Consumer medicine information

Liposomal Doxorubicin SUN

Doxorubicin hydrochloride (liposomal)

BRAND INFORMATION

Brand name

Liposomal Doxorubicin SUN

Active ingredient

Doxorubicin hydrochloride (liposomal)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Liposomal Doxorubicin SUN.

What is in this leaflet

This leaflet answers some common questions about Liposomal Doxorubicin SUN. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Liposomal Doxorubicin SUN against the benefits it is expected to have for you.

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

Keep this leaflet. You may need to read it again.

What is Liposomal Doxorubicin SUN used for

Liposomal Doxorubicin SUN is used to treat cancer cells, shrink the size and delay the growth of the tumour.

Liposomal Doxorubicin SUN is also used in combination with another medicine called bortezomib to treat multiple myeloma, which is a cancer of the plasma cell. Plasma cells are produced in the bone marrow and are a component of the immune system.

Liposomal Doxorubicin SUN is also used to treat Kaposi's sarcoma, another type of cancer. Liposomal Doxorubicin SUN produces an improvement in Kaposi's sarcoma including flattening, lightening and shrinkage of the cancer of the breast and ovary. It is used to kill cancer. Other symptoms of Kaposi's sarcoma, such as swelling around the tumour, may also improve or disappear.

Liposomal Doxorubicin SUN belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

Liposomal Doxorubicin SUN contains a medicine called Liposomal Doxorubicin hydrochloride which is able to interact with cells in such a way as to selectively kill cancer cells. The Liposomal Doxorubicin hydrochloride in Liposomal Doxorubicin SUN is enclosed in tiny spheres called liposomes which help to deliver the medicine from the blood stream to the cancerous tissue rather than healthy normal tissue.

Your doctor, however, may prescribe Liposomal Doxorubicin SUN for another purpose.

Ask your doctor if you have any questions about why Liposomal Doxorubicin SUN has been prescribed for you.

Before you are given Liposomal Doxorubicin SUN

When you must not be given it

Do not use Liposomal Doxorubicin SUN if you have an allergy to Liposomal Doxorubicin SUN, Liposomal Doxorubicin hydrochloride or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, hives or flushed, red skin.

Do not use Liposomal Doxorubicin SUN if you are pregnant or breast-feeding.

Before you are given it

Your doctor must know about all of the following before you are given Liposomal Doxorubicin SUN.

Tell your doctor or pharmacist if you have allergies to:

  • any medicines (including other anti-cancer medicines)
  • any other substances, such as foods, preservatives or dyes

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

  • heart problems
  • liver problems
  • diabetes
  • recent surgery to remove your spleen.

Tell your doctor if you have had any or are on other anti-cancer medicines.

Tell your doctor if you are pregnant/planning to become pregnant or breast-feeding. Liposomal Doxorubicin SUN is not recommended in pregnancy and breast-feeding. Your doctor will discuss the possible risks and benefits of using Liposomal Doxorubicin SUN during pregnancy and breast-feeding.

It is important that you or your partner use a reliable method of contraception to avoid pregnancy during Liposomal Doxorubicin SUN treatment and for 6 months after treatment is stopped. This applies to both female and male patients on Liposomal Doxorubicin SUN treatment.

If you have not told your doctor about any of the above, tell them before you are given Liposomal Doxorubicin SUN.

Taking or being given other medicines

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

Some medicines may affect the way other medicines work. Your doctor or pharmacist will be able to tell you what to do when being given Liposomal Doxorubicin SUN with other medicines

How is Liposomal Doxorubicin SUN given

Liposomal Doxorubicin SUN is given by your doctor in a drip (called an infusion) into a vein. Depending on the dose this may take from 30 minutes to more than one hour.

Your doctor will decide how much Liposomal Doxorubicin SUN you will be given and for how long.

The usual dose for cancer of the breast or ovary is 50 mg per square meter of body surface area. This dose is repeated every four weeks for as long as the disease does not progress and you are able to tolerate the treatment.

For multiple myeloma the usual dose is 30 mg per square meter of body surface area. This dose is repeated every three weeks as long as the disease has a satisfactory response and you are able to tolerate the treatment.

For Kaposi's sarcoma the usual dose is 20 mg per square meter of body surface area. This dose is repeated every 2 to 3 weeks for 2-3 months, then as often as necessary to maintain an improvement.

Overdose

As Liposomal Doxorubicin SUN is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any side effects after being given Liposomal Doxorubicin SUN, tell your doctor immediately. You may need urgent medical attention.

Symptoms of a Liposomal Doxorubicin SUN overdose include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature.

While you are using Liposomal Doxorubicin SUN

Things you must do

If the drip stings or hurts while you are receiving a dose of Liposomal Doxorubicin SUN, tell your doctor immediately.

If the medicine starts to upset you or your symptoms become worse, tell your doctor.

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have your follow-up doses of Liposomal Doxorubicin SUN at the appropriate times to get the best effects from your treatments.

Tell any other doctors, dentists, and pharmacists who are treating you that you are on Liposomal Doxorubicin SUN treatment.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are on Liposomal Doxorubicin SUN treatment.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are on Liposomal Doxorubicin SUN treatment.

Tell your doctor, if you or your partner become pregnant during Liposomal Doxorubicin SUN treatment or 6 months after treatment is stopped.

Liposomal Doxorubicin SUN can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.
  • Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
  • Avoid contact sports or other situations where you may bruise or get injured.

Things to be careful of

Be careful driving or operating machinery until you know how Liposomal Doxorubicin SUN affects you. Liposomal Doxorubicin SUN may cause dizziness, tiredness or sleepiness in some people. Make sure you know how you react to Liposomal Doxorubicin SUN before you drive a car, operate machinery, or do anything else that could be dangerous if you are light-headed or sleepy.

Do not drive or operate machinery, if you feel light-headed or sleepy.

If you get reddening painful skin on your hands and feet, any heart problems or mouth sores or if you develop a temperature or any sign of an infection while being given, or soon after stopping Liposomal Doxorubicin SUN, tell your doctor immediately.

Side Effects

Tell your doctor, nurse, or pharmacist as soon as possible if you do not feel well while you are being given Liposomal Doxorubicin SUN.

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

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

During the infusion of Liposomal Doxorubicin SUN the following reactions may occur:

  • flushing of the face, shortness of breath, headache, chills, back pain, tightness in the chest and/or throat, low blood pressure and possibly dizziness and puffing of the face.
  • Stinging or swelling of the skin at the site of injection may also occur.
  • Convulsions or fits.

Tell your doctor, nurse or pharmacist if you notice any of the above reactions or if the drip stings or hurts while you are receiving Liposomal Doxorubicin SUN.

Tell your doctor if you notice any of the following and they worry you.

These are the more common side effects of Liposomal Doxorubicin SUN:

  • general feeling of tiredness, sleepiness, or weakness
  • loss of appetite, weight loss
  • stomach pains, sickness (nausea and vomiting), diarrhoea, constipation
  • hair loss, skin rash
  • depression or anxiety
  • sore muscles or back pain
  • taste perversion.
  • dark or pale areas of skin

These are some of the more common side effects of Liposomal Doxorubicin SUN.

Tell your doctor immediately if you notice any of the following.

These are the more serious side effects. You may need urgent medical attention.

  • heart problems such as irregular heartbeat, shortness of breath and/or swelling of feet or hands
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers, persistent cough, pain/difficulty or increased frequency of passing urine, sore or red nose
  • bruising more easily than normal
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • redness, swelling and sores on the palms of your hands and feet
  • sores in the mouth, oral thrush (a fungal infection in the mouth), tongue inflammation
  • respiratory problems such as difficulty in breathing which may be linked to infections you have caught as a result of your disease
  • problems with vision, sore or irritated eyes
  • feelings of pins and needles
  • pain, redness and dryness of skin if previously experienced during treatment with radiotherapy may also happen with Liposomal Doxorubicin SUN.

A few people may be allergic to some medicines.

Tell your doctor or nurse immediately if you notice any of the following:

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • shortness of breath
  • skin problems such as rash or itchiness
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • dizziness, light-headedness, fainting.

If you have these, you may have had a serious allergic reaction to Liposomal Doxorubicin SUN. You may need urgent medical attention.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice any other effects.

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

After Liposomal Doxorubicin SUN has been stopped

Tell your doctor immediately if you notice any of the following side effects, even if they occur several weeks after stopping treatment with Liposomal Doxorubicin SUN.

  • any heart problems such as shortness of breath or irregular heart beat
  • fever or any other sign of infection
  • redness, swelling or sores on the palms of hands and feet.

Tell your doctor if you notice any other effects.

Tell your doctor, if you or your partner becomes pregnant during the 6 months after Liposomal Doxorubicin SUN treatment is stopped.

Storage

Liposomal Doxorubicin SUN will be stored in the Pharmacy or on the ward and looked after by your doctor, pharmacist or nurse. This medicine is a concentrated suspension for infusion and is stored at 2°C to 8°C in the refrigerator. Do not freeze.

Do not use Liposomal Doxorubicin SUN if the expiry date (EXP) printed on the pack has passed.

Product Description

What it looks like

Liposomal Doxorubicin SUN comes as a sterile, translucent red suspension (2 mg per 1 ml) in a glass vial. It is available as 20 mg/10 ml or 50 mg/25 ml vials with one vial inside each pack.

Ingredients

Active ingredient

Pegylated liposomal Liposomal Doxorubicin hydrochloride (2 mg per 1 ml)

Inactive ingredients:

  • sodium methoxy PEG-40-carbonyl-distearoylphosphatidyl-ethanolamide (MPEG-DSPE)
  • hydrogenated soy phosphatidylcholine (HSPC)
  • cholesterol
  • ammonium sulphate
  • sucrose
  • histidine
  • Water for Injections
  • hydrochloric acid
  • sodium hydroxide

Supplier

Liposomal Doxorubicin SUN is supplied in Australia by:

Sun Pharma ANZ Pty Ltd
12 Waterloo Road
Macquarie Park, Sydney
NSW 2113 Australia
Tel: 1800 726229
Email: [email protected]

Liposomal Doxorubicin SUN 20mg/10ml concentrated solution for injection

AUSTR 202826

Liposomal Doxorubicin SUN 50mg/25ml concentrated solution for injection

AUSTR 202827

This leaflet was last updated in February 2024

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Liposomal Doxorubicin SUN

Active ingredient

Doxorubicin hydrochloride (liposomal)

Schedule

S4

 

1 Name of Medicine

Liposomal doxorubicin hydrochloride.

2 Qualitative and Quantitative Composition

Liposomal Doxorubicin SUN, a pegylated liposomal formulation of doxorubicin hydrochloride, contains doxorubicin encapsulated in liposomes having surface-bound methoxypolyethylene glycol groups (pegylated liposomes). This process is known as pegylation and protects the liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.
Each vial contains 20 mg or 50 mg doxorubicin hydrochloride (HCl) at a concentration of 2.0 mg/mL in a pegylated liposomal formulation.
The drug substance, doxorubicin hydrochloride is an orange-red crystalline powder. It is soluble in water, slightly soluble in methanol and practically insoluble in ethanol and acetone.

3 Pharmaceutical Form

Liposomal Doxorubicin SUN is a concentrate for infusion presented as a sterile, translucent, red suspension in glass vials containing 10 mL or 25 mL for single-use intravenous infusion. The pH of the suspension is 6.5.

4 Clinical Particulars

4.1 Therapeutic Indications

Liposomal Doxorubicin SUN, as monotherapy, is indicated for the treatment of metastatic breast cancer.
Liposomal Doxorubicin SUN is also indicated for the treatment of:
Advanced epithelial ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen.
AIDS-related Kaposi's sarcoma (KS) in patients with low CD4 counts (< 200 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.
Liposomal Doxorubicin SUN may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and doxorubicin (or other anthracycline).
Liposomal Doxorubicin SUN is also indicated, in combination with bortezomib, for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant.

4.2 Dose and Method of Administration

Liposomal Doxorubicin SUN should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.
Liposomal Doxorubicin SUN exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin HCl.

Breast cancer/ ovarian cancer.

Liposomal Doxorubicin SUN is administered intravenously at a dose of 50 mg/m2 once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.
For doses < 90 mg: dilute Liposomal Doxorubicin SUN in 250 mL 5% (50 mg/mL) glucose solution for infusion.
For doses ≥ 90 mg: dilute Liposomal Doxorubicin SUN in 500 mL 5% (50 mg/mL) glucose solution for infusion.
To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent Liposomal Doxorubicin SUN infusions may be administered over a 60-minute period.
In the breast cancer trial program, modification of the infusion was permitted for those patients experiencing an infusion reaction as follows:
5% of the total dose was infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate was doubled over the next 15 minutes. If tolerated, the infusion was completed over the next hour for a total infusion time of 90 minutes.
Subsequent Liposomal Doxorubicin SUN infusions may be administered over a 60 minute period.

Multiple myeloma.

Liposomal Doxorubicin SUN is administered at 30 mg/m2 on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment.
For doses < 90 mg: dilute Liposomal Doxorubicin SUN in 250 mL of 5% (50 mg/mL) glucose solution for infusion.
For doses > 90 mg: dilute Liposomal Doxorubicin SUN in 500 mL of 5% (50 mg/mL) glucose solution for infusion.
The intravenous catheter and tubing should be flushed with 5% glucose solution for infusion between administrations of the 2 medicinal products. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart. The first infusion of Liposomal Doxorubicin SUN should be administered over 90 minutes, as follows:
10 mL over first 10 minutes;
20 mL over next 10 minutes;
40 mL over next 10 minutes;
then, complete the infusion over a total of 90 minutes.
Subsequent doses of Liposomal Doxorubicin SUN will be administered over 1 hour, as tolerated. If an infusion reaction to Liposomal Doxorubicin SUN occurs, stop the infusion and after the symptoms resolve, attempt to administer the remaining Liposomal Doxorubicin SUN over 90 minutes, as follows:
10 mL over first 10 minutes;
20 mL over next 10 minutes;
40 mL over next 10 minutes;
then, complete the remaining infusion over a total of 90 minutes.
Infusion may be given through a peripheral vein or a central line.

AIDS related Kaposi's sarcoma.

Liposomal Doxorubicin SUN should be administered intravenously at 20 mg/m2 every two-to three weeks. Intervals shorter than 10 days should be avoided as drug accumulation and increased toxicity cannot be ruled out. Patients should be treated for two-to-three months to achieve a therapeutic response. Treatment should be continued as needed to maintain a therapeutic response.
Liposomal Doxorubicin SUN, diluted in 250 mL 5% glucose intravenous infusion, is administered by intravenous infusion over 30 minutes.

All patients.

If the patient experiences early symptoms or signs of infusion reaction, see Section 4.4 Special Warnings and Precautions for Use, immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.
To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Liposomal Doxorubicin SUN dose modification secondary to these adverse effects are provided in Tables 1-3. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC) (US).
The tables for PPE and stomatitis provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle). If these toxicities occur in patients with AIDS related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner. See Tables 1 to 3.
For multiple myeloma patients treated with Liposomal Doxorubicin SUN in combination with bortezomib who experience PPE or stomatitis, the Liposomal Doxorubicin SUN dose should be modified as described in Table 1 and 2, respectively. For more detailed information on bortezomib dosing and dosage adjustments, see the PI for bortezomib. See Table 4.

AIDS-KS patients with splenectomy.

As there is no experience with Liposomal Doxorubicin SUN in patients with splenectomy, treatment with Liposomal Doxorubicin SUN is not recommended.

Instructions for use/ handling.

Liposomal doxorubicin SUN must not be given by the intramuscular or subcutaneous route.
Do not use material that shows evidence of precipitation or any foreign particulate matter.
Do not mix with other drugs.
Do not administer as a bolus injection or undiluted solution.
Determine the dose of Liposomal Doxorubicin SUN to be administered (based upon the recommended dose and the patient's surface area). Each Liposomal Doxorubicin SUN vial contains a deliverable volume of 10 mL for the 20 mg vial or 25 mL for the 50 mg vial (there is a small overage of solution in the vial to account for losses during withdrawal). Take the appropriate volume of Liposomal Doxorubicin SUN up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Liposomal Doxorubicin SUN. The appropriate dose of Liposomal Doxorubicin SUN must be diluted in 5% glucose intravenous infusion prior to administration. For doses < 90 mg, dilute doxorubicin in 250 mL, and for doses ≥ 90 mg, dilute doxorubicin in 500 mL.
The use of any diluent other than 5% glucose intravenous infusion or the presence of any bacteriostatic agent such as benzyl alcohol may cause precipitation of Liposomal Doxorubicin SUN.
After dilution with 5% glucose intravenous infusion, the diluted Liposomal Doxorubicin SUN solution should be used immediately. Diluted product not for immediate use should be prepared under aseptic conditions and in line with good pharmaceutical practice should be stored at 2°C to 8°C for no longer than 24 hours. Partially used vials should be discarded.
It is recommended that the Liposomal Doxorubicin SUN infusion line be connected through the side port of an intravenous infusion of 5% glucose intravenous infusion to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with in-line filters.
Caution should be exercised in handling Liposomal Doxorubicin SUN solution. The use of gloves is required. If Liposomal Doxorubicin SUN comes into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Liposomal Doxorubicin SUN should be handled and disposed of in a manner consistent with that of other anti-cancer drugs.
Liposomal Doxorubicin SUN contains no antimicrobial preservative. Use on one patient on one occasion only.

4.3 Contraindications

Liposomal Doxorubicin SUN is contraindicated in patients who have a history of hypersensitivity reactions to its components or to doxorubicin HCl.
Liposomal Doxorubicin SUN should not be administered during pregnancy or while breast feeding.
Liposomal Doxorubicin SUN should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic alfa-interferon.

4.4 Special Warnings and Precautions for Use

For common adverse events that required dose modification or discontinuation, see Section 4.8 Adverse Effects (Undesirable Effects).

Cardiac risk.

The long-term cardiac effects of PLDH relative to the conventional formulation of doxorubicin HCl have not been adequately evaluated. Until further clinical data are available, the risk of developing cardiomyopathy is assumed to be similar to that of standard doxorubicin.
All patients receiving Liposomal Doxorubicin SUN should routinely undergo frequent ECG monitoring.
Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias, are not considered mandatory indications for the suspension of Liposomal Doxorubicin SUN therapy. However reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e. endomyocardial biopsy, should be considered.
More specific methods for evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by multiple gated angiography (MUGA). These methods should be applied routinely before the initiation of Liposomal Doxorubicin SUN and should be repeated periodically during treatment. In a phase-III clinical trial comparing PLDH (50 mg/m2 every 4 weeks) versus doxorubicin (60 mg/m2 every 3 weeks), the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with PLDH than with doxorubicin (HR=3.16, p < 0.001). At cumulative doses between 450 mg/m2 and 600 mg/m2 there was no increased risk of cardiac toxicity with PLDH. The evaluation of left ventricular function is considered to be mandatory before each additional dose of Liposomal Doxorubicin SUN that exceeds a lifetime cumulative dose of 600 mg/m2 or where a lifetime cumulative dose of 450 mg/m2 of other anthracyclines has been administered.
In the multiple myeloma study, LVEF decrease was defined as an absolute decrease of > 15% over baseline or a > 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the PLDH plus bortezomib arm (13%) experienced a reduction in LVEF.
The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy should be employed in the following order, ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Liposomal Doxorubicin SUN therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.
In patients with cardiac disease requiring treatment, administer Liposomal Doxorubicin SUN only when the benefit outweighs the risk to the patient. Caution should be exercised in patients with impaired cardiac function who receive Liposomal Doxorubicin SUN.
Whenever cardiomyopathy is suspected, i.e. the left ventricular ejection fraction has substantially decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 45%), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.
Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy.
Caution should be observed in patients who have received other anthracyclines. The total dose of doxorubicin HCl should also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g. 5-Fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m2 in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.

Myelosuppression.

Many patients treated with PLDH have baseline myelosuppression due to such factors as their HIV disease or numerous concomitant or previous medications, or tumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m2, myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropaenic infection or sepsis.
Moreover, in a controlled clinical trial of PLDH Vs. topotecan, the incidence of treatment related sepsis was substantially less in the PLDH-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving PLDH in a first-line trial. In contrast to the experience in patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limiting adverse event in patients with AIDS-KS, see Section 4.8 Adverse Effects (Undesirable Effects).
Because of the potential for bone marrow suppression, periodic blood counts should be performed frequently during the course of Liposomal Doxorubicin SUN, and at a minimum, prior to each dose of Liposomal Doxorubicin SUN.
Persistent myelosuppression, although not seen in patients with breast or ovarian cancer, may result in superinfection or haemorrhage.
In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with PLDH. Patients and doctors must be aware of this higher incidence and take action as appropriate.
In the pivotal multiple myeloma study, myelosuppression (all grades) occurred more frequently in the PLDH plus bortezomib group, compared to bortezomib monotherapy. While the incidence of anaemia was similar for both treatment groups, Grade 3 or 4 neutropaenia and thrombocytopaenia occurred more frequently in the PLDH plus bortezomib group, see Section 4.8 Adverse Effects (Undesirable Effects).
Given the difference in pharmacokinetic profiles and dosing schedules, Liposomal Doxorubicin SUN [Pegylated Liposomal Doxorubicin Hydrochloride] should not be used interchangeably with other formulations of doxorubicin hydrochloride.

Infusion-associated reactions.

Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like or anaphylactoid-like reactions, may occur within minutes of starting the infusion of Liposomal Doxorubicin SUN. Symptoms include asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, headache, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of Liposomal Doxorubicin SUN. Very rarely, convulsions also have been observed in relation to infusion reactions, see Section 4.8 Adverse Effects (Undesirable Effects). Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (e.g. antihistamines, corticosteroids, adrenaline and anticonvulsants), as well as emergency equipment, should be available for immediate use. In most patients treatment can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute, see Section 4.2 Dose and Method of Administration.

Palmar-plantar erythrodysesthesia (hand-foot syndrome).

Palmar-plantar erythrodysesthesia (PPE) is characterised by painful, red macular and/or papular bullous skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. In most patients it clears in one or two weeks, with or without treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg per day has been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE, which may be initiated 4 to 7 days after treatment with Liposomal Doxorubicin SUN include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight-fitting). It appears to be dose- and schedule-related and can be reduced by extending the dose interval 1-2 weeks or reducing the dose, see Section 4.2 Dose and Method of Administration. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment.

Extravasation injury.

Although local necrosis following extravasation has been reported very rarely, Liposomal Doxorubicin SUN should be considered an irritant. Although animal studies indicate that the administration of doxorubicin HCl as a liposomal formulation reduces the potential for extravasation injury, the possibility of doxorubicin-related skin injury exists, and care should be taken to avoid extravasation of Liposomal Doxorubicin SUN. If any signs or symptoms of extravasation occur (e.g. stinging, erythema) the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Liposomal Doxorubicin SUN must not be given by the intramuscular or subcutaneous route.

Radiation recall reaction.

Recall of skin reaction due to prior radiotherapy has rarely occurred with Liposomal Doxorubicin SUN administration.

Diabetic patients.

It should be noted that each vial of Liposomal Doxorubicin SUN contains sucrose and is administered in 5% glucose intravenous infusion.

Secondary oral neoplasms.

Very rare cases of secondary oral cancer have been reported in patients with long term (more than one year) exposure to Liposomal Doxorubicin SUN or those receiving a cumulative Liposomal Doxorubicin SUN dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, during treatment with Liposomal Doxorubicin SUN, and up to 6 years after the last dose.
Patients should be examined at regular intervals for the presence of oral ulceration or any oral discomfort that may be indicative of secondary oral cancer.

Use in hepatic impairment.

Prior to Liposomal Doxorubicin SUN administration, hepatic function should be evaluated using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase and bilirubin. In a small number of patients with impaired hepatic function (bilirubin values up to 70 micromoles/L) administered 20 mg/m2 of Liposomal Doxorubicin SUN, there appeared to be no change in the clearance and terminal half-life of Liposomal Doxorubicin SUN. However, until further experience is gained, the Liposomal Doxorubicin SUN dosage should be reduced in patients with impaired hepatic function, based on experience from the breast and ovarian clinical trial programs as follows:
At initiation of therapy, if the bilirubin is between 20 - 51 micromoles/L, the first dose is reduced by 25%. If the bilirubin is > 51 micromoles/L, the first dose is reduced by 50%. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e. if reduced by 25% for the first dose, increase to full dose for cycle 2; if reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Liposomal Doxorubicin SUN can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. No data are available for patients with severe hepatic impairment.

Use in renal impairment.

As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required with Liposomal Doxorubicin SUN. Population-based analysis confirms that changes in renal function over the range tested (estimated creatinine clearance 30-156 mL/min) do not alter the pharmacokinetics of Liposomal Doxorubicin SUN. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 mL/min.

Use in the elderly.

Population based analysis demonstrates that age across the range tested (21-75 years) does not significantly alter the pharmacokinetics of Liposomal Doxorubicin SUN.

Paediatric use.

The safety and effectiveness in patients less than 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been conducted with PLDH, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies. Caution should be exercised in the concomitant use of drugs known to interact with doxorubicin HCl. Although not formally studied, Liposomal Doxorubicin SUN, like other doxorubicin HCl preparations, may potentiate the toxicity of other anti-cancer therapies.
In patients with solid tumours (including breast and ovarian cancer) who received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS-KS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with doxorubicin HCl. Caution should be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

PLDH resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 and 12 mg/kg, respectively. Decreased testicular weights and hypospermia were present in rats after repeat doses of 0.25 mg/kg/day given once every 3 days, and in rabbits of 1 mg/kg given once every 5 days. Diffuse degeneration of the seminiferous epithelium was observed in dogs after 10 doses of 0.25 mg/kg given once every 21 days.
(Category D)
PLDH is embryotoxic at doses of 1 mg/kg/day in rats (about 1/3 the recommended human dose on a mg/m2 basis). PLDH is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (about % the recommended human dose on a mg/m2 basis). Embryotoxicity was characterised by increased embryo-foetal deaths and reduced litter sizes.
There are no adequate and well-controlled studies in pregnant women. If Liposomal Doxorubicin SUN is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the foetus and such treatment should only proceed with the patient's complete informed consent. Women of childbearing potential should be advised to avoid pregnancy while they or their male partner are receiving Liposomal Doxorubicin SUN and in the six months following discontinuation of Liposomal Doxorubicin SUN therapy.
It is not known whether this drug is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Liposomal Doxorubicin SUN, mothers should discontinue nursing prior to taking this drug. Health experts recommend that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects on Ability to Drive and Use Machines

Although PLDH should not affect driving performance, in studies to date, dizziness and somnolence were associated infrequently (< 5%) with the administration of Liposomal Doxorubicin. Patients who suffer from these effects should avoid driving and operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Breast cancer patients (dosage: 50 mg/m2).

254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with PLDH at a dose of 50 mg/m2 every 4 weeks in a phase III clinical trial (I97-328). The most frequently reported treatment related adverse effects included palmar plantar erythrodysesthesia (PPE) (48.0%) and nausea (37.0%) (see Table 5). Severe (Grade III) cases reported in 17.0% and 3.0% respectively, and no reported incidences of life threatening (Grade IV) cases for either PPE or nausea. These effects resulted in permanent treatment discontinuation (7.0% and 0% respectively).
Pronounced alopecia (or total hair loss) was seen in only 7.0% of PLDH-treated patients as compared with 54.0% of patients treated with doxorubicin.
Anaemia, neutropaenia, leucopaenia and thrombocytopaenia were infrequently reported at incidences of 5.0%, 4.0% 2.0% and 1.0% respectively. Life threatening (Grade IV) haematological effects were reported at incidences of < 1.0%. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients respectively).
Clinically significant laboratory abnormalities (Grades III and IV) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (< 1%). Clinically significant haematologic measurements were infrequent as measured by leucopaenia (4.3%), anaemia (3.9%), neutropaenia (1.6%) and thrombocytopaenia (1.2%). Sepsis was reported at an incidence of 1%. No clinically significant increases in serum concentration were reported.
In 150 patients with advanced breast cancer who had failed a prior first or second line taxane-containing chemotherapy regimen and were subsequently treated with PLDH at a dose of 50 mg/m2 every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile (see Table 6) was consistent with that reported for PLDH in previous studies using the same dosage regimen. The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving PLDH as first-line therapy, with the exception of leucopaenia (20%).
Undesirable effects reported between 1% and 5% in 404 PLDH-treated breast cancer patients, not previously reported in PLDH clinical trials (≥ 1%) were breast pain, leg cramps, oedema, leg oedema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculo-skeletal pain, thrombocythemia, cold sores (non-herpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation, and blurred vision.
A 12.4% incidence of infusion-related adverse events was observed in pivotal breast cancer trials. Permanent treatment discontinuation was reported at 1.5%.

Ovarian cancer patients (dosage 50 mg/m2).

Based on the experience in 512 patients with ovarian cancer treated at a dose of 50 mg/m2, the frequency of adverse events reported in clinical trials is listed below and classified according to body systems:

Cardiovascular.

Common (≥ 1% and < 10%): cardiovascular disorder, vasodilatation, cardiac toxicity (see All patients).
Uncommon (> 0.1% and < 1%): palpitation.

Dermatological.

Very common (≥ 10%): palmar-plantar erythrodysesthesia (PPE), rash, alopecia.
Common (≥ 1% and < 10%): skin discolouration, dry skin, pruritus, vesiculobullous rash, skin disorder, exfoliative dermatitis, maculopapular rash, acne, skin ulcer.
Uncommon (> 0.1% and < 1%): PPE (Grade IV - life threatening), nail disorder.
The overall incidence of PPE was very common at 46.1%. This comprised, in decreasing order of frequency, Grade III (severe) 19.5%, Grade II (Moderate) 16.4%, Grade I (Mild) 9.6%, and Grade IV (life threatening) 0.6%.

Gastrointestinal.

Very common (≥ 10%): stomatitis, nausea, vomiting, constipation, diarrhoea, anorexia.
Common (≥ 1% and < 10%): stomatitis (Grade III - severe), abdominal pain, dyspepsia, weight loss, oesophagitis, gastritis, dysphagia, mouth ulceration, nausea and vomiting, oral moniliasis, gingivitis, flatulence, dry mouth, hyperbilirubinaemia (usually in patients with liver metastases).
Uncommon (> 0.1% and < 1%): stomatitis (Grade IV - life threatening), increased AST.

Haematological.

Very common (≥ 10%): anaemia (32.2%), leucopaenia (33.2%), neutropaenia (31.6%), thrombocytopaenia (10.7%).
Common (≥ 1% and < 10%): neutropaenia (Grade IV - life threatening) (2.9%), leucopaenia (Grade IV - life threatening) (1.6%), hypochromic anaemia.
Uncommon (> 0.1% and < 1%): anaemia (Grade IV - life threatening) (0.4%), thrombocytopaenia (Grade IV - life threatening) (0.2%), sepsis related to leucopaenia.
In the 512 patients with ovarian cancer treated at a dose of 50 mg/m2, myelosuppression was mostly mild or moderate and manageable. Growth factor was required infrequently (< 5%) and transfusion support was required in approximately 15% of the patients, see Section 4.2 Dose and Method of Administration.

Musculoskeletal.

Common (≥ 1% and < 10%): myalgia.

Neurological.

Common (≥ 1% and < 10%): paraesthesia, somnolence, dizziness, depression, insomnia, anxiety, neuropathy.
Uncommon (> 0.1% and < 1%): peripheral neuritis.

Ocular.

Common (≥ 1% and < 10%): conjunctivitis.
Uncommon (> 0.1% and < 1%): amblyopia.

Respiratory.

Common (≥ 1% and < 10%): dyspnoea, increased cough, pharyngitis.
Uncommon (> 0.1% and < 1%): rhinitis.

Urogenital.

Common (≥ 1% and < 10%): urinary tract infection, dysuria, vaginitis, increased serum creatinine.

General.

Very common (≥ 10%): asthenia, mucous membrane disorder, Infusion reactions.
Common (> 1% and < 10%): fever, pain, headache, peripheral oedema, allergic reaction, dehydration, chills, infection, chest pain, back pain, malaise, sweating, taste perversion, herpes zoster, cachexia, hypertonia.
Uncommon (> 0.1% and < 1%): enlarged abdomen, facial oedema.

Multiple myeloma patients (dosage: 30 mg/m2).

Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of PLDH 30 mg/m2 as a one-hour intravenous infusion administered on day 4 following bortezomib, which is administered at 1.3 mg/m2 on days 1, 4, 8, and 11, every three weeks or with bortezomib monotherapy in a phase III clinical trial.
In both treatment groups, the median number of cycles received was 5, and the median duration was 105 days. The mean and median cycle lengths were similar between the two groups and consistent with the protocol of 21 days. Monotherapy patients received 24.4 mg/m2 mean cumulative bortezomib dose compared with 23.3 mg/m2 in the combination therapy group. The median of the mean PLDH dose per patient was 29.83 mg/m2/day.
Treatment discontinuation of one or both agents in the combination therapy group occurred in 38% of patients, compared to 24% of patients in the monotherapy group. Common adverse events that led to treatment discontinuation of bortezomib and PLDH included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopaenia, decreased ejection fraction, and fatigue.
See Table 7 for treatment-related adverse effects reported in > 2% of patients treated with combination therapy of PLDH plus bortezomib or bortezomib alone.
The combination therapy was associated with a higher incidence of grade 3 or 4 myelosuppression, constitutional symptoms, and Gl and dermatologic toxicities. Grade 3 or 4 adverse drug reactions were more frequent in the combination therapy group (68% vs 52%). This was mostly due to an increase in grade 3 or 4 haematologic or grade 3 Gl adverse events. Neutropaenia, thrombocytopaenia, and anaemia were the most frequently reported haematologic events reported with both combination therapy of PLDH plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropaenia was higher in the combination therapy group than in the monotherapy group (28% vs. 14%). The incidence of grade 3 and 4 thrombocytopaenia was higher in the combination therapy group than in the monotherapy group (22% vs. 14%). The incidence of grade 3 and 4 anaemia was similar in both treatment groups (7% vs. 5%).
Nausea and vomiting were reported more frequently in the combination therapy group (40% and 28%) than in the monotherapy group (32% and 15%) and were mostly grade 1 and 2 in severity. Stomatitis was reported more frequently in the combination therapy group (16%) than in the monotherapy group (3%), and most cases were grade 2 or less in severity. Grade 3 stomatitis was reported in 2% of patients in the combination therapy group. No grade 4 stomatitis was reported.
The most frequently reported treatment-related adverse events in combination therapy were nausea (40%), diarrhoea (35%), neutropaenia (33%), thrombocytopaenia (29%), vomiting (28%), fatigue (27%), and constipation (22%). PPE was reported in 16% of multiple myeloma patients treated with combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported.
Other adverse effects reported in > 1% but < 2% of PLDH and bortezomib combination therapy treated patients are mouth ulceration, oral candidiasis, aphthous stomatitis, alanine aminotransferase increased, hyponatraemia, hypocalcaemia, musculoskeletal chest pain, syncope, dysaesthesia, scrotal erythema, hypertension and phlebitis.
The incidence of treatment-related heart dysfunction events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary oedema and pulmonary oedema) was similar -1% and 2% in the monotherapy and combination therapy, respectively.

AIDS-KS patients (dosage: 20 mg/m2).

PLDH has been evaluated for safety in 825 AIDS-KS patients treated in 5 clinical trials. Myelosuppression was the most prevalent side effect considered related to PLDH treatment occurring in approximately half of the patients.

Cardiovascular.

Uncommon (≥ 0.1% and < 1%): congestive heart failure, cardiomyopathy and cardiotoxicity (see All patients).

Gastrointestinal.

Very common (≥ 10%): nausea.
Common (≥ 1% and < 10%): abdominal pain, anorexia, constipation, diarrhoea, glossitis, mouth ulceration, oral moniliasis, nausea and vomiting, vomiting, weight loss, stomatitis, increased alkaline phosphatase, increased AST and hyperbilirubinaemia (believed to be disease-related).

Haematological.

Very common (≥ 10%): leucopaenia, anaemia.
Common (≥ 1% and < 10%): thrombocytopaenia, laboratory abnormalities.
Uncommon (≥ 0.1% and < 1%): sepsis related to leucopaenia.
Leucopaenia is the most common adverse event experienced with PLDH in this population; and can occur during all cycles of administration of PLDH. In clinical trials, patients rarely discontinued treatment due to myelosuppression. Haematological toxicity may require dose reduction or suspension or delay of therapy, see Section 4.2 Dose and Method of Administration. The haematological toxicity for ovarian cancer patients is less severe than in the AIDS-KS setting (see section for Ovarian cancer patients above).

Dermatological.

Common (≥ 1% and < 10%): alopecia, palmar-plantar erythrodysaesthesia, rash.
Rare (≥ 0.01% and < 0.1%): recall of skin reaction due to prior radiotherapy has rarely occurred with Liposomal Doxorubicin administration.

Respiratory.

Very common (≥ 10%): opportunistic infections (may be related to HIV-induced immunodeficiency). The most frequently observed Ol's in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia and Mycobacterium avium complex.
Common (≥ 1% and < 10%): dyspnoea.

Ocular.

Common (≥ 1% and < 10%): retinitis.

General.

Very common (≥ 10%): asthenia.
Common (≥ 1% and < 10%): allergic reaction, fever, paraesthesia, vasodilatation, infusion-associated reactions characterised by flushing, shortness of breath, facial oedema, headache, chills, back pain, tightness in the chest and throat and/or hypotension.
Uncommon (≥ 0.1% and < 1%): anaphylactoid reactions, convulsion, tumour necrosis.

All patients.

100 out of 929 patients (10.8%) with solid tumours were described as having an infusion-associated reaction during treatment with PLDH as defined by the following Costart terms: allergic reaction, anaphylactoid reaction, asthma, face oedema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnoea, pharyngitis, rash, pruritus, sweating, injection site reaction and drug interaction. Permanent treatment discontinuation rates were infrequently reported at 2%. Very rarely, convulsions have been observed in relation to infusion reactions. In patients with multiple myeloma receiving PLDH plus bortezomib, infusion-associated reactions have been reported at a rate of 3%. In all patients, infusion related reactions occurred primarily during the first infusion, see Section 4.4 Special Warnings and Precautions for Use.
Myelosuppression associated with anaemia, thrombocytopaenia, leucopaenia, and rarely febrile neutropaenia, has been reported in PLDH-treated patients.
Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of PLDH greater than 460 mg/m2 indicate no evidence of anthracycline-induced cardiomyopathy. However, until further clinical data are available, the risk of developing cardiomyopathy is assumed to be similar to that of standard doxorubicin. The recommended dose of Liposomal Doxorubicin SUN for AIDS-KS patients is 20 mg/m2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern (> 400 mg/m2) would require more than 20 courses of Liposomal Doxorubicin SUN therapy over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumour patients (including patients with ovarian or breast cancer) with cumulative anthracycline doses of 509 mg/m2-1,680 mg/m2. The range of Billingham cardiotoxicity scores was grades 0 - 1.5. These grading scores are consistent with no or mild cardiac toxicity.
In the pivotal phase III trial versus doxorubicin, 10/254 patients randomised to receive PLDH (treated at a dose of 50 mg/m2 every 4 weeks) versus 48/255 patients randomised to receive doxorubicin (treated at a dose of 60 mg/m2/every 3 weeks) met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the LVEF became abnormal (less than the lower limit for normal). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 PLDH administration patients who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin patients who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.
In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m2, the incidence of clinically significant cardiac dysfunction was low. Of the 929 patients treated with PLDH administration 50 mg/m2/cycle, baseline measurement of left ventricular ejection fraction (LVEF) and at least one follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of these 418 patients, 88 patients had a cumulative anthracycline dose of > 400 mg/m2, an exposure level associated with an increased risk of cardiovascular toxicity with the conventional formulation of doxorubicin. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (who received a cumulative dose of 944 mg/m2), discontinued study treatment because of clinical symptoms of congestive heart failure.

Post marketing.

Following the marketing of PLDH, serious skin conditions including erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis and lichenoid keratosis have been reported very rarely.
Patients with cancer are at increased risk for thromboembolic disease. In patients treated with PLDH, cases of thrombophlebitis and venous thrombosis are seen uncommonly, as well as rare cases of pulmonary embolism.

Secondary oral neoplasms.

Very rare cases of secondary oral cancer have been reported in patients with long term (more than one year) exposure to PLDH or those receiving a cumulative PLDH dose greater than 720 mg/m2 (see Section 4.4).

Secondary acute myeloid leukemia and myelodusplastic syndrome.

As with other DNA damaging antineoplastic agents, secondary acute myeloid leukemia and myelodysplastic syndrome have been reported rarely in patients having received combined treatment with doxorubicin.

Reporting suspected adverse effects.

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

4.9 Overdose

Acute overdosage with doxorubicin HCl worsens the toxic effects of mucositis, leucopaenia and thrombocytopaenia. Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The active ingredient of Liposomal Doxorubicin SUN is doxorubicin HCl, a cytotoxic anthracycline antibiotic. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effect. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.

Clinical trials.

Breast cancer.

A phase III randomised study of PLDH versus doxorubicin hydrochloride in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between PLDH and doxorubicin was met (see Table 8). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.
301 patients with advanced breast cancer who had failed a taxane-containing regimen were randomised in a phase III comparative study to PLDH versus an approved salvage regimen (vinorelbine or mitomycin C + vinblastine). Progression-free survival (PFS) was similar for PLDH and the active comparator. See Table 9.

Ovarian cancer.

PLDH was compared to topotecan in a randomised, open-label trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy. The median age of patients was 60 years (range 25-87). Approximately half the patients were platinum-sensitive, defined as response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment.
The PLDH dose was 50 mg/m2 infused intravenously over one hour every 4 weeks and the topotecan dose 1.5 mg/m2 infused intravenously daily for 5 consecutive days every 3 weeks. The median duration of follow up was 56.3 months (range 49.9-71.5) for PLDH, and 56.5 months (range 49.9-72.0) for topotecan.
PLDH was at least equivalent to topotecan in time to disease progression and survival (see Table 10):
PLDH was also at least equivalent to topotecan in the 4 predefined subgroups, platinum-sensitive, platinum-refractory, tumour size ≤ 5 cm and tumour size > 5 cm.
PLDH-treated patients had similar health-related quality-of-life scores assessed by the EORTC QLQ-C30 questionnaire as topotecan-treated patients. However, over the period of 15 months following randomisation, patients treated with PLDH had an average of 1.1 months longer without disease symptoms or grade 3-4 drug toxicity (TWiST) compared with topotecan-treated patients, 95% Cl [0.5, 1.8].

Multiple myeloma.

A phase III randomised, parallel-group, open-label, multicentre study was conducted in 646 patients with multiple myeloma, comparing the safety and efficacy of PLDH plus bortezomib combination therapy with bortezomib monotherapy. Patients had not previously received bortezomib, and had disease which progressed during or after at least one prior therapy. All subjects received prior therapies, and 56% had undergone stem cell transplantation.
In both treatment groups bortezomib 1.3 mg/m2 was administered as an IV bolus on Days 1, 4, 8 and 11 every 21 days. In the combination therapy arm PLDH 30 mg/m2 was administered as an infusion after bortezomib on Day 4 of each cycle.
The primary endpoint was time to progression (TTP), defined as the time from randomisation to the first occurrence of progressive disease or death due to progressive disease. The median TTP was 6.5 months for bortezomib monotherapy treated patients compared to 9.3 months for PLDH plus bortezomib combination therapy treated patients (p < 0.0001), which triggered protocol-defined early study termination for efficacy. This planned interim analysis was performed with a total of 249 subjects with TTP events (39% of ITT population).
The secondary endpoints for overall survival and response rate were assessed at the interim analysis. Survival data were not mature, and were not statistically significant, although there was a trend of overall survival benefit for PLDH plus bortezomib treated patients (HR 1.48, 95% CI 0.91 - 2.41). Overall response rates were not significantly different between treatment groups. See Table 11.

AIDS-KS.

Five clinical studies in patients with AIDS-KS were evaluated. The primary study was conducted in 258 patients and was an open, randomised comparative study comparing the efficacy and safety of PLDH (133 patients) versus Adriamycin, bleomycin and vincristine (ABV, 125 patients). The other studies, which provide supportive data, were open, non-randomised studies of the use of PLDH for the treatment of AIDS-related KS.
In the primary study, PLDH was administered at a dose of 20 mg/m2 by intravenous infusion every 2 weeks. The doses of ABV were Adriamycin 20 mg/m2, bleomycin 10 U/m2 and vincristine 1.0 mg every 2 weeks. Both treatment arms were to continue for a maximum of 6 cycles of treatment. The two groups were well matched for age, sex, weight, prior chemotherapy, HIV risk factor, immune status and severity of KS. All patients were assessed for tumour burden, immune competence and systemic illness factors using the AIDS Clinical Trials Group criteria for staging KS. In each arm, 31% of patients were poor risk for all three criteria. The median CD4+ cell count was 12.5 cells/mm3 in the PLDH arm and 13 cells/mm3 in the ABV arm. The majority of patients had 25 or more lesions (74.6% in the PLDH group and 69.7% in the ABV group).
Most patients in each arm were taking a variety of medication. In the PLDH arm, 52.6% of patients were taking anti-retroviral drugs compared with 63.2% in the ABV arm. More than half the patients (56.4% PLDH and 57.6% ABV) were taking acyclovir, 64.7% of PLDH patients were taking co-trimoxazole compared with 64.0% of ABV patients and fluconazole was used in 72.2% of PLDH patients and 71.2% of patients receiving ABV.
Overall there were significantly more responders in the patients randomised to PLDH.
The response rate for those receiving PLDH was 46% compared with 26% for those receiving ABV (p < 0.001). The median time to CR or PR was 38 days for PLDH and 50 days for ABV (p=0.014) where the time to response was recorded as the time the best response occurred relative to the time of beginning treatment. Once response occurred, the duration of response was very similar in each group, the median duration of response was 90 days for the PLDH group compared with 92 days for ABV (p=0.234). The response rate at the end of treatment was 36.1% for the PLDH group and 21.5% for those receiving ABV (p=0.023). Two-thirds of the patients randomised to PLDH completed 6 cycles of treatment and one-third of those randomised to ABV completed the protocol. This corresponded to a total number of doses of 692 in the PLDH group and 479 in the ABV group. Of those patients who discontinued early, adverse events were the cause of discontinuation for 14 patients in the PLDH arm and 46 in the ABV arm.
With respect to the efficacy of PLDH in patients who have failed prior chemotherapy, a retrospective analysis was conducted in refractory patients enrolled into one of the non-randomised studies. For the best conservative response (best response maintained for at least 3 weeks) in the 77 patients in this group, the response rate by the investigator assessment was 44%. The response was reached in a mean time of 128 days and continued for 118 days. In forty-nine of these patients who had received prior doxorubicin, the response rate by investigator assessment was 44.9%, and in 43 patients who had disease progression on prior doxorubicin the response rate was 39.5%.

5.2 Pharmacokinetic Properties

Absorption.

At equivalent doses, the plasma concentration and AUC values of PLDH (containing 90% to 95% of the measured doxorubicin) are significantly higher than those achieved with standard doxorubicin HCl preparations.

Distribution.

Liposomal Doxorubicin SUN is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in Kaposi's sarcoma (KS) tumours than in normal skin. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the Liposomal Doxorubicin SUN liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nanometre) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumours has been seen in mice with C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin HCl encapsulated during liposome residence time in circulation.
The plasma pharmacokinetics of pegylated liposomal doxorubicin hydrochloride in humans differs significantly from those reported in the literature for standard doxorubicin HCl preparations. At lower doses (10 mg/m2 - 20 mg/m2) pegylated liposomal doxorubicin hydrochloride [PLDH] displayed linear pharmacokinetics. Over the dose range of 10 mg/m2 - 60 mg/m2 pegylated liposomal doxorubicin hydrochloride displayed non-linear pharmacokinetics. Standard doxorubicin HCl displays extensive tissue distribution (volume of distribution, 700 to 1,100 L/m2) and a rapid elimination clearance (24 to 73 L/h/m2). In contrast, the pharmacokinetic profile of pegylated liposomal doxorubicin hydrochloride indicates that pegylated liposomal doxorubicin hydrochloride [PLDH] is confined mainly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment.

Population pharmacokinetics.

The pharmacokinetics of PLDH were evaluated in 120 patients from 10 different clinical trials using the population pharmacokinetic approach. The pharmacokinetics of PLDH over the dose range of 10 mg/m2 to 60 mg/m2 was best described by a two compartment non-linear model with zero order input and Michaelis-Menten elimination. The mean intrinsic clearance of PLDH was 0.030 L/h/m2 (range 0.008 to 0.152 L/h/m2) and the mean volume of distribution at steady state was 2.43 L/m2 (range 1.10 - 4.85 L/m2). The apparent half-life ranged from 24 - 231 hours, with a mean of 73.9 hours.
There were no data for patients with severe renal or hepatic impairment.

Breast cancer patients.

The pharmacokinetics of PLDH determined in 18 patients with breast carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 L/h/m2 (range 0.009 - 0.027 L/h/m2), the mean central volume of distribution was 1.46 L/m2 (range 1.10 - 1.64 L/m2). The mean apparent half-life was 71.5 hours (range 45.2 - 98.5 hours).

Ovarian cancer patients.

The pharmacokinetics of PLDH determined in 11 patients with ovarian carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.021 L/h/m2 (range 0.009 - 0.041 L/h/m2), the mean volume of distribution at steady state was 1.95 L/m2 (range 1.67 - 2.40 L/m2). The mean apparent half-life was 75.0 hours (range 36.1 - 125 hours).

AIDS-KS patients.

The plasma pharmacokinetics of PLDH were evaluated in 23 patients with Kaposi's sarcoma who received single doses of 20 mg/m2 administered by a 30-minute infusion. The pharmacokinetic parameters of PLDH (primarily representing liposome-encapsulated doxorubicin and low levels of unencapsulated doxorubicin HCl) observed after the 20 mg/m2 doses are presented in Table 12.
In patients receiving 20 mg/m2 PLDH the concentration of total (liposome encapsulated and unencapsulated) doxorubicin in the KS lesions was a median of 19 (range 3-53) times higher than in normal skin at 48 hours post-treatment.
The concentration of bioavailable (unencapsulated) doxorubicin in tissues is unknown because the assay procedure cannot distinguish between liposome encapsulated and unencapsulated doxorubicin.

5.3 Preclinical Safety Data

Genotoxicity.

Although no studies have been conducted with Liposomal Doxorubicin SUN, doxorubicin HCl, the pharmacologically active ingredient of Liposomal Doxorubicin SUN is mutagenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic at dose levels exceeding the maximum tolerated dose of Liposomal Doxorubicin SUN.

Carcinogenicity.

Although no studies have been conducted with Liposomal Doxorubicin SUN, doxorubicin HCl, the pharmacologically active ingredient of Liposomal Doxorubicin SUN is carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic at dose levels exceeding the maximum tolerated dose of Liposomal Doxorubicin SUN.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each mL contains doxorubicin HCl 2 mg, sodium methoxy-PEG-40-carbonyl- distearoylphosphatidylethanolamine (MPEG-DSPE) 3.19 mg, hydrogenated soy phosphatidylcholine [HSPC] 9.58 mg, cholesterol 3.19 mg, ammonium sulfate qs, sucrose 100 mg, histidine 1.50 mg, Water for Injections qs, hydrochloric acid and sodium hydroxide qs pH 6.5.
The pegylated liposome consists of sodium methoxy-PEG-40-carbonyl-distearoyl phosphatidyl-ethanolamine (MPEG-DSPE), hydrogenated soy phosphatidylcholine (HSPC) and cholesterol.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2°C to 8°C. Refrigerate. Do not freeze.

6.5 Nature and Contents of Container

Each clear Type I glass vial contains 20 mg or 50 mg doxorubicin hydrochloride (HCl) at a concentration of 2.0 mg/mL in a pegylated liposomal formulation.
Liposomal Doxorubicin SUN injections are supplied in single vial packs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The chemical structure of doxorubicin hydrochloride is:

CAS number.

25316-40-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes