Consumer medicine information

Istodax

Romidepsin

BRAND INFORMATION

Brand name

Istodax

Active ingredient

Romidepsin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Istodax.

SUMMARY CMI

ISTODAX®

Consumer Medicine Information (CMI) summary

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

1. Why am I given ISTODAX?

ISTODAX contains the active ingredient romidepsin. ISTODAX is used to treat a type of cancer called peripheral T-cell lymphoma, or PTCL, in patients who have received at least one previous treatment for this condition.

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

2. What should I know before I am given ISTODAX?

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given ISTODAX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ISTODAX 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 am I given ISTODAX?

  • ISTODAX will be given to you as an intravenous (IV) infusion into your vein by your doctor or nurse.
  • Your doctor will choose the correct dose of ISTODAX for you.

More instructions can be found in Section 4. How am I given ISTODAX? in the full CMI.

5. What should I know while receiving ISTODAX?

Things you should do
  • Remind any doctor, dentist, pharmacist, nurses or healthcare professionals you visit that you are using ISTODAX.
  • Tell all doctors, dentists, and pharmacists who are treating you that you are being given ISTODAX.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are being given ISTODAX.
  • Drink plenty of fluid while taking ISTODAX.
  • Keep all of your doctor's appointments so that your progress can be checked.
Driving or using machines
  • ISTODAX may cause tiredness or the feeling of weakness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

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

6. Are there any side effects?

Like all medicines, ISTODAX can cause side effects. Your doctor will discuss potential side effects with you and will explain the risks and benefits of your treatment. Some side effects can be serious and you may require medical attention. Contact your doctor immediately or go to the Emergency Department at your nearest hospital if you have any signs or symptoms (changes to your normal self), particularly if they are getting worse or do not go away.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ISTODAX® (ISS toe dax)

Active ingredient(s): romidepsin (roe" mi dep' sin)

Consumer Medicine Information (CMI)

This leaflet provides important information about using ISTODAX. 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 ISTODAX.

Where to find information in this leaflet:

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

1. Why am I given ISTODAX?

ISTODAX contains the active ingredient romidepsin. ISTODAX is a type of anti-cancer medicine that belongs to a group of medicines known as histone deacetylase or HDAC inhibitors.

ISTODAX is used to treat a type of cancer called peripheral T-cell lymphoma, or PTCL, in patients who have received at least one previous treatment for this condition.

PTCL is a disease in which a type of white blood cell from your immune system, called T-cells, grows abnormally. ISTODAX works by slowing or stopping the growth of these cancer cells. This medicine has also been shown to kill cancer cells.

2. What should I know before I am given ISTODAX?

Warnings

Do not use ISTODAX if:

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

Some of the symptoms of an allergic reaction may include:

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

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes.
  • have a history of heart problems or are taking medicines used to help treat abnormal rhythms of the heart (anti-arrhythmics).
    ISTODAX treatment has been associated with the occurrence of abnormal heart rhythms. Your doctor may conduct a heart function (electrocardiograph [ECG]) test before and during treatment to monitor the activity of your heart.
  • have a history of blood conditions which affect the number of blood cells in your body.
    This medicine can cause a reduction in the numbers of blood cells. Your doctor will ask you to take regular blood tests to monitor the levels of your blood cells.
  • have a history of frequent infections, or a history of hepatitis B or Epstein Barr virus infection.
    This medicine can cause a reduction in the numbers of blood cells used by the body to fight infection. Your doctor will ask you to take regular blood tests to monitor the levels of your blood cells.
  • are pregnant or plan to become pregnant.
    ISTODAX can harm your unborn baby. Your doctor will ask you to have a pregnancy test prior to starting treatment with ISTODAX. Your doctor can discuss with you the risks and benefits of using this medicine during pregnancy.
  • use reliable means of contraception during treatment and treatment interruptions, and for at least 4 weeks after ISTODAX treatment has stopped.
    Your doctor will tell you what method of contraception to use.
  • are breast-feeding or plan to breast-feed.
    It is not known if ISTODAX passes into breast milk. Your doctor will help to decide if you should stop breast-feeding when you start treatment with this medicine.
  • have a history of kidney problems.
  • have problems with the amount of potassium or magnesium in your blood.

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.

ISTODAX is not recommended for use in pregnant women. ISTODAX can harm your unborn baby. Your doctor will ask you to have a pregnancy test prior to starting treatment with ISTODAX. Your doctor can discuss with you the risks and benefits of using this medicine during pregnancy.

Use reliable means of contraception during treatment and treatment interruptions, and for at least 4 weeks after ISTODAX treatment has stopped. Your doctor will tell you what method of contraception to use.

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

It is not known if ISTODAX passes into breast milk. Your doctor will help to decide if you should stop breast-feeding when you start treatment with this medicine.

3. What if I am taking other medicines?

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

Some medicines may interfere with each other. These include:

  • warfarin or any other blood thinner used to prevent blood clots
  • medicines used to treat heart problems such as arrhythmia (irregular beating of the heart)
  • medicines used to treat fungal infections (such as ketoconazole)
  • medicines used to treat tuberculosis (such as rifampin)
  • oestrogen-containing oral contraceptive pills for women
  • St John's Wort.

These medicines may be affected by ISTODAX or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ISTODAX.

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

4. How am I given ISTODAX?

How is ISTODAX given

ISTODAX will be given to you as an intravenous (IV) infusion into your vein by your doctor or nurse.

Your doctor will choose the correct dose of ISTODAX for you.

Your dose will depend on your general condition and your height and weight.

Your dose will be calculated based on your body surface area, with the usual dose of 14 mg ISTODAX per metre squared of body surface area.

ISTODAX will be given to you over a 4-hour period on Days 1, 8 and 15 of a 28-day cycle. These cycles may be repeated for as long as you continue to receive benefit from ISTODAX.

Your doctor will check your progress and may change your dose if necessary.

Your doctor may also give you another medicine to help stop you feeling sick (nausea) and vomiting.

If you have any questions on the use of ISTODAX, ask your doctor.

If you miss a dose of ISTODAX

It is very important for you to keep all appointments to receive ISTODAX. If you miss an appointment, ask your doctor when to schedule your next dose.

If you are given too much ISTODAX

As ISTODAX is given to you under the supervision of your doctor, it is unlikely that you will be given too much.

However, if you experience any side effects after being given ISTODAX, tell your doctor immediately.

5. What should I know while receiving ISTODAX?

Things you should do

Tell all doctors, dentists, pharmacists, nurses or healthcare professionals who are treating you that you are being given ISTODAX.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given ISTODAX.

It may affect other medicines used during or after the surgery.

Drink plenty of fluid while taking ISTODAX. Discuss with your doctor how much water you should drink.

Having enough fluids may help to reduce the chances of dehydration.

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

Your doctor will need to perform regular ECG (heart function) tests and blood tests.

Call your doctor straight away if you:

  • become pregnant while being given ISTODAX.

Remind any doctor, dentist, pharmacist, nurses or healthcare professionals you visit that you are using ISTODAX.

Driving or using machines

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

ISTODAX may cause tiredness or the feeling of weakness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

6. Are there any side effects?

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

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

Serious side effects

Serious side effectsWhat to do
  • Sudden signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips or tongue or other parts of the body; and/or shortness of breath, wheezing or trouble breathing.
  • Symptoms of infection such as fever, chills, sore throat, cough, shortness of breath with or without chest pain, mouth ulcers, burning with urination, flu-like symptoms or any other sign of infection.
    You may have a low number of white blood cells that fight infection. Patients receiving ISTODAX can develop serious infections that sometimes lead to death.
  • Abnormal heart-beat, or feeling dizzy or faint.
    This could be due to a change in your heart-rate and/or low levels of potassium or magnesium in your blood.
  • Sudden pain in your chest or difficulty in breathing.
    This may be due to blood clots in the artery leading to your lungs.
  • Pain or swelling in your legs, especially in your lower leg or calves.
    This may be due to blood clots in the veins of your leg.
  • Heavy bleeding in the absence of injury.
    You may have a very low number of platelets, which are the blood cells that help to clot your blood.
  • Racing heart, extreme fatigue, headaches.
    You may have a very low number of red blood cells that carry oxygen.
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.

Other side effects

Common side effectsWhat to do
  • gastro-intestinal problems such as nausea, vomiting, diarrhoea, constipation, stomach pain, indigestion, a loss of appetite, weight loss, or changes in taste.
  • easy bleeding or bruising in the absence of injury. You may have a low number of platelets, which are the blood cells that help to clot your blood.
  • weakness, tiredness, dizziness, shortness of breath or pale colour. You may have a low number of red blood cells that carry oxygen.
  • swelling of hands, ankles or feet; muscle pain or spasms.
  • signs of dehydration such as dry mouth, increasing thirst, weakness or light-headedness.
Speak to your doctor if you have any of these side effects and they worry you.

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

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

Reporting side effects

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

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

7. Product details

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

What ISTODAX contains

Active ingredient
(main ingredient)		romidepsin
Other ingredients
(inactive ingredients)		Povidone
SolventPropylene glycol
Anhydrous ethanol
Potential allergensDoes not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

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

What ISTODAX looks like

ISTODAX is supplied as a dual pack with one vial containing the white to off-white Istodax powder and the other vial containing a clear solvent.

Registration Numbers

ISTODAX (romidepsin) 10mg powder for injection vial and solvent for reconstitution vial (AUST R 198854)

Who distributes ISTODAX

Bristol-Myers Squibb Australia Pty Ltd
4 Nexus Court, Mulgrave
Victoria 3170, Australia
Toll free number: 1800 067 567
Email: [email protected]

ISTODAX® is a trademark of Celgene Corporation, a Bristol Myers Squibb Company

This leaflet was prepared in January 2025.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Istodax

Active ingredient

Romidepsin

Schedule

S4

 

1 Name of Medicine

Australian approved name: romidepsin.

2 Qualitative and Quantitative Composition

Each vial contains 11 mg of romidepsin (inclusive of 10% overfill).
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

Romidepsin is a white to off-white powder, with a melting point of 272°C. Romidepsin is generally more soluble in organic solvents and is very slightly soluble in water (about 0.3 mg/mL). The partition coefficient (n-octanol/water) is approximately 1.9.

3 Pharmaceutical Form

Istodax is supplied in a composite pack including a sterile 10 mg single-use vial containing 10 mg of lyophilised romidepsin and 20 mg of povidone, and a second sterile vial containing 2.2 mL of solvent. The solvent vial contains 80% propylene glycol and 20% anhydrous ethanol. Both romidepsin and solvent vials contain an overfill to ensure the recommended volume can be withdrawn at a concentration of 5 mg/mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Istodax is indicated for the treatment of peripheral T cell lymphoma in patients who have received at least one prior systemic therapy.

4.2 Dose and Method of Administration

Dosage.

The recommended dose is 14 mg/m2 administered intravenously over a 4-hour period on Days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

Method of administration.

Istodax should be administered under the supervision of a physician qualified in the use of chemotherapeutic agents. Serum potassium and magnesium should be within the normal range before each administration of Istodax.
Istodax is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when preparing and handling Istodax solutions. The use of gloves is recommended.
Any unused product or waste material should be disposed of in accordance with local requirements for disposal of cytotoxic compounds.

Preparation and administration.

Istodax must be reconstituted with the solvent provided and further diluted with 0.9% sodium chloride injection before intravenous infusion using the following guidelines.
1. Each 10 mg single use vial of Istodax (vial contains overfill to 11 mg of romidepsin) must be reconstituted with 2.2 mL of the supplied diluent (vial contains overfill to 2.4 mL of solvent). The final reconstituted 10 mg single use vial contains 2.2 mL of Istodax solution 5 mg/mL.
2. With a suitable syringe, aseptically withdraw 2.2 mL of solvent from the solvent vial provided, and slowly inject it into the Istodax vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain Istodax 5 mg/mL.
3. Before intravenous infusion, further dilute the reconstituted solution: extract the appropriate amount of the reconstituted Istodax solution from the vials to deliver the desired dose. Then, using proper aseptic technique, dilute with 500 mL 0.9% sodium chloride injection.
The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles. Parenteral drug products should be inspected visually for particulate matter and discolouration before administration, whenever solution and container permit.
Istodax is for single use in one patient only, and any residue should be discarded.
Istodax does not contain antimicrobial preservatives. To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2-8°C for not more than 24 hours.
4. Administer intravenously over a 4 hour period.

Recommended dose adjustments during treatment.

Haematological toxicities.

Administration of Istodax should be delayed when patients experience Grade 3 or 4 neutropenia or thrombocytopenia until the specific cytopenia returns to ANC ≥ 1.5 x 109/L and/or platelet count ≥ 75 x 109/L or baseline, then therapy may be restarted at 14 mg/m2.
Patients who develop Grade 4 febrile (≥ 38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion should have subsequent doses of Istodax delayed until the specific cytopenia returns to Grade 1 or baseline. The Istodax dose should then be permanently reduced to 10 mg/m2.

Non-haematologic toxicities (except alopecia).

Treatment with Istodax should be delayed if patients develop Grade 2 or 3 NCI CTCAE toxicity until toxicity returns to Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs or Grade 4 toxicity is observed, treatment with Istodax should be delayed until toxicity returns to Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.
Istodax should be permanently discontinued for NCI CTCAE Grade 3 or 4 toxicity that is recurrent despite dose reduction.

Use in patients with hepatic impairment.

Dose adjustment is not required for patients with mild hepatic impairment. Dose adjustment is recommended in patients with moderate and severe hepatic impairment.
For patients with moderate hepatic impairment, a dose adjustment of 7 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle (50% dose reduction) is recommended. Cycles are to be repeated every 28 days provided that the patient continues to tolerate treatment with Istodax and continues to benefit from treatment. (See Table 1).
For patients with severe hepatic impairment, a dose adjustment of 5 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle (64% dose reduction) is recommended. Cycles are to be repeated every 28 days provided that the patient continues to tolerate treatment with Istodax and continues to benefit from treatment. (See Table 1).
Table 1 lists the recommendations for dose adjustment in Patient with Hepatic Impairment.

Use in patients with renal impairment.

No formal studies have been conducted in patients with renal impairment. Patients with serum creatinine > 176.8 micromol/L were excluded from the pivotal study. However, renal excretion does not play a significant role in the elimination of romidepsin as metabolism is primarily hepatic. A population PK analysis showed that romidepsin PK were not affected by different levels of renal impairment. However, as the effect of end-stage renal disease has not been studied, patients with end-stage renal disease should be treated with caution.

4.3 Contraindications

Hypersensitivity to romidepsin or any of the excipients.

4.4 Special Warnings and Precautions for Use

Haematological toxicity.

Treatment with Istodax can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia) and anaemia; therefore, these haematological parameters should be monitored during treatment with Istodax, and the dose should be modified as necessary.

Infection.

Serious and sometimes fatal infections, including pneumonia, sepsis, and viral reactivation (including hepatitis B and Epstein Barr viruses) have been reported in clinical trials with Istodax. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow.
Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations. Consider monitoring or prophylaxis in patients with evidence of a past history of hepatitis B.
Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

Electrocardiographic changes.

QTc prolongation as well as several treatment emergent morphological changes in ECGs (including T wave and ST segment changes) have been reported in clinical studies. Many of the ECG morphologic abnormalities were also observed at baseline. These ECG changes were transient and were not associated with functional cardiovascular changes or with symptoms. The clinical significance of these treatment emergent changes is unknown.
In view of potential ECG changes, an ECG should be performed at baseline in all patients. Serum potassium and magnesium should be within the normal range before each administration of Istodax.
Appropriate cardiovascular monitoring precautions should be considered in patients with congenital long QT syndrome, a history of significant cardiovascular disease, and those taking antiarrhythmic medicines or medicinal products that lead to significant QT prolongation. Such precautions include the monitoring of ECGs at baseline and periodically during treatment.
Patients with a significant cardiac history have been excluded from the clinical trials. Hence, safety data for subjects with significant cardiac history is not available.

Gastrointestinal disturbances.

Nausea and vomiting have very commonly been reported with Istodax; therefore, antiemetic use is recommended.

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) has been reported to occur in 2% of patients with stage III/IV PTCL in clinical trials. Patients with advanced stage disease and/or high tumour burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

Hypersensitivity.

Hypotension and other symptoms possibly representing hypersensitivity to the compound have been observed uncommonly during the infusion of Istodax.

Use in the elderly.

No specific dose adjustments are recommended for the elderly. The population PK analysis of romidepsin showed that age did not appear to influence the romidepsin PK.

Paediatric use.

The safety and efficacy of romidepsin in children and adolescents under 18 years of age has not been established.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Haematological toxicity, Electrocardiographic changes.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Warfarin or warfarin derivatives.

Prolongation of prothrombin time (PT) and elevation of International Normalisation Ratio (INR) were observed in a patient receiving Istodax concomitantly with warfarin. Although the interaction potential between Istodax and warfarin or warfarin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered Istodax and warfarin or warfarin derivatives.

Medicines that prolong the QT interval.

Appropriate cardiovascular monitoring precautions should be considered in patients taking antiarrhythmic medicines or medicinal products that lead to significant QT prolongation. Such precautions include the monitoring of ECGs at baseline and periodically during treatment.

Medicines that inhibit or induce cytochrome P450 3A4 enzymes.

Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic medicine interaction trial, the strong CYP3A4 inhibitor, ketoconazole, increased romidepsin exposure (AUC0-∞) by approximately 25%. Monitor for toxicity related to increased romidepsin exposure when romidepsin is coadministered with strong CYP3A4 inhibitors.
Avoid coadministration of Istodax with rifampin. In a pharmacokinetic medicine interaction trial with coadministered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, coadministration of CYP3A4 inducers decreases concentrations of medicines metabolised by CYP3A4. The reasons for this increase are not understood. It is unknown if other potent CYP3A4 inducers would alter the exposure of Istodax. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

Medicines that inhibit medicine transport systems.

Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). Although romidepsin is a substrate, P-gp inhibitors are not likely to affect pharmacokinetics of romidespin as it is extensively metabolized before elimination.

Oestrogen containing contraceptives.

An in vitro binding assay determined that romidepsin competes with beta-oestradiol for binding to oestrogen receptors. Women of childbearing potential should be advised that Istodax may reduce the effectiveness of oestrogen containing contraceptives. Therefore, alternate methods of nonoestrogen containing contraception (e.g. condoms, intrauterine device) should be used in patients receiving romidepsin. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Formal studies to assess the effect of romidepsin on fertility have not been conducted.
Based on nonclinical findings, male and female fertility may be compromised by treatment with Istodax.
In a 26 week toxicology study, romidepsin administration resulted in testicular degeneration in rats at ≥ 0.33 mg/kg/week (approximately 2% of the exposure level in patients receiving the recommended dose of 14 mg/m2/dose). Atrophy was seen in the ovary, uterus, vagina and mammary gland of female rats administered doses at ≥ 0.1 mg/kg/week (approximately 0.3% of the exposure level in patients receiving the recommended dose of 14 mg/m2/dose).
Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day, approximately 2% of the estimated human weekly dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were also observed.
Testicular degeneration was observed in dogs and mice, and atrophy of the prostate was also seen in dogs following administration of romidepsin at exposures below the clinical AUC.
(Category D)
There are no adequate and well-controlled studies of Istodax in pregnant women. Women of childbearing potential should have a pregnancy test prior to starting treatment with Istodax. Based on its mechanism of action and findings in animals, Istodax can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Istodax.
Women of childbearing potential should be advised to use effective contraception during treatment with Istodax and for at least 1 month after the last dose. Istodax may reduce the effectiveness of oestrogen-containing contraceptives. Therefore, alternative methods of non-oestrogen containing contraception (e.g. condoms, intrauterine device) should be used in patients receiving Istodax.
Male patients treated with Istodax are advised to use effective contraception and to avoid fathering a child during and up to 1 month after treatment.
 There is no information regarding the presence of romidepsin in human milk, the effects of Istodax on the nursing infant, or the effects of Istodax on milk production. A risk to the newborn or infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue or abstain from Istodax therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects of Istodax on the ability to drive or operate machines have been performed. Treatment with romidepsin in clinical trials was commonly associated with asthenia and fatigue, which can be severe. If affected, patients are to be instructed not to drive or use machines or perform hazardous tasks.

4.8 Adverse Effects (Undesirable Effects)

Tabulated summary of adverse events.

In a single arm study, 131 patients with PTCL were exposed to romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 of a 28 day cycle. The mean duration of treatment and number of doses were 5.6 months and 15.5 doses, respectively, corresponding to about 6 cycles.
Table 2 lists the adverse events that occurred at a frequency of ≥ 10% and adverse drug reactions (considered related to the treatment) that occurred at a frequency of ≥ 5% in subjects. The table also provides the respective ≥ grade 3 events under each section.

Summary of adverse reactions.

The principal clinically important groups of adverse drug reactions in patients with PTCL treated with romidepsin are gastrointestinal disturbances, asthenic conditions, infections, haematological toxicities and clinical chemistry abnormalities.

Gastrointestinal disturbances.

Gastrointestinal (GI) reactions, such as nausea, vomiting and diarrhoea were commonly reported but generally mild to moderate in intensity and nonserious, and most patients continued romidepsin despite the occurrence of GI events. In accordance with the study protocols, antiemetic support was commonly used. Dehydration concurrent with vomiting and/or diarrhoea was uncommon.

Asthenic conditions.

Asthenic conditions generally presented early during treatment and were mostly grade 1 or 2 in intensity and nonserious. However, grade 3 or 4 and/or serious asthenic conditions have been reported. Asthenic conditions were an infrequently reported cause of discontinuation in patients with PTCL (< 2%).

Haematological toxicities and clinical chemistry.

The incidence of haematologic toxicities including neutropenia and thrombocytopenia was common in patients with PTCL, and were more often grade 3 or 4. Both thrombocytopenia and neutropenia commonly led to a dose being held, or less commonly to dose reduction or discontinuation in a few patients. Hypokalaemia was also commonly observed in PTCL.
In a separate phase 2, multicenter, open label study designed to evaluate the activity and tolerability of romidepsin in patients with PTCL who had received prior systemic therapy conducted by the National Cancer Institute (NCI), study 1312, a higher incidence of adverse drug reactions related to clinical chemistry abnormalities were noted compared to the pivotal trial, due to more intensive monitoring and routine reporting of laboratory abnormalities as adverse events without consideration of their clinical significance. These include the following (frequency provided for the NCI study versus that in the pivotal trial): hypocalcaemia (47% vs. 2%), increased aspartate transaminase (34% vs. 3%), increased alanine transaminase (32% vs. 3%), hypoalbuminemia (32% vs. 0%), hypomagnesaemia (26% vs. 5%), hyperglycaemia (17% vs. 1%), and hypokalaemia (15% vs. 5%). Most patients continued treatment unchanged despite the occurrence of these reactions, and only two patients were required to permanently discontinue therapy due to these reactions.

Infections.

In patients with PTCL, infections were commonly observed (57%), and the most commonly reported types were upper respiratory tract infection (9%), pneumonia and urinary tract infection (7%), oral candidiasis (6%), and sepsis and nasopharyngitis (5%).

Tumour lysis syndrome.

Tumour lysis syndrome (TLS) has been reported to occur in patients with advanced disease and 2% of patients with stage III/IV PTCL.

Discontinuations.

Discontinuation due to an adverse event occurred in 19% of patients in the study. Thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients.

Serious adverse events.

Infections were the most common type of serious adverse events (SAEs) reported, with 20% of patients experiencing a serious infection during the study. SAEs reported in ≥ 2% of patients in the study were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnoea, and dehydration (2%).
Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations. Consider monitoring or prophylaxis in patients with evidence of a past history of hepatitis B.

Deaths.

In the clinical trial, deaths within 30 days of the last dose occurred in 8 patients (6%), most frequently due to disease progression. There were 5 deaths due to infections in the setting of disease progression concurrent with multiorgan failure/ sepsis, pneumonia, septic shock, candida sepsis, and sepsis/ cardiogenic shock.

Postmarketing data.

Viral reactivation (hepatitis B and Epstein Barr viruses) was reported from clinical trials in the postmarketing setting.

Reporting of suspected adverse reactions.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Expected manifestations of overdose could include GI disturbances (nausea, vomiting, diarrhoea, and constipation), haematologic toxicity (thrombocytopenia, neutropenia, and anaemia), asthenic conditions (e.g. fatigue, asthenia, and lethargy), infections, and ECG changes. No specific information is available on the treatment of overdosage of Istodax. There is no known antidote for romidepsin and it is not known if romidepsin is dialyzable.
In the event of an overdose, close clinical monitoring may be instituted and supportive therapy given as required. For information on the management of overdose, in Australia, contact the Poisons Advisory Centre on 13 11 26. In New Zealand. Contact the National Poisons Centre on 0800 POISON or 0800 764 766 for advise on management.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cytostatic anticancer therapy.

Mechanism of action.

Romidepsin is an antineoplastic agent that belongs to the class of drugs known as histone deacetylase (HDAC) inhibitors. At nanomolar concentrations, romidepsin exhibited anticancer activity against both haematological and solid tumour lines. Romidepsin has been shown to have pleiotropic activity including HDAC inhibition, induction or repression of gene expression, cell cycle arrest, cell differentiation, cell growth inhibition, and induction of apoptosis. Romidepsin exposure has been shown to cause both the induction and repression of a number of key regulatory genes in vitro and in vivo.

Cardiac electrophysiology.

The potential effect of romidepsin on the QTc/QTcF interval (heart rate corrected) was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4 hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1 hour infusion. No concentration dependent effect of romidepsin on the duration of the QTc interval was identified at maximum plasma concentrations (Cmax) up to 2.5-fold higher on average than observed with the clinical dose regimen of 14 mg/m2 administered as a 4 hour infusion. Central tendency and categorical analyses also showed no effect of romidepsin on the duration of the QTc/QTcF interval. Based on these results, romidepsin does not appear to prolong the QTc interval to a clinically significant extent in patients with advanced cancer.
Romidepsin was associated with a delayed concentration dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute (bpm) occurring at the 6 hour time point for patients receiving 14 mg/m2 as a 4 hour infusion. At 24 hours after the start of romidepsin infusion, the mean increase in heart rate was 4.7 bpm.

Clinical trials.

Istodax was evaluated in a multicenter, single arm, international clinical study in patients with peripheral T cell lymphoma (PTCL) who had failed at least 1 prior systemic therapy (study GPI-06-0002). Patients in the USA, Europe and Australia were treated with Istodax at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 of every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.
Primary assessment of efficacy was based on the complete response (CR) rate (comprising CR and unconfirmed CR [CRu]) along with duration of response, as determined by an Independent Review Committee (IRC). The IRC were blinded to investigator evaluations, and conducted a prospective 2 step assessment including review of radiological data and relevant clinical and pathological data using the International Workshop Criteria (IWC).
Supportive measures of efficacy included IRC assessment of objective disease response (comprising objective response rate [ORR], CR, CRu and partial response [PR]) and investigator assessments of CR, objective disease response and duration of response. Additional secondary endpoints included time to objective disease progression and change in ECOG performance status.
Most patients (91 [70%]) had stage III or IV disease at the time of initial PTCL diagnosis. All patients had received prior systemic therapy for PTCL. Twenty-one patients (16.2%) had received prior autologous stem cell transplant.
Efficacy outcomes for the HC population (n = 130) as determined by the IRC and investigators are provided in Table 3. The CR rate was 15% and ORR was 26% as determined by the IRC. Stable disease was reported as best response in 25% of patients. Similar CR rates were observed by the IRC across all major subtypes of PTCL: PTCL NOS (14.5%); AITL (22.2%); and ALK-1 negative ALCL (19.0%).
Among the 49 patients whose best response to last prior therapy was progressive disease, 9 (18.4%) achieved CR (8 of these 9 patients achieved a complete response with durations of response ≥ 6 months, including 4 patients with durations ≥ 12 months) and 14 (28.6%) achieved objective disease response.
Responses to romidepsin generally occurred early in the course of therapy. Median time to objective response was 1.8 months ([observed at ~ 2 cycles] [range - 1.4 to 5.3 months]) for the 34 patients who achieved CR, CRu or PR, and the median time to CR was 3.5 months ([observed at ~ 4 cycles] [range - 1.6 to 9.2 months]) for patients with CR, based on IRC review. There are insufficient data from the pivotal study to support guidance on the potential benefit of haematopoietic stem cell transplantation in patients achieving a complete response with romidepsin.

5.2 Pharmacokinetic Properties

Absorption.

Romidepsin exhibited linear pharmacokinetics (PK) across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.
Following the start of a 4 hour infusion at 14 mg/m2 in patients with advanced malignancies, romidepsin plasma concentrations increased rapidly and reached a plateau (~ 90% of Cmax) at approximately 1 hour postinfusion initiation. After the end of the infusion (i.e. 4 hour), concentrations declined in an apparent multiphasic manner. Based on the noncompartmental analysis, romidepsin AUC0-∞ [geometric mean (geometric CV%)] was 3,157 nanogram.hr/mL (33.9%) with a mean peak plasma concentration (Cmax) of 761 nanogram/mL (31.2%).

Distribution.

Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 nanogram/mL to 1000 nanogram/mL with alpha-1-acid-glycoprotein (AAG) being the principal binding protein.
Romidepsin is not a substrate for BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2 transporters. At therapeutically relevant concentrations, romidepsin did not cause a notable inhibition of BCRP, MDR1, BSEP, MRP2, OAT1, OAT3, OATP1B3, or OCT2. Therefore, romidepsin is not anticipated to cause or be subject to clinically relevant interactions when coadministered with substrates or inhibitors of these transporters. Romidepsin caused modest inhibition of OATP1B1 (36-80% at 1-10 microM). Clinical drug-drug interactions with OATP1B1 substrates cannot be excluded.

Metabolism.

Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro. At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP P450 induction or inhibition by romidepsin when coadministered with CYP P450 substrates.

Excretion.

Based on the noncompartmental analysis following 4 hour intravenous administration of romidepsin at 14 mg/m2, romidepsin clearance [geometric mean (geometric CV%)] was 8.4 L/hr (36.8) and terminal elimination half-life was 3.7 hr (8.3%).

Effect of hepatic impairment.

In patients with cancer, the pharmacokinetics of romidepsin in 12 patients with normal hepatic function (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN), 8 patients with mild hepatic dysfunction (B1: bilirubin ≤ ULN and AST > ULN; B2: bilirubin > ULN but ≤ 1.5 x ULN and any AST), 5 patients with moderate hepatic dysfunction (bilirubin > 1.5 x ULN to ≤ 3 x ULN and any AST), and 6 patients with severe hepatic dysfunction (bilirubin > 3 x ULN and any AST) were compared following a single 4-hour intravenous infusion dose administration of romidepsin at 14 mg/m2, 14 mg/m2, 7 mg/m2, and 5 mg/m2, respectively. The geometric mean Cmax values after administration of 14, 7, and 5 mg/m2 romidepsin in patients with mild, moderate, and severe hepatic impairment were approximately 115%, 96%, and 95% of the corresponding value after administration of 14 mg/m2 romidepsin in patients with normal hepatic function, respectively. The geometric mean (AUCinf) values in patients with mild, moderate, and severe hepatic impairment were approximately 144%, 114%, and 116%, respectively of the corresponding value in patients with normal hepatic function. For the 4 cohorts, moderate inter-patient variability was noted for the exposure parameters, as coefficient of variation (CV) ranged from 29 to 56%. Consistent with the overall exposure (AUCinf) results, compared to the normal hepatic function cohort, romidepsin clearance decreased with increase hepatic impaired function.
The ranges of individual Cmax and AUCinf values observed from mild, moderate and severe hepatic impaired patients are similar to the range observed from the normal hepatic function patients. This suggests that for patients with mild, moderate, and severe impaired hepatic function, a dose of 14, 7, and 5 mg/m2, respectively, provide similar exposure as compared to patients with normal hepatic function. Therefore, for patients with mild, moderate, and severe hepatic dysfunction, it is recommended to use a starting romidepsin dose of 14 mg/m2, 7 mg/m2, and 5 mg/m2, respectively, administered as a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle.

Medicine interactions.

Ketoconazole.

A medicine interaction clinical trial with the strong CYP3A4 inhibitor, ketoconazole, was conducted in patients with advanced cancer. Following coadministration of 8 mg/m2 Istodax (4 hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ was statistically significant. Coadministration of ketoconazole slightly decreased the romidepsin clearance and volume of distribution, but did not have a statistically significant effect on peak exposure (Cmax).

Rifampin.

A medicine interaction clinical trial with the strong CYP3A4 inducer, rifampin, was conducted in patients with advanced cancer. Following coadministration of 14 mg/m2 Istodax (4 hour infusion) with rifampin, the overall romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the two treatments was statistically significant. Coadministration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The reasons for this increase are not understood.

5.3 Preclinical Safety Data

Genotoxicity.

Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Carcinogenicity.

Carcinogenicity studies have not been performed with romidepsin.

6 Pharmaceutical Particulars

6.1 List of Excipients

Istodax contains Povidone 22 mg per vial (inclusive of 10% overfill used).

Solvent.

2.4 mL (inclusive of overfill to ensure 2.2 mL deliverable volume) of a solution comprising 80% propylene glycol and 20% anhydrous ethanol.

6.2 Incompatibilities

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

6.3 Shelf Life

Unopened vial of Istodax (romidepsin) for injection: 36 months.
Unopened vial of diluent for Istodax: 36 months.

6.4 Special Precautions for Storage

Store unopened vials of Istodax and solvent below 25°C. Store vials in carton until use.

6.5 Nature and Contents of Container

Istodax is supplied as a composite pack with a sterile 10 mg single-use vial containing 10 mg of lyophilised romidepsin (vial contains an overfill to 11 mg of romidepsin), and a second sterile vial containing 2.2 mL of diluent (vial contains an overfill to 2.4 mL of solvent).

Istodax 10 mg powder vial.

10 mL glass vial (type I) with a 20 mm butyl rubber stopper.

Solvent.

2 mL glass vial (type I) with a 13 mm butyl Teflon-faced plug stopper.
Istodax composite pack containing 1 vial of romidepsin and 1 vial of solvent.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements for disposal of cytotoxic compounds.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

128517-07-7.
Molecular formula: C24H36N4O6S2.
Molecular weight: 540.71.
ATC code: L01XX39.
Chemical name: (1S,4S,7Z,10S,16E,21R)-7-ethylidene- 4,21-bis(1-methylethyl)-2-oxa-12,13-dithia- 5,8,20,23-tetraazabicyclo[8.7.6]tricos- 16-ene-3,6,9,19,22-pentone.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes