Consumer medicine information

Signifor

Pasireotide

BRAND INFORMATION

Brand name

Signifor

Active ingredient

Pasireotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Signifor.

What is in this leaflet

This leaflet answers some common questions about Signifor.

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 taking this medicine against the benefits they expect it will provide.

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

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

What Signifor is used for

Signifor is used to treat Cushing's Disease, a condition caused by an enlargement in the pituitary gland (pituitary adenoma, a benign tumour) which produces too much of a hormone called adrenocorticotropic hormone (ACTH). This overproduction of ACTH causes the body to produce too much of another hormone called cortisol. Too much cortisol leads to a variety of signs and symptoms such as weight gain with abdominal obesity, moon-shaped face, easy bruising, menstrual abnormalities, excessive body and facial hair, muscle wasting with generalized weakness and tiredness, depression and decreased libido. Signifor is designed to block the production of ACTH and therefore cortisol and help to reduce the symptoms caused by excess of cortisol.

Signifor contains pasireotide, a synthetic substance that mimics the action of somatostatin, a substance normally found in the human body, which can block the production of certain hormones such as ACTH. The advantage of pasireotide over somatostatin is that its effect is stronger and lasts longer.

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

This medicine is not addictive.

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

Before you inject Signifor

When you must not take it

Do not take Signifor if you have an allergy to pasireotide, the active ingredient, or to 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 take this medicine if you suffer from severe liver disorder.

Do not take this medicine 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 using it

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

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

  • problems with your blood glucose levels, either too high (hyperglycemia/diabetes) or too low (hypoglycaemia)
  • problems with your liver
  • a heart disorder or a heart rhythm disorder, such as an irregular heartbeat or an abnormal electrical signal called "prolongation of the QT interval, or QT prolongation"
  • low levels of potassium or magnesium in your blood
  • gallstones.

Tell your doctor if you are taking, or have ever taken, medicines to:

  • control your heart rate (antiarrhythmics) or medicines that may have an unwanted effect on the function of the heart beat (QT prolongation)
  • control your blood pressure (such as beta-blockers or calcium channel blockers) or agents to control electrolytes (potassium, magnesium) balance in your body

Your doctor may want to take special precautions.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Signifor is not recommended during pregnancy. Your doctor will discuss with you the potential risk of taking Signifor during pregnancy.

You should not breastfeed your child while using Signifor. It is not known if Signifor passes into breast milk.

Women of child-bearing potential should use an effective method of contraception during treatment. Ask your doctor about the need for contraception before you start taking Signifor.

Taking other medicines

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

Some medicines and Signifor may interfere with each other. These include:

Anti-arrhythmics used to treat irregular heart rate such as:

  • amiodarone
  • disopyramide
  • procainamide
  • sotalol
  • quinidine

Medicines that may have an unwanted effect on the function of the heart (QT prolongation) such as:

  • ketoconazole
  • chloroquine
  • halofantrine
  • clarithromycin
  • haloperidol
  • methadone
  • bepridil
  • pimozide

Certain other medicines, such as:

  • cyclosporin
  • terfenadine
  • bromocriptine

You may need to take different medicines. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start taking this medicine.

How to inject Signifor

Your doctor or nurse will instruct you on how to inject yourself with Signifor.

Follow all directions given to you by your doctor or nurse. They may differ from the information contained in this leaflet.

If you have any questions, contact your doctor, nurse or pharmacist.

How much to inject

The recommended dosage range of Signifor is 300 to 900 micrograms (mcg) injected under the skin (subcutaneous) two times a day (approximately every 12 hours).

If you have high blood glucose levels or liver problems before you start using Signifor, your doctor may want to start your treatment with a lower dose two times a day.

Your doctor will monitor how you respond to the treatment with Signifor and may ask you to change to a higher or lower dose.

How to inject it

This medicine comes in an ampoule ie a small glass container. Your doctor or nurse will have instructed you on how to use Signifor ampoules. However before using the ampoule, please read the following instructions carefully. If you are not sure about how to give the injection or you have any questions, please ask your doctor or nurse for help.

The injection can be prepared using either two different needles to draw up and inject the solution or one short fine injection needle for both steps. Based on the local clinical practice, your doctor or nurse will tell you which method to use. Please follow their instructions.

Store Signifor ampoules according to the storage condition listed at the bottom of this leaflet.

Important Safety Information

  • Always use new disposable needles and syringes every time you give yourself an injection.
  • Use syringes and needles only once. NEVER share needles and syringes with someone else.
  • Carefully inspect the ampoule prior to use. DO NOT USE if it is broken or if the liquid looks cloudy, coloured or contains particles. In all these cases, return the entire pack to the pharmacy.
  • For sterility reasons, ampoules should be opened just prior to administration.
  • This medicine is for single use in one patient only. Discard any residue.

Signifor is intended for subcutaneous use. This means that it is injected through a short needle into the fatty tissue just under the skin.

The injection site is the place on your body where you are going to give yourself the injection.

The TOP OF THIGHS and the ABDOMEN are recommended areas for subcutaneous injection. It is important to rotate the site of your injections, that is, you should choose a different site each time you inject.

You should also avoid injections at sites that are sore, where the skin is irritated, the navel, waistline, bruises and scars.

To reduce local discomfort, it is recommended that the solution should be at room temperature before injection.

Do not inject Signifor solution for injection into a vein or muscle.

PREPARING A DOSE

  1. Wash your hands thoroughly with soap and water.
  2. Take ampoule out of the box and carefully inspect the ampoule (as above).
  3. Read the label first. Check the dose on the ampoule is the dose your doctor has prescribed for you.
  4. Signifor solution for injection is filled in a break-off ampoule. The coloured dot on the top part marks the position of the breaking point on the neck of the ampoule.

TAP the ampoule with your finger in order to make sure there is no liquid in the top part when you open the ampoule.
  1. Recommended procedure:
Hold the ampoule in an upright position with the coloured dot facing away from you. Hold the base of the ampoule in one hand. Keeping your thumbs together above and below the neck, break off the top of the ampoule at the breaking point.

Once the ampoule is open, put it upright on a clean, flat surface.
  1. Take the sterile syringe and attach the needle to it.
If you have been told to use two needles, you should use the long thick blunt drawing up needle for this step.

Before you proceed to the next step, clean the injection site with an alcohol wipe or similar.
  1. Remove the cover from the needle. Put the needle into the ampoule and pull the plunger to draw up the entire contents of the ampoule into the syringe.

If you have been told to use two needles, you should now replace the long needle with the short giving needle.
  1. Hold the syringe in one hand between two fingers with your thumb at the bottom of the plunger. Tap the syringe with your fingers to get rid of air bubbles. Make sure there is no air bubble in the syringe by pressing the plunger until the first drop appears on the tip of the needle.

Do not let the needle touch anything. You are now ready to inject.

INJECTING A DOSE

  1. Gently pinch the skin at the injection site and holding the needle at an angle advised by your doctor or nurse, insert it into the skin.

  1. Keeping your skin pinched, slowly press down the plunger as far as it will go until all the solution is injected. Hold this position for 5 seconds.

  1. Slowly release the skin and gently pull the needle out.

IMPORTANT: If you injected yourself, put the cover back on the needle. If a carer has carried out the injection, they should not recap the needle in case of needle-stick injury.

  1. Dispose of every used syringe and needle immediately in a standard approved sharps container. Any unused medicine or waste material should be disposed of in a manner that meets local requirements. Your doctor or nurse can provide disposal information as well as your local council.

Seek advice if you plan to travel.

When to inject it

Take Signifor twice a day (approximately every 12 hours).

Using Signifor at the same time each day will help you remember when to use your medicine.

How long to inject it

Do not stop taking Signifor unless your doctor tells you to. This medicine helps to control your condition, but does not cure it. If you interrupt your treatment with Signifor your cortisol level may increase again and your symptoms may come back. Therefore, you should not stop using Signifor without discussing it with your doctor.

If you forget to inject it

If you forget to administer a dose of Signifor simply take your next injection at the scheduled time.

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

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

If you inject too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Signifor. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

While you are using Signifor

Things you must do

If you experience extreme weakness, weight loss, nausea, vomiting and low blood pressure seek urgent medical attention. These are some of the signs and symptoms associated with a lack of cortisol.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may wish to monitor the following:

  • your blood glucose levels
    You may need to start taking or adjust your anti-diabetic medication.
  • your heart rate using a test called electrocardiogram or ECG
    If you take a heart medication, your doctor may also need to adjust its dosage.
  • your gallbladder, liver enzymes and pituitary hormones periodically

If you become pregnant while taking this medicine, tell your doctor immediately. It may affect your developing baby. Your doctor will discuss the risks and benefits of continuing treatment in this case.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Things you must not do

Do not give this medicine to anyone else, even if their condition seems similar to 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 Signifor affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Signifor even if you do not think it is connected with the medicine.

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 the following lists of side effects. You may not experience any of them.

Most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment.

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

Tell your doctor as soon as possible if you notice any of the following:

  • low cortisol levels (you may experience extreme weakness, weight loss, nausea, vomiting, low blood pressure)
  • high blood glucose level (you may experience excessive thirst, high urine output, increased appetite with weight loss, tiredness, nausea, vomiting, abdominal pain, fruity scented breath, trouble breathing and confusion)
  • Bile flow from liver to intestine can be reduced (cholestasis). The symptoms may include yellowing of the skin/eye, dark urine, pale stool, and itching.
  • low blood glucose levels
  • slow heart rate
  • irregular heart rate
  • gallstones (you may experience sudden back pain or pain on the right side of your abdomen).

The above list includes serious side effects which require immediate medical attention.

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

  • diarrhoea
  • nausea
  • abdominal pain
  • inflammation of gallbladder with signs of upper abdominal pain (cholecystitis).
  • fatigue
  • local pain at injection site
  • change in glucose levels in blood
  • loss of appetite
  • vomiting
  • headache
  • dizziness
  • common cold
  • hair loss
  • weakness
  • swelling due to fluid retention
  • anxiety
  • flu like symptoms
  • insomnia
  • muscle pain
  • joint pain
  • itch
  • constipation
  • low blood pressure (hypotension)
  • back pain
  • dry skin
  • pain in the extremities
  • vertigo
  • abdominal expansion

Some people may have other side effects not yet known or mentioned in this leaflet.

Some of these side effects, for example, anaemia, changes in liver function, pancreatic function, blood coagulation parameters and abnormal blood test results (sign of high level of fat in the blood) can only be found when your doctor does tests from time to time to check your progress.

After using Signifor

Storage

  • Keep this medicine in the original package in order to protect it from light.
  • Store it in a cool, dry place below 30°C.
  • Do not leave it in the car or on window sills.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine you have left over.

Product description

What it looks like

Signifor is supplied as a solution for injection in a 1 mL one point-cut colourless glass ampoule.

Signifor comes in packs of 6, 30 or 60 ampoules. Not all pack sizes are marketed.

Ingredients

The active substance of Signifor is pasireotide. Each ampoule contains 300 micrograms (mcg) or 600 micrograms (mcg) or 900 micrograms (mcg) pasireotide. It also contains:

  • mannitol
  • tartaric acid
  • sodium hydroxide
  • water for injections

Sponsor

Signifor® is supplied in Australia by:

Recordati Rare Diseases Australia Pty Ltd
Suite 1802, Level 18, 233
Castlereagh Street,
Sydney, NSW, 2000
Australia
Phone: +61 (0) 408 061 403
[email protected]

®= Registered Trademark

This leaflet was prepared in April 2022.

Australian Registration Numbers:

Signifor 300 mcg AUST R 201485

Signifor 600 mcg AUST R 201484

Signifor 900 mcg AUST R 201486

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Signifor

Active ingredient

Pasireotide

Schedule

S4

 

1 Name of Medicine

Pasireotide (as diaspartate).

2 Qualitative and Quantitative Composition

Each ampoule of 1 mL contains:
300 microgram pasireotide (as diaspartate);
600 microgram pasireotide (as diaspartate);
900 microgram pasireotide (as diaspartate).
Pasireotide 300 microgram/1 mL, 600 microgram/1 mL and 900 microgram/1 mL solution for injection is clear and colourless.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection, solution.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed.

4.2 Dose and Method of Administration

Dose.

The recommended dosage range of Signifor is 300 microgram to 900 microgram by subcutaneous injection, twice a day. The recommended initial dose is 600 microgram or 900 microgram twice a day. Titrate dose based on response and tolerability.
For patients who are started on 600 microgram twice a day, a dosage increase to 900 microgram twice a day may be considered based on the response to the treatment as long as the 600 microgram dosage is well tolerated by the patient. Individualised dose reduction may be considered for patients with a stable response at the discretion of the treating physician.
Patients should be evaluated for treatment response (clinically meaningful reduction in urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease) and should continue receiving therapy with Signifor as long as benefit is derived. Maximum urinary free cortisol reduction is typically seen by two months of treatment. Patients who do not experience clinical benefit from Signifor should be considered for discontinuation.
Management of suspected adverse reactions may require temporary dose reduction of Signifor. Dose reduction by decrements of 300 microgram twice a day is suggested.
If a dose of Signifor is missed, the next injection should be administered at the scheduled time. Doses should not be doubled to make up for a missed dose.

Dose adjustment.

Renal insufficiency.

No dosage adjustment is required in patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties).

Hepatic insufficiency.

Dose adjustment is not required in patients with mildly impaired hepatic function (Child-Pugh A). The recommended initial dose for patients with moderately impaired hepatic function (Child-Pugh B) is 300 microgram twice a day (see Section 5.2). The maximum recommended dose for patients with moderate hepatic impairment is 600 microgram twice a day only following careful consideration of the perceived risks and benefits to the individual, and with frequent clinical review and monitoring of liver function. Signifor should not be used in patients with severe hepatic impairment (Child-Pugh C) (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Diabetes.

For patients with prediabetes or diabetes mellitus an initial dose of 600 microgram twice a day may be considered (see Section 4.4).

Paediatric patients.

Signifor is not recommended for use in paediatric Cushing's disease patients as there are no clinical data available in patients under 18 years of age.

Elderly patients.

There are limited data on the use of Signifor in patients older than 65 years but there is no evidence suggesting that a dose adjustment is required in elderly patients (see Section 5.2).

Method of administration.

Signifor is to be administered subcutaneously by self injection. Patients should receive instructions from the physician or a health care professional on how to inject Signifor subcutaneously.
Use of the same injection site for two consecutive injections is not recommended. Sites showing signs of inflammation or irritation should be avoided. Preferred injection sites for subcutaneous injections are the top of the thighs and the abdomen (excluding the navel and waistline). To reduce local discomfort, it is recommended that the solution should be at room temperature before injection.
No compatibility data with other products have been generated. Pasireotide solution for injection is to be used without any dilution and must not to be mixed with other medicinal products.
Ampoules should be opened just prior to administration. Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Severe hepatic impairment (Child-Pugh C).

4.4 Special Warnings and Precautions for Use

Hypocortisolism.

Treatment with Signifor leads to a rapid suppression of ACTH (adrenocorticotropic hormone) secretion in Cushing's disease patients. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism. Cases of hypocortisolism have been reported in the phase III study in Cushing's disease patients (see Section 4.8 Adverse Effects (Undesirable Effects)), generally within the first two months of treatment. It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). In case of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of treatment with Signifor may be necessary.

Hyperglycaemia/ hypoglycaemia and diabetes.

Elevations in blood glucose levels have been seen in healthy volunteers and patients treated with Signifor. In the phase 3 trial, nearly all patients (including those with normal glucose status at baseline, prediabetes, and diabetes) developed worsening glycaemia in the first two weeks of treatment. Cushing's disease patients with poor glycaemic control (as defined by HbA1c values > 8% while receiving antidiabetic therapy) may be at a higher risk of developing severe hyperglycaemia and associated complications, e.g. ketoacidosis. Because of this predictable adverse reaction, the glycaemic status must be assessed prior to starting treatment with Signifor and regularly monitored.
Hypoglycaemia was also observed in subjects participating in clinical trials with pasireotide (see Section 4.8) but less frequently than hyperglycaemia.
In patients with uncontrolled diabetes mellitus intensive antidiabetic therapy should be initiated prior to treatment with Signifor. During treatment, additional monitoring and dose adjustments of the antidiabetic therapy (including insulin) may be necessary.
FPG/ HbA1c monitoring during treatment should follow established guidelines. Self monitoring of blood glucose and/or FPG assessments should be done every week for the first two to three months and periodically thereafter, as clinically appropriate, as well as over the first two to four weeks after any dose increase. After treatment discontinuation, glycaemic monitoring (e.g. FPG or HbA1c) should be done according to clinical practice.
If hyperglycaemia develops in a patient treated with Signifor, the initiation or adjustment of antidiabetic treatment is recommended, following the established treatment guidelines for the management of hyperglycaemia. The optimal treatment for the management of Signifor induced hyperglycaemia is not known. If uncontrolled hyperglycaemia persists despite appropriate medical management the dose of Signifor should be reduced or the treatment discontinued. There have been post-marketing cases of ketoacidosis with Signifor in patients with and without a history of diabetes. In some cases, factors predisposing to ketoacidosis such as illness, infection, pancreatic disorders (e.g. pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history.
In patients with poor glycaemic control, diabetes management and monitoring should be intensified prior to initiation and during pasireotide therapy.

Cardiovascular related events.

Bradycardia has been reported with the use of pasireotide (see Section 4.8). Patients with cardiac disease and/or risk factors for bradycardia, such as: history of clinically significant bradycardia or acute myocardial infarction, high grade heart block, congestive heart failure (NYHA class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, should be carefully monitored. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control electrolyte balance, may be necessary.
Pasireotide has been shown to prolong the QT interval on the ECG in two healthy volunteer studies (see Section 5.1 Pharmacodynamic Properties). The clinical significance of this prolongation is unknown.
In clinical studies in Cushing's disease patients, QTcF of > 500 msec was observed in two out of 201 patients. These episodes were sporadic and of single occurrence with no clinical consequence observed. Episodes of torsade de pointes were not observed either in those studies or in clinical studies in other patient populations.
Pasireotide should be used with caution in patients who are at significant risk of developing prolongation of QT, such as those:
with congenital long QT syndrome;
with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia;
taking antiarrhythmic medicinal products or other substances that are known to lead to QT prolongation;
with hypokalaemia and/or hypomagnesemia.
Monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Signifor and as clinically indicated. Hypokalaemia or hypomagnesemia must be corrected prior to Signifor administration and should be monitored periodically during therapy.

Liver tests.

Mild transient elevations in aminotransferases have been commonly observed in healthy subjects and patients treated with pasireotide. A few cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN (upper limit normal) and bilirubin greater than 2 x ULN have also been observed (see Section 4.8). Monitoring of liver function is recommended prior to treatment with Signifor and after the first 1 to 2 weeks and then monthly for 3 months. Thereafter liver function should be monitored as clinically indicated.
Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding. If the finding is confirmed, the patient should be followed with frequent liver function monitoring until values return to pretreatment levels. Therapy with pasireotide should be discontinued if the patient develops jaundice or other signs suggestive of clinically significant liver impairment, in the event of a sustained increase in AST (aspartate aminotransferase) or ALT of 5 x ULN or greater, or if ALT or AST elevations greater than 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN. Following discontinuation of treatment with pasireotide, patients should be monitored until resolution. Treatment should not be restarted.

Gallbladder and related events.

Cholelithiasis (gallstones) is a recognised adverse drug reaction associated with long-term use of somatostatin analogues and has been frequently reported in clinical studies with pasireotide (see Section 4.8). There have been post-marketing cases of cholangitis in patients taking Signifor, which in the majority of cases was reported as a complication of gallstones. Ultrasonic examination of the gallbladder before, and at 6 to 12 month intervals during Signifor therapy is therefore recommended. The presence of gallstones in Signifor treated patients is largely asymptomatic; symptomatic stones should be managed according to clinical practice.

Pituitary hormones.

Deficiency of pituitary secreted hormones is common after trans-sphenoidal surgery and even more frequently observed postradiation therapy of the pituitary gland. Cushing's disease patients with persistent or recurrent disease might therefore present with deficiency of one or more pituitary hormones. As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, cannot be ruled out. Therefore, monitoring of pituitary function (e.g. TSH/ free T4, GH/ IGF-1) prior to initiation of therapy with Signifor and periodically during treatment should be conducted as clinically appropriate.

Use in the elderly.

There are limited data on the use of Signifor in patients older than 65 years but there is no evidence suggesting that a dose adjustment is required in elderly patients (see Section 5.2).

Paediatric use.

Signifor is not recommended for use in paediatric Cushing's disease patients as there are no clinical data available in patients under 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical studies have been performed to assess drug-drug interaction potential.
Pasireotide has moderate protein binding and is metabolically highly stable. Pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein) but is not an inducer of P-gp. In addition, at therapeutic dose levels, pasireotide is not expected to be:
a substrate, inhibitor or inducer of CYP450;
a substrate of the efflux transporter BCRP (breast cancer resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1) and OATP (organic anion transporting polypeptide) 1B1, 1B3 or 2B1;
an inhibitor of UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1, influx transporter OATP 1B1 or 1B3, efflux transporter P-gp, BCRP, MRP2 (multiresistance protein 2) or BSEP (bile salt export pump).
Based on all these in vitro data, the potential for protein binding, metabolism and/or transporter mediated DDI is low between pasireotide and comedications in vivo.

Anticipated interactions resulting in effects on other drugs.

Limited published data suggest that somatostatin analogs might have an indirect effect in decreasing the metabolic clearance of compounds metabolised by CYP450 enzymes, via suppression of growth hormone secretion. The possibility that pasireotide may exert such an indirect effect cannot be excluded based on available data. Caution should be exercised when administering pasireotide concomitantly with drugs possessing a low therapeutic index and which are metabolised mainly by CYP3A4 (e.g. quinidine, terfenadine).
In dogs, pasireotide has been found to decrease blood level of cyclosporin by reducing its intestinal absorption. It is unknown whether such interaction occurs in humans. Therefore dose adjustments of cyclosporin may be required when coadministering pasireotide and cyclosporin (see Section 4.4).
Limited data with other somatostatin analogues suggest that coadministration with bromocriptine may increase the availability of bromocriptine. Available data cannot exclude the possibility that pasireotide may exert such an effect.

Anticipated pharmacokinetic interactions resulting in effects on pasireotide.

In vitro, pasireotide has been shown to be a P-gp substrate. There is potential for strong P-gp inhibitors, e.g. ketoconazole, ciclosporin, verapamil, clarithromycin, to increase concentrations of pasireotide but the clinical implications of this potential effect are not known.

Medicinal products that prolong the QT interval.

Pasireotide should be used with caution in patients who are concomitantly receiving medicinal products that prolong the QT interval, such as class Ia antiarrhythmics (e.g. quinidine, procainamide, disopyramide), class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin), certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone), certain antihistamines (e.g. terfenadine, astemizole, mizolastine), antimalarials (e.g. chloroquine, halofantrine, lumefantrine), certain antifungals (ketoconazole, except in shampoo) (see Section 4.4).

Bradycardic medicinal products.

Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patients receiving pasireotide concomitantly with bradycardic medicinal products, such as beta-blockers (e.g. metoprolol, carteolol, propranolol, sotalol), anticholinergics (e.g. ipratropium bromide, oxybutynin), certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil), certain antiarrhythmics (see Section 4.4).

Insulin and antidiabetic medicinal products.

Dose adjustments (decrease or increase) of insulin and antidiabetic medicinal products (e.g. metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly with pasireotide (see Section 4.4).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A reduction or normalisation of serum cortisol levels in female patients with Cushing's disease treated with pasireotide may affect fertility. Women of childbearing potential should be informed of this possibility and are recommended to use effective contraception during treatment with pasireotide.
Studies in rats with pasireotide via the s.c. route have shown effects on female reproductive parameters. The clinical relevance of these effects in humans is unknown.
In female rats, fertility was decreased at daily doses of 0.1 mg/kg/day (0.5-fold the MRHD based on surface area, mg/m2) as shown by decreased numbers of implantation sites and viable fetuses. Decreased corpora lutea and abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the MRHD based on surface area, mg/m2). This effect is consistent with the pharmacological action of pasireotide to inhibit IGF-1 secretion.
Pasireotide did not affect fertility in male rats at subcutaneous doses up to 10 mg/kg/day (a dose 51-fold higher than the maximum recommended human dose (MRHD) based on surface area, mg/m2).
(Category B3)
There are no adequate and well controlled studies in pregnant women and women of childbearing age. Studies in animals have shown evidence of an increased occurrence of fetal damage. The potential risk for humans is not known. Women of childbearing potential are recommended to use effective contraception during treatment with pasireotide.
In embryofetal development studies in rats and rabbits, no direct teratogenic effect of pasireotide was observed at maternally toxic doses (respectively 10 and 5 mg/kg/day by subcutaneous injection) leading to exposures (plasma AUC 0 to 24 hrs) respectively 145 and 40-fold higher than in patients at the MRHD. At 10 mg/kg/day in rats, the frequency of early/ total resorptions and malrotated limbs was increased, fetal weight was decreased and ossification was impaired. At 5 mg/kg/day in rabbits, increased abortions, reduced fetal weights and ensuing skeletal variations were observed. Reduced fetal weight and ensuing delayed ossification were also seen in rabbits at 1 mg/kg/day (6.5-fold the plasma AUC at the MRHD).

Labour and delivery.

No data in humans are available.
Pasireotide had no effects on labour and delivery in rats administered up to 10 mg/kg/day (52-fold higher than the MRHD based on surface area, mg/m2).
Signifor should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.
 It is not known whether pasireotide is excreted in human milk. Available data in rats have shown excretion of pasireotide in milk. As a risk to the breastfed child cannot be excluded, Signifor should not be used by the nursing mother.
Retardation of physiological growth, attributed to GH inhibition was observed at all doses tested (≥ 2 mg/kg/day by subcutaneous injection; ≥ 10-fold higher than the MRHD based on surface area, mg/m2) in a pre- and postnatal study in rats. After weaning, bodyweight gains in the rat pups exposed to pasireotide were comparable to controls, showing reversibility.

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)

A total of 201 Cushing's disease patients received Signifor in phase II and phase III studies. The safety profile of Signifor was consistent with the somatostatin analogue class, except for the occurrence of hypocortisolism and degree of hyperglycaemia.
The data described below reflect exposure of 162 Cushing's disease patients to Signifor in the phase III study. At study entry patients were randomised to receive twice a day (b.i.d.) doses of either 600 microgram or 900 microgram of Signifor. The mean age of patients was approximately 40 years old with a predominance of female patients (77.8%). The majority of the patients had persistent or recurrent Cushing's disease (83.3%) and few patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment up to the cutoff date of the primary efficacy and safety analysis was 10.37 months (0.03 to 37.8) with 67.9% of patients having at least six months exposure.
The frequency and severity of adverse drug reactions (ADRs) was comparable between the two dose groups. Grade 1 and 2 ADRs were reported in 57.4% of patients. Grade 3 ADRs were observed in 35.8% of patients and grade 4 ADRs were observed in 2.5% of patients. Grade 3 and 4 ADRs were mostly related to hyperglycaemia. The most common ADRs (incidence ≥ 10%) were diarrhoea, nausea, abdominal pain, cholelithiasis, hyperglycaemia, diabetes mellitus, fatigue and glycosylated haemoglobin increased. There were no deaths during the study.
Adverse events reported up to the cutoff date of the analysis, with an overall frequency higher than 5% are presented in Table 1 by randomised dose group and overall. Adverse events are ranked by frequency, with the most frequent reactions listed first.
Other notable adverse events which occurred with a frequency less than 5% were: anaemia (4%), cholecystitis ((3%) includes cholecystitis acute), cholestasis (3%), glucose tolerance impaired (3%), blood amylase increased (2%) and prothrombin time prolonged (2%).
Adverse reaction 'diabetic ketoacidosis' has been reported for Signifor from post-marketing data (see Section 4.4). This reaction was reported voluntarily from a population of uncertain size and it is not always possible to reliably estimate its frequency hence frequency is 'not known'.

Description of selected adverse drug reactions.

Glucose metabolism disorders.

Elevated glucose was the most frequently reported grade 3 laboratory abnormality (23.2% of patients) in the phase III study in Cushing's disease patients. Mean HbA1c increases were less pronounced in patients with normal glycaemia at study entry in comparison to prediabetic patients or diabetic patients (see Table 2).
Mean fasting plasma glucose (FPG) levels commonly increased within the first month of treatment with decreases and stabilisation observed in subsequent months. Fasting plasma glucose and HbA1c values generally decreased over the 28 days following pasireotide discontinuation but remained above baseline values. Long-term follow-up data are not available. Adverse reactions of hyperglycaemia and diabetes mellitus led to study discontinuation in 5 (3.1%) and 4 patients (2.5%), respectively.
Monitoring of blood glucose levels in patients treated with Signifor is recommended (see Section 4.4).

Gastrointestinal disorders.

As with other somatostatin analogues, gastrointestinal disorders were frequently reported with the use of Signifor. These events were usually of low grade, required no intervention and improved with continued treatment.

Injection site reactions.

Injection site reactions were reported in 13.6% of patients enrolled in the phase III trial in Cushing's disease. Injection site reactions have also been reported in clinical trials in other populations. The events were most frequently reported as local pain, erythema, hematoma, haemorrhage and pruritus. These events resolved spontaneously and required no intervention.

Thyroid function.

Central hypothyroidism is a commonly described comorbidity in Cushing's disease. Thyroid dysfunction is also a common adverse reaction associated with the use somatostatin analogs.
Hypothyroidism with the use of Signifor was reported for seven patients participating in the phase III study in Cushing's disease, two of which were considered to be drug related by the investigator. However, all seven patients presented with a TSH close to or below the lower limit of normal at study entry, which precludes establishing a conclusive relationship between the adverse event and the use of Signifor.

Liver enzymes.

Transient elevations in liver enzymes have been reported with the use of somatostatin analogs and were also observed in healthy subjects and patients receiving pasireotide in clinical studies. The elevations were mostly asymptomatic, of low grade and reversible with continued treatment. A few cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have been observed. All cases of concurrent elevations were identified within ten days of initiation of treatment with Signifor. The individuals recovered without clinical sequelae and liver function test results returned to baseline values after discontinuation of treatment.
Monitoring of liver enzymes is recommended prior and during treatment with Signifor (see Section 4.4), as clinically appropriate.

Pancreatic enzymes.

Asymptomatic elevations in lipase and amylase have been observed in patients receiving pasireotide in clinical studies. The elevations were mostly low grade and reversible while continuing treatment. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the association between cholelithiasis and acute pancreatitis.

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

No cases of overdosage have been reported in patients receiving pasireotide subcutaneously. Doses up to 2.1 mg twice a day have been used in healthy volunteers with adverse reactions of diarrhoea being observed at a high frequency.
In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pasireotide is a cyclohexapeptide, injectable somatostatin analogue. Like natural peptide hormones somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor [SRIF]) and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding to somatostatin receptors. Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogues bind to hsst receptors with different potencies (Table 3). Pasireotide binds with high affinity to four of the five hssts.

Pharmacodynamics.

Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours where hormones are excessively secreted including adrenocorticotropic hormone (ACTH) in Cushing's disease. Due to its broad binding profile to somatostatin receptors, pasireotide has the potential to treat diseases characterised by expression of those receptors in the target tissues.
In vitro studies have shown that corticotroph tumour cells from Cushing's disease patients display a high expression of hsst5 whereas the other receptor subtypes are either not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors of the corticotrophs in ACTH producing adenomas resulting in inhibition of ACTH secretion. The high affinity of pasireotide for four of the five hssts, especially to hsst5 (see Table 3), provides the basis for pasireotide to be an effective treatment for Cushing's disease patients.

Cardiac electrophysiology.

The effect of Signifor on the QT interval was assessed in two open label, controlled, crossover dedicated QT studies. In both studies, an effect of pasireotide on the QTc interval was observed with the maximum placebo subtracted mean change from baseline occurring at 2 hours postdose. In one of the studies investigating a 1950 microgram b.i.d. dose, the maximum mean placebo subtracted QTcF change from baseline was 17.5 ms (90% CI: 15.53; 19.38). In the other study, investigating doses of 600 microgram b.i.d. and 1950 microgram b.i.d., the maximum mean placebo subtracted QTcI change from baseline was 13.19 ms (90% CI: 11.38; 15.01) and 16.12 ms (90% CI: 14.30; 17.95 ms), respectively. Both pasireotide doses decreased heart rate, with a maximal difference to placebo observed at 1 hour for pasireotide 600 microgram b.i.d. (10.39 bpm) and at 0.5 hours for pasireotide 1950 microgram b.i.d. (-14.91 bpm). No episodes of torsade de pointes (transient or sustained) were observed.

Clinical trials.

A phase III, multicenter, randomised study was conducted to evaluate the safety and efficacy of two dose levels of Signifor over a 6 month treatment period in Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery.
Patients with a baseline 24 hour urine free cortisol (UFC) > 1.5 x upper limit of normal (ULN) were randomised to receive a Signifor dosage of either 600 microgram subcutaneous b.i.d. or 900 microgram subcutaneous b.i.d. After three months of treatment, patients with a mean 24 hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomised dose until month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 300 microgram b.i.d. After the initial six months in the study, patients entered an additional 6 month open label treatment period. The dosage could be reduced by 300 microgram b.i.d. at any time during the study for intolerability.
A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24 hour UFC for all patients was 565 nanomol/24 hours (normal range 30 to 145 nanomol/24 hours). About two-thirds of all randomised patients completed six months of treatment.
The primary efficacy endpoint was the proportion of patients who achieved normalisation of mean 24 hour UFC levels after six months of treatment and did not dose increase during this period.
At month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 600 microgram b.i.d. and 900 microgram b.i.d. groups, respectively (Table 4). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 600 microgram bid and 41% in the 900 microgram bid groups. Dose increases appeared to have minimal effect on 24 hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 4.
Signifor resulted in a decrease in the mean 24 hour UFC after 1 month of treatment (see Figure 1). For patients (n = 78) who stayed in the trial, similar UFC lowering was observed at month 12.

Note.

Patients were randomised to Signifor 0.6 mg or 0.9 mg bid at baseline. At least three 24 hour UFC assays contributed to patient mean results at months 0 (baseline), 3, 6 and 12. At least two 24 hour UFC assays contributed to patient mean results at other time points. The reference line is the upper limit normal for UFC, which is 145 nanomol/24 h; ± standard errors are displayed.
Decreases from baseline for blood pressure were observed at month 6, including patients who did not receive any antihypertensive medication. However, due to the fact that the study allowed initiation of antihypertensive medication and dose increases in patients already receiving such medications, the individual contribution of Signifor or of antihypertensive medication adjustments cannot be clearly established.
Facial rubor improved in 36.7% (18/49) and 59.6% (28/47) of patients treated with 600 and 900 mg b.i.d., respectively. More than a third of patients in either treatment group also demonstrated improvement in supraclavicular fat pad and dorsal fat pad. Similar findings were recorded at the month 12 visit. Baseline mean and median global Cushing QoL scores were similar for the two dose groups.
Individual patients showed varying degrees of improvement in Cushing's disease manifestations but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of Signifor.

5.2 Pharmacokinetic Properties

In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a wide dose range from 2.5 microgram to 1500 microgram. In Cushing's disease patients, pasireotide demonstrates linear dose exposure relationship in a dose range from 300 microgram to 1200 microgram.

Absorption.

In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are approximately dose proportional following administration of single and multiple doses.
No studies have been conducted to evaluate the bioavailability of pasireotide in humans. Food effect is unlikely to occur since Signifor is administered via parenteral route.

Distribution.

In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F > 100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.
Pasireotide has low passive permeability and is likely to be a substrate of P-gp, but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. Pasireotide is not a substrate of BCRP (breast cancer resistance protein), OCT1 (organic cation transporter 1), nor OATP (organic anion transporting polypeptides) 1B1, 1B3, or 2B1.

Metabolism.

Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and faeces.

Excretion.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days postdosing, including 48.3 ± 8.16% of the radioactivity in faeces and 7.63 ± 2.03% in urine.
The clearance (CL/F) of pasireotide in healthy volunteers and Cushing's disease patients is ~7.6 litres/h and ~3.8 litres/h, respectively.

Steady-state pharmacokinetics.

Following multiple s.c. doses, pasireotide demonstrates linear and time independent pharmacokinetics in the dose range of 50 microgram to 600 microgram once a day (q.d.) in healthy volunteers, and 300 microgram to 1200 microgram twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t½, eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 50, 200 and 600 microgram q.d. doses).

Special populations.

Elderly patients in the target population.

Age has been found to be a covariate contributing to increased exposure in the population PK analysis of Cushing's disease patients. Decreased total body clearance and increased PK exposures have been seen with increasing age. In the studied age range 18 to 73 years, the area under the curve at steady state for one dosing interval of 12 hours (AUCss) is predicted to range from 86% to 110% of that of the typical patient of 41 years. This variation is moderate and considered of minor significance considering the wide age range in which the effect was observed.
Data on Cushing's disease patients older than 65 years are limited but do not suggest any clinically significant differences in safety and efficacy in relation to younger patients.

Paediatric patients.

No studies have been performed in paediatric patients.

Patients with renal impairment.

Clinical studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide.

Patients with hepatic impairment.

In a clinical study, a single 600 microgram dose of pasireotide was administered as Signifor s.c. in subjects with impaired hepatic function (Child-Pugh A, B and C). Subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon correction for covariate effect (age, BMI and albumin) AUCinf was increased by 60% and 79%, Cmax increased by 67% and 69%, and CL/F decreased by 37% and 44%, respectively, in the moderate and severe hepatic impairment groups relative to the control group.

Demographics.

Population PK analyses of Signifor suggest that race and gender do not influence PK parameters.
Lean bodyweight, which subtracts the estimated weight of body fat from the total bodyweight, has been found to be a covariate in the population PK analysis of Cushing's disease patients. In the studied lean bodyweight range 33 to 83 kg, the AUCs is predicted to range from 67% to 134% of that of the typical patient of 49 kg (the corresponding range of total bodyweight was 43.0 to 175 kg, with a median of 77.4 kg). This variation is considered as moderate and of minor clinical significance.

5.3 Preclinical Safety Data

Genotoxicity.

Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in bacteria and a test for clastogenicity in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test at subcutaneous doses up to 50 mg/kg, approximately 250-fold the maximum recommended human dose (MRHD) based on surface area, mg/m2.

Carcinogenicity.

Carcinogenicity studies by the subcutaneous route were (2 years duration) conducted in rats and transgenic mice (6 months). No carcinogenic activity was observed with pasireotide in transgenic mice, involving administration of doses up to 2.5 mg/kg/day (yielding plasma AUC values 10-13 times higher than in patients at the maximum recommended human dose [MRHD]). Injection site tumours (fibromas) were increased in incidence in male rats at a dose of 0.3 mg/kg/day (> 16 times the maximum recommended human dose on a mg/kg basis). This finding is consistent with a response to continuous irritation/ inflammation at the repeatedly injected site and is not considered to indicate a carcinogenic potential in humans. No treatment related increase in systemic tumours in male rats or tumours in female rats was seen up to the highest dose tested (0.3 mg/kg/day; yielding 14 times [males] and 7 times [females] the plasma AUC in patients at the MRHD).

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are mannitol, tartaric acid, sodium hydroxide and water for injections. The formulations are isotonic and the pH is 4.2.

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 below 30°C. Store in original package (in order to protect it from light). Signifor must be kept out of the reach and sight of children.

6.5 Nature and Contents of Container

Pasireotide solution for injection is a clear, colourless solution in a 1 mL one point cut colourless glass ampoule.
Pack sizes 300 microgram/1 mL, 600 microgram/1 mL and 900 microgram/1 mL: packs containing *6 ampoules or multipacks containing *30 x (5 packs of 6) or 60 x (10 packs of 6) ampoules.
*Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Pasireotide diaspartate is a white to slightly greyish powder. The free base is pasireotide and salt form is pasireotide diaspartate. The drug substance is freely soluble in water and pKa has been determined at 10.2 and 9.1.
Molecular weight: 1313.41 (for the diaspartate salt).

Chemical structure.


CAS number.

Pasireotide diaspartate CAS No.: 396091-77-3.
Pasireotide CAS No.: 396091-73-9.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes