Consumer medicine information

Yondelis

Trabectedin

BRAND INFORMATION

Brand name

Yondelis

Active ingredient

Trabectedin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yondelis.

SUMMARY CMI

YONDELIS

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using YONDELIS?

YONDELIS contains the active ingredient trabectedin. YONDELIS is used for the treatment of patients with liposarcoma or leiomyosarcoma, which are types of soft tissue sarcoma, when previous medicines have been unsuccessful, or the patients are unsuited to receive them.

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

2. What should I know before I use YONDELIS?

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. Women of childbearing potential must use effective contraception during and for 3 months after YONDELIS treatment. Men of fertile age must use effective contraception during and for 5 months after YONDELIS treatment.

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

3. What if I am taking other medicines?

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

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

4. How is YONDELIS given?

  • The usual dose is 1.5 mg/m2 of body surface area.
  • YONDELIS will be given to you as an infusion (a drip) into a vein (intravenously) over a period of 24 hours.

More instructions can be found in Section 4. How is YONDELIS given? in the full CMI.

5. What should I know while using YONDELIS?

Things you must do
  • If you are about to be started on any new medicine, remind your doctor that you are being given YONDELIS
  • Remind any doctor dentist or pharmacist you visit that you are using YONDELIS.
  • If you become pregnant while being given this medicine, tell your doctor immediately.
Things you must not do
  • Do not take this medicine if you are pregnant or breastfeeding.
  • Do not take this medicine if you have any serious infections.
  • Do not take this medicine if you have problems with your liver, kidney or heart.
  • Do not take this medicine if you will receive yellow fever vaccine.
Driving or using machines
  • During your treatment with YONDELIS you may feel tired and experience loss of strength. Do not drive or use any tools or machines if you are experiencing any of these side effects.
Drinking alcohol
  • Alcohol consumption must be avoided during treatment with YONDELIS as this may harm the liver.

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

6. Are there any side effects?

The most common side effect is the increased levels of the yellow pigment bilirubin in the blood which might cause jaundice (a yellowing of the skin, mucous membranes and eyes). Serious side effects include fever, severe muscle pain or weakness, reaction at the site of injection, allergic reaction (when your body reacts to the medicine) and capillary leak syndrome (excessive accumulation of fluid in your tissues). For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

YONDELIS

Active ingredient(s): trabectedin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using YONDELIS?

YONDELIS contains the active ingredient trabectedin. YONDELIS is an anti-cancer medicine that works by preventing the tumour cells from multiplying.

YONDELIS is used for the treatment of patients with liposarcoma or leiomyosarcoma, which are types of soft tissue sarcoma, when previous medicines have been unsuccessful, or the patients are unsuited to receive them. Soft tissue sarcoma is a malignant disease that starts somewhere in the soft tissues, such as the muscles, fat or other tissues (for example cartilages or vessels).

2. What should I know before I use YONDELIS?

Warnings

Do not use YONDELIS if:

  • you are allergic to trabectedin, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have liver, kidney or heart problems
  • you have any serious infections
  • you are pregnant or plan to become pregnant
  • you are breast-feeding
  • you will receive yellow fever vaccine
  • you are a child or adolescent

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • have liver or kidney problems
  • cardiac problems or a history of cardiac problems
  • left ventricular ejection fraction (LVEF) under the lower limit of normal
  • received high anthracycline dose treatment in the past

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. YONDELIS must not be used during pregnancy.

Tell your doctor immediately if you become pregnant. Genetic counselling is recommended since YONDELIS can cause genetic damage.

Adequate contraceptive precautions must be used by:

  • women of childbearing potential when receiving YONDELIS and for 3 months following the end of treatment.
  • men in fertile age when receiving YONDELIS and for 5 months following the end of treatment.

Tell your doctor if you are planning to have children.

Patients should seek advice on ovules or sperm conservation prior to treatment because of the risk of irreversible infertility due to therapy with YONDELIS. Genetic counselling is also recommended for patients wishing to have children after therapy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

YONDELIS must not be given to patients who are breast-feeding. Therefore you must stop breast-feeding before you start your treatment and you must not begin breast-feeding again until your doctor has confirmed that it is safe to do so.

YONDELIS contains potassium

This medicine contains potassium, less than 1 mmol (39 mg) per vial, and can therefore be considered as essentially “potassium-free”.

3. What if I am taking other medicines?

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

You must not use YONDELIS if you will receive yellow fever vaccine. It is not recommended that you use YONDELIS if you will receive a vaccine containing live virus particles. The effect of medicines containing phenytoin (for epilepsy) may be decreased if given together with YONDELIS and this is therefore not recommended.

Some medicines may interfere with YONDELIS and affect how it works, therefore you should avoid the use of YONDELIS together with the medicines listed below.

Medicines that may increase the effect of YONDELIS include medicines that contain:

  • ketoconazole or fluconazole (for fungal infections),
  • ritonavir (for human immunodeficiency virus [HIV] infection),
  • clarithromycin (for bacterial infections),
  • aprepitant (to prevent nausea and vomiting),
  • cyclosporin (inhibit the defensive system of the body)
    or
  • verapamil (for high blood pressure and heart conditions).

Medicines that may reduce the effect of YONDELIS include medicines that contain:

  • rifampicin (for bacterial infections),
  • phenobarbital (for epilepsy) or
  • St. John's Wort (Hypericum perforatum, an herbal medicine for depression).

If you are given YONDELIS together with a medicine that might cause damage to the liver or to the muscles (rhabdomyolysis), you may need to be closely monitored, as there could be an increased risk of liver or muscle damage. Medicines containing statins (for lowering cholesterol levels and preventing cardiovascular disease) is an example of medicines that may cause muscle damage.

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

4. How is YONDELIS given?

YONDELIS is given to you in the hospital or clinic under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic medicines.

How much is given

  • The usual dose is 1.5 mg/m2 of body surface area.
  • During the treatment period, your doctor will carefully monitor you and decide the most appropriate dosage of YONDELIS to give to you.
  • The recommended dose in Japanese patients is lower than the usual dose for all other races and is 1.2 mg/m2 of body surface area.

How it is given

  • Before YONDELIS is given to you, it will be reconstituted and diluted for intravenous use.
  • YONDELIS will be given to you as an infusion (a drip) into a vein (intravenously) over a period of 24 hours.
  • In order to avoid irritation at the site of injection it is recommended that YONDELIS is given to you through a central venous line.
  • You will be given a medicine before and as needed during the treatment with YONDELIS in order to protect your liver and to reduce the risk of side effects such as feeling sick (nausea) and vomiting.

How long it will be given for

  • The infusion is given to you every 3 weeks, although occasionally your doctor may recommend dose delays to ensure that you receive the most appropriate dose of YONDELIS.
  • The length of your whole treatment period will depend on your progress and how well you feel. Your doctor will tell you how long your treatment lasts.

If too much is given (overdose)

As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. In the unlikely event of an overdose, your doctor will monitor you for side effects treat any of your symptoms as required.

If you have any further questions on the use of this medicine, ask your doctor.

5. What should I know while using YONDELIS?

If you receive YONDELIS and feel any of the symptoms mentioned under Section 6. Are there any side effects? during your treatment, your doctor or nurse must be informed. In case you suffer these symptoms, the YONDELIS dose may be omitted temporarily or reduced depending on the severity.

Things you must do

  • If you are about to be started on any new medicine, remind your doctor that you are being given YONDELIS.
  • Remind any doctor, dentist or pharmacist you visit that you are using YONDELIS.
  • Tell your doctor or nurse straight away if you experience an allergic reaction or feel unwell during the infusion.

Typical symptoms associated with allergic reactions are redness of the face or chest, itching, coughing, shortness of breath, chest discomfort, etc. Other symptoms may occur as well.

These side effects mostly occur during or after the infusion of the first dose. You will be monitored for signs of these effects during and after the infusion.

Depending on the seriousness of the allergic reactions, your infusion of YONDELIS may be interrupted. You may require additional treatment to prevent complications and reduce your symptoms.

When the symptoms go away or improve, the infusion can be continued more slowly, and speeded up gradually if the symptoms do not recur. Your doctor may decide not to continue YONDELIS treatment if you have a strong infusion reaction.

Your doctor may want to take additional precautions.

Call your doctor straight away if you become pregnant while being given this medicine.

Things you must not do

  • Do not take this medicine if you are pregnant or breastfeeding.
  • Do not take this medicine if you have any serious infections.
  • Do not take this medicine if you have problems with your liver, kidney or heart.
  • Do not take this medicine if you will receive yellow fever vaccine.

Driving or using machines

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

During your treatment with YONDELIS you may feel tired and experience loss of strength. Do not drive or use any tools or machines if you are experiencing any of these side effects.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol consumption must be avoided during treatment with YONDELIS as this may harm the liver.

Storage

YONDELIS will be stored in the pharmacy or on the ward. The medicine is kept in its original packaging in the refrigerator where the temperature stays between 2°C and 8°C.

6. Are there any side effects?

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

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

Your doctor will perform certain checks periodically to test for side effects that may affect the blood, liver, kidneys, heart and muscle.

Less serious side effects

Less serious side effectsWhat to do
General or affecting different parts of the body:
  • Tiredness
  • More likely to get infections
  • Headache
  • Sleeping problems
  • Hair loss (alopecia)
  • Dizziness, low blood pressure and flushing or skin rash
Muscle or pain related:
  • Pain in back and joints
Stomach and digestive system related:
  • Stomach pain including cramps and aches
  • Loss of appetite
  • Nausea. Symptoms include stomach discomfort, feeling sick or the feeling that you are going to vomit
  • Vomiting
  • Constipation
  • Diarrhoea
  • Mucosal inflammation as a swelling redness of the inside of the mouth leading to painful ulcers, mouth sores and inflammation of the mouth (stomatitis)
  • Loss of water from the body, weight loss, digestive discomfort and a change in your sense of taste
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General or affecting different parts of the body:
  • Fever which may cause side-effects affecting your blood and liver
  • YONDELIS infusion leaks out of your vein while you are being given it. It could lead to damage and death of your tissue cells around the injection site (tissue necrosis) which may require surgery
  • Allergic reaction (hypersensitivity). Symptoms include fever, difficulty in breathing, redness or flushing of skin or a rash, feeling sick (nausea) or being sick (vomiting)
  • Unexplained partial or general swelling (oedema), with possible lightheadedness, dizziness or thirst (low blood pressure). It could be a sign of a condition (capillary leak syndrome) that can cause excessive accumulation of fluid in your tissues
  • Infusion leaks out of your vein while you are being given it (extravasation). Symptoms include some redness, swelling, itchiness and discomfort at the injection site. This could lead to damage and death of your tissue cells around the injection site (tissue necrosis) which may require surgery. Some of the symptoms or signs of extravasation may not be visible until several hours after it occurred. There may be blistering, peeling and darkening of the skin over the site. It is possible for it to take a few days before the full extent of tissue damage is visible.
  • Excess of fluid in the body (oedema). You may experience an abnormal build-up of fluid in the lungs, which leads to swelling (pulmonary oedema)
  • Difficulty breathing and coughing
Infection related:
  • Serious blood infections (sepsis) if your immune system is greatly compromised due to low white blood cell counts
Blood related:
  • Decreased white blood cell count, sometimes associated with blood infections, which could lead to severe infections and death
  • Decreased platelet count. Symptoms include difficulty in breathing, irregular heartbeat, decreased urine output, abrupt change in mental status, areas of mottled skin or extremely low blood pressure.
  • Decreased red blood cell count or abnormal red blood cells. This results in reduced oxygen flow to the body's organs. Symptoms include feeling tired and weak, shortness of breath, dizziness or lightheadedness
Liver related:
  • Increased levels of the yellow pigment bilirubin in the blood which might cause jaundice (a yellowing of the skin, mucous membranes and eyes), pain in the upper right area of your abdomen, nausea, vomiting, a general sense of not feeling well, difficulty in breathing, disorientation or confusion, or sleepiness could be signs that indicate the inability of the liver to perform its normal function
  • Liver damage. If you are given YONDELIS together with a medicine that might cause damage to the liver, there could be an increased risk of liver damage
Heart related:
  • Heart muscle problems including heart failure. Symptoms include chest pain, shortness of breath, tiredness, swelling of your legs, ankles, or feet, or you feel like your heart is beating too hard or too fast in your chest (palpitations)
Stomach and digestive system related:
  • Feel sick, vomit or unable to drink fluids and therefore pass less urine despite being given anti-sickness medicines
Muscle or pain related:
  • Severe muscle aches and pain, stiffness, muscle weakness or darkening of the urine colour could be a sign of damage to your muscles (rhabdomyolysis). In very severe cases this could lead to kidney failure.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems and to Specialised Therapeutics Pharma at [email protected]. By reporting side effects, you can help provide more information on the safety of this medicine.

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

7. Product details

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

What YONDELIS contains

Active ingredient
(main ingredient)		Trabectedin
Other ingredients
(inactive ingredients)		Sucrose
Potassium dihydrogen phosphate
Phosphoric acid
Potassium hydroxide

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

What YONDELIS looks like

YONDELIS is a powder for solution for intravenous infusion.

The powder has a white to off-white colour.

1 mg powder (1 vial): AUST R 332001

Who distributes YONDELIS

Specialised Therapeutics Pharma Pty Ltd
Level 2, 17 Cotham Road,
Kew, Victoria 3101
Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com

This leaflet was prepared in June 2023.

Published by MIMS August 2023

BRAND INFORMATION

Brand name

Yondelis

Active ingredient

Trabectedin

Schedule

S4

 

1 Name of Medicine

Yondelis 1 mg powder for solution for infusion.

2 Qualitative and Quantitative Composition

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for solution for infusion.
White to off-white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Yondelis is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

4.2 Dose and Method of Administration

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.

Instructions for handling.

Yondelis is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised during handling. Procedures for proper handling and disposal of cytotoxic medicinal products must be followed. Personnel should be trained in the correct techniques to reconstitute and dilute the medicinal product and should wear protective clothing including mask, goggles and gloves during the reconstitution and dilution. Pregnant staff must be excluded from working with this medicinal product.
Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water.
No incompatibilities have been observed between Yondelis and type I glass bottles, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium implantable vascular access systems.

Dosage.

The recommended dose is 1.5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles.
All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to Yondelis, not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed.
The following criteria are required to allow treatment with Yondelis:
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
Platelet count ≥ 100 x 109/L.
Bilirubin ≤ upper limit of normal (ULN).
Alkaline phosphatase ≤ 2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or gamma glutamyl transpeptidase (GGT), if the elevation could be osseous in origin).
Albumin ≥ 25 g/L.
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 x ULN.
Creatinine clearance ≥ 30 mL/min.
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
Haemoglobin ≥ 90 g/L.
The same criteria as above must be met prior to re-treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.
Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.
The same dose should be given for all cycles provided that no grade 3-4 toxicities are seen and that the patient fulfils the re-treatment criteria.

Dose adjustments during treatment.

Prior to re-treatment, patients must fulfill the baseline criteria defined above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to Table 1, for subsequent cycles:
Neutropaenia < 0.5 x 109/L lasting for more than 5 days or associated with fever or infection.
Thrombocytopaenia < 25 x 109/L.
Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN.
Increase of aminotransferases (AST or ALT) > 2.5 x ULN which has not recovered by day 21.
Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue).
Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.
Permanently discontinue Yondelis for:
Rhabdomyolysis.
Capillary leak syndrome.
Grade 3 or 4 cardiac adverse events (AEs) indicative of cardiomyopathy or for subjects with an LVEF that decreases below the lower limit of normal.
In the event that further dose reductions are necessary, treatment discontinuation should be considered.

Duration of treatment.

Treatment should be continued until the onset of progressive disease or unacceptable toxicity. In the ET743-SAR-3007 trial long-term follow-up, Yondelis has been administered for 6 or more cycles in 42% of patients. The monotherapy regimen has been used for up to 44 cycles (median 4.0, range: 1-44). No cumulative toxicities have been observed in patients treated with multiple cycles.

Method of administration.

Intravenous administration through a central venous line is strongly recommended due to development of a potentially severe injection site reaction when Yondelis is administered through a peripheral venous line.
Extravasation may cause tissue necrosis requiring debridement. There is no specific antidote for extravasation and this should be managed by local standard practice.

Preparation for intravenous infusion.

Yondelis must be reconstituted and further diluted prior to intravenous infusion. Appropriate aseptic techniques must be used to prepare the infusion solution (see Instructions for reconstitution and for dilution).
Instructions for reconstitution.

Yondelis 1 mg.

Each vial containing 1 mg of trabectedin is reconstituted with 20 mL of water for injections.
A syringe is used to inject the 20 mL of sterile water for injections into the vial. The vial must be shaken until complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowish solution, essentially free of visible particles.
This reconstituted solution contains 0.05 mg/mL of trabectedin. It requires further dilution and is for single-use only.
Instructions for dilution. The reconstituted solution should be diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion. The required volume should be calculated as follows (see Equation 1):
If administration is to be made through a central venous line, the appropriate amount of reconstituted solution should be withdrawn from the vial and added to an infusion bag containing ≥ 50 mL of diluent (sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion), the concentration of trabectedin in the infusion solution being ≤ 0.030 mg/mL.
If central venous access is not feasible and a peripheral venous line has to be used, the reconstituted solution should be added to an infusion bag containing ≥ 1,000 mL of diluent (sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion).
Parenteral solutions should be inspected visually for particles prior to administration. Once the infusion is prepared, it should be administered immediately. For infusion times exceeding 4 hours, an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter can be used to further reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation.

Special populations.

Paediatric population.

Yondelis should not be used in children below 18 years with paediatric sarcomas because of efficacy concerns (see Section 5.1 for results of paediatric sarcoma study).

Elderly.

No specific studies in older people have been performed. Overall 20% of the 1,681 patients in an integrated safety analysis of monotherapy clinical trials were aged 65 years or over. In a population pharmacokinetic analysis plasma clearance and distribution volume of trabectedin were not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.

Japanese population.

A population pharmacokinetic analysis showed that plasma trabectedin concentrations observed in Japanese subjects at dose level 1.2 mg/m2 were equivalent to those obtained in the non-Japanese western population at 1.5 mg/m2.

Hepatic impairment.

Special caution is advised and dose adjustments may be necessary in patients with hepatic impairment since systemic exposure to trabectedin is increased and the risk of hepatotoxicity might be increased. Patients with elevated serum bilirubin levels at baseline must not be treated with Yondelis. Liver function tests should be monitored during treatment with Yondelis as dose adjustments may be indicated (see Table 1 and see Section 4.4).

Renal impairment.

Studies including patients with renal insufficiency (creatinine clearance < 30 mL/min) have not been conducted and therefore Yondelis must not be used in this patient population (see Section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see Section 5.2), no dose adjustments are warranted in patients with mild or moderate renal impairment.

4.3 Contraindications

Hypersensitivity to trabectedin or to any of the excipients listed, see Section 6.1.
Concurrent serious or uncontrolled infection.
Breast-feeding (see Section 4.6).
Combination with yellow fever vaccine (see Section 4.4).

4.4 Special Warnings and Precautions for Use

Use in hepatic impairment.

Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since the systemic exposure to trabectedin is on average approximately doubled (see Section 5.2) due to hepatic impairment and therefore the risk of toxicities might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated serum bilirubin levels must not be treated with Yondelis (see Section 4.2).

Use in renal impairment.

Creatinine clearance must be monitored prior to and during treatment. Yondelis must not be used in patients with creatinine clearance < 30 mL/min (see Section 4.2).

Neutropaenia and sepsis.

Neutropaenia and neutropaenic sepsis, including fatal cases, can occur with Yondelis. Grade 3 or 4 neutropaenia is very common.
A full blood cell count including differential must be performed at baseline, weekly for the first two cycles and then once between cycles (see Section 4.2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.
Yondelis should not be administered to patients with baseline neutrophil counts of less than 1.5 x 109/L. If severe neutropenia (ANC < 0.5 x 109/L) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended (see Section 4.2).

Thrombocytopaenia.

Grade 3 or 4 thrombocytopaenia is also very common following trabectedin administration. Platelet counts should be performed at baseline, weekly for the first two cycles and then once between cycles (see Section 4.2). Yondelis should not be administered to patients with baseline platelets count of less than 100 x 109/L.

Nausea and vomiting.

Anti-emetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients (see Section 4.2).

Rhabdomyolysis and severe CPK elevations (> 5 x ULN).

Yondelis must not be used in patients with CPK > 2.5 x ULN (see Section 4.2). Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with Yondelis should be discontinued until the patient fully recovers.
Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), are administered concomitantly with Yondelis, since the risk of rhabdomyolysis may be increased.

Hepatotoxicity.

Hepatotoxicity, including hepatic failure, can occur with Yondelis. Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients, and grade 3 or 4 abnormalities are common.
LFTs should be assessed prior to each administration of Yondelis and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose adjustments (see Section 4.2).
Yondelis must not be used in patients with elevated bilirubin or those with AST, ALT or alkaline phosphatase > 2.5x ULN.
Caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased.

Injection site reactions.

The use of central venous access is strongly recommended (see Section 4.2). Patients may develop a potentially severe injection site reaction when Yondelis is administered through a peripheral venous line.
Yondelis extravasation may cause tissue necrosis requiring debridement. There is no specific antidote for extravasation of Yondelis. Extravasation should be managed by local standard practice.

Allergic reactions.

During post-marketing experience, hypersensitivity reactions with very rare occurrence of fatal outcome, have been reported in association with Yondelis administration (see Section 4.3; Section 4.8).

Cardiac dysfunction.

Cardiac dysfunction including cardiac failure, congestive heart failure, decreased ejection fraction, diastolic dysfunction, or right ventricular dysfunction can occur with Yondelis.
Patients should be monitored for cardiac-related adverse events or myocardial dysfunction.
A thorough cardiac assessment including determination of left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan (MUGA) should be conducted before initiation of Yondelis and at 2 to 3-month intervals thereafter until Yondelis is discontinued.
Patients with LVEF less than the lower limit of normal (LVEF < LLN), a prior cumulative anthracycline dose of > 300 mg/m2, aged > 65 years, or a history of cardiovascular disease (especially in those receiving cardiac medication) may be at increased risk of cardiac dysfunction at treatment with Yondelis.
For patients with Grade 3 or 4 cardiac adverse events indicative of cardiac dysfunction or for patients with a LVEF that decreases below the LLN (assessed as either an absolute decrease of LVEF of ≥ 15% or < LLN with an absolute decrease of ≥ 5%), Yondelis should be discontinued.

Capillary leak syndrome (CLS).

Cases of Capillary Leak Syndrome (CLS) have been reported with Yondelis (including cases with fatal outcomes). If symptoms of possible CLS develop, such as unexplained oedema with or without hypotension, the treating physician should reassess serum albumin level. A rapid decline in serum albumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of other causes, the treating physician should discontinue Yondelis and initiate CLS treatment according to institutional guidelines (see Section 4.2; Section 4.8).

Others.

Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided (see Section 4.5). If this is not possible, close monitoring of toxicities are required and dose reductions of Yondelis should be considered.
Concomitant use of Yondelis with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of Yondelis with phenytoin or live attenuated vaccines is not recommended and with yellow fever vaccine is specifically contraindicated (see Section 4.3).
The concomitant use of Yondelis with alcohol must be avoided (see Section 4.5).
Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see Section 5.3).
Men in fertile age must use effective contraception during treatment and 5 months after treatment (see Section 4.6).
This medicine contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially "potassium-free".

Use in the elderly.

No age-related dose adjustment is required for Yondelis.

Paediatric use.

The safety and efficacy of Yondelis in the paediatric population was studied in SAR-2005 phase I-II study (see Section 5.1, Clinical trials).
Adverse reactions included reversible elevation of liver enzymes and haematological events; in addition, fever, infection, dehydration and thrombosis/embolism were also reported.

Effects on laboratory tests.

No effects on laboratory tests have been observed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other substances on trabectedin.

Interaction studies have only been performed in adults.
Since trabectedin is metabolised mainly by CYP3A4, the concentrations of trabectedin in plasma are likely to be increased in patients who are co-administered drugs that potently inhibit the activity of this isoenzyme. Similarly, the co-administration of trabectedin with potent inducers of CPY3A4 may increase the metabolic clearance of trabectedin. Two in vivo drug-drug interaction phase 1 studies have confirmed trends toward increased and decreased trabectedin exposures when administered with ketoconazole and rifampicin, respectively.
When ketoconazole was co-administered with trabectedin, the plasma exposure of trabectedin was increased by approximately 21% for Cmax and 66% for AUC. Close monitoring of toxicities is required in patients receiving trabectedin in combination with potent CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) and such combinations should be avoided if possible. If such combinations are needed, appropriate dose adjustments should be applied in the event of toxicities (see Section 4.2; Section 4.4).
When rifampicin was co-administered with trabectedin, it resulted in reduced plasma exposure of trabectedin by approximately 22% for Cmax and 31% for AUC. Therefore, the concomitant use of trabectedin with strong CYP3A4 inducers (e.g. rifampicin, phenobarbital, St. John's wort) should be avoided if possible (see Section 4.4).
Alcohol consumption must be avoided during treatment with Yodelis due to the hepatotoxicity of the medicinal product (see Section 4.4).
Nonclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or elimination. The relevance of this interaction e.g. central nervous system (CNS) toxicity has not been established. Caution should be taken in such situations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Men in fertile age must use effective contraception during treatment and 5 months after treatment (see Section 4.4).
Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Yondelis.
Genetic counselling is also recommended for patients wishing to have children after therapy.
Fertility studies with trabectedin were not performed in nonclinical studies, but limited histopathological changes were observed in the gonads in the repeat dose toxicity studies. Considering the nature of the compound (cytotoxic and mutagenic), it is likely to affect the reproductive capacity.
(Category D)
No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. Trabectedin crossed the placenta when administered to pregnant rats. Yondelis should not be used during pregnancy. If pregnancy occurs during treatment, the patient must be informed of the potential risk to the fetus (see Section 5.3) and be monitored carefully. If Yondelis is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see Section 5.3).
If pregnancy occurs during treatment the possibility of genetic counselling should be considered.
Trabectedin was not embryofetotoxic or teratogenic in rats or rabbits at the highest doses tested (15 microgram/m2/day and 24 microgram/m2/day IV, respectively). These doses were well below the human dose (on a mg/m2 basis), but could not be increased because of excessive maternal toxicity.
 It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breast-feeding is contraindicated during treatment and 3 months thereafter (see Section 4.3).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of the ability to drive and to use machines have been performed. However, fatigue and/or asthenia have been reported in patients receiving Yondelis. Patients who experience any of these adverse reactions during therapy must not drive or operate machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

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

Summary of the safety profile.

Most patients treated with Yondelis can be expected to have adverse reactions of any grade (97.6%) and approximately 63.2% of patients experience serious adverse reactions of grade 3 or 4 severity. The most common adverse reactions of any severity grade were neutropaenia, nausea, vomiting, increase in AST/ALT, anaemia, fatigue, thrombocytopaenia, anorexia and diarrhoea.
Fatal adverse reactions have occurred in 3.8% of patients treated with Yondelis. They were often the result of a combination of events including pancytopaenia, febrile neutropaenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.

Tabulated summary of adverse reactions.

The following safety profile of Yondelis is based on adverse events and reactions reported in clinical trials, post-authorisation safety studies and spontaneous reporting. See Table 2.
Table 3 displays the adverse reactions reported in patients with soft tissue sarcoma that were treated with Yondelis. Both adverse reactions and laboratory values have been used to provide frequencies.
Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1000).

Description of selected adverse reactions.

Most frequent adverse reactions.

Blood and lymphatic system disorders.

Neutropaenia.

Neutropaenia is the most common haematological toxicity. It followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred at a median of 15 days and recovered within a week. The analysis per cycle performed in patients treated with Yondelis showed neutropaenia of grade 3 and 4 in approximately 19% and 8% of cycles respectively. In this population febrile neutropaenia occurred in 2% of patients and in < 1% of cycles.

Thrombocytopaenia.

Bleeding events associated to thrombocytopaenia occurred in < 1% of patients treated with Yondelis. The analysis per cycle performed in these patients showed thrombocytopaenia of grade 3 and 4 in approximately 3% and < 1% of cycles respectively.

Anaemia.

Anaemia occurred in 93% of patients treated with Yondelis. The percentages of patients anaemic at baseline were 46%. The analysis per cycle performed in patients showed anaemia of grade 3 and 4 in approximately 3% and 1% of cycles respectively.
Hepatobiliary disorders.

Hepatic failure.

Rare cases of hepatic failure (including cases with fatal outcomes) have been reported in patients with serious underlying medical conditions treated with trabectedin, both in clinical trials and in post-marketing setting. Some potential risk factors that may have contributed to increased trabectedin toxicity observed in these cases were dose management inconsistent with recommended guidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 substrates or CYP3A4 inhibitors, or lack of dexamethasone prophylaxis.

AST/ALT increases.

The median time to reach the peak values was 5 days for both AST and ALT. Most of the values had decreased to grade 1 or resolved by day 14-15 (see Section 4.4). The analysis per cycle performed in patients showed grade 3 elevations of AST and ALT in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.

Hyperbilirubinemia.

Bilirubin peaks approximately a week after onset and resolves approximately two weeks after onset.
Liver function tests predicting severe toxicity (meeting Hy´s law) and clinical manifestations of severe hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in less than 1% of patients.

Other adverse reactions.

Capillary leak syndrome (CLS).

Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes) (see Section 4.4).

Post-marketing adverse effects.

The following adverse reactions have been identified during post-approval use of Yondelis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. See Table 4.

4.9 Overdose

There is limited data on the effects of trabectedin overdose. The major anticipated toxicities are gastrointestinal, bone marrow suppression and hepatic toxicity. There is no specific antidote for trabectedin currently available. In the event of an overdose, patients should be closely monitored and symptomatic supportive care measures instituted as required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.

Mechanism of action.

Trabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Pharmacodynamic effects.

Trabectedin has been shown to exert antiproliferative in vitro activity against a range of human tumour cell lines and experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian and melanoma. In vivo activity against tumour xenografts in nude mice has been observed for some tumour types, including some soft tissue sarcomas.

Electrocardiogram (ECG) investigations.

In a placebo-controlled QT/QTc study, trabectedin did not prolong the QTc interval in patients with advanced solid malignancies.

Clinical trials.

The clinical efficacy and safety of Yondelis in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in the pivotal trial ET743-SAR-3007 (NCT01343277), a randomised (2:1), open-label, active-controlled trial comparing treatment with Yondelis 1.5 mg/m2 as a 24-hour continuous intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 3 weeks. Treatment continued in both arms until disease progression or unacceptable toxicity; all patients in the Yondelis arm were required to receive dexamethasone 20 mg intravenous injection prior to each Yondelis infusion. Patients were required to have unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen.
Randomisation was stratified by subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs. ≥ 2). The efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Patients in the dacarbazine arm were not offered Yondelis at the time of disease progression.
A total of 518 patients were randomised, 345 to the Yondelis arm and 173 patients to the dacarbazine arm. The median patient age was 56 years (range: 17 to 81); 30% were male; 76% White, 12% Black, and 4% Asian; 73% had leiomyosarcomas and 27% liposarcomas; 49% had an ECOG PS of 0; and 89% received ≥ 2 prior chemotherapy regimens. The most common (≥ 20%) pre-study chemotherapeutic agents administered were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%). Approximately 10% of patients had received pazopanib.
Trial ET743-SAR-3007 demonstrated a statistically significant improvement in PFS. An exploratory analysis of independent radiology committee-determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. Efficacy results from Trial ET743-SAR-3007 are presented in Table 5. See Figure 1.

Paediatric population.

Trabectedin has not been studied in paediatric subjects with leiomyosarcoma of liposarcoma. In a phase I-II study (SAR-2005) in 50 paediatric patients with rhabdomyosarcoma, Ewing sarcoma or non-rhabdomyosarcoma soft tissue sarcoma, the objective response rate was 2.5% (95% CI: 0.1%-13.2%).

5.2 Pharmacokinetic Properties

Distribution.

Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at doses up to and including 1.8 mg/m2. Trabectedin pharmacokinetic profile is consistent with a multiple-compartment disposition model.
Following intravenous administration, trabectedin demonstrates a high apparent volume of distribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin in plasma is protein bound). The distribution volume at steady state of trabectedin in human subjects exceeds 5,000 l.

Metabolism.

Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative metabolism of trabectedin in vitro at clinically relevant concentrations. Other P450 enzymes may contribute to metabolism. Trabectedin at clinically relevant concentrations did not induce or inhibit major cytochrome P450 enzymes in vitro.

Excretion.

Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is 58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for plasma clearance of trabectedin (30.9 L/h) and blood/plasma ratio (0.89), the clearance of trabectedin in whole blood is approximately 35 L/h. This value is approximately one-half the rate of human hepatic blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patient variability of the population estimate for plasma clearance of trabectedin was 49% and intra-patient variability was 28%.

Special populations.

A phase 1 study showed that the plasma clearance of trabectedin is not influenced by age (range 19-83 years), gender, total body weight (range: 36 to 148 kg) or body surface area (range: 0.9 to 2.8 m2).
For information regarding the Japanese population see Section 4.2 Dose and Method of Administration, Special populations.

Renal impairment.

There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (≥ 30.3 mL/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of less than 30.3 mL/min. The low recovery (< 9% in all studied patients) of total radioactivity in the urine after a single dose of 14C-labelled trabectedin indicates that renal impairment has little influence on the elimination of trabectedin or its metabolites.

Hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of trabectedin was assessed in 15 cancer patients at doses ranging from 0.58 to 1.3 mg/m2 administered as 3-hour infusion. The geometric mean dose normalised trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in 6 patients with moderate hepatic impairment (increased serum bilirubin levels from 1.5 to 3 x ULN and increase of aminotransferases (AST or ALT) < 8 x ULN) following administration of a single trabectedin dose of 0.58 mg/m2 (n=3) or 0.9 mg/m2 (n=3) compared to 9 patients with normal liver function following administration of a single trabectedin dose of 1.3 mg/m2 (see Section 4.2; Section 4.4).

5.3 Preclinical Safety Data

Genotoxicity.

Trabectedin was genotoxic in both in vitro, Ames test and lymphoma assays and in vivo mouse micronucleus test.

Carcinogenicity.

Long-term carcinogenicity studies have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sucrose, monobasic potassium phosphate, phosphoric acid, potassium hydroxide.

6.2 Incompatibilities

Yondelis must not be mixed or diluted with other medicinal products except those mentioned, see Section 4.2.

6.3 Shelf Life

Unopened vials.

60 months.

After reconstitution.

Chemical and physical stability has been demonstrated for 30 hours up to 25°C.
From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If not diluted and used immediately, do not store for longer than 24 hours at 2°C to 8°C. For use in one patient on one occasion only. Discard any residue.

After dilution.

Chemical and physical stability has been demonstrated for 30 hours up to 25°C.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C-8°C). Refrigerate. Do not freeze.
For storage conditions after reconstitution and dilution of the medicinal product, see Section 6.3.

6.5 Nature and Contents of Container

Yondelis 1 mg.

Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip-off seal containing 1 mg of trabectedin.
Each carton contains one vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
See Section 4.2 for Instructions for handling Yondelis.

6.7 Physicochemical Properties

Chemical structure.

(1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14-trihydroxy-7',9dimethoxy-4,10,23-trimethyl-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-19-one.
Molecular Formula: C39H43N3O11S.
Molecular Weight: MW: 761.84.
Chemical structure:

CAS number.

114899-77-3.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes