or progression of the disease, including chemotherapeutic agents, H2 antagonists, antimotility agents, drugs affecting glycaemic states, solutions for electrolyte and fluid support or hyperalimentation, antihypertensive diuretics and anti-diarrhoeal agents.
Octreotide has been reported to produce a reduction in the intestinal absorption of cyclosporin, and a delay in that of cimetidine.
Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.
Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, possibly due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs which are mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine) should be used with caution.
Since octreotide has also been associated with alterations in nutrient absorption, its effect on absorption of any orally administered drugs should be carefully considered.
Where symptoms are severe and octreotide therapy is added to other therapies used to control glycaemic states such as sulphonylureas, insulin, diazoxide, and to beta blockers or agents for the control of fluid and electrolyte balance, patients must be monitored closely and adjustment made in the other therapies as the symptoms of the disease are controlled. Evidence currently available suggests these imbalances in fluid and electrolytes or glycaemic states are secondary to correction of pre-existing abnormalities and not to a direct metabolic action of octreotide. Adjustment of the dosage of drugs, such as insulin, affecting glucose metabolism may be required following initiation of octreotide therapy in patients with diabetes (see Section 4.4 Special Warnings and Precautions for Use, Effects on glucose regulation).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction studies have been performed in rats and rabbits at doses up to 1 mg/kg and have revealed no evidence of any adverse effect of octreotide on fertility or morphogenesis. Foetal and post-natal growth retardation was seen in rats, probably due to suppression of growth hormone.
(Category C)
There are no adequate and well-controlled studies in pregnant women. In the post-marketing 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 octreotide s.c. or 20 to 30 mg/month of octreotide 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.
Octreotide should only be prescribed to pregnant women under compelling circumstances.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization 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.
It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during octreotide treatment.

4.8 Adverse Effects (Undesirable Effects)

The most frequent adverse effects reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.
The most commonly reported adverse effects in clinical trials with octreotide administration were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia and constipation. Other commonly reported adverse effects 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.
Local reactions may occur and include pain, a sensation of stinging, tingling or burning at the site of injection, with redness, swelling, irritation and rash. They rarely last more than fifteen minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection or by injecting a smaller volume using a more concentrated solution.
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.
Occurrence of gastrointestinal side effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.
Acute pancreatitis has been reported in rare instances. Generally, the effect is seen within the first hours or days of octreotide treatment and resolves on withdrawal of the drug. In addition, pancreatitis may develop in patients on long-term octreotide treatment who develop gallstones.
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 non-specific 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).
Adverse drug reactions (see Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse effects are ranked in order of decreasing seriousness.
Flushing and oedema, events attributable to the underlying condition, have been observed.

Post-marketing experience.

Spontaneously reported adverse effects, presented in Table 2, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.

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.

4.2 Dose and Method of Administration

Acromegaly.

Initially 0.05-0.1 mg by subcutaneous injection every 8 or 12 hours. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH < 2.5 nanogram/mL; IGF-1 within normal range) and on clinical symptoms, and on tolerability. In most patients the optimal daily dose will be 0.2 to 0.3 mg. A maximum dose of 1.5 mg per day should not be exceeded. For patients on a stable dose of octreotide, assessment of biochemical markers should be made periodically.
If no relevant reduction of GH levels and no improvement of clinical symptoms have been achieved within three months of starting treatment with octreotide, therapy should be discontinued.

Gastro-entero-pancreatic endocrine tumours.

Initially 0.05 mg once or twice daily by subcutaneous injection. Depending on clinical response, the effect on levels of circulating tumour products, and on tolerability, dosage can be gradually increased to 0.2 mg 3 times daily. Under exceptional circumstances higher doses may be required, however experience with doses above 750 microgram per day is limited. Maintenance doses can be variable, depending on differences in tumour activity and rate of progression.

Complications following pancreatic surgery.

0.1 mg three times daily by subcutaneous injection for seven consecutive days, starting on the day of operation at least one hour before laparotomy.

Administration of octreotide.

Patients who are to self-administer the drug by subcutaneous injection must receive precise directions from the physician or the nurse.
To reduce local discomfort, it is recommended that the solution reaches room temperature before injection. Multiple injections at short intervals at the same site should be avoided.
Ampoules should be opened just prior to administration and any unused portion discarded.
The product is for single use in one patient only.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use if particulates and/or discolouration are observed.

Paediatric use.

Experience with octreotide in children is very limited.

Use in the elderly.

In elderly patients treated with octreotide, there was no evidence for reduced tolerability or altered dosage requirements.

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.

4.9 Overdose

Symptoms.

A limited number of accidental overdoses of octreotide LAR have been reported. The doses ranged from 100 mg to 163 mg/month of octreotide LAR. The only adverse event reported was hot flushes. Cancer patients receiving doses of octreotide 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glacial acetic acid, sodium acetate trihydrate, sodium chloride and water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2-8°C (Refrigerate. Do not freeze). Protect from light.

6.5 Nature and Contents of Container

Ampoules.
50 microgram/1 mL (i.e. 0.05 mg in 1 mL) - box of 5.
100 microgram/1 mL (i.e. 0.1 mg in 1 mL) - box of 5.
500 microgram/1 mL (i.e. 0.5 mg in 1 mL) - box of 5.

6.6 Special Precautions for Disposal

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

Summary Table of Changes